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
