DuRvalumab With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma

Inclusion Criteria:

• Adults (18 years or over) with a histological diagnosis of epithelioid pleuralmesothelioma that is not amenable to curative surgical resection. Histologicaldiagnosis requires tumour tissue from an open biopsy, or a core biopsy with a needleof 19 gauge or wider.

• Measurable disease as per modified RECIST 1.1 (mRECIST 1.1) criteria for assessmentof response in pleural mesothelioma, without prior radiotherapy to these sites.

• Body weight >30 kg,

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Tumour tissue (Formalin-Fixed Paraffin-Embedded [FFPE]) available from standard ofcare diagnostic biopsy for PD-L1 testing and other correlative biomarker testing ata central laboratory.

• Life expectancy of at least 12 weeks.

• Adequate blood tests (done within 14 days prior to randomisation) and with valueswithin the ranges specified below. Blood transfusions are permissible if completedat least 7 days prior to treatment start.

• Haemoglobin ≥ 9.0 g/L

• Absolute neutrophil count ≥ 1.5 x 10^9/L

• Platelets ≥ 100 x 10^9/L

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except participants withGilbert's Syndrome, who are eligible with bilirubin ≤ 2.5 ULN)

• Alanine transaminase ≤ 2.5 x upper limit of normal (ULN), unless livermetastases or invasion are present, in which case it must be ≤ 5 x ULN

• Aspartate aminotransferase ≤ 2.5 x ULN, unless liver metastases or invasion arepresent, in which case it must be ≤ 5 x ULN

• Creatinine clearance (CrCl) ≥ 45 mL/min (Cockcroft-Gault formula). NOTE:Carboplatin AUC 5 must be the initial platinum agent of choice in patients withcreatinine Cl <60 mL/min but ≥ 45 mL/min, or those with clinically reportedhearing loss.

• Patient consent must be appropriately obtained in accordance with applicable localand regulatory requirements. Each patient or legal representative must sign aconsent form prior to enrolment in the trial to document their willingness toparticipate.

• Willing and able to comply with all study requirements, including treatment, timingand/or nature of required assessments.

• Women of childbearing potential must use a reliable means of contraception duringtreatment and for at least 90 days thereafter. Breastfeeding is not permissibleduring or for at least 90 days after the final study treatment. Men must have beensurgically sterilised or use a barrier method of contraception if they are sexuallyactive with a woman of child bearing potential.

• Evidence of post-menopausal status or negative serum pregnancy test for femalepre-menopausal patients. Women will be considered post-menopausal if they have beenamenorrheic for 12 months without an alternative medical cause.

Exclusion Criteria:

• Non-epithelioid histology (biphasic or sarcomatoid).

• Prior chemotherapy or other systemic anti-cancer or immunotherapy for PM.

• Diagnosis based only on cytology or aspiration biopsy with a needle narrower than 19gauge.

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions tothis criterion:

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable onhormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Patients without active disease in the last 5 years may be included

5. Patients with celiac disease controlled by diet alone

• Any condition requiring systemic treatment with either corticosteroids (>10 mg dailyprednisone or equivalent dose of an alternative corticosteroid) or otherimmunosuppressive medications within 28 days of durvalumab or ipilimumab ornivolumab administration. Intranasal, inhaled or topical steroids or local steroidinjections (e.g. intra-articular injection) are permitted in the absence of activeautoimmune disease. Standard steroid premedication given prior to chemotherapy or asprophylaxis for imaging contrast allergy should not be counted for this criterion.

• Participants with symptomatic or uncontrolled brain metastases or leptomeningealdisease are excluded.

• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, orany other antibody or drug specifically targeting T cell co-stimulation or immunecheckpoint pathways.

• Current treatment or treatment within the last 12 months with any investigationalanti-cancer products.

• Concurrent enrolment in another clinical study testing an anticancer treatment.

• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470msec in screening ECG measured using standard institutional method or history offamilial long QT syndrome.

• Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of study treatment on protocol. Note: Local surgery of isolatedlesions for palliative intent is acceptable. Limited pleural biopsy procedures donot apply.

• No other malignancy that requires active treatment. Participants with a past historyof adequately treated carcinoma in situ, non-melanoma skin cancer or lentigo malignawithout evidence of disease or superficial transitional cell carcinoma of thebladder are eligible.

• Hearing loss or peripheral neuropathy considered by the investigators tocontraindicate administration of either cisplatin, carboplatin or pemetrexed.

• History of allergy or hypersensitivity to investigational product, cisplatin,carboplatin, pemetrexed, ipilimumab, nivolumab or any excipient.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive cardiac failure, uncontrolled hypertension,unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, activepeptic ulcer disease or gastritis, serious chronic gastrointestinal conditionsassociated with diarrhoea, active bleeding diatheses.

• Hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Exceptions includepast or resolved Hepatitis B (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) and patients positive for hepatitis C (HCV)antibody if polymerase chain reaction is negative for HCV RNA. HIV testing is notrequired in absence of clinical suspicion of HIV.

• Known history of primary immunodeficiency, allogeneic organ transplant, pneumonitisor active tuberculosis.

• Receipt of live attenuated vaccination within 30 days prior to enrolment or within 30 days of receiving durvalumab, ipilimumab, nivolumab.

• Specific comorbidities or conditions or concomitant medications which may interactwith the investigational product(s).

• Any condition that, in the opinion of the investigator, would interfere withevaluation of study treatment or interpretation of patient safety or study results.

• Serious medical or psychiatric conditions or social situation that might limitcompliance with study requirements, substantially increase risk of incurring adverseevents or compromise the ability of the patient to give written informed consent.