The same medical eligibility criteria apply to both study stages. For Stage 1, references to randomization correspond to the first study treatment date; for Stage 2, they correspond to the randomization date.
Inclusion Criteria:
1. Age 18 years or older; able to understand the study information, voluntarily participate, and provide written informed consent.
2. Diagnosis of adult-type isocitrate dehydrogenase (IDH)-wildtype glioblastoma according to the current World Health Organization diagnostic framework, with pathological and key molecular information available for review.
3. Previous pathological diagnosis obtained by tumor resection or biopsy. Participants must have completed the planned first-line radiotherapy course, including standard fractionation or an appropriate hypofractionated regimen, with concurrent temozolomide. Initiation or completion of all planned cycles of adjuvant temozolomide is not required. The participant must now have the first unequivocal recurrence or progression after initial diagnosis.
4. Recurrence or progression meeting Response Assessment in Neuro-Oncology 2.0 criteria and the protocol definition. Recurrence should generally occur at least 12 weeks after completion of radiotherapy. Within 12 weeks, eligibility requires a new enhancing lesion clearly outside the radiation field or histopathological confirmation of tumor progression.
5. A quality-assured baseline brain magnetic resonance imaging scan completed within 14 days before the first study treatment or randomization, showing at least one measurable contrast-enhancing lesion according to Response Assessment in Neuro-Oncology 2.0 criteria. For bidimensional measurement, both perpendicular diameters must be at least 10 mm on at least two consecutive slices, excluding the surgical cavity and cystic or necrotic components. Corticosteroid dose must be stable or decreasing for at least 5 days before the baseline scan and remain stable or decreasing until study entry. A repeat qualifying scan is required if the dexamethasone-equivalent dose subsequently increases by at least 2 mg/day or by a clinically significant amount, or if neurologic status worsens.
6. No previous systemic treatment with bevacizumab or another vascular endothelial growth factor or vascular endothelial growth factor receptor-targeted agent.
7. Karnofsky Performance Status of at least 70, estimated life expectancy of at least 12 weeks, and ability, in the investigator's judgment, to receive study treatment and complete the principal study follow-up.
8. Adequate bone marrow, hepatic, renal, and coagulation function: absolute neutrophil count at least 1.5 × 10\^9/L; platelet count at least 100 × 10\^9/L; hemoglobin at least 90 g/L; total bilirubin no greater than 1.5 times the upper limit of normal; alanine aminotransferase and aspartate aminotransferase no greater than 2.5 times the upper limit of normal; serum creatinine no greater than 1.5 times the upper limit of normal or estimated creatinine clearance at least 50 mL/min; and international normalized ratio and activated partial thromboplastin time no greater than 1.5 times the upper limit of normal unless receiving protocol-permitted stable anticoagulation.
9. Blood pressure, urinary protein, bleeding and thrombotic risks, wound healing, and gastrointestinal risks compatible with bevacizumab treatment. Blood pressure must be below 150/100 mmHg. Urine dipstick protein must be less than 2+; if 2+ or greater, 24-hour urinary protein must be less than 2 g/24 hours. Major surgery must have occurred at least 28 days previously with adequate wound healing; minor surgery or tumor biopsy must have occurred at least 7 days previously with adequate wound healing.
10. Able to swallow the oral study treatment, with the participant or a caregiver able to support scheduled administration, medication recording, and study visits.
11. Women of childbearing potential must have a negative pregnancy test within 7 days before the first study treatment and agree to use effective contraception from before the first study treatment until 6 months after the last study treatment. Pregnancy testing will be repeated every 4 weeks during treatment. Participants must not breastfeed during treatment or for 6 months after the last study treatment.
12. Following documented discussion by a multidisciplinary neuro-oncology team, the participant is currently considered unsuitable for repeat surgical resection or has explicitly declined repeat surgery after receiving adequate information regarding feasible surgical options, expected benefits, and risks. The multidisciplinary team must confirm that bevacizumab-based salvage treatment is in the participant's best interest and document the conclusion, participating members, and date.
Exclusion Criteria:
1. Histopathological diagnosis of gliosarcoma.
2. Second or subsequent recurrence, or receipt of systemic anticancer treatment or re-irradiation for the current recurrence. Surgery or biopsy for the current recurrence is permitted if the applicable washout and wound-healing requirements are met and a measurable residual enhancing lesion remains.
3. Previous treatment with bevacizumab or another vascular endothelial growth factor pathway-targeted agent; current use of entacapone; or previous entacapone use for any indication when adequate washout cannot be completed or the investigator considers the residual safety risk unacceptable.
4. Pseudoprogression, radiation necrosis, or another non-neoplastic cause cannot be reasonably excluded.
5. No measurable enhancing lesion according to Response Assessment in Neuro-Oncology 2.0 criteria; need for urgent anticancer treatment; availability of another treatment that the multidisciplinary team considers should be prioritized and that the participant is willing to receive; or absence of the required written multidisciplinary team assessment.
6. Active systemic bleeding, clinically significant active intracranial hemorrhage on baseline magnetic resonance imaging, or another unacceptable bleeding risk. Asymptomatic punctate microhemorrhages or clearly stable postoperative hemorrhagic changes may be permitted after investigator assessment.
7. Any of the following: uncontrolled hypertension or clinically significant proteinuria; myocardial infarction, unstable angina, stroke, transient ischemic attack, or another serious arterial thromboembolic event within 6 months; clinically unstable venous thromboembolism or pulmonary embolism; uncontrolled congestive heart failure or clinically significant serious arrhythmia; gastrointestinal perforation, gastrointestinal fistula, or intra-abdominal abscess within 6 months; an unhealed wound, active ulcer, unhealed fracture, or another condition unsuitable for bevacizumab treatment.
8. Active serious infection or another medical condition that precludes safe administration of study treatment.
9. Severe or persistent diarrhea, inflammatory bowel disease, microscopic colitis, or another condition likely to substantially impair absorption of the oral study treatment.
10. Moderate or severe hepatic impairment (Child-Pugh class B or C), active serious liver disease, biliary obstruction, or an unacceptable risk of entacapone exposure in the investigator's judgment.
11. History of a serious hypersensitivity reaction to entacapone, bevacizumab, matching placebo, or any related excipient.
12. Required use of a nonselective monoamine oxidase inhibitor, a relevant catecholamine medication, or another drug with an unacceptable interaction that cannot be safely substituted or discontinued.
13. Requirement for therapeutic anticoagulation that cannot be safely managed. Protocol-permitted stable anticoagulation may be allowed when clinically indicated, at a stable dose for at least 14 days, without active bleeding, and with coagulation parameters within the applicable therapeutic range. Dual antiplatelet therapy is not permitted.
14. Failure to meet the protocol-specified washout periods for surgery, chemotherapy, targeted or immune therapy, radiotherapy, or another investigational drug; or previous treatment-related toxicity not recovered to Grade 1 or lower or to baseline. Required washouts include at least 28 days after major surgery, at least 7 days after minor surgery or biopsy, at least 4 weeks after temozolomide or another cytotoxic agent, at least 6 weeks after a nitrosourea, and at least 4 weeks or 5 drug half-lives, whichever is longer, after a targeted agent, immunotherapy, or investigational drug. Alopecia, stable endocrine replacement therapy, and residual toxicities considered clinically insignificant may be permitted.
15. Another active malignancy requiring systemic treatment or likely to substantially interfere with progression-free survival, overall survival, or safety assessment. Successfully treated nonmelanoma skin cancer, carcinoma in situ, or another malignancy considered unlikely to interfere with study assessments may be permitted.
16. Pregnancy or breastfeeding.
17. Seizures that remain uncontrolled despite appropriate treatment, or another progressive neurologic disorder that could interfere with safe treatment administration, imaging assessment, or follow-up.
18. Inability to provide valid informed consent, take or record the study medication, complete required imaging or follow-up, or any circumstance in which the investigator considers participation not to be in the participant's best interest.
