Phase II Trial Evaluating Nivolumab In Patients With IDH-Mutant Gliomas With And Without Hypermutator Phenotype
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 62
- 试验地点
- 1
- 主要终点
- Median Progression Free Survival (PFS) Rate at 6 Months
研究概览
简要总结
Background:
Gliomas are the most common malignant brain tumors. Some have certain changes (mutations) in the genes isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2). If there are a high number of mutations in a tumor, it is called hypermutator phenotype (HMP). The drug nivolumab helps the immune system fight cancer. Researchers think it can be more effective in patients with IDH1 or IDH2 mutated gliomas with HMP. They will test gliomas with and without HMP.
Objectives:
To see if nivolumab stops tumor growth and prolongs the time that the tumor is controlled.
Eligibility:
Adults 18 years or older with IDH1 or IDH2 mutated gliomas
Design:
Participants will be screened with:
Medical history
Physical exam
Heart, blood, and pregnancy tests
Review of symptoms and activity levels
Brain magnetic resonance imaging (MRI). Participants will lie in a cylinder that takes pictures in a strong magnetic field.
Tumor samples
Participants will get the study drug in 4-week cycles. They will get it through a small plastic tube in a vein (intravenous [IV]) on days 1 and 15 of cycles 1-4. For cycles 5-16, they will get it just on day 1.
On days 1 and 15 of each cycle, participants will repeat some or all screening tests.
After cycle 16, participants will have 3 follow-up visits over 100 days. They will answer health questions, have physical and neurological exams, and have blood tests. They may have a brain MRI.
Participants whose disease did not get worse but who finished the study drug within 1 year of treatment may have imaging studies every 8 weeks for up to 1 year.
Participants will be called or emailed every 6 months with questions about their health.
详细描述
BACKGROUND:
- Glioma is the most common malignant brain tumor. Genes coding for isocitrate dehydrogenases 1and 2 (IDH1 and IDH2), metabolic enzymes, are frequently mutated in gliomas, particularly lower-grade gliomas (LGGs). IDH1/2 mutation causes a unique tumor biology, including the accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite, which in turn causes genomic hypermethylation and tumorigenesis.
- IDH-mutant LGGs undergo a slow but unremitting progression to higher grade transformation (HT) and eventually become high grade gliomas (HGGs) with a significant increase in the number of somatic mutations. A subset of patients with transformed HGGs develop a hypermutator phenotype (HMP), possibly related, but not limited, to previous treatment with alkylating agents and radiotherapy. The mechanisms of this clinical phenomenon are not fully understood, and no effective treatments are available for the HMP HGGs.
- High tumor mutation burden (TMB) is a characteristic finding in many of the transformed tumors. Furthermore, this increased mutation burden, with commensurate increase in neoantigen expression, may be correlated with a better response to immune checkpoint inhibitor (ICPIs) treatment.
- Nivolumab is a monoclonal antibody that binds to the programmed cell death protein 1 (PD1) receptor and blocks its interaction with programmed death-ligand 1 (PD L1) and PD L2 and subsequently releasing PD 1 pathway mediated inhibition of the immune response, including antitumor immune response.
- The United States (US) Food and Drug Administration granted approval to nivolumab for the treatment of unresectable or metastatic melanoma, advanced non-small cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck, locally advanced or metastatic urothelial carcinoma, microsatellite instability-high or mismatched repair deficient metastatic colorectal cancer and hepatocellular carcinoma.
- The first randomized clinical trial in glioblastoma with nivolumab (CheckMate-143) was completed in early 2017. Unfortunately, the study didn't meet its primary endpoint of improved overall survival over bevacizumab monotherapy. The objective response rate (ORR) was lower in nivolumab arm than bevacizumab arm. However, the response with nivolumab was more durable. The safety profile of nivolumab was very consistent with what has been observed in other tumor types.
OBJECTIVE:
-To determine the 6-month progression free survival rate in IDH-mutant gliomas patients with and without HMP in responses to nivolumab treatment.
ELIGIBILITY:
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Arm1/Nivolumab
Intravenous (IV) nivolumab
干预措施: Nivolumab (Drug)
结局指标
主要结局
Median Progression Free Survival (PFS) Rate at 6 Months
时间窗: 6 months
PFS is defined from the day of study entry until imaging is confirmed to show disease progression or death, whichever occurs first. Disease progression was assessed by the Immunotherapy Response Assessment neuro-oncology Criteria. Disease progression is \>25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new enhancing measurable lesion that exceeds a 25% increase in cross-sectional area; clear clinical deterioration not attributable to other causes apart from the tumor and/or failure to return for evaluation due to death or deteriorating condition. PFS was analyzed by the Kaplan-Meier method and is reported with a 95% confidence interval.
次要结局
- Overall Survival(Until the death of the last surviving participant, a median of 7.4 months in Cohort 1 and a median of 31.6 months in Cohort 2.)
- Tumor Mutation Burden(During the screening period (14 days prior to study therapy))
- Mean Symptom Interference Score Per Treatment Cycle Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDSAI-BT)(Baseline and Cycles 2, 4, 6, 8, 10, 12, 14, and 16 (approximately 32 weeks +/- 3 days).)
- Mean Symptom Severity Score Per Treatment Cycle Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDSAI-BT)(Baseline and Cycles 2, 4, 6, 8, 10, 12, 14, and 16 (approximately 32 weeks +/- 3 days).)
- Median Percentage of Participants That Have Progressive Disease At 12 Months(At 12 months)
- Number of Participants Responses Received and Were Expected Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDSAI-BT) Forms(Baseline and Cycles 2, 4, 6, 8, 10, 12, 14, and 16 (approximately 32 weeks +/- 3 days).)
- Proportion of Participants Rating Symptoms 5 or Greater (on a 0-10 Scale) Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDSAI-BT)(Baseline and Cycles 2, 4, 6, 8, 10, 12, 14, and 16 (approximately 32 weeks +/- 3 days).)
研究者
Jing Wu, M.D.
Principal Investigator
National Cancer Institute (NCI)