Niraparib Efficacy in Patient With Unresectable Mesothelioma (NERO)

Primary Outcome Measures

1. Progression-free survival [ Time Frame: From date of randomisation until the date of the first documented progression or date of death from any cause, whichever came first, assessed up to 18 months ]
   Progression-free survival is the determined by modified RECIST (pleural disease), RECIST 1.1 (for non-pleural disease), investigator reported progression or death from any cause (whichever event comes first)

Secondary Outcome Measures

1. Overall Survival [ Time Frame: From date of randomisation until the date of the first documented progression or date of death from any cause, whichever came first, assessed up to 18 months ]
   Time from randomisation to death from any cause
2. Best overall response (progressive disease, stable disease, partial or complete response) [ Time Frame: From date of randomisation until the date of the first documented progression or date of death from any cause, whichever came first, assessed up to 18 months ]
   The best overall response is the best response recorded from the start of treatment until disease progression or death
3. Disease Control [ Time Frame: 12 and 24 weeks post randomisation ]
   Stable disease, partial or complete response
4. Duration of response [ Time Frame: From date of randomisation until the date of the first documented progression or date of death from any cause, whichever came first, assessed up to 18 months ]
   Time from complete or partial response (where this occurs) until progression or death
5. Treatment compliance [ Time Frame: Up to 24 weeks ]
   Assessed by summarising the percentage of the received dose relative to the intended dose at each cycle
6. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: At the end of each treatment cycle (each cycle is 21 days, with a maximum of 8 cycles of treatment) for 100 days post treatment discontinuation and for ongoing drug-related AE’s until resolved, return to baseline, or deemed irreversible ]
   Summary statistics and listings will be reported for patients in the safety population and will be summarised by treatment arm with classification by the latest version of MedDRA. Grade will be reported on the CTCAE toxicity scale (version 5.0). Both all cause and treatment related or emergent AEs will be included in the analysis.

Other Outcome Measures

1. Correlate homologous recombination gene alterations and clinical outcome [ Time Frame: From date of randomisation until the date of the first documented progression or date of death from any cause, whichever came first, assessed up to 18 months ]
   Response, progression-free and overall survival will be correlated with somatic alteration of HR genes
2. To identify causes of acquired resistance to Niraparib in a subset of patients undergoing optional re-biopsy at disease progression [ Time Frame: From date of randomisation until the date of the first documented progression or date of death from any cause, whichever came first, assessed up to 18 months ]
   Response, progression-free and overall survival will be correlated with somatic alteration of HR genes

Inclusion Criteria

• 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.
• Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study
• 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.
• Patients must have received prior systemic therapy (any number of lines) for pleural or peritoneal mesothelioma.
• Disease progression must be confirmed per Investigator’s assessment prior to screening.
• Any prior treatment must be completed at least 14 days prior to receiving study treatment, where all toxicities have recovered or returned to grade 1, with the exception of alopecia and neuropathy due to chemotherapy which should have returned to grade 2.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1.
• Radiologically assessable disease by modified RECIST (pleural mesothelioma) or RECIST 1.1 (non-pleural mesothelioma or where measurements for modified RECIST cannot be obtained).
• Age ≥ 18 years old.
• Consent to provide mandatory diagnostic tissue blocks and blood samples for translational research, including an optional rebiopsy at progression.
• Adequate organ function, including suitable bone marrow reserve and creatinine clearance.
• Screening laboratory values must meet the following criteria within 48 hours prior to commencement of treatment:
  1. White blood cells ≥ 2 x 109/L
  2. Neutrophils ≥ 1.5 x 109/L
  3. Platelets ≥ 100 x 109/L
  4. Haemoglobin ≥ 90 g/L
  5. Serum creatinine of ≤ 1.5 X ULN or creatinine clearance (CrCl) > 50 mL/minute (using Cockcroft/Gault formula)
  6. AST ≤ 3 x ULN OR ALT ≤ 3 x ULN (if both are assessed, both need to be ≤ 3 x ULN)
  7. Total bilirubin ≤ 1.5 x ULN (except patients with Gilbert Syndrome, who must have total bilirubin < 51.3 μmol/L)
• Reproductive status:
  1. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of Human Chorionic Gonadotropin) at enrolment and within 24 hours prior to the start of study treatment. An extension up to 3 days prior to the start of study treatment may be permissible in situations where results cannot be obtained within a 24-hour window.
  2. Women must not be breastfeeding
  3. WOCBP must agree to use a highly effective method of contraception for the duration of treatment and 180 days after the last dose ASC+Niraparib.
  4. Men who are sexually active with WOCBP must use the contraceptive methods outlines in the protocol for the duration of treatment and for 90 days after the last dose of ASC+Niraparib
• Expected survival of at least 12 weeks per Investigator’s assessment

Exclusion Criteria

• Patients with untreated, symptomatic central nervous system (CNS) metastases, including carcinomatous meningitis, leptomeningeal disease, and radiographic signs of CNS haemorrhage are excluded.
• Patients with untreated third space fluid collection requiring therapeutic drainage are excluded
• Second malignancy within 5 years except cancers definitely treated curative intent (e.g. basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ bladder cancer or in situ cervical cancer).
• 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.
• Difficulty swallowing or previous significant resection of the stomach or small bowel.
• 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.
• Prior exposure to PARP inhibitor or known hypersensitivity to the components of niraparib.
• New York Heart Associated class II or greater heart failure, hepatic [AST > 3XULN, ALT > 3XUL, Total bilirubin > 1.5XULN] or renal impairment [Serum creatinine of >1.5 X ULN or creatinine clearance (CrCL) ≤ 50 mL/minute (using Cockcroft/Gault formula)].
• Known alcohol or drug abuse.
• Patients are not permitted to enter any other interventional studies.
• Any patient not able to give consent.
• Any pregnant or breastfeeding patient.
• Patient with known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML)
• Patient with known history of active tuberculosis.
• Patients with uncontrolled hypertension.
• Participants have current active pneumonitis within 90 days of planned start of the study or a known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis requiring steroid treatment.
• Patients that have received colony-stimulating factors (eg, granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 2 weeks prior to the first dose of study treatment.
• Live vaccines within 30 days prior to the first dose of study treatment and while participating in this clinical study.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.