A Phase II Study of Checkpoint Blockade Immunotherapy in Patients With Somatically Hypermutated Recurrent WHO Grade 4 Glioma
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 37
- 试验地点
- 808
- 主要终点
- Overall response rate
研究概览
简要总结
This phase II trial studies the effect of immunotherapy drugs (ipilimumab and nivolumab) in treating patients with glioma that has come back (recurrent) and carries a high number of mutations (mutational burden). Cancer is caused by changes (mutations) to genes that control the way cells function. Tumors with high number of mutations may respond well to immunotherapy. Immunotherapy with monoclonal antibodies such as ipilimumab and nivolumab may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving ipilimumab and nivolumab may lower the chance of recurrent glioblastoma with high number of mutations from growing or spreading compared to usual care (surgery or chemotherapy).
详细描述
PRIMARY OBJECTIVE:
I. To determine whether the combination of ipilimumab and nivolumab increases the tumor response rate assessed by modified Response Assessment in Neuro-Oncology (RANO) Criteria in patients with hypermutated recurrent glioblastoma.
SECONDARY OBJECTIVES:
I. Estimate the overall survival distribution, median survival, and one-year survival rate of patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and nivolumab.
II. Estimate the progression-free survival distribution and median progression-free survival of patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and nivolumab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •PRE-REGISTRATION ELIGIBILITY CRITERIA:
- •Histologically confirmed glioblastoma (World Health Organization [WHO] grade IV) presenting at first or second recurrence including secondary glioblastoma
- •Glioblastoma IDH-wildtype central nervous system (CNS) WHO grade 4
- •Diffuse, astrocytic glioma IDH-wildtype with one or more of the following histological or genetic features: microvascular proliferation, necrosis, TERT promoter mutation, EGFR gene amplification, +7/-10 chromosome copy-number changes
- •Astrocytoma, IDH-mutant CNS WHO grade 4
- •Diffuse astrocytic glioma IDH-mutant (with frequent ATRX and/or TP53 mutation and absence of 1p/19q codeletion), with necrosis and/or microvascular proliferation or one with lower grade histological features displaying homozygous deletion of CDKN2A and/or CDKN2B
- •NOTE: The eligibility criteria were changed to include the new diagnostic language from the WHO 2021 pathology classification change. The above diagnoses therefore reflect the change and include the entities that were previously eligible but now carry updated pathologic classification
- •Presence of measurable disease, as defined by a bidimensionally measurable lesion on magnetic resonance imaging (MRI) with a minimum diameter of 10 mm in both dimensions, prior to resection or biopsy of recurrent tumor
- •Tissue available from surgical resection or biopsy of recurrent tumor =< 28 days prior to pre-registration, or planned surgery or biopsy of recurrent tumor =< 28 days after pre-registration
- •Does not require > 4 mg dexamethasone beyond the perioperative period defined as the time =< 2 weeks after surgical procedure
- •No active autoimmune disease or history of autoimmune disease
- •These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease
- •Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
- •No prior treatment with checkpoint blockade therapies (anti-CTLA4, anti-PD1/PD-L1) or bevacizumab
- •No prior treatment with laser ablation at the time of recurrent tumor tissue sampling. Patients who have previously undergone laser ablation >= 4 months prior to recurrent tumor tissue sampling can be included
- •Age >= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- •Able to undergo brain MRI with contrast
- •Absolute neutrophil count >= 1500/mm^3
- •Platelet count >= 100,000/mm^3
- •Total bilirubin =< 1.5 x upper limit of normal (ULN)
- •If Gilbert syndrome, then total bilirubin =< 3 x ULN
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x ULN
- •Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)
- •History of active malignancy (outside of the patient's glioblastoma) that has required treatment within the previous 2 years. Participant with prior history of in situ cancer or basal or squamous cell skin cancer are eligible
- •REGISTRATION ELIGIBILITY CRITERIA: Tissue obtained from biopsy or resection at first or second recurrence exhibits TMB >= 10 on FoundationOne CDx testing
排除标准
- 未提供
研究组 & 干预措施
Treatment (nivolumab, ipilimumab)
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (nivolumab, ipilimumab)
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the study.
干预措施: Ipilimumab (Biological)
Treatment (nivolumab, ipilimumab)
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the study.
干预措施: Nivolumab (Biological)
结局指标
主要结局
Overall response rate
时间窗: Up to 32 months
Assessed by the Response Assessment in Neuro-Oncology Criteria (RANO). The proportion of patients who have a confirmed tumor response will be computed as the number of patients with a confirmed complete response or confirmed partial response as determined by RANO criteria divided by the number of evaluable patients, which are eligible patients who have measurable disease and completed one cycle of treatment. Will be estimated with a binomial point estimate that will be computed as the number of responses divided by the number of evaluable patients. Exact 95% binomial confidence intervals will be generated and reported.
Overall response rate
时间窗: Up to 32 months
Assessed by the Response Assessment in Neuro-Oncology Criteria (RANO). The proportion of patients who have a confirmed tumor response will be computed as the number of patients with a confirmed complete response or confirmed partial response as determined by RANO criteria divided by the number of evaluable patients, which are eligible patients who have measurable disease and completed one cycle of treatment. Will be estimated with a binomial point estimate that will be computed as the number of responses divided by the number of evaluable patients. Exact 95% binomial confidence intervals will be generated and reported.
次要结局
- Progression-free survival (PFS)(From the time of treatment initiation until disease progression as measured using RANO criteria or death, whichever occurs first, assessed up to 3 years)
- Incidence of adverse events (AEs)(Up to 3 years)
- Overall survival (OS)(From the time of treatment initiation until death from any cause, assessed up to 3 years)