Reirradiation and Niraparib in Patients With Recurrent Glioblastoma

The goal of this clinical trial is to investigate a drug called niraparib in patients with glioblastoma that was previously treated but has returned (called recurrent glioblastoma, or rGBM).Through this study, investigators would like to find out the best dose of niraparib to give to treat the disease when given together with radiotherapy (known in this study as reirradiation, or re-RT).Patients receive 10 doses of reirradiation over approximately 2 weeks. At the same time, niraparib capsules are taken orally at home, every day. Niraparib treatment continues until the patient is required to stop either because the treatment stops working or because of side-effects.Participants will come into clinic weekly for blood tests and clinical examinations in the first month of treatment. After this, the assessments will be done monthly.Once the patient has finished niraparib treatment, the patient will enter follow-up and be seen once a year to see if there are any late side-effects from trial treatment, how the disease is doing, and if further treatments have been received for it. This follow-up continues until the end of the trial.

Inclusion Criteria:Local recurrence of GBM which can be resected or which is not amenable for surgical resection. Patients who have had surgery may also be included if there is residual enhancing disease on the immediate post-operative MRI or if enhancing disease develops on subsequent follow-up imagingRecurrent tumour visible on MRI-T1-Gd with the diameter measuring ≤6cmPrior history of standard dose, conventionally fractionated CNS radiotherapy (i.e. 54-60Gy in 28-33 fractions)At least 6 months since the end of pre-irradiation< 2 prior lines of chemotherapyKarnofsky Performance Score (KPS) ≥ 70%Age ≥ 18 yearsWritten informed consentAdequate organ and marrow function as defined below:absolute neutrophil count ≥ 1.5x109/Lplatelets ≥ 100 x109/Lhaemoglobin > 9.0 g/dLtotal bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤2.0 in patients with known Gilbert's syndrome) OR direct bilirubin ≤ 1 x ULNAspartate or alanine transferase (AST or ALT) ≤2.5 x ULNSerum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equationNegative serum or urine pregnancy test for women of childbearing potential (WOCBP)Willing to comply with the contraceptive requirements of the trial (see section 6.3 of protocol for details)Patients receiving corticosteroids may continue to receive them as long as their dose is stable (i.e. not increased by >2mg) for at least 1-2 weeks prior to initiating protocol therapyAgree to not donate blood during trial treatment or for 90 days after the last dose of niraparibNormal blood pressure or adequately treated and controlled hypertensionExclusion Criteria:Concurrent participation in another interventional clinical trialTumour progression or recurrence within 3 months of initial concurrent chemoradiationHeart failure (compensate or decompensate)Previous treatment with PARP inhibitorsPrevious treatment with re-RTWomen who are pregnant or breast feeding or plan to breastfeed during trial treatment or for 30 days after the last dose of niraparibMajor surgical procedure within 3 weeks prior to the first dose niraparib. Note: Patient must have recovered from any surgical effects before the first dose of niraparibReceived any investigational therapy within 4 weeks prior to, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, the first dose of niraparibKnown hypersensitivity to niraparib components or excipientsReceived a transfusion (platelets or red blood cells) within 4 weeks prior to the first dose of niraparibReceived colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior to the first dose of niraparibKnown history of Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatmentKnown history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)Known history of a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days of registration) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consentPrior malignancy (known diagnosis, detection, or treatment of another type of cancer) within 2 years prior to the first dose of niraparib (except basal or squamous cell carcinoma of the skin and cervical cancer that has been definitively treated)Known leptomeningeal disease, multifocal GBM, or radiologic signs of CNS hemorrhageKnown active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative] is detected) infectionsLive vaccines within 30 days prior to the first dose of niraparib while participating in this clinical studyIf being considered for 300mg dose only:patient weight <77Kgplatelet count of <150 x 109/LPatient is immunocompromised. Patients with splenectomy are not excluded. Patients with known human immunodeficiency virus (HIV) are not excluded if they meet the following criteria:Cluster of differentiation 4 (CD4) ≥350/μL and viral load <400 copies/mLNo history of acquired immunodeficiency syndrome-defining opportunistic infections within 12 months prior to enrolment.No history of HIV-associated malignancy for the past 5 years.Concurrent antiretroviral therapy as per the most current National Institutes of Health (NIH) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV [NIH, 2021] started <4 weeks prior to study enrolment.