Niraparib efficacy in patients with unresectable mesothelioma: a randomised Phase II trial of niraparib versus active symptom control in patients with previously treated mesothelioma
Unresectable mesothelioma
Mesothelioma patients with any histological subtype (epithelioid or non-epithelioid) and any site (pleural or peritoneal) who have previously received an approved systemic therapy containing platinum, will be recruited from a secondary care setting. NERO is not restricted by line of therapy. Once all screening procedures have been completed and the patient is confirmed eligible, they will be randomised in a 2:1 ratio between the experimental arm and the control arm. Randomisation will be completed using an online randomisation system called ALEA. Patients will be treated for up to 24 weeks, or until disease progression, withdrawal, death or development of significant treatment-limiting toxicity. Patients in the experimental arm will receive Active Symptom Control (ASC) and niraparib 200/300 mg orally once a day in a 3-weekly cycle. Patients randomised to the control arm will receive ASC, patients in this arm of the trial will be managed symptomatically. During treatment, patients will be seen in clinic every 3 weeks for physical exams and blood tests to monitor safety. Patients will have a CT scan every 6 weeks from baseline, during treatment to assess their disease. Patients will have to provide a mandatory biopsy sample for research purposes and they will be asked to have an optional one (for research) at progression, if they were randomised to the experimental arm. Following disease progression patients will be monitored for overall survival.
1. 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 2. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study. 3. Histologically confirmed diagnosis of mesothelioma. Any histological subtype (epithelioid, biphasic or sarcomatoid) and any site (e.g. pleural or peritoneal) with an available tissue block. Tissue blocks will be requested at the time of screening 4. Patients must have received prior systemic therapy (any number of lines) for pleural or peritoneal mesothelioma 5. Disease progression must be confirmed per Investigator's assessment prior to screening 6. Any prior treatment must be completed at least 14 days prior to receiving study treatment, with no ongoing toxicity of CTCAE Grade 3 or above. 7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 (see appendix 1) 8. Radiologically assessable disease by modified RECIST (pleural mesothelioma) or RECIST 1.1 (non-pleural mesothelioma or where measurements for modified RECIST cannot be obtained) 9. Age ≥18 years old 10. Consent to provide mandatory diagnostic tissue blocks and blood samples for translational research, including an optional rebiopsy at progression 11. Adequate organ function, including suitable bone marrow reserve and creatinine clearance 12. Screening laboratory values must meet the following criteria within 48 hours prior to commencement of treatment: 12.1. White blood cells ≥2 x 10e9/l 12.2. Neutrophils ≥1.5 x 10e9/l 12.3. Platelets ≥100 x 10e9/l 12.4. Haemoglobin ≥90 g/l 12.5. Serum creatinine of ≤1.5 X ULN or creatinine clearance (CrCl) >50 ml/minute (using Cockcroft/Gault formula) 12.5.1. Female CrCl= [(140 - age in years) x weight in kg x 0.85) ÷ (72 x serum creatinine in μmol/
1. Patients with untreated, symptomatic central nervous system (CNS) metastases are excluded, including carcinomatous meningitis, leptomeningeal disease, and radiographic signs of CNS haemorrhage are excluded 2. Patients with untreated third space fluid collection requiring therapeutic drainage are excluded 3. Second malignancy within 5 years except cancers with definitely treated with curative intent (eg. basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ bladder or in situ cervical cancer) 4. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patient to receive protocol therapy 5. Difficulty swallowing or previous significant resection of the stomach or small bowel 6. Patients who have not recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment 7. Prior exposure to PARP Inhibitor or known hypersensitivity to the components of niraparib 8. New York Heart associated class II or greater heart failure, hepatic [AST > 3 x ULN, ALT >3 x ULN Total bilirubin >1.5 x ULN] or renal impairment [serum creatinine of >1.5 x ULN or creatinine clearance (CrCl) ≤50 ml/minute (using Cockcroft/Gault formula)] 9. Known alcohol or drug abuse 10. Patients are not permitted to enter any other interventional studies 11. Any patient not able to give consent 12. Any pregnant or breastfeeding patient 13. Patient with known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) 14. Patient with known history of active tuberculosis 15. Patients with uncontrolled hypertension 16. Participants have current pneumonitis within 90 days of the planned start of the study or a known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis requiring ste