Status and phase
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About
This study will be conducted as a randomized, double-blind, placebo-controlled, multi-center Phase 3 study. Approximately 300 subjects with newly diagnosed glioblastoma who meet all eligibility criteria will be enrolled.
Enrollment
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Volunteers
Inclusion and exclusion criteria
Patient Inclusion Criteria:
Patients must meet all the following inclusion criteria to be eligible for enrollment into the study:
Signed informed consent
Age ≥ 18 years with life expectancy > 12 weeks
Histologically proven, newly diagnosed supratentorial glioblastoma (IDH mutant is excluded) based on the WHO classification (2016) which includes gliosarcoma (GS); prior diagnosis of lower grade astrocytoma that has been upgraded to histologically confirmed glioblastoma is eligible if chemotherapy and radiation therapy treatment-naïve
Randomization must occur within approximately 6 weeks after resection (patients undergoing biopsy only are excluded from the study)
Craniotomy site must be adequately healed, free of drainage or cellulitis and the underlying cranioplasty must appear intact prior to start of study treatment
DGM1 biomarker status (positive or negative) is available prior to randomization
Availability of tumor tissue representative of glioblastoma from surgery, and MGMT promoter methylation status is determined prior to study randomization
Karnofsky performance status (KPS) ≥ 70 (Appendix 1)
Stable or decreasing corticosteroids within 5 days prior to study treatment start
Willing to forego the use of Tumor Treating Fields therapy (Optune®)
Adequate organ function within 14 days prior to randomization:
Bone marrow
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L;
Platelet count ≥ 100 x 109/L;
Hemoglobin ≥ 10 g/dL (eligibility level for hemoglobin may be met by transfusion) Renal
Serum creatinine < 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min as calculated using an appropriately validated prediction equation for the estimation of eGFR (eg, Cockcroft-Gault or MDRD method).
Hepatic
Total serum bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert syndrome;
Aspartate and Alanine transaminase (AST/SGOT and ALT/SGPT) ≤ 2.5 x ULN;
Alkaline phosphatase (ALP) ≤ 2.5 x ULN
Negative serum pregnancy test (for females of childbearing potential) within 7 days prior to the first study treatment
Male and female patients of reproductive potential must agree to use an effective method of contraception (eg, oral contraceptives, intrauterine device, barrier method) throughout the study and for at least 3 months after the last dose of study treatment, or 6 months for female patients in regard to the last dose of temozolomide (TMZ), whichever is later
Willing and able to comply with the protocol
Patient Exclusion Criteria:
Patients with any of the following characteristics/conditions will be excluded from study:
Unable to swallow tablets or capsules
Pregnant or breastfeeding
Prior chemotherapy (including carmustine-containing wafers (Gliadel®), immunotherapy (including vaccine therapy), or investigational products for GBM or GS (previous 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) administered prior to surgery to aid in optimal surgical resection is permitted)
Glioblastoma IDH mutant
Prior radiation therapy to the brain
Unable to discontinue use of enzyme-inducing anti-epileptic drugs (EIAEDs), see Section 5.1.2.4.1; if previously taking EIAEDs, must have been discontinued ≥ 2 weeks prior to randomization
Use of a strong inducer or moderate or strong inhibitor of CYP3A4 (Appendix 2) within 7 days prior to randomization or expected requirement for use on study therapy
Use of warfarin that cannot be stopped prior to the study.
Use of any medication that can prolong the QT/QTc interval (Appendix 3) within 7 days prior to start of study therapy, or plan to use such a medication during the study
Active bacterial, fungal or viral infection requiring systemic treatment
Personal or family history of abnormal long QT interval, QTc interval > 450 msec (males) or > 470 msec (females) as read on the printout of the electrocardiogram (ECG) at screening (recommended that QTc be calculated using Fridericia's correction formula, QTcF: see Section 7.3.2.2), or a history of unexplained syncope
Unstable angina; myocardial infarction or coronary artery bypass graft/percutaneous stent placement within 6 months of starting study treatment, congestive heart failure requiring treatment (New York Heart Association [NYHA] Grade ≥2)
History of significant cardiac arrhythmia (ventricular tachycardia or fibrillation, Torsades de Pointe) or second- or third-degree A-V block, symptomatic bradycardia (unless controlled with a pacemaker)
Persistent electrolyte abnormalities such as hypokalemia or hypomagnesemia that do not respond to treatment
History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)
Evidence of chronic hepatitis C infection as indicated by antibody to hepatitis C virus (HCV) with positive HCV ribonucleic acid (RNA)
Evidence of active or chronic hepatitis B infection as indicated by either:
hepatitis B surface antigen (HBsAg) positive, or hepatitis B core antibody (HBcAb) positive with hepatitis B virus-deoxyribonucleic acid (HBV-DNA) positive (any detectable amount is considered positive)
Any contraindication to temozolomide listed in the local product label
Another malignancy except adequately treated non-melanoma skin cancer; patients who have had another primary malignancy in the past, but have been disease-free for more than 5 years, and patients who have had a localized malignancy treated with curative intent and disease free for more than 2 years are eligible
Participation in other studies involving investigational product(s) within 30 days prior to randomization
Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for participation in this study
Primary purpose
Allocation
Interventional model
Masking
260 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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