Phase II Trial Evaluating the Association of Peripheral Blood Immunologic Response to Therapeutic Response to Adjuvant Treatment With Immune Checkpoint Inhibition (ICI) in Patients With Newly Diagnosed Glioblastoma or Gliosarcoma

  • End date
    Dec 31, 2024
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 20 October 2022
platelet count
neutrophil count
complete resection
malignant glioma
gross total resection
beam radiation
blood urea nitrogen



Glioblastoma (GBM) is a type of malignant glioma. These cancers are nearly always fatal. People who develop these cancers get aggressive treatments. But the tumors almost always recur. Researchers want to study people with newly diagnosed disease to learn more.


To study people with newly diagnosed GBM or gliosarcoma to look at the changes in immune cells in the blood of those who take ipilimumab and nivolumab, along with temozolomide.


Adults ages 18 and older with newly diagnosed GBM or gliosarcoma, who have had surgical removal of their tumor and have completed standard initial chemotherapy and radiation therapy.


Participants will be screened with the following:

Medical record review

Medical history

Physical exam

Tests to assess their nervous system and their ability to do typical activities

Blood tests

Tumor assessment. For this, they will have magnetic resonance imaging (MRI). They may get a contrast dye through an intravenous (IV) catheter. The MRI scanner makes noise. They will get earplugs.

Electrocardiogram. It measures heart rate and rhythm. They will lie still. Sticky pads will be placed on their chest, arms, and legs.

Screening tests will be repeated during the study.

Treatment will be given in cycles. Each cycle lasts 4 weeks. Participants will get nivolumab and ipilimumab via IV. They will take temozolomide by mouth. They will keep a pill diary.

Participants will fill out surveys about their symptoms.

Participants will have follow-up visits about 60 days and 100 days after treatment ends. Then they will be contacted every 6 months for the rest of their life.



Glioblastoma (GBM) represents an aggressive malignancy with limited therapeutic options. The immunosuppressive nature of GBM may be reversible with immune checkpoint inhibitor (ICI) treatment, however, initial studies have yet to demonstrate this. It is postulated that trafficking of peripherally activated lymphocytes may play a role in generating a robust intracranial immune response. Therefore, a blood-based assay to identify peripheral blood response may both predict response and better identify the ideal patient populations for future ICI clinical trials.


Determine if the outcomes, as measured by overall survival, is improved in patients with newly diagnosed glioblastoma when treatment with immune checkpoint inhibitors result in an immune response in peripheral blood T lymphocytes.


Histologically confirmed, newly diagnosed primary glioblastoma or gliosarcoma;

Age greater than or equal to 18 years;

Adequate organ function;

Karnofsky performance score greater than or equal to 70;

Subjects must recently complete resection and chemoradiation;

Subjects must not have prior immunotherapy, other current investigational agents, or corticosteroid treatment > 30mg cortisone-equivalents per day.


Open-label, investigator-initiated exploratory study of newly-diagnosed GBM who have completed resection and chemoradiation.

Participants will be randomized to be treated in Arm 1 or 2, consistent of adjuvant chemotherapy (temozolomide (TMZ)) and immunotherapy (nivolumab + ipilimumab):

TMZ (150-200 mg/m2 PO on days 1-5 q28 days for cycles 1-6)

Arm 1:

Nivolumab (1 mg/kg IV q2weeks for cycles 1-4, then 480 mg IV q4weeks for cycles 5-16) + ipilimumab (1 mg/kg IV q4 weeks for cycles 1-4)

Arm 2:

Nivolumab (1 mg/kg IV q2weeks for cycles 1-4, then 480 mg IV q4weeks for cycles 5-16) + ipilimumab (3 mg/kg IV q4 weeks for cycles 1-4)

For the primary objective, serial examination of peripheral blood, including comprehensive flow cytometric analysis of leukocyte populations and cytokines, and Interferon- >= (IFN- >=) ELISPOT functional analysis of CD4+/8+ response to common recall antigens will be used to determine systemic response to ICI treatment.

For the secondary objectives, correlative studies assess peripheral blood T cells' ability to respond to an in vitro stimulation paradigm, including nivolumab and ipilimumab, in a microbead-based model. The T cell response to pretreatment in vitro stimulation would be compared to post-treatment in vivo stimulation to determine if this in vitro model can predict in vivo response.

Additional exploratory studies are planned to characterize the in vivo immune response to adjuvant chemotherapy and immunotherapy, including but not limited to:

Phospho-flow functional analysis of NK cell response to IFN/IL-15 stimulation.

Condition Glioblastoma, Gliosarcoma, Malignant Glioma
Treatment Nivolumab, TMZ, Ipilimumab 1mg/kg, ipilimumab 3mg/kg
Clinical Study IdentifierNCT04817254
SponsorNational Cancer Institute (NCI)
Last Modified on20 October 2022


Yes No Not Sure

Inclusion Criteria

Patients must have newly diagnosed histologically confirmed primary glioblastoma or gliosarcoma
Patients must have undergone a gross total or near gross total resection of unifocal, confined to the supratentorial compartment tumor
Patient must have completed chemoradiation (external beam radiation with concurrent temozolomide) a maximum of 5 weeks prior to initiation of study therapy
Age greater than or equal to 18 years
Karnofsky greater than or equal to 70%
Patients must have adequate organ and marrow function as defined below
Absolute neutrophil count greater than or equal to 1,500/mcL
Platelet Count >100,000/mcL
Hemoglobin > 9.0 g/dL (may be transfused to achieve this level)
BUN less than or equal to 30 mg/dL
Serum creatinine less than or equal to 1.7 mg/dL or creatinine clearance as measured by 24 hour urine collection as > 60 ml/min
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 study treatment on the developing human fetus are unknown. For this
Barrier method of contraception: condoms (male or female) with or without a spermicidal agent, diaphragm, or cervical cap with spermicide
reason, participants of reproductive potential must agree to use adequate
contraception which includes a combination of TWO of the following
Hormone-based contraceptive
Tubal ligation
Note: Consider use in females only or both male and female participants starting from the
enrollment and for the duration of study treatment and up to 6 months (women) after the
last dose of the study and 6 months (men) after the last dose of the drug temozolomide
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

Exclusion Criteria

Definitive clinical or radiologic evidence of progressive disease
Patients who are receiving any other investigational agents
Prior placement of Gliadel wafer or local brachytherapy. Note: Tumor Treating Fields
History of allergic reactions attributed to gadolinium contrast
are allowed
History of severe hypersensitivity reaction to any monoclonal antibody
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, ipilimumab or temozolomide
Prior or concurrent malignancy unless its natural history or treatment does not have
the potential to interfere with the safety or efficacy assessment of the
investigational regimen
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
Note: Patients with vitiligo, endocrine deficiencies including thyroiditis managed with
would limit compliance with study requirements
replacement hormones including physiologic corticosteroids are eligible. Patients with
rheumatoid arthritis and other arthropathies, Sjogren s syndrome and psoriasis controlled
breastfeeding should be discontinued
with topical medication and patients with positive serology, such as antinuclear antibodies
Known active, chronic or history of hepatitis infection
(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. Patients must
have stopped corticosteroids above this threshold at least 7 days prior to initiation of
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
Pregnant women are excluded from this study because study treatment potential for
teratogenic or abortifacient effects is unknown. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to study treatment of the mother
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