We present the protocol of the Desire3R trial. Methods and analysis This multicentre open-label randomised trial will recruit 480 treatment-na?ve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500?mg plus 3-weekly doublet chemotherapy (cisplatin 75?mg/m2 or carboplatin, Area Under the Curve, AUC 5 and pemetrexed 500?mg/m2) 4C6 cycles, followed by 4-weekly durvalumab 1500?mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4C6 cycles, followed by observation. additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is usually 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is usually stratified by age (18C70 years vs 70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features recognized in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (Desire) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be put together for validation of radiological steps of response, and studies of possible radiomic biomarkers in mesothelioma. Ethics and dissemination The protocol was approved by human research ethics review AVN-944 committees for all those participating sites. Results will be disseminated in peer-reviewed journals AVN-944 and at scientific conferences. Drug Supply AstraZeneca. Protocol version CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021. Trial registration number ClinicalTrials.gov Identifier: “type”:”clinical-trial”,”attrs”:”text”:”NCT04334759″,”term_id”:”NCT04334759″NCT04334759 ACTRN 12620001199909. in the absence of disease progression, unacceptable toxicity, withdrawal of consent or other reasons for discontinuation. Control arm (arm B) Standard doublet chemotherapy followed by close observation (observe table 2). Table 2 Control arm treatment thead Agent (s)DoseRouteDurationScheduleFrequency /thead Cisplatin br / or br / carboplatin75 mg/m2 br / or br / AUC 5IntravenousPer institution practiceDay 1 each cycleEvery 3 weeks RNF75 x 4 to 6 6 cyclesPemetrexed500 mg/m2 IntravenousPer institution practiceDay 1 each cycleEvery 3 weeks x 4 to 6 6 cycles Followed by Close observation per standard of care Open in a separate windows In both arms Carboplatin Area Under the Curve, AUC 5 is the initial platinum agent of choice in participants with an estimated CrCl 45C59?mL/min, or those with clinically reported hearing loss. Carboplatin AVN-944 or cisplatin may be chosen for other participants at the discretion of investigators. Participants going through unacceptable cisplatin toxicities may be treated AVN-944 subsequently with carboplatin AUC 5 every 3 weeks. Regimens for antiemetic and hydration are as per local institutional guidelines. Trial oversight and monitoring Desire3R is an investigator-initiated, academic trial, conducted as a collaboration between the Thoracic Oncology Group of Australasia, the NHMRC Clinical Trials Centre at the University or college of Sydney, and PrECOG, a non-profit research organization that focuses on cancer clinical trials. The University or college of Sydney is the sponsor in Australia and AVN-944 New Zealand, PrECOG is the sponsor in USA. This international study will be conducted through a number of regional coordinating centres, each responsible for their own ethics and regulatory approvals, regional monitoring, medical oversight and facilitation of data collection and query resolution. The NHMRC Clinical Trials Centre will be responsible for study coordination, data acquisition, management and statistical analysis. All patients will be given written informed consent prior to study enrolment. The trial will be monitored by an Independent Security and Data Monitoring Committee (ISDMC) approximately every 6 months. The ISDMC will advise the Trial Monitoring Committee (TMC) regarding safety, specified matters related to the integrity and potential conclusions of trial data and the appropriateness of continued trial conduct. The International Trial Steering Committee (ITSC) will oversee study planning, monitoring, progress, review of information from related research and implementation of recommendations from other study committees and external body (eg, ethics committees). The ITSC will consider recommendations from your ISDMC about whether to continue the study as.