RiNG: Reirradiation and Niraparib in Patients With Recurrent Glioblastoma

Sponsor

University College, London (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05666349

Collaborator

GlaxoSmithKline (Industry)

Enrollment

Arm

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Glioblastoma	Drug: Niraparib Radiation: Re-irradiation (re-RT)	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Reirradiation (Re-RT) and Niraparib (NIRA) in Patients With Recurrent Glioblastoma (rGBM)

Anticipated Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2024

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Niraparib and re-irradiation (re-RT) Patients will be treated with IMRT-based re-RT for a total dose of 35 Gy in 10 daily fractions over approx. 2 weeks. Patients will take niraparib daily from the first day of re-RT until documented progression or discontinuation due to unacceptable treatment-related toxicity or any other cause (whichever occurs sooner). Patients will be recruited in cohorts of 3. Following the completion of each dosing cohort and once the patients have completed the dose limiting toxicity (DLT) assessment window, the independent data monitoring committee (IDMC) will review the data for each patient. In conjunction with the statistical recommendations from the continual reassessment method (CRM), the IDMC will advise whether the dose for the next cohort should be escalated, de-escalated or stay at the current niraparib dose.	Drug: Niraparib 100 mg, 200 mg, or 300mg oral niraparib once daily. Other Names: Zejula Radiation: Re-irradiation (re-RT) Intensity modulated radiotherapy (IMRT)-based re-RT for a total dose of 35 Gy in 10 daily fractions.

Arm

Intervention/Treatment

Experimental: Niraparib and re-irradiation (re-RT)

Patients will be treated with IMRT-based re-RT for a total dose of 35 Gy in 10 daily fractions over approx. 2 weeks. Patients will take niraparib daily from the first day of re-RT until documented progression or discontinuation due to unacceptable treatment-related toxicity or any other cause (whichever occurs sooner). Patients will be recruited in cohorts of 3. Following the completion of each dosing cohort and once the patients have completed the dose limiting toxicity (DLT) assessment window, the independent data monitoring committee (IDMC) will review the data for each patient. In conjunction with the statistical recommendations from the continual reassessment method (CRM), the IDMC will advise whether the dose for the next cohort should be escalated, de-escalated or stay at the current niraparib dose.

Drug: Niraparib

100 mg, 200 mg, or 300mg oral niraparib once daily.

Other Names:

Zejula

Radiation: Re-irradiation (re-RT)

Intensity modulated radiotherapy (IMRT)-based re-RT for a total dose of 35 Gy in 10 daily fractions.

Outcome Measures

Primary Outcome Measures

Dose limiting toxicity (DLT) as assessed by CTCAE v5.0 [DLTs with an onset date within the first cycle of treatment (typically 28 days) will be assessed.]
DLTs will be assessed in order to determine the maximum tolerated dose of niraparib given concurrently with re-RT.

Secondary Outcome Measures

Safety and tolerability of niraparib given concurrently with re-RT. [Adverse events will be reported until 30 calendar days post last niraparib and/or post last investigational treatment (re-RT) administration.]
Safety and tolerability of niraparib given concurrently with re-RT, characterised in terms of adverse events as assessed by CTCAE v5.0.
Overall survival (OS) [From trial treatment start date until date of death, assessed at 9 months]
Death
Progression-free survival (PFS) [From trial treatment start date until disease progression or death, whichever occurs first, assessed up to 9 months.]
Disease progression or death
Best Overall Objective Response Rate [From trial treatment start date through to end of trial, assessed at 12 months]
Frequency and percentage of patients who experienced a Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD)
Time to treatment failure (TTF) [From trial treatment start date until early treatment discontinuation, progression, starting further treatment or death, whichever occurs first assessed up to 9 months.]
Treatment failure classified as early treatment discontinuation, progression, starting further treatment or death.
Duration on Treatment [From trial treatment start date until treatment discontinuation, assessed at 12 months]
Median time on trial treatment will be presented.
Treatment Compliance [From trial treatment start date until treatment discontinuation, assessed at 12 months]
Reasons for treatment delays, dose omissions, dose reductions and treatment discontinuation.
Health-related Quality of life (HRQoL): QLQ-C30 [From screening up to 9 months, at specific time points]
HRQoL assessed by European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, scored according to EORTC manual guideline. Score range is 0-100, with 100 being the highest response level.
Health-related Quality of life (HRQoL): QLQ-BN20 [From screening up to 9 months, at specific time points]
HRQoL assessed by European Organisation for Research and Treatment of Cancer (EORTC) QLQ-BN20, scored according to EORTC manual guidelines.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.