Clinical trial NCT06388733: A Study Comparing Niraparib With Temozolomide in Adult Participants With Newly-diagnosed, MGMT Unmethylated Glioblastoma
Official title: A Phase 3, Open-label, Randomized 2-arm Study Comparing the Clinical Efficacy and Safety of Niraparib With Temozolomide in Adult Participants With Newly-diagnosed, MGMT Unmethylated Glioblastoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Glioblastoma
GBM
Brain Neoplasms, Adult, Malignant
Brain Tumor
Lead sponsor: NeuroTrials, LLC
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2024-04-29
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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 criteria: 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 and genomic analysis. If insufficient tissue is available, approval 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 laboratory manual.
* 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 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).
* 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).
* 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.

Primary outcomes:
measure: Progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR)
timeFrame: 24 months
measure: Overall survival
timeFrame: 24 months
Secondary outcomes:
measure: Overall response rate
timeFrame: 24 months
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Changes from baseline in neurocognitive function assessed by Hopkins Verbal Learning Test
timeFrame: 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
measure: Changes from baseline in neurocognitive function assessed by Controlled Oral Word Association
timeFrame: 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
measure: Changes from baseline in neurocognitive function assessed by Trail Making Test Parts A and B
timeFrame: 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
measure: Number of participants with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs)
timeFrame: 24 months
measure: Number 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
timeFrame: 24 months
measure: Frequency and severity of symptomatic AEs based on PRO-CTCAE
timeFrame: 24 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Ivy Brain Tumor Center
state: Arizona
city: La Jolla
country: United States
facility: Scripps Cancer Center
state: California
city: La Jolla
country: United States
facility: Moores UCSD Cancer Center
state: California
city: Baton Rouge
country: United States
facility: The NeuroMedical Center
state: Louisiana
city: South Portland
country: United States
facility: MaineHealth Maine Medical Center Care
state: Maine
city: New York
country: United States
facility: New York University Ambulatory Care Center
state: New York
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Burlington
country: United States
facility: The University of Vermont Medical Center
state: Vermont
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Marseille cedex 05
country: France
facility: Hôpital de la Timone
state: Bouches-du-Rhône
city: Montpellier Cedex 5
country: France
facility: Institut du Cancer de Montpellier
state: Herault
city: Bron
country: France
facility: Centre Hospitalier Universitaire de Lyon-Hospices Civils de Lyon-Hopital Pierre Wertheimer
state: Rhone
city: Lyon
country: France
facility: Centre Leon Berard
state: Rhone
city: Amiens
country: France
facility: CHU Amiens-Picardie - Site Sud
state: Somme
city: Dijon Cedex
country: France
facility: Centre Georges François Leclerc
city: Paris
country: France
facility: Groupe Hospitalier Pitie-Salpetriere
city: Tübingen
country: Germany
facility: Universitaetsklinikum Tuebingen
state: Baden Wuerttemberg
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
state: Sachsen
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
city: Maastricht
country: Netherlands
facility: Maastricht UMC
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF, Radiumhospitalet
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
Study officials:
affiliation: Ivy Brain Tumor Center
name: Nader Sanai, MD
role: STUDY_CHAIR
References: