By incorporating a platform trial protocol design, SELECTmeso will spearhead a next-generation precision medicine trial platform in relapsed mesothelioma for the UK enabling early evaluation of hypothesis-driven targeted therapies. The SELECTmeso Platform trial protocol allows incorporation of a range of identified and yet-to-be-identified candidates as potential treatments for patients with relapsed mesothelioma into the platform. Candidate Specific Trials (CSTs) will be added into the trial via treatment-specific CSTs of this platform trial protocol as appendices. Having one platform trial protocol ensures different candidates are evaluated in the same consistent manner and that opening up new trials for new candidates is more efficient.

SELECTmeso1 is our first Candidate Specific Trial (CST) on the platform. SELECTmeso1 is investigating if a drug called BMS-986504 is effective in shrinking mesothelioma tumours as a targeted treatment for patients with tumours that have specific genetic biomarkers. Biomarkers are molecules that can indicate normal or abnormal processes taking place in the body or tumour, they can indicate how effective certain treatments will be. BMS-986504 has shown to be tolerated and promising signs of activity on patients with MTAP-deficient solid tumours, in a previous mesothelioma trial.

SELECTmeso Platform: Participants will consent to the platform and some of the tissue collected from a previous biopsy will be analysed in a laboratory to find out which biomarkers are present in the tumour. Participants will not need to provide any more tissue or attend hospital for this step. Depending on the biomarker(s) present, the participant will then be offered the opportunity to take part in a study looking at a drug that is thought to be best for that biomarker, or possibly a drug for patients without any biomarkers.

If following this screening step, the participant is not eligible for any treatments, they will return to standard care with their doctor. They may be contacted regarding future treatments within the SELECTmeso trial if new treatments are added that they would be eligible for.

SELECTmeso1: This is the first Candidate Specific Trial on the SELECTmeso platform and is investigating if a drug called BMS-986504 is effective in shrinking mesothelioma tumours in participants with MTAP-deficient solid tumours. Once participants are screened and confirmed eligible, they will start treatment with BMS-986504 which will be administered orally in the form of a 3 tablets once a day. Participants will take a 600mg dose. Participants will have a clinic visit every 21 days where they will have routine blood tests and assessment to monitor their health. Some clinic visits will include additional trial bloods. During treatment, participants will have CT scans (computerised tomography scan) every 6 weeks to monitor the effect of the treatment. These are the same type of scans and frequency they would have normally to monitor their health. Treatment will stop after a maximum of 24 weeks (8 cycles) and participants will have an end of treatment visit, followed by a safety visit 30 days later.

SELECTmeso Platform Inclusion Criteria:

1. Histological confirmation of malignant mesothelioma (pleural, or non-pleural)
2. Evidence of disease progression on CT scan
3. Available archival tissue block for molecular screening or existing molecular screening result via validated NHS diagnostic grade immunohistochemistry-based assays
4. Previous treatment with at least 1st line licensed systemic anti-cancer therapy. Patients can have received more than one prior line of systemic therapy
5. No progressing central nervous system disease and not receiving any concurrent systemic therapy at the time of screening
6. ECOG performance status 0-1*
7. 16 years of age and older
8. Expected survival of ≥12 weeks
9. Consent to provide baseline tumour tissue sample for trial
10. Patients must have signed and dated a REC-approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal patient care

SELECTmeso1 Inclusion Criteria:

A. Evidence of MTAP deficient. MTAP deficiency detected by a validated immunohistochemistry test conducted under the SELECTmeso master protocol, in the Leicester NHS pathology department B. Willing to consent and able to undergo required procedures to provide blood C. 18 years of age and older

D. Adequate organ function, including the following:

1. Adequate bone marrow reserve:

   i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, ii. WBC ≥ 3 x 109/L, iii. Haemoglobin ≥ 85g/L, iv. Platelet count ≥100 × 109/L

2. Adequate liver function and renal:

   i. Bilirubin < 1.5 x ULN ii. AST & ALT <3 x ULN iii. Creatinine clearance > 45ml/min.

3. INR ≤ 1.5 × institutional ULN unless on a stable dose of an anticoagulant with no unexplained elevation of INR E. Participants must provide informed consent to SELECTmeso1 before any study specific procedures. The PI must confirm the eligibility of a participant in the participant's medical notes before enrolment F. Women of childbearing potential (WOCBP) participants agree to use contraception (see Section 5.3) while participating in this study, and for a period of 6 months after the last dose of study treatment G. Men whose partner is a WOCBP agree to use contraception (see Section 5.3) while participating in this study, and for a period of 6 months after the last dose of study treatment

SELECTmeso Platform Exclusion Criteria:

1. Patients with a diagnosis of a second malignancy (except prostate or cervical cancer in remission, patients with a diagnosis of basal cell carcinoma or non-muscle invasive bladder cancer, who can all be included)
2. New York Heart Association Class II or greater congestive heart failure
3. Patients requiring long term oxygen therapy
4. Any other significant disease or disorder which, in the opinion of the investigator, may either put the participant 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
5. Patients on active treatment in another clinical trial

SELECTmeso1 Exclusion Criteria:

H. Diagnosis, detection, or treatment of another type of cancer 5 years prior to initiating protocol therapy (except basal or squamous cell carcinoma of the skin, non-muscle invasive bladder cancer that has been definitively treated), or prostate or cervical cancer in remission I. Have received treatment with an agent that has no marketing authorisation, within 14 days of study entry. If the Participants has participated in a different SELECTmeso CST, they must comply with the washout period for that CST J. Participants who are pregnant or breast feeding K. Uncontrolled CNS disease. Asymptomatic brain metastases are allowed if previously treated with radiotherapy > 28 days prior to starting BMS-986504 L. Palliative radiotherapy within the mRECIST 1.1 area in the 4 weeks prior to baseline CT scan M. Participants with severe hepatic insufficiency or severe renal impairment N. Uncontrolled/symptomatic or significant cardiovascular conditions within 6 months prior to enrolment, including, but not limited to, any of the following: i) Cardiac angioplasty or stenting, unstable angina pectoris, myocardial infarction, stroke/transient ischemic attack, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, New York Heart Association (NYHA) class III-IV congestive heart failure, pericarditis, atrial fibrillation or other arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be switched to alternative treatment prior to study entry

O. Participant has any of the following cardiac criteria:

i. Mean resting corrected QT interval (QTcF) >470 msec ii. Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block iii. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval (including IV ondansetron) iv. Ejection fraction (EF) <50% or the lower limit of normal of the institutional standard. A historic measurement of EF no older than 6 months prior to first administration of trial drug can be accepted provided that there is clinical evidence that the Participant's cardiac disease has not significantly worsened since this measurement in the opinion of the Investigator or of the treating physician or both P. Active bleeding, significant risk of haemorrhage (e.g. previous severe gastrointestinal bleeding, previous haemorrhagic stroke at any time), or current bleeding disorder (e.g. haemophilia, von Willebrand disease) Q. Recovery from the adverse effects of prior therapy at the time of enrolment to baseline or ≤ Grade 1 (excluding alopecia, peripheral neuropathy, and parameters superseded by other eligibility criteria [eg, haematology parameters]). Note: Participants with prior endocrine adverse effects are permitted to enrol if they are stably maintained on appropriate replacement therapy and are asymptomatic. Major surgery, open biopsy or significant traumatic injury within 28 days before the start of study treatment or planned within 6 months after screening R. Participants who have received live/attenuated vaccine within 30 days of first treatment. The use of inactivated seasonal influenza vaccines will be permitted on study without restriction S. Pre-existing duodenal stent and/or history of gastrointestinal disease or other gastrointestinal conditions (e.g., uncontrolled nausea, vomiting, malabsorption syndrome) likely to alter absorption of study treatment or result in inability to swallow oral medications T. Previous significant surgical resection of stomach or small bowel U. Participants who have difficulty swallowing V. Participants who have received prior treatment with a PRMT5 inhibitor including BMS-986504, or MAT2A inhibitor W. Participants with active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment) fungal infection or detectable viral infection or viral load (such as known human immunodeficiency virus positivity) X. Active viral hepatitis, including the following: i) Any positive test result for hepatitis B virus (HBV) indicating presence of virus, eg, HBV DNA positive would be excluded. Participants with anti-HBsAg positive in line with prior vaccination are eligible to enrol. ii) Any positive test result for hepatitis C virus (HCV) indicating presence of active viral replication (detectable HCV-RNA). iii) Participants with positive HCV antibody and an undetectable HCV RNA are eligible to enrol. Screening is not required for enrolment Y. Known HIV positive with an AIDS-defining opportunistic infection within the last year, or a current CD4 count < 350 cells/μL. Participants with HIV are eligible if they have received established ART for at least 4 weeks prior to randomization and continue on ART as clinically indicated while enrolled on study. Viral serology only to be conducted if locally mandated and, if done, must be performed within 28 days prior to randomization. Screening is not required for enrolment Z. Known severe hypersensitivity to study treatment and/or any of its excipients AA. Ongoing need for a medication known as a strong inhibitor or strong inducer of CYP3A4 and/or P-glycoprotein or a proton-pump inhibitor that cannot be switched to an alternative treatment prior to enrolment. The following drug interaction databases and other literature can be utilized to determine the CYP3A4/P-gp inhibitors and inducers. Examples of CYP3A4/P-gp inhibitors and inducers are also provided in See Section 7.8 for further information BB. Prior organ allograft CC. Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended to treat the disease under study within 4 weeks prior to treatment. The concurrent use of any botanical preparation is not permitted while on study