Entacapone Combined With Bevacizumab in Patients With Glioblastoma at First Recurrence Based on the MYOF/p-STAT3 Signaling Axis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 96
- 试验地点
- 1
- 主要终点
- Number of Participants With Dose-Limiting Toxicities
研究概览
简要总结
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.
详细描述
Glioblastoma commonly recurs after surgery and standard chemoradiotherapy, and treatment options at recurrence remain limited. Preclinical research by the study team indicates that myoferlin (MYOF) facilitates the nuclear translocation of phosphorylated STAT3 and that entacapone can target MYOF and inhibit glioma growth in experimental models. This study evaluates a drug-repurposing strategy combining inhibition of the MYOF/p-STAT3 signaling pathway with bevacizumab-based antiangiogenic treatment.
Stage 1 is an open-label, single-target-dose safety lead-in. Participants will receive entacapone 400 mg orally three times daily together with bevacizumab 10 mg/kg intravenously every 2 weeks. Six participants evaluable for dose-limiting toxicity will be enrolled in two sequential cohorts of 3. If 0 or 1 participant in the first cohort experiences a dose-limiting toxicity during the initial 28-day evaluation period, enrollment of the second cohort may proceed after review by the independent data and safety monitoring board. If 2 or more participants experience dose-limiting toxicity at any time, enrollment and study treatment will be paused for safety review. Transition to Stage 2 requires no more than 1 dose-limiting toxicity among 6 evaluable participants, acceptable overall safety, written support from the data and safety monitoring board, ethics committee stage review, and institutional authorization. Up to 3 participants who are not evaluable for non-toxicity reasons may be replaced.
Stage 2 will enroll 90 new participants. Participants will be randomly assigned in a 1:1 ratio to entacapone 400 mg orally three times daily or matching placebo. Both groups will receive bevacizumab 10 mg/kg intravenously every 2 weeks. If treatment-related adverse reactions occur, entacapone or matching placebo may be reduced to 200 mg three times daily and may not subsequently be increased. Oral study treatment may continue for up to 13 cycles or 364 days, subject to protocol-defined discontinuation criteria.
Tumor imaging will be performed every 8 weeks. The primary efficacy endpoint is progression-free survival, defined as the time from randomization to 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 in the safety lead-in will not enter the randomized stage, and their data will not be included in the primary efficacy analysis of Stage 2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Stage 1 is an open-label safety lead-in. In Stage 2, participants, investigators, and outcome assessors are masked to the assignment of entacapone or matching placebo. Designated unblinded pharmacists, drug-code administrators, and necessary statistical personnel have restricted access to treatment assignments and are separated from clinical efficacy assessment and the primary analysis.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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.
- •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.
- •No previous systemic treatment with bevacizumab or another vascular endothelial growth factor or vascular endothelial growth factor receptor-targeted agent.
- •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.
- •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.
- •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.
- •Able to swallow the oral study treatment, with the participant or a caregiver able to support scheduled administration, medication recording, and study visits.
- •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.
- •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.
排除标准
- •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.
- •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.
- •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.
- •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.
- •Active serious infection or another medical condition that precludes safe administration of study treatment.
- •Severe or persistent diarrhea, inflammatory bowel disease, microscopic colitis, or another condition likely to substantially impair absorption of the oral study treatment.
- •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.
- •History of a serious hypersensitivity reaction to entacapone, bevacizumab, matching placebo, or any related excipient.
- •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.
- •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.
- •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.
- •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.
- •Pregnancy or breastfeeding.
- •Seizures that remain uncontrolled despite appropriate treatment, or another progressive neurologic disorder that could interfere with safe treatment administration, imaging assessment, or follow-up.
- •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.
研究组 & 干预措施
Placebo Plus Bevacizumab
Participants randomized to this arm in Stage 2 receive matching placebo orally three times daily plus bevacizumab 10 mg/kg intravenously every 2 weeks. If a treatment-related adverse reaction occurs, matching placebo may be reduced to the equivalent of 200 mg three times daily without subsequent dose re-escalation. Oral study treatment may continue for up to 13 cycles (364 days), subject to protocol-defined discontinuation criteria.
干预措施: Placebo (Drug)
Open-Label Safety Lead-in
Participants in Stage 1 receive open-label entacapone 400 mg orally three times daily plus bevacizumab 10 mg/kg intravenously every 2 weeks. Six participants evaluable for dose-limiting toxicity are enrolled in two sequential cohorts of three. Up to three participants who cannot complete the 28-day dose-limiting toxicity evaluation for reasons unrelated to toxicity may be replaced.
干预措施: Bevacizumab (Drug)
Entacapone Plus Bevacizumab
Participants randomized to this arm in Stage 2 receive entacapone 400 mg orally three times daily plus bevacizumab 10 mg/kg intravenously every 2 weeks. If a treatment-related adverse reaction occurs, entacapone may be reduced to 200 mg three times daily without subsequent dose re-escalation. Oral study treatment may continue for up to 13 cycles (364 days), subject to protocol-defined discontinuation criteria.
干预措施: Bevacizumab (Drug)
Open-Label Safety Lead-in
Participants in Stage 1 receive open-label entacapone 400 mg orally three times daily plus bevacizumab 10 mg/kg intravenously every 2 weeks. Six participants evaluable for dose-limiting toxicity are enrolled in two sequential cohorts of three. Up to three participants who cannot complete the 28-day dose-limiting toxicity evaluation for reasons unrelated to toxicity may be replaced.
干预措施: Entacapone (Drug)
Placebo Plus Bevacizumab
Participants randomized to this arm in Stage 2 receive matching placebo orally three times daily plus bevacizumab 10 mg/kg intravenously every 2 weeks. If a treatment-related adverse reaction occurs, matching placebo may be reduced to the equivalent of 200 mg three times daily without subsequent dose re-escalation. Oral study treatment may continue for up to 13 cycles (364 days), subject to protocol-defined discontinuation criteria.
干预措施: Bevacizumab (Drug)
Entacapone Plus Bevacizumab
Participants randomized to this arm in Stage 2 receive entacapone 400 mg orally three times daily plus bevacizumab 10 mg/kg intravenously every 2 weeks. If a treatment-related adverse reaction occurs, entacapone may be reduced to 200 mg three times daily without subsequent dose re-escalation. Oral study treatment may continue for up to 13 cycles (364 days), subject to protocol-defined discontinuation criteria.
干预措施: Entacapone (Drug)
结局指标
主要结局
Number of Participants With Dose-Limiting Toxicities
时间窗: From the first dose through Day 28
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
时间窗: From randomization until disease progression or death from any cause, assessed up to 30 months
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.
次要结局
- Overall Survival(From randomization until death from any cause, assessed up to 30 months)
- Progression-Free Survival Rate at 6 Months Assessed by Blinded Independent Central Review(At 6 months after randomization)
- Objective Response Rate Assessed by Blinded Independent Central Review(From randomization until disease progression or initiation of subsequent anticancer therapy, assessed up to 30 months)
- Duration of Response Assessed by Blinded Independent Central Review(From the first documented objective response until disease progression or death, assessed up to 30 months)
- Investigator-Assessed Progression-Free Survival(From randomization until disease progression or death from any cause, assessed up to 30 months)
- Change From Baseline in Karnofsky Performance Status(Baseline and every 8 weeks during disease follow-up, assessed up to 30 months)
- Change From Baseline in Neurologic Assessment in Neuro-Oncology Scale Score(Baseline and every 8 weeks during disease follow-up, assessed up to 30 months)
- Change From Baseline in EORTC QLQ-C30 Scores(Baseline, every 8 weeks, and at the end-of-treatment visit, assessed up to 30 months)
- Change From Baseline in Dexamethasone-Equivalent Daily Corticosteroid Dose(Baseline, every 8 weeks, and at the end-of-treatment visit, assessed up to 30 months)
- Adherence to Oral Study Treatment(From the first dose through the end of oral study treatment, up to 364 days)
- Duration of Exposure to Oral Study Treatment(From the first dose through the last dose of oral study treatment, up to 364 days)
- Number of Participants With Treatment-Emergent Adverse Events(From the first dose through 30 days after the last dose of any study treatment, assessed up to 36 months)
- Number of Participants With Serious Adverse Events(From informed consent through 30 days after the last dose of any study treatment, assessed up to 36 months)
- Number of Participants With Adverse Events of Special Interest(From the first dose through 30 days after the last dose of any study treatment, assessed up to 36 months)
- Number of Participants With Clinically Significant Liver Test Abnormalities(From the first dose through 30 days after the last dose of any study treatment, assessed up to 36 months)