This investigator-initiated, multicenter clinical trial will evaluate the safety and preliminary effectiveness of adding entacapone to bevacizumab in adults with isocitrate dehydrogenase (IDH)-wildtype glioblastoma at first recurrence after standard first-line treatment. Participants must not have previously received bevacizumab. A multidisciplinary neuro-oncology team must determine that repeat tumor resection is not appropriate, or the patient must decline repeat surgery after being informed of its potential benefits and risks.
The study has two stages. In the first stage, 6 participants who can be evaluated for dose-limiting toxicity will receive open-label entacapone 400 mg by mouth three times daily plus bevacizumab. Enrollment will occur in two cohorts of 3, with safety review by an independent data and safety monitoring board. Up to 3 participants who cannot complete the 28-day toxicity evaluation for reasons unrelated to toxicity may be replaced.
If the combination has acceptable safety and the required approvals are obtained, 90 new participants will enter the second stage and be randomly assigned in a 1:1 ratio to entacapone or matching placebo. Both groups will receive bevacizumab. The primary endpoint of the randomized stage is progression-free survival assessed by blinded independent central review. The study plans to obtain data from 96 evaluable participants, with no more than 99 participants receiving study treatment.
Age 18 years or older; able to understand the study information, voluntarily participate, and provide written informed consent.
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.
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.
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.
Histopathological diagnosis of gliosarcoma.
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.
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.
Pseudoprogression, radiation necrosis, or another non-neoplastic cause cannot be reasonably excluded.
Parallel
Entacapone
DrugEntacapone is administered orally at a starting dose of 400 mg three times daily in the open-label safety lead-in and the experimental arm of the randomized stage. If a treatment-related adverse reaction occurs, the dose may be reduced to 200 mg three times daily and may not subsequently be increased. Treatment may continue for up to 13 cycles (364 days), subject to protocol-defined discontinuation criteria.
Bevacizumab
DrugBevacizumab is administered intravenously at a dose of 10 mg/kg every 2 weeks as background treatment in all three study arms. Treatment is continued or discontinued according to disease status, safety, participant preference, and the protocol-defined treatment discontinuation criteria.
Placebo
DrugA matching placebo is administered orally three times daily in the control arm of Stage 2. If a treatment-related adverse reaction occurs, the blinded study treatment may be reduced using the same dose-reduction procedure corresponding to entacapone 200 mg three times daily, without subsequent dose re-escalation. Treatment may continue for up to 13 cycles (364 days), subject to protocol-defined discontinuation criteria.
Number of Participants With Dose-Limiting Toxicities
The number of dose-limiting toxicity-evaluable participants who experience at least one protocol-defined dose-limiting toxicity during the initial 28-day safety evaluation period will be reported. Each participant will be counted once, regardless of the number of dose-limiting toxicities experienced. A lower number indicates better tolerability.
Progression-Free Survival Assessed by Blinded Independent Central Review
Progression-free survival is defined as the time from randomization to the first documented disease progression according to Response Assessment in Neuro-Oncology 2.0 criteria, as determined by blinded independent central review, or death from any cause, whichever occurs first. Participants without an event will be censored at the date of their last adequate blinded independent central review assessment.
Overall Survival
Overall survival is defined as the time from randomization to death from any cause. Participants who are alive at the time of analysis will be censored at the date on which they were last known to be alive.
Progression-Free Survival Rate at 6 Months Assessed by Blinded Independent Central Review
The proportion of participants who are alive and free from disease progression at 6 months after randomization will be estimated using the Kaplan-Meier method. Disease progression will be determined by blinded independent central review according to Response Assessment in Neuro-Oncology 2.0 criteria.
Objective Response Rate Assessed by Blinded Independent Central Review
Objective response rate is defined as the proportion of randomized participants whose best overall response is complete response or partial response, as determined by blinded independent central review according to Response Assessment in Neuro-Oncology 2.0 criteria.
Duration of Response Assessed by Blinded Independent Central Review
Among participants who achieve a complete or partial response, duration of response is defined as the time from the first documented objective response to disease progression, as determined by blinded independent central review according to Response Assessment in Neuro-Oncology 2.0 criteria, or death from any cause, whichever occurs first.
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First Affiliated Hospital of Wenzhou Medical University
Lead sponsor
Jinhua Municipal Central Hospital
Collaborator
Second Affiliated Hospital, Zhejiang University, School of Medicine
Collaborator
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