A study comparing niraparib with temozolomide in adult participants with newly-diagnosed, MGMT unmethylated glioblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Neurotrials LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Dec 2024 → ongoing

Decision date (initial)

2024-12-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

GlaxoSmithKline (GSK) · Neurotrials LLC

External identifiers

EU CT number

2024-513077-48-00

ClinicalTrials.gov

NCT06388733

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Efficacy, Pharmacokinetic, Pharmacogenomic

* Test whether niraparib compared with temozolomide significantly extends overall survival in participants with newly-diagnosed, MGMT promoter unmethylated glioblastoma

Secondary objectives 5

1. Test whether niraparib improves objective tumor response compared with temozolomide
2. Evaluate the impact of niraparib compared to temozolomide on symptoms and function domains and global HRQoL
3. Evaluate whether treatment with niraparib is associated with better neurocognitive function over time versus temozolomide
4. Evaluate safety and tolerability in participants treated with niraparib versus temozolomide
5. Test whether niraparib compared with temozolomide significantly extends progression-free survival in participants with newly-diagnosed, MGMT promoter unmethylated glioblastoma

Conditions and MedDRA coding

O6-methylguanine methyltransferase (MGMT) unmethylated glioblastoma

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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 as defined in the protocol.
5. Suitability for SOC RT to 60 Gy in 30 fractions using ESTRO-EANO 'single phase' targeting approach, 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. Participants on other corticosteroids must not exceed an equivalent dose. .
14. Ability to swallow oral medications whole.

Exclusion criteria 23

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival, defined as the time from the date of randomization to the date of death due to any cause

Secondary endpoints 5

1. Overall response rate, defined as confirmed complete response or confirmed partial response, as per RANO 2.0 by BICR assessment
2. Compare symptoms, function, and HRQoL at baseline to the specified timepoints in the schedule of assessments
3. Changes from baseline in neurocognitive function assessed by Hopkins Verbal Learning Test, Controlled Oral Word Association, and Trail Making Test Parts A and B
4. • Incidence of AEs, SAEs, and AESIs • 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 • Frequency and severity of symptomatic AEs based on PRO-CTCAE
5. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Neurotrials LLC

Sponsor organisation

Neurotrials LLC

Address

2910 North 3rd Avenue

City

Phoenix

Postcode

85013-4434

Country

United States

Scientific contact point

Organisation

Neurotrials LLC

Contact name

Nader Sanai, MD

Public contact point

Organisation

Neurotrials LLC

Contact name

Study Navigator

Third parties 6

Locations

8 EU/EEA countries · 53 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 136 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications