Biomarker-Driven Therapy Using Immune Activators With Nivolumab in Patients With First Recurrence of Glioblastoma

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.