Nivolumab, BMS-986205, and Radiation Therapy With or Without Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma
Nivolumab, BMS-986205, and Radiation Therapy With or Without Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma
This phase I trial studies the side effects of nivolumab, BMS-986205, and standard radiation
 therapy with or without temozolomide in treating patients with new diagnosed glioblastoma.
 Immunotherapy with nivolumab, may induce changes in body?s immune system and may interfere
 with the ability of tumor cells to grow and spread. BMS-986205 may stop the growth of tumor
 cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high
 energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as
 temozolomide, work in different ways to stop the growth of tumor cells, either by killing the
 cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab
 and BMS-986205 may work better compared to radiation therapy and temozolomide alone in
 treating patients with newly diagnosed glioblastoma.
PRIMARY OBJECTIVES:

 I. To determine the safety and tolerability of nivolumab in combination with IDO1 inhibitor
 BMS-986205 (BMS986205) and radiation in newly diagnosed MGMT promoter unmethylated
 glioblastoma and MGMT promoter methylated glioblastoma.

 SECONDARY OBJECTIVES:

 I. Descriptive survival analyses (overall survival [OS] and OS at 12 months [OS12]) in
 patients with MGMT unmethylated and MGMT methylated promoter.

 II. Progression free survival (PFS) and PFS at 6 months (PFS6) in patients with MGMT
 unmethylated and MGMT methylated promoter.

 III. Radiographic response rates (RR) as determined by Response Assessment in Neuro-Oncology
 (RANO) and immunotherapy (i)RANO criteria in patients with MGMT unmethylated and MGMT
 methylated promoter.

 EXPLORATORY OBJECTIVES:

 I. Determine the T-cell changes that occur in glioblastoma (GBM) treated with nivolumab in
 combination with BMS-986205 and radiation.

 II. Correlate T-cell changes and IDO1 expression with patient outcomes.

 OUTLINE: This is a dose-escalation study of IDO1 inhibitor BMS-986205. Patients are assigned
 to 1 of 2 cohorts.

 COHORT I:

 RADIATION THERAPY: Patients with MGMT methylated promoter undergo radiation therapy 5 days
 per week (Monday-Friday) for up to 6 weeks. Patients also receive temozolomide orally (PO)
 once daily (QD), IDO1 inhibitor BMS-986205 PO QD, and nivolumab intravenously (IV) over 30
 minutes every 2 weeks for up to 6 weeks in the absence of disease progression, unacceptable
 toxicity, withdrawal of consent, the study ends, or until Q4W dosing begins.

 MAINTENANCE THERAPY: Patients receive IDO1 inhibitor BMS-986205 PO QD on days 1-28 and
 nivolumab IV over 30 minutes on days 1 and 15 of cycles 1-5 and on day 1 of subsequent
 cycles. Within 4 weeks of radiation therapy completion, patients also receive temozolomide PO
 QD on days 1-5 of cycles 2-6. Cycles repeats every 28 days for up to 2 years in the absence
 of disease progression or unacceptable toxicity.

 COHORT II:

 RADIATION THERAPY: Patients with MGMT unmethylated promoter undergo radiation therapy 5 days
 per week (Monday-Friday) for up to 6 weeks. Patients also receive IDO1 inhibitor BMS-986205
 PO QD and nivolumab IV over 30 minutes every 2 weeks for up to 6 weeks in the absence of
 disease progression or unacceptable toxicity.

 MAINTENANCE THERAPY: Patients receive IDO1 inhibitor BMS-986205 PO QD on days 1-28 and
 nivolumab IV over 30 minutes on days 1 and 15 of cycles 1-5 and on day 1 of subsequent
 cycles. Cycles repeats every 28 days for up to 2 years in the absence of disease progression,
 unacceptable toxicity, withdrawal of consent, the study ends, or until Q4W dosing begins.

 After completion of study treatment, patients are followed up at 30 days and then every 3
 months thereafter.
Inclusion Criteria:

 -  Patients must have a newly diagnosed histologically confirmed diagnosis of any grade
 IV glioma with documentation of MGMT methylation status. The histological diagnosis
 can be obtained either from a brain biopsy or from a neurosurgical resection of the
 tumor

 -  Note: Study enrollment is to be within 5 weeks from diagnostic surgery or biopsy

 -  Note: Pyrosequencing to determine MGMT methylation status will be performed at
 Northwestern Memorial Hospital as standard of care (SOC)

 -  Tumor tissue specimens from the GBM surgery or biopsy for central pathology review and
 exploratory analysis of immunocorrelative studies, if available (no minimum
 requirement)

 -  For subjects who had undergone tumor resection, preoperative gadolinium (Gd)-magnetic
 resonance imaging (MRI) and immediate postoperative Gd-MRI performed within < 72 hours
 after surgery or biopsy is recommended. If computed tomography (CT) scans were
 performed perioperatively, an MRI should be performed before initiation of study
 treatment

 -  Patients must exhibit a Karnofsky performance score of >= 70%

 -  Stable or decreasing dose of steroids for >= 7 days prior to registration

 -  Note: Patients must be off of all steroids at the time of initiation of study
 treatment (day 1 [D#1])

 -  Patients must have adequate organ and bone marrow function at registration, as defined
 below:

 -  Absolute neutrophil count >= 1500/mm^3

 -  Platelets >= 100,000/mm^3

 -  Creatinine or creatinine clearance =<1.5 times upper limit of normal or >= 60 mL/min

 -  Hemoglobin >=10 mg/dL

 -  Blood transfusion allowed

 -  Total bilirubin =< 1.5 times upper limit of normal

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SPGT]) =<
 2.5 times above upper limit of normal

 -  Alkaline phosphatase =< 2.5 times above upper limit of normal

 -  Females of child-bearing potential (FOCBP) and males must agree to use adequate
 contraception prior to study entry, for the duration of study participation, and for 5
 months following completion of therapy. Should a female patient become pregnant or
 suspect she is pregnant while participating in this study, she should inform her
 treating physician immediately. Due to the potential interaction with study drug(s),
 contraceptions that use hormones are not considered to be highly effective for FOCBP
 participants in this study.

 -  NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a
 tubal ligation, or remaining celibate by choice) who meets the following
 criteria:

 -  Has not undergone a hysterectomy or bilateral oophorectomy. Has had menses
 at any time in the preceding 12 consecutive months (and therefore has not
 been naturally postmenopausal for > 12 months)

 -  Males who are sexually active with FOCBP must agree to follow instructions for
 method(s) of contraception 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).
 In addition, male participants must be willing to refrain from sperm donation during
 this time. Male participants with partners who are FOCBP are required to use a condom
 for study duration and until end of relevant systemic exposure defined as 7 months
 after the end of study treatment. This criteria applies to azoospermic males as well

 -  FOCBP must have a negative serum pregnancy test within 14 days of registration on
 study and within 24 hours of beginning study treatment

 -  Clinically normal cardiac function without history of ischemic heart disease in the
 past 6 months and normal 12 lead electrocardiogram (ECG)

 -  Patients must have recovered from the effects of surgery, postoperative infection, and
 other complications before study registration

 -  Patients must have the ability to understand and the willingness to sign a written
 informed consent prior to registration on study

 Exclusion Criteria:

 -  Patients who have had chemotherapy within 2 years prior to entering the study are not
 eligible

 -  Patients who have received brain radiation therapy (RT) are not eligible

 -  Patients may not be receiving any other investigational agents. Patients may not have
 received an investigational agent within the past 30 days prior to the initiation of
 study treatment

 -  Patients with a condition requiring systemic treatment with either corticosteroids or
 other immunosuppressive medications are not eligible

 -  Note: Inhaled or topical steroids, and adrenal replacement steroid doses >= 10 mg
 daily prednisone equivalent, are permitted in the absence of active autoimmune
 disease

 -  Patients with an active, known or suspected autoimmune disease are not eligible.
 Patients with type I diabetes mellitus, hypothyroidism only requiring hormone
 replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
 systemic treatment, or conditions not expected to recur in the absence of an external
 trigger are permitted to enroll

 -  Participants with a personal or family (i.e., in a first-degree relative) history or
 presence of cytochrome b5 reductase deficiency (previously called methemoglobin
 reductase deficiency) or other diseases that puts them at risk of methemoglobinemia
 are not eligible. All participants will be screened for methemoglobin levels prior to
 registration

 -  Participants with a history of G6PD deficiency or other congenital or autoimmune
 hemolytic disorders are not eligible. All participants will be screened for G6PD
 levels prior to registration

 -  Participants with active interstitial lung disease (ILD)/pneumonitis or with a history
 of ILD/pneumonitis requiring steroids are not eligible

 -  Patients with a history of recent prior malignancy are not eligible. Subjects with
 curatively treated cervical carcinoma in situ or non-melanoma basal cell carcinoma of
 the skin, or subjects who have been free of other malignancies for >= 2 years are
 eligible for this study

 -  Patients who have a history of allergic reactions attributed to compounds of similar
 chemical or biologic composition to nivolumab, temozolomide or BMS-986205 are not
 eligible

 -  Patients who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2,
 anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
 co-stimulation or checkpoint pathways are not eligible

 -  Patients who have had prior treatment with BMS-986205 or any other IDO1 inhibitors are
 not eligible

 -  Patients who have received treatment with botanical preparations (e.g., herbal
 supplements or traditional Chinese medicines) intended for general health support or
 to treat the disease under study within 14 days prior to registration are not eligible

 -  Patients who have an uncontrolled intercurrent illness including, but not limited to
 any of the following, are not eligible:

 -  Hypertension that is not controlled on medication

 -  Ongoing or active infection requiring systemic treatment

 -  Symptomatic congestive heart failure

 -  Unstable angina pectoris

 -  Cardiac arrhythmia

 -  Psychiatric illness/social situations that would limit compliance with study
 requirements

 -  Any other illness or condition that the treating investigator feels would
 interfere with study compliance or would compromise the patient?s safety or study
 endpoints

 -  Female patients who are pregnant or nursing are not eligible

 -  Patients who have quantitative or qualitative G6PD assay results suggesting underlying
 G6PD deficiency are not eligible

 -  Patients who have blood methemoglobin > upper limit of normal (ULN), assessed in an
 arterial or venous blood sample or by co-oximetry are not eligible

 -  Patients with a concurrent illness, including severe infection, which may jeopardize
 the ability of the subject to receive the procedures outlined in this protocol with
 reasonable safety are not eligible. Concomitant use of strong inhibitors of CYP3A4/1A2
 within 1 week or 5 half-lives (whichever is longer) or strong inducers of CYP3A4/1A2
 within 2 weeks or 5 halflives (whichever is longer) is not permitted

 -  Patients with a placement of Gliadel wafer at surgery are not eligible

 -  Patients receiving Optune therapy are not eligible

 -  Patients who are unable to undergo Gd-MRI are not eligible

 -  Patients with current known alcohol dependence or drug abuse are not eligible

 -  Patients with a history or presence of hypersensitivity or idiosyncratic reaction to
 methylene blue are not eligible

 -  Patients with a prior history of serotonin syndrome are not eligible

 -  Known history of positive test for human immunodeficiency virus (HIV) or known
 acquired immunodeficiency syndrome (AIDS).

 -  Note: Testing for HIV must be performed at sites where mandated locally

 -  Patients who have any positive test result for hepatitis B virus or hepatitis C virus
 indicating presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia
 antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if hepatitis c
 virus [HCV] ribonucleic acid [RNA] negative) are not eligible

 -  Patients with the presence of any familial, sociological or geographical condition
 potentially hampering compliance with the study protocol and follow-up schedule are
 not eligible; those conditions should be assessed with the patient before registration
 in the trial

 -  Patients with major medical illnesses or psychiatric impairments that in the
 investigator's opinion will prevent administration or completion of protocol therapy
 are not eligible