Overview
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 questions it aims to answer are:
Does niraparib improve progression-free survival (PFS) compared to TMZ?
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
Eligibility
Inclusion Criteria:
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- Histologic documentation of a newly-diagnosed intracranial GBM, per 2021 WHO classification guidelines through local pathology review.
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2. Age ≥18 years at the time of signing informed consent.
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3. Sufficient tissue available for retrospective central pathology review and
genomic analysis. If insufficient tissue is available, approval may be granted
on a case-by-case basis after a review.
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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 laboratory manual.
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5. Suitability for SOC RT to 60 Gy in 30 fractions using ESTRO-EANO 'single phase'
targeting approach [Niyazi, 2023], per investigator's judgment.
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6. No prior treatment for GBM (including brachytherapy or BCNU wafers), other than
surgical resection or biopsy.
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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.
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8. Male participants: Must agree to the following during the study intervention
period and for at least 90 days 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).
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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.
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10. Karnofsky performance status of ≥70.
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11. Adequate organ function
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12. Normal blood pressure (BP) or adequately treated and controlled hypertension
(defined as systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg).
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13. Stable or decreased dose of dexamethasone, requiring no more than 5 mg daily
equivalent dose, within 7 days before randomization.
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14. Ability to swallow oral medications whole.
Exclusion Criteria:
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- Presence of metastatic or predominant leptomeningeal disease.
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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.
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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).
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4. Any clinically significant gastrointestinal abnormalities that may alter
absorption such as malabsorption syndrome or major resection of the stomach
and/or bowels.
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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.
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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.
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7. MDS/AML or with features suggestive of MDS/AML.
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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.
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9. Prior history of posterior reversible encephalopathy syndrome (PRES).
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10. Any psychological, familial, sociological, or geographical condition
potentially hampering compliance with the study requirements and/or follow-up
procedures.
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11. Inability to undergo MRI brain with IV contrast.
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12. Biopsy and/or resection (whichever is later) occurring >6 weeks prior to
planned RT start date.
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13. Surgical wound complication recovery at the time of enrollment.
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14. Known hypersensitivity to the components of niraparib, TMZ, or their
formulation excipients.
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15. Known hypersensitivity to dacarbazine (DTIC).
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16. Prior therapy with PARP inhibitors for systemic cancer.
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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.
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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.
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19. Treatment with another investigational drug or other intervention within 5
half-lives of the investigational product.
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20. Treatment with tumor treating fields (e.g., Optune) for GBM.
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21. Presence of known isocitrate dehydrogenase (IDH) mutation.
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22. Presence of known H3 mutation.
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23. Previous diagnosis of WHO Grade 2 or 3 glioma.