IRB Study Number 25-008
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Test whether niraparib compared with temozolomide significantly extends progression-free survival in participants with newly-diagnosed, MGMT promoter unmethylated glioblastoma
Test whether niraparib compared with temozolomide significantly extends overall survival in participants with newly-diagnosed, MGMT promoter unmethylated glioblastoma
Secondary Objectives
Test whether niraparib improves objective tumor response compared with temozolomide
Evaluate the impact of niraparib compared to temozolomide on symptoms and function domains and global HRQoL
Evaluate whether treatment with niraparib is associated with better neurocognitive function over time versus temozolomide
Evaluate safety and tolerability in participants treated with niraparib versus temozolomide
Inclusion Criteria
5.1.1. Type of participant and disease characteristics
Histologic documentation of a newly-diagnosed intracranial GBM, per 2021 WHO classification guidelines through local pathology review.
Age ≥18 years at the time of signing informed consent.
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.
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.
Suitability for SOC RT to 60 Gy in 30 fractions using ESTRO-EANO ‘single phase’ targeting approach [Niyazi, 2023], per investigator’s judgment.
No prior treatment for GBM (including brachytherapy or BCNU wafers), other than surgical resection or biopsy.
5.1.2. Sex and contraceptive/barrier requirements
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- Female participants: Not pregnant, planning to get pregnant, or breastfeeding, and 1 of the following conditions apply:
o Is a WONCBP as defined in Section 10.3. OR
o Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Section 10.3, from the screening visit through at least 180 days after the last dose of study intervention, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention. AND
o Breastfeeding is contraindicated during the study and for 1 month after the last dose of study intervention.
o A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 72 hours before the first dose of study intervention (see Section 8.3.6).
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
o Additional requirements for pregnancy testing during and after study intervention are provided in Section 8.3.6.
o The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- 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:
o Refrain from donating sperm.
PLUS either:
o Be abstinent from heterosexual activity as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent. OR
o Must agree to use a male condom, as well as 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) as described in Section 10.3, as a condom may break or leak.
5.1.3. Informed consent
- The participant must be capable of giving signed informed consent as described in Section 10.1, including compliance with the requirements and restrictions listed in the ICF and in this protocol.
5.1.4. Performance status and organ function
Karnofsky performance status of ≥70.
Adequate organ and bone marrow function as defined in Table 4.
5.1.5. Other inclusion criteria
Normal BP or adequately treated and controlled hypertension (defined as systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg).
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.
Ability to swallow oral medications whole.
Exclusion Criteria
5.2.1. Medical conditions
Presence of metastatic or predominant leptomeningeal disease.
Current active pneumonitis or any history of pneumonitis requiring steroids (any dose) or immunomodulatory treatment within 90 days of planned start of the study.
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).
Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
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.
Known HIV unless participants meet all the following criteria:
o Cluster of differentiation 4 ≥350/μL and viral load <400 copies/mL.
o No history of acquired immunodeficiency syndrome-defining opportunistic infections within 12 months prior to enrollment.
o No history of HIV-associated malignancy for the past 5 years.
o Concurrent antiretroviral therapy as per the most current NIH Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV [NIH, 2023] started >4 weeks prior to study enrollment.
MDS/AML or with features suggestive of MDS/AML.
History of another malignancy within 2 years prior to registration. Patients 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. Patients 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.
Prior history of PRES.
Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study requirements and/or follow-up procedures. Those conditions should be discussed with the participants before study entry.
Inability to undergo MRI brain with IV contrast.
5.2.2. Prior/concomitant therapy
Biopsy and/or resection (whichever is later) occurring >6 weeks prior to planned RT start date.
Surgical wound complication recovery at the time of enrollment.
Known hypersensitivity to the components of niraparib, TMZ, or their formulation excipients.
Known hypersensitivity to dacarbazine (DTIC).
Prior therapy with PARP inhibitors for systemic cancer.
Received a live vaccine within 30 days before the planned start of study intervention. COVID-19 vaccines that do not contain live viruses are allowed. Note: mRNA and adenoviral-based COVID-19 vaccines are considered non-live.
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.
5.2.3. Prior/concurrent clinical study experience
Treatment with another investigational drug or other intervention within 5 half-lives of the investigational product.
Treatment with tumor-treating fields (e.g., Optune) for GBM.
5.2.4. Diagnostic assessments
Presence of known IDH mutation.
Presence of known H3 mutation.
Previous diagnosis of WHO Grade 2 or 3 glioma.
Patient has a QT interval corrected using Fridericia's formula (QTcF) ≥ 480 msec
