Phase 2 Study to Evaluate the Clinical Efficacy and Safety of Tislelizumab Plus Low-dose Bevacizumab in Bevacizumab Refractory Recurrent Glioblastoma With PTEN or TERT Gene Mutations
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Overall response rate
研究概览
简要总结
The purpose of this study is to evaluate the clinical efficacy and safety of Tislelizumab (one anti-PD-1 antibody same as nivolumab approved in China) in combination with bevacizumab in patients with recurrent or progressive glioblastoma (GBM) who have progressed on bevacizumab with or without PTEN or TERT gene mutations.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
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
- •Written informed consent and HIPAA authorization obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations
- •Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of thestudy, including disease assessment by MRI and tumor in situ fluid (TISF) collection
- •Histologically confirmed diagnosis of glioma
- •Resection surgery done at the study center (Henan Provincial People'sHospital), with an reservoir intraoperatively implanted connecting the surgical cavity and the subscalp for postoperative noninvasive TISF collection
- •An interval of > 28 days and full recovery (i.e., no ongoing safety issues) from surgical resection prior to grouping
- •Karnofsky performance status (KPS) of 70 or higher
- •Life expectancy > 12 weeks
排除标准
- •More than two recurrences of GBM
- •Presence of extracranial metastatic, significant leptomeningeal disease or tumors primarily localized to the brainstem or spinal cord
- •Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
- •Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring chronic and systemic immunosuppressive treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects have any other condition requiring systemic treatment with corticosteroids or other immunosuppressive agents within 14 days. Inhaled or topical steroids and adrenal replacement doses >10mg daily prednisone equivalent are permitted in absence of active autoimmune disease
- •Previous radiation therapy with anything other than standard radiation therapy (i.e., focally directed radiation) administered as first line therapy
- •Previous treatment with carmustine wafer except when administered as first line treatment and at least 6 months prior to randomization
- •Previous bevacizumab or other VEGF or anti-angiogenic treatment
- •Previous treatment with a PD-1, PD-L1 or CTLA-4 targeted therapy
- •Evidence of > Grade 1 CNS hemorrhage on the baseline MRI scan
- •Inadequately controlled hypertension (defined as systolic blood pressure ≥160 mmHg and /or diastolic blood pressure ≥100 mmHg) within 7 days of first study treatment
- •Prior history of hypertensive crisis, hypertensive encephalopathy, reversible posterior leukoencephalopathy syndrome (RPLS)
- •Prior history of gastrointestinal diverticulitis, perforation, or abscess
- •Clinically significant (i.e., active) cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment
- •Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment. Any previous venous thromboembolism ≥ NCI CTCAE Grade 3 within 3 months prior to start of study treatment
- •History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red blood per episode) within 1 month prior to randomization
- •History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
- •Current or recent (within 10 days of study enrollment) use of anticoagulants that, in the opinion of the investigator, would place the subject at significant risk for bleeding. Prophylactic use of anticoagulants is allowed
- •Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to first study treatment, or anticipation of need for major surgical procedure during the course of the study
- •Minor surgical procedure (e.g., stereotactic biopsy within 7 days of first study treatment; placement of a vascular access device within 2 days of first study treatment)
- •History of intracranial abscess within 6 months prior to randomization
- •History of active gastrointestinal bleeding within 6 months prior to randomization
研究组 & 干预措施
Cohort 1
Patients with bevacizumab-refractory recurrent glioma with PTEN or TERT gene mutations,determined according to the dynamics of TISF (Tumor in Situ Fluid) ctDNA.
干预措施: Tislelizumab plus Bevacizumab (Drug)
Cohort 2
Patients with bevacizumab-refractory recurrent glioma without PTEN or TERT gene mutations,determined according to the dynamics of TISF (Tumor in Situ Fluid) ctDNA.
干预措施: Tislelizumab plus Bevacizumab (Drug)
结局指标
主要结局
Overall response rate
时间窗: Up to 2 years after beginning treatment
Proportion of participants in the analysis population who have complete response (CR) or partial response (PR) using RANO criteria. Participants without efficacy evalaluation data or survival data censored at day 1. Participants without measurable disease will not be included.
Duration of response
时间窗: Up to 2 years after beginning treatment
Time from first RANO response to disease progression in participants who achieve a PR or better.
Number of participants with treatment-emergent adverse events
时间窗: Up to 3 months after beginning therapy
Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) are reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, performance status evaluations, magnetic resonance imaging, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 90 days after the last dose of durvalumab. AEs are considered to be treatment emergent if they occur or worsen in severity after the first dose of study treatment.
次要结局
- Overall survival(Up to 2 years after beginning treatment)