Clinical trial NCT03718767: Nivolumab in Patients With IDH-Mutant Gliomas With and Without Hypermutator Phenotype
Official title: Phase II Trial Evaluating Nivolumab In Patients With IDH-Mutant Gliomas With And Without Hypermutator Phenotype
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Glioma
Glioblastoma
High Grage Glioma
Low Grade Glioma
Malignant Glioma
Keywords: PD 1 Pathway
High Tumor Mutational Load
Immune Checkpoint
Quality of Life
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-10-24
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: * INCLUSION CRITERIA:
* Patients must have recurrent diffuse glioma (histologically confirmed by NIH Laboratory of Pathology) with IDH1 or IDH2 mutation (confirmed by DNA sequencing, FoundationOne is preferable for confirmation of mutation, but not necessary).
* Patients must have tumor specific mutation burden (number of somatic mutations per exome) tested at NIH: Must have either result of tumor mutation burden from the most recent surgical tumor sample or must provide adequate genomic materials of the sample for tumor testing. The tumor tissue (e.g. block or 15 unstained slides) must be available for molecular and immune profiling. Fresh or frozen tumor sample will be used if available, but not mandatory.
* Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of nivolumab in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
* Patient must be able to tolerate an MRI study with intravenous gadolinium contrast.
* Karnofsky greater than or equal to 60%
* Patients must have adequate organ and marrow function as defined below:

  * Absolute neutrophil count greater than or equal to 1,500/mcL
  * Platelet Count greater than or equal to 100,000/MCL
  * Hemoglobin greater than 9.0 g/dL (may be transfused to achieve this level)
  * BUN less than or equal to 30 mg/dL and
  * Serum creatinine less than or equal to 1.7 mg/dL
  * Total bilirubin (except patients with Gilbert s Syndrome, who are eligible for the study but exempt from the total bilirubin eligibility criterion) less than or equal to 2.0 mg/dL
  * ALT and AST less than or equal to 2.5x institutional upper limit of normal.
* The effects of nivolumab on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and up to 5 months (women). Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
* The patient must be able to understand and be willing to sign a written informed consent document.

EXCLUSION CRITERIA:

* Patients who are receiving any other investigational agents.
* Patients who have a history of receiving immune therapy.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab.
* History of severe hypersensitivity reaction to any monoclonal antibody.
* Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years prior to initiation of study therapy.
* Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or CIDP, myasthenia gravis; systemic autoimmune disease such as 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. Such diseases should be excluded because of the risk of recurrence or exacerbation of disease.

  --Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sj(SqrRoot)(Delta)gren 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.
* The patient must not be currently on a corticosteroid dose greater than dexamethasone 1 mg per day or its equivalent.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations (within timeframes identified in the bullets below) that would limit compliance with study requirements.
* Known HIV-positive or acquired immune deficiency syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS is based on the lack of information regarding the safety of nivolumab in patients with active HIV infection
* Pregnant women are excluded from this study because nivolumab s potential for teratogenic or abortifacient effects is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, breastfeeding should be discontinued if the mother is treated with nivolumab.

Primary outcomes:
measure: 6-month progression free survival rate
timeFrame: 6 months
Secondary outcomes:
measure: Proportion of patients that have improvement in quality of life
timeFrame: Study Calendar -last collection of QOL questioner.
measure: Median amount of time subject survives after therapy and Proportion of patients that have progressive disease after 12 months
timeFrame: 12 months and death
measure: Correlation between neoantigen burden of tumor and proportion of subjects that survive after 6 and 12 months
timeFrame: 6 months and 12 months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Jing Wu, M.D.
role: PRINCIPAL_INVESTIGATOR
References: