Clinical trial NCT05666349: Reirradiation and Niraparib in Patients With Recurrent Glioblastoma
Official title: Reirradiation (Re-RT) and Niraparib (NIRA) in Patients With Recurrent Glioblastoma (rGBM)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Recurrent Glioblastoma
Keywords: Niraparib
Glioblastoma
Re-irradiation
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2022-12-27
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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 imaging
* Recurrent tumour visible on MRI-T1-Gd with the diameter measuring ≤6cm
* Prior 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 chemotherapy
* Karnofsky Performance Score (KPS) ≥ 70%
* Age ≥ 18 years
* Written informed consent
* Adequate organ and marrow function as defined below:

  * absolute neutrophil count ≥ 1.5x109/L
  * platelets ≥ 100 x109/L
  * haemoglobin \> 9.0 g/dL
  * total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤2.0 in patients with known Gilbert's syndrome) OR direct bilirubin ≤ 1 x ULN
  * Aspartate or alanine transferase (AST or ALT) ≤2.5 x ULN
  * Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
* Negative 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 therapy
* Agree to not donate blood during trial treatment or for 90 days after the last dose of niraparib
* Normal blood pressure or adequately treated and controlled hypertension

Exclusion Criteria:

* Concurrent participation in another interventional clinical trial
* Tumour progression or recurrence within 3 months of initial concurrent chemoradiation
* Heart failure (compensate or decompensate)
* Previous treatment with PARP inhibitors
* Previous treatment with re-RT
* Women who are pregnant or breast feeding or plan to breastfeed during trial treatment or for 30 days after the last dose of niraparib
* Major 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 niraparib
* Received 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 niraparib
* Known hypersensitivity to niraparib components or excipients
* Received a transfusion (platelets or red blood cells) within 4 weeks prior to the first dose of niraparib
* Received 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 niraparib
* Known 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 treatment
* Known 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 consent
* Prior 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 hemorrhage
* Known 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) infections
* Live vaccines within 30 days prior to the first dose of niraparib while participating in this clinical study
* If being considered for 300mg dose only:
* patient weight \<77Kg
* platelet count of \<150 x 109/L
* Patient 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/mL
* No 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.

Primary outcomes:
measure: Dose limiting toxicity (DLT) as assessed by CTCAE v5.0
timeFrame: DLTs with an onset date within the first cycle of treatment (typically 28 days) will be assessed.
Secondary outcomes:
measure: Safety and tolerability of niraparib given concurrently with re-RT.
timeFrame: Adverse events will be reported until 30 calendar days post last niraparib and/or post last investigational treatment (re-RT) administration.
measure: Overall survival (OS)
timeFrame: From trial treatment start date until date of death, assessed at 9 months
measure: Progression-free survival (PFS)
timeFrame: From trial treatment start date until disease progression or death, whichever occurs first, assessed up to 9 months.
measure: Best Overall Objective Response Rate
timeFrame: From trial treatment start date through to end of trial, assessed at 12 months
measure: Time to treatment failure (TTF)
timeFrame: From trial treatment start date until early treatment discontinuation, progression, starting further treatment or death, whichever occurs first assessed up to 9 months.
measure: Duration on Treatment
timeFrame: From trial treatment start date until treatment discontinuation, assessed at 12 months
measure: Treatment Compliance
timeFrame: From trial treatment start date until treatment discontinuation, assessed at 12 months
measure: Health-related Quality of life (HRQoL): QLQ-C30
timeFrame: From screening up to 9 months, at specific time points
measure: Health-related Quality of life (HRQoL): QLQ-BN20
timeFrame: From screening up to 9 months, at specific time points
Other outcomes:
Locations:
Study officials:
affiliation: The Christie NHS Foundation Trust
name: Dusan Milanovic
role: PRINCIPAL_INVESTIGATOR
References: