Brain Neoplasms, Adult, Malignant, Brain Tumor, GBM, Glioblastoma
Conditions
Brief summary
The goal of this Phase 3 clinical trial is to compare the efficacy of niraparib versus temozolomide (TMZ) in adult participants with newly-diagnosed, MGMT unmethylated glioblastoma multiforme (GBM). The main question it aims to answer is: Does niraparib improve overall survival (OS) compared to TMZ? Participants will be randomly assigned to one of two treatment arms: niraparib or TMZ. * study drug (Niraparib) or * comparator drug (Temozolomide - which is the standard approved treatment for MGMT unmethylated glioblastoma). The study medication will be taken daily while receiving standard of care radiation therapy (RT) for 6-7 weeks. Participants may continue to take the niraparib or TMZ adjuvantly as long as the cancer does not get worse or completion of 6 cycles of treatment (TMZ). A total of 450 participants will be enrolled in the study. Participants' tasks will include: * Complete study visits as scheduled * Complete a diary to record study medication
Interventions
DRUGNiraparib
Participants will receive niraparib 200 mg orally once daily starting on Day 1 of RT. Following completion of RT, participants will continue niraparib adjuvant therapy orally once daily on Days 1 to 28 of each 28-day cycle until progression by BICR
DRUGTemozolomide
Participants randomized to the comparator arm (Arm B) will receive SOC TMZ 75 mg/m2 orally once daily with RT starting on Day 1 of RT. Following completion of RT, participants will complete a 4-week rest period, and then receive adjuvant TMZ 150 to 200 mg/m2 orally once daily on Days 1 to 5 of each 28-day cycle until progression by BICR or for a maximum of 6 cycles.
Sponsors
Ivy Brain Tumor Center
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Blinded Independent Central Review is composed of independent radiologists and will be utilized to assess progression of disease
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Histologic documentation of a newly-diagnosed intracranial GBM, per 2021 WHO classification guidelines through local pathology review. * 2\. Age ≥18 years at the time of signing informed consent. * 3\. Sufficient tissue available for retrospective central pathology review, retrospective central confirmation of MGMT promoter methylation status and genomic analysis. If insufficient tissue is available,pproval may be granted on a case-by-case basis after a review. * 4\. Unmethylated MGMT promoter region determined locally by a validated PSQ or qMS-PCR assay compliant to local regulations. Numerical cut-off for an MGMT unmethylated tumor will be defined in the protocol. * 5\. Suitability for SOC RT to 60 Gy in 30 fractions using ESTRO-EANO 'single phase' targeting approach \[Niyazi, 2023\], per investigator's judgment. * 6\. No prior treatment for GBM (including brachytherapy or BCNU wafers), other than surgical resection or biopsy. * 7\. Female participants: Not pregnant, planning to get pregnant, or breastfeeding and one of the following conditions apply: is of nonchildbearing potential or is of childbearing potential AND using a contraceptive method that is highly effective (with a failure rate of \<1% per year) from screening through at least 180 days after the last dose of study intervention. Breastfeeding is contraindicated during the study and for one month after the last dose of study intervention. * 8\. Male participants: Must agree to the following during the study intervention period and for at least 6 months after the last dose of study intervention: refrain from donation sperm PLUS be abstinent from heterosexual activity or agree to use a male condom and be advised of the benefit for a female partner to use a contraceptive method that is highly effective (with a failure rate of \<1% per year). * 9\. The participant must be capable of providing signed informed consent, including compliance with the requirements and restrictions listed in the ICF and in this protocol. * 10\. Karnofsky performance status of ≥70. * 11\. Adequate organ function * 12\. Normal blood pressure (BP) or adequately treated and controlled hypertension (defined as systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg). * 13\. Stable or decreased dose of dexamethasone, requiring no more than 5 mg daily equivalent dose, within 7 days before randomization. * 14\. Ability to swallow oral medications whole.
Exclusion criteria
* 1\. Presence of metastatic or predominant leptomeningeal disease. * 2\. Current active pneumonitis or any history of pneumonitis requiring steroids (any dose) or immunomodulatory treatment within 90 days of planned start of the study. * 3\. Participant is at an increased bleeding risk due to concurrent conditions (e.g., major injuries or major surgery within the past 28 days prior to start of study treatment with the exception of tumor resection). * 4\. Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels. * 5\. Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice. NOTE: Stable noncirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones), hepatobiliary involvement of malignancy, or chronic stable HBV infection (in a participant for whom HDV infection has been excluded) or chronic HCV infection is acceptable if the participant otherwise meets entry criteria. * 6\. Known human immunodeficiency virus (HIV) unless participants meet all of the following criteria: * Cluster of differentiation 4 ≥350/µL and viral load \<400 copies/mL. * No history of acquired immunodeficiency syndrome-defining opportunistic infections within 12 months prior to enrollment. * 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 enrollment. * 7\. MDS/AML or with features suggestive of MDS/AML. * 8\. History of another malignancy within 2 years prior to registration. Participants with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Participants with a history of other malignancies are eligible if they have been treated with curative intent or continuously disease free for at least 2 years after definitive primary treatment. * 9\. Prior history of posterior reversible encephalopathy syndrome (PRES). * 10\. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study requirements and/or follow-up procedures. * 11\. Inability to undergo MRI brain with IV contrast. * 12\. Biopsy and/or resection (whichever is later) occurring \>6 weeks prior to planned RT start date. * 13\. Surgical wound complication recovery at the time of enrollment. * 14\. Known hypersensitivity to the components of niraparib, TMZ, or their formulation excipients. * 15\. Known hypersensitivity to dacarbazine (DTIC). * 16\. Prior therapy with PARP inhibitors for systemic cancer. * 17\. Received a live vaccine within 30 days before the planned start of study intervention. Coronavirus disease 2019 (COVID-19) vaccines that do not contain live viruses are allowed. Note: mRNA and adenoviral-based COVID-19 vaccines are considered non-live. * 18\. Received a transfusion (platelets or red blood cells) or colony-stimulating factors (e.g., granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks of the planned start of study intervention. * 19\. Treatment with another investigational drug or other intervention within 5 half-lives of the investigational product. * 20\. Treatment with tumor treating fields (e.g., Optune) for GBM. * 21\. Presence of known isocitrate dehydrogenase (IDH) mutation. * 22\. Presence of known H3 mutation. * 23\. Previous diagnosis of WHO Grade 2 or 3 glioma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | 24 months | Overall survival, defined as the time from the date of randomization to the date of death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR) | 24 months | Progression-free survival, defined as the time from the date of randomization to the date of first disease progression per RANO 2.0 by BICR assessment or death from any cause, whichever occurs first. |
| Overall response rate | 24 months | Percentage of patients who achieved confirmed complete response or confirmed partial response to treatment evaluated using RANO 2.0 by BICR. |
| Compare symptoms, function, and Health-related quality of life (HRQoL) and symptoms by EORTC QLQ-C30-item Core module (EORTC QLQ-C30) (Scores on a scale) | on Day 1 pre-dose or up to 7 days prior, on any day during the 6th week of RT, and on days of MRI at 4- and 12- weeks after RT, every 16 weeks thereafter on days of MRI | EORTC QLQ-C30 is a validated questionnaire to assess overall health-related quality of life in participants with cancer. |
| Compare symptoms, function, and Health-related quality of life (HRQoL) and symptoms by EORTC QLQ-BN20-item Core module (EORTC QLQ-BN20) (Scores on a scale) | on Day 1 pre-dose or up to 7 days prior, on any day during the 6th week of RT, and on days of MRI at 4- and 12- weeks after RT, every 16 weeks thereafter on days of MRI | EORTC QLQ-BN20 is a clinically valid and useful tool for assessing disease- and treatment-specific symptoms in brain neoplasm participants. |
| Compare symptoms, function, and Health-related quality of life (HRQoL) and symptoms by EQ-5D-3L | on Day 1 pre-dose or up to 7 days prior, on any day during the 6th week of RT, and on days of MRI at 4- and 12- weeks after RT, every 16 weeks thereafter on days of MRI | The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. |
| Changes from baseline in neurocognitive function assessed by Hopkins Verbal Learning test | on Day 1 pre-dose or up to 7 days prior, on any day during the 6th week of RT, and on days of MRI at 4- and 12- weeks after RT, every 16 weeks thereafter on days of MRI | The Hopkins Verbal Learning Test is designed to evaluate memory. It requires participants to memorize a list of 12 items for 3 consecutive tests (recall), to identify the same 12 items from a list of semantically related or unrelated items (recognition), and to recall the same 12 items after a 15-minute delay (delayed recall). |
| Changes from baseline in neurocognitive function assessed by Controlled Oral Word Association | on Day 1 pre-dose or up to 7 days prior, on any day during the 6th week of RT, and on days of MRI at 4- and 12- weeks after RT, every 16 weeks thereafter on days of MRI | The Controlled Oral Word Association Test is designed to evaluate verbal fluency. It requires participants to name words beginning with a specific letter with increasing associated activity, in 3 one-minute periods. |
| Changes from baseline in neurocognitive function assessed by Trail Making Test Parts A and B | on Day 1 pre-dose or up to 7 days prior, on any day during the 6th week of RT, and on days of MRI at 4- and 12- weeks after RT, every 16 weeks thereafter on days of MRI | The Trail Making Test Part A is designed to evaluate visual motor scanning speed, and the Trail Making Test Part B is designed to evaluate executive function. These tests require participants to connect circles in numerical (Part A) or alternating numerical and alphabetical sequence (Part B) within a timed interval of less than 5 minutes for each test. |
| Incidence of participants with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) | 24 months | AEs, SAEs and AESIs will be collected |
| Incidence of treatment discontinuations, dose interruptions, and dose reductions due to AEs, SAEs, or AESIs, changes in Karnofsky performance status, changes in clinical laboratory results, and vital sign measurements | 24 months | Treatment discontinuations, dose interruptions, and dose reductions |
| Frequency and severity of symptomatic AEs based on PRO-CTCAE | 24 months | The PRO-CTCAE is a patient-reported outcome measure developed to evaluate symptomatic toxicity in patients on cancer clinical trials. |
Countries
Australia, Canada, France, Germany, Italy, Netherlands, Norway, Spain, Switzerland, United Kingdom, United States
Contacts
STUDY_CHAIRNader Sanai, MD
Ivy Brain Tumor Center
Outcome results
None listed