Clinical Trials /

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

NCT03718767

Description:

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 the drug nivolumab increases the time it takes for certain gliomas to get worse. 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.

Related Conditions:
  • Glioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab in People With IDH-Mutant Gliomas With and Without Hypermutator Phenotype
  • Official Title: A Phase II Trial of Nivolumab for IDH-mutated Gliomas With Hypermutator Phenotype

Clinical Trial IDs

  • ORG STUDY ID: 190006
  • SECONDARY ID: 19-C-0006
  • NCT ID: NCT03718767

Conditions

  • Glioma
  • Glioblastoma
  • High Grage Glioma
  • Low Grade Glioma
  • Malignant Glioma

Interventions

DrugSynonymsArms
Nivolumab1/Nivolumab

Purpose

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 the drug nivolumab increases the time it takes for certain gliomas to get worse. 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 well understood, and no effective treatments are available for the
           HMP HGGs.

        -  High tumor mutational load (TML) is a characteristic finding in many of the transformed
           tumors. Furthermore, this increased mutational load, 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 phenotype in responses to nivolumab treatment.

      ELIGIBILITY:

        -  Patients with glioma, confirmed by NCI Laboratory of Pathology

        -  IDH 1 or IDH 2 mutation confirmed by DNA sequencing

        -  Patients must have TML status performed at NIH

        -  Age greater than or equal to 18 years,

        -  KPS greater than or equal to 60%

      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.
    

Trial Arms

NameTypeDescriptionInterventions
1/NivolumabExperimentalNivolumab is given IV as flat dose of 240 mg for Cycles 1-4 and 480 mg for Cycles 5-16.
  • Nivolumab

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have 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 mutational load (number of somatic mutations per
             exome) performed at NIH. Must have either result of previous NIH testing or must
             provide adequate tissue sample for testing.

          -  Age (Bullet) 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
                  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 and men 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) and 7 months (men)
             after the last dose of the drug. Should a woman become pregnant or suspect she is
             pregnant while she or her partner 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, such as a vaccine therapy,
             dendritic cell vaccine or intracavitary or convectional enhanced delivery of 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 physiologic
             replacement dosing defined as 30 mg of cortisone 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 patients on combination antiretroviral therapy are excluded because
             of the potential for pharmacokinetic interactions of antiretroviral therapy with
             nivolumab.

          -  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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:6-month progression free survival rate
Time Frame:6 months
Safety Issue:
Description:Proportion of patients that do not have progressive disease after 6 months

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • PD 1 Pathway
  • High Tumor Mutational Load
  • Immune Checkpoint
  • Quality of Life

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