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

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:

-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 TML 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.

- INCLUSION CRITERIA:

- Patients must have recurrent 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.

- 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 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 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.

- Known active, chronic or history of hepatitis infection.