A randomised phase II trial of niraparib versus active symptom control in patients with previously treated mesothelioma: NERO.

Abstract

TPS8600 Background: Malignant mesothelioma is a universally lethal cancer that has been increasing over the last three decades. No treatment has been licenced for patients with relapsed mesothelioma after receipt of licenced systemic anti-cancer therapy in the UK. A previous single-arm phase IIa trial (MiST1) evaluated the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibition in mesothelioma, which met its primary endpoint with 15% of patients having durable responses exceeding 1 year. Therefore, there is a need to evaluate PARP inhibitors in a randomised trial in relapsed mesothelioma patients. NERO is currently in progress in this setting. Methods: Co-ordinated by the CRUK Southampton Clinical Trials Unit, NERO is a multicentre, two arm, open-label UK randomised phase II trial comparing niraparib + Active Symptom Control (ASC) versus ASC alone in mesothelioma patients who have relapsed after previously receiving platinum-based systemic therapy. NERO is not restricted by line of therapy and treatment allocation ratio is 2:1 (niraparib + ASC:ASC), stratified by histology and response to prior platinum-based therapy. Participants will receive either niraparib + ASC or ASC alone for a period of 24 weeks. Participants will be treated until disease progression, withdrawal, death or development of significant treatment limiting toxicity. Participants randomised to niraparib will receive 200/300 mg every day in a 21-day cycle. The primary endpoint is progression-free survival, where progression is determined by modified RECIST or RECIST 1.1; investigator reported progression; or death from any cause, whichever comes first. Time to event data will be analysed and presented using Kaplan-Meier curves according to the intention to treat principle, with treatment-related intercurrent events handled using the treatment strategy policy, and study withdrawal following the “while on study” strategy. A Cox proportional hazards model will be used to calculate the Hazard Ratio, 95% CIs and p-value adjusted for stratification factors. Median PFS and 6 and 12 month PFS will also be reported. Secondary endpoints include overall survival, best overall response, 12 and 24 week disease control, duration of response, treatment compliance and safety/tolerability. Patients consent to provide mandatory diagnostic tissue blocks, blood samples and an optional stool sample for translational research. These will be used to interrogate homologous recombination deficiency and its association with response in NERO, translational research comprising multi-omic analysis with multiplex immune landscape phenotyping will be analysed and correlated with clinical outcome using machine learning. NERO opened in July 2022 and will be run in approximately 10 UK secondary care hospitals with the aim of recruiting 84 evaluable patients (recruitment is currently 24 on 11-Jan-2023). Clinical trial information: NCT05455424 .