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Nivolumab

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NCI NOB Referral Group

Jing Wu, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Gliomas are the most common malignant brain tumors. Some have certain changes (mutations) in the genes IDH1 or 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 (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.

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 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 diffuse 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 1-2, then doses of 480 mg every 4 weeks for cycles 3-16. A maximum of 20 treatments will be given (16 cycles).
* A maximum of 29 patients with IDH-mutant glioma with HMP (Cohort 1) and 30 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 3 or more patients are progression-free at 6 months, the cohort will move to stage II and an additional 15 patients will be accrued in stage II, resulting in a total sample size of 30. Among these 30 patients, if 10 or more patients are progression-free at 6 months, we will claim that the treatment is promising for patients with NHMP IDH-mutant gliomas.

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

Phase II Trial Evaluating Nivolumab In Patients With IDH-Mutant Gliomas With And Without Hypermutator Phenotype

.BTRIS: All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@dbGaP: All large scale genomic sequencing data will be shared with subscribers to dbGaP.

Proportion of patients that do not have progressive disease after 6 months

To longitudinally evaluate patient reported outcome measures using self-reported symptom severity and interference with daily activities using the MDASI-BT.

To determine the 1-year progression free survival rate and overall survival in IDH-mutant gliomas patients with and without HMP in response to nivolumab treatment.

To determine whether the neoantigen burden in tumor prior to the treatment is correlated with treatment response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Nivolumab in Patients With IDH-Mutant Gliomas With and Without Hypermutator Phenotype	NCT03718767	Glioma Glioblastoma High Grage Glio... Low Grade Gliom... Malignant Gliom...	Nivolumab	18 Years -	National Institutes of Health Clinical Center (CC)
Nivolumab in Patients With IDH-Mutant Gliomas With and Without Hypermutator Phenotype	NCT03718767	Glioma Glioblastoma High Grage Glio... Low Grade Gliom... Malignant Gliom...	Nivolumab	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for high tumor mutational load