PRIMARY OBJECTIVE
1. To determine safety of each of the following study agents, anti-GITR, IDO1 inhibitor, and
ipilimumab, in combination with nivolumab (BMS-936558) flat dose in patients with first
recurrence of GBM.
SECONDARY OBJECTIVES
1. To estimate toxicity
2. To estimate progression-free survival
3. To estimate overall survival
4. To evaluate pain for patients undergoing the treatment of anti-GITR, IDO1 inhibitor, and
ipilimumab, in combination with nivolumab.
EXPLORATORY OBJECTIVES
1. To characterize the immune response during and after treatment as measured by
immunohistochemistry, and other T cells etc. in peripheral blood
2. To characterize the pharmacodynamic and genomic activity in tumor tissue as target
inhibition
3. To characterize radiographic response
4. Genetic characterization of correlative samples
Inclusion Criteria:
- Patient must have histologically proven glioblastoma or gliosarcoma which is
progressive or recurrent following radiation therapy with or without temozolomide.
- Patient must be in first recurrence of glioblastoma following radiation therapy with
or without temozolomide. Patients with previously grade 3 astrocytoma who after first
recurrence after radiotherapy with or without temozolomide are found to have GBM are
eligible. Patients with previously grade 3 glioma found to have conclusively
progressed to GBM at the time screening tissue is taken are eligible. Patients who
have received Gliadel wafers during their initial surgery are eligible.
- Patient must be undergoing repeat surgery that is clinically indicated as determined
by their care providers, where a significant debulking or a gross total surgical
resection of the contrast-enhancing area is intended.
- Patient must consent to our acquiring tumor tissue removed before, during, or after
the study, if it becomes available.
- Patient must be able to undergo MRI of the brain with gadolinium.
- Patient must have recovered from severe toxicity of prior therapy. An interval of at
least 12 weeks must have elapsed since the completion of radiation therapy or
placement of Gliadel wafers, and at least 6 weeks must have elapsed from the last dose
of temozolomide (TMZ) before starting Nivolumab. Patients must stop using the Optune
device prior to starting nivolumab. No prior therapies are allowed other than
radiation, temozolomide, Optune device, and Gliadel wafers (placed during the first
surgery at diagnosis of high grade glioma (HGG)).
- Patients must be 18 years of age or older.
- Patients must have a Karnofsky Performance Status (KPS) ≥ 60% (i.e. the patient must
be able to care for himself/herself with occasional help from others).
- Patients must have the following organ and marrow function:
- Absolute lymphocyte count ≥ 500/mcl
- Absolute neutrophil count ≥ 1,500/mcl
- Platelets ≥ 100,000/mcl
- Hemoglobin ≥ 9 g/dl
- Total bilirubin ≤ institutional upper limit of normal (except for patients with
Gilberts' syndrome who must have normal direct bilirubin)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤
3 × institutional upper limit of normal
- Creatinine ≤ institutional upper limit of normal OR Creatinine clearance ≥ 60
ml/min/1.73m2 for patients with creatinine levels above institutional normal
- activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) ≤
1.5 x institutional upper limit of normal
- Patient must be able to provide written informed consent.
- Women of childbearing potential (WOCBP) must agree to have a negative serum pregnancy
test within -7 days prior to treatment start. Women of childbearing potential must
agree to use non-hormonal (due to induction of Cyp3a4) (barrier method of birth
control; abstinence) prior to study entry, for the duration of study treatment, and
through at least 5 months after the last dose of study drug. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately. Males who are sexually active with WOCBP
must agree to use a condom during penile vaginal intercourse for the duration of
treatment with study treatment plus 7 months after the last dose of the study
treatment (i.e., 90 days [duration of sperm turnover] plus the time required for
nivolumab to undergo approximately 5 half-lives). This criteria applies to azoospermic
males as well.
- Patient must not have another malignancy unless disease free for ≥ 5 years. Curatively
treated basal or squamous cell carcinoma of the skin, totally excised melanoma of
stage IIA or lower, low- or intermediate-grade localized prostate cancer (Gleason sum
≤7), and curatively-treated carcinoma in situ of the cervix, breast, or bladder are
allowed regardless.
Exclusion Criteria:
- Patient is/has received any other investigational agent(s).
- Patient has a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to IO agents used in this study.
- Patient has active or a known history of known or suspected autoimmune disease.
(Subjects with Type 1 diabetes mellitus, hypothyroidism only requiring hormone
replacement, and skin disorders (vitiligo, psoriasis, or alopecia) not requiring
systemic treatment, are permitted to enroll.
- Patient has a condition requiring systemic treatment with either corticosteroids
(other than for brain tumor management, cerebral edema or hypothalamic-pituitary
dysfunction) or other immunosuppressive medications within 14 days of study entry.
- Patient has evidence of significant mass effect.
- Patient has evidence of significant hematologic, renal, or hepatic dysfunction. (NOTE:
Patients with underlying hepatocellular disease should be given careful risk/benefit
consideration prior to enrollment).
- Patient has a known history of any chronic hepatitis as evidenced by the following:
- Positive test for hepatitis B surface antigen (HBsAg)
- Positive test for qualitative hepatitis C viral load (by PCR) (Note: Subjects
with positive hepatitis C antibody and negative quantitative hepatitis C by PCR
are eligible. History of resolved hepatitis A virus infection is not an exclusion
criterion.)
- History of alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune
hepatitis, or previous grade 3-4 drug-related hepatitis, or any form of chronic
liver disease.
- Patient has a confirmed history of encephalitis or meningitis in the year prior to
signing informed consent.
- Patients with uncontrolled or significant cardiovascular disease including, but not
limited to, any of the following are ineligible:
- Myocardial infarction or stroke/transient ischemic attack (TIA) within the 6
months prior to consent
- Uncontrolled angina within the 3 months prior to consent
- Any history of clinically significant arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or torsades de pointes)
- QTc prolongation > 480 msec
- History of other clinically significant cardiovascular disease (i.e.,
cardiomyopathy, myocarditis, congestive heart failure with New York Heart
Association (NYHA) functional classification III-IV, pericarditis, significant
pericardial effusion, significant coronary stent occlusion, deep venous
thrombosis, etc.)
- Cardiovascular disease-related requirement for daily supplemental oxygen
- Patient has another uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection that requires systemic antibacterial, antiviral or
antifungal therapy < 7 days prior to the first dose of study drug, or psychiatric
illness/social situations that would limit compliance with study requirements, are
ineligible.
- Patient is pregnant or breastfeeding.
- Patient has a known history of testing positive for human immunodeficiency virus (HIV)
or known acquired immunodeficiency syndrome (AIDS)
- Participants with a personal or family (i.e., in a first-degree relative) history of
cytochrome b5 reductase deficiency (previously called methemoglobin reductase
deficiency) or other diseases that put them at risk of methemoglobinemia. All
participants will be screened for methemoglobin levels prior to arm assignment.
- Patient has a history of G6PD deficiency or other congenital or autoimmune hemolytic
disorders
- Patient has/had prior organ or tissue allograft.
- Patient has a history of life-threatening toxicity related to prior immune therapy.
- Patient has quantitative or qualitative G6PD assay results suggesting underlying G6PD
deficiency.
- Patient has blood methemoglobin > ULN, assessed in an arterial or venous blood sample
or by cooximetry.
- Patient has a history or presence of hypersensitivity or idiosyncratic reaction to
methylene blue.
- Patient has a history of serotonin syndrome.
- Participants with active interstitial lung disease (ILD) or pneumonitis or with recent
history of ILD or pneumonitis requiring steroids (excluding radiation pneumonitis)
- Patient has active interstitial lung disease (ILD) or pneumonitis or with recent
history of ILD or pneumonitis requiring steroids (excluding radiation pneumonitis).
- Patient has condition(s) known to interfere significantly with the absorption of oral
medication, as per investigator judgement.
- Patient is taking any prohibited medications unless discontinued at least 10 days
prior to initiation of therapy (unless otherwise specified in the protocol).
- Patient is taking any restricted medications that per investigator judgement would put
the patient at increased risk.
