Nivolumab in Patients With IDH-Mutant Gliomas With and Without Hypermutator Phenotype

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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 ...

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 well 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 PD1 receptor and blocks its interaction with PD L1 and PD L2 and subsequently releasing PD 1 pathway mediated inhibition of the immune response, including antitumor immune response. The 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:<TAB> -To determine the 6-month progression free survival rate in IDH-mutant gliomas patients with and without HMP in responses to nivolumab treatment. ELIGIBILITY: Patients with glioma, confirmed by NCI Laboratory of Pathology Age greater than or equal to 18 years KPS greater than or equal to 60% IDH 1 or IDH 2 mutation confirmed by DNA sequencing Patients must have TMB status performed at NIH Tumor tissue or slides should be available for molecular and immune profiling DESIGN: This study is an open label phase II clinical trial of the immune checkpoint inhibitor, nivolumab, in patients with HMP and NHMP IDH-mutant gliomas. Patients with HMP and NHMP will receive nivolumab at a standard dose of 240 mg intravenously every 2 weeks for cycles 1-4, then doses of 480 mg every 4 weeks for cycles 5-16. A maximum of 20 treatments will be given (16 cycles). A maximum of 29 patients with IDH-mutant glioma with HMP (Cohort 1) and 46 patients with NHMP (Cohort 2) will be evaluated. A Simon's optimal two-stage design will be used to conduct the HMP arm and the NHMP arm independently. For the HMP cohort, in stage I, a total number of 10 patients are accrued. If 9 or more patients progress by 6 months, the cohort will be terminated early; otherwise, additional 19 patients will be accrued in stage II, resulting in a total sample size of 29. Among these 29 patients, if 6 or more patients are progression-free at 6 months, we will claim that the treatment is promising for patients with HMP IDH-mutant gliomas. For NHMP cohort, in stage I, a total number of 15 patients are accrued. If 10 or more patients progress by 6 months, the cohort will be terminated early; otherwise, additional 31 patients will be accrued in stage II, resulting in a total sample size of 46. Among these 46 patients, if 19 or more patients are progression-free at 6 months, we will claim that the treatment is patients with NHMP IDH-mutant gliomas.

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