Anti-LAG-3 Alone & in Combination w/ Nivolumab Treating Patients w/ Recurrent GBM (Anti-CD137 Arm Closed 10/16/18)

PRIMARY OBJECTIVES:

I. To determine a maximum tolerated dose or maximum administrated dose of anti-lymphocyte
activation gene-3 (LAG-3) antibody (BMS-986016) (anti-LAG-3 monoclonal antibody BMS-986016)
and anti-cluster of differentiation 137 (CD137) antibody (BMS- 663513) (urelumab) given
independently and in combination with anti-programmed death-1 (PD-1) antibody (nivolumab,
BMS-936558) safely in patients with recurrent glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

I. To estimate overall survival. II. To estimate 1 year progression-free survival (PFS) rate.
III. To estimate radiographic response (radiographic assessment in neuro-oncology [RANO] and
immunotherapy response assessment for neuro-oncology [iRANO]).

TERTIARY OBJECTIVES:

I. To assess the pharmacodynamic effects of anti-LAG-3 antibody (BMS-986016), anti-CD137
antibody (BMS- 663513), and/or anti-PD-1 antibody (BMS-936558) on biomarkers in peripheral
blood, including the T cell compartments, and serum proteins (cytokines and other immune
modulators).

II. To assess the pharmacodynamic activity in tumor tissue and peripheral blood in treated
subjects who undergo optional tumor biopsies.

III. To explore potential associations between biomarker measures and anti-tumor activity by
analyzing markers of inflammation, immune activation, host tumor growth factors, and
tumor-derived proteins in the pre-treatment and on-treatment setting.

IV. To further characterize the occupancy and immune cell function at multiple dose levels of
anti-LAG-3 antibody (BMS-986016), anti-CD137 antibody (BMS-663513), and/or anti-PD-1 antibody
(BMS-936558).

V. To explore characteristics of tumor immune microenvironment changes after the treatment of
anti-LAG-3, anti-CD137, and its combination treatment with anti- PD-1 in surgically indicated
patients undergoing tumor resection

OUTLINE:

PART A: This is a dose-escalation study of the monotherapy of Anti-LAG-3 monoclonal antibody
BMS-986016 and Anti-CD137 (urelumab). Patients are assigned to 1 of 2 arms.

ARM I: Patients receive anti-LAG-3 monoclonal antibody BMS-986016 intravenously (IV) on days
1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive anti-CD137 (urelumab) IV on day 1. Treatment repeats every 21 days
for up to 15 courses in the absence of disease progression or unacceptable toxicity.

PART B: This is the dose-escalation combination therapy portion study of Anti-LAG-3
monoclonal antibody BMS-986016 plus Anti-PD-1(nivolumab) and Anti-CD137 (urelumab) plus
Anti-PD-1 (nivolumab). Patients are assigned to 1 of 2 arms.

ARM I: Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes and anti-LAG-3 monoclonal
antibody BMS-986016 IV on days 1 and 15. Treatment repeats every 28 days for up to 24 courses
in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive Anti-PD-1 (nivolumab) IV over 60 minutes on days 1 and 15 and
urelumab IV on day 1. Treatment repeats every 28 days for up to 24 courses in the absence of
disease progression or unacceptable toxicity.

(2pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by
BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on
treatment may continue.)

INTRATUMORAL STUDIES: Patients enrolled on the Intratumoral Studies surgical arm
pre-operatively receive either anti-LAG-3 monoclonal antibody BMS-986016 as in Part A Arm I,
urelumab as in as in Part A Arm II, nivolumab and anti-LAG-3 monoclonal antibody BMS-986016
as in Part B Arm I, or nivolumab and urelumab as in Part B Arm II. Within 45 days of surgical
resection, patients post-operatively receive either anti-LAG-3 monoclonal antibody BMS-986016
as in Part A Arm I, urelumab as in as in Part A Arm II, nivolumab and anti-LAG-3 monoclonal
antibody BMS-986016 as in Part B Arm I, or nivolumab and urelumab as in Part B Arm II.

(3pts enrolled before the Anti-CD137 antibody (BMS-663513 - urelumab) treatment arm closed by
BMS on 10/16/18 due to closure of BMS Urelumab development program. Subjects currently on
treatment may continue.)

After completion of study treatment, patients are followed up at 60 days, every 2 months for
2 years, and then every 6 months thereafter. Patients taken off treatment for other reasons
than disease progression are followed up every 2 months for 1 year.

Inclusion Criteria:

- Patients must have histologically proven glioblastoma or gliosarcoma which is
progressive or recurrent following radiation therapy and temozolomide

- Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT)
methylation status must be available; results of routinely used methods for MGMT
methylation testing (e.g. mutagenically separated polymerase chain reaction
[MSPCR] or quantitative polymerase chain reaction [PCR]) are acceptable

- Patients must have measurable contrast-enhancing disease (defined as at least 1
cm x 1 cm) by magnetic resonance imaging (MRI) imaging within 21 days of starting
treatment (patients may have gross total resection, but should have measurable
disease post-operatively); patients must be able to undergo MRI of the brain with
gadolinium; patients must be maintained on a stable corticosteroid regimen (no
increase for 5 days) prior to this baseline MRI

- Patients must be in first recurrence of glioblastoma following radiation therapy
and temozolomide

- Patients 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); no prior therapies are allowed other than
radiation, temozolomide, and Gliadel wafers (placed during the first surgery at
diagnosis of GBM)

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must
be able to care for himself/herself with occasional help from others)

- Absolute lymphocyte count >= 1000/ul

- Absolute neutrophil count >= 1,500/ul

- Platelets >= 100,000/ul

- Hemoglobin >= 9 g/dl

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
[SGPT]) =< 3 x institutional upper limit of normal

- Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60
ml/min/1.73m^2 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

- Patients must be able to provide written informed consent

- Women of childbearing potential must have a negative serum pregnancy test within
24 hours prior to treatment start; women of childbearing potential must agree to
use two methods of contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of study treatment, and
through 23 weeks 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; men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for
the duration of study participation, and through 31 weeks after the last dose of
study drug

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast,
or bladder; patients with prior malignancies must be disease-free for >= five
years

Exclusion Criteria:

- Patients receiving any other investigational agents are ineligible

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to anti-LAG-3, anti-CD137, and anti-PD1 are
ineligible; the investigator brochures can be referenced for more information

- Patients with active or recent history of known or suspected autoimmune disease
are ineligible; 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

- Patients with a condition requiring systemic treatment with either
corticosteroids or other immunosuppressive medications within 14 days of study
entry are ineligible

- Patients must not be receiving greater than 1 mg dexamethasone/day (or an
equivalent amount of an alternative corticosteroid) for at least 1 week prior to
treatment start

- Patients must have no evidence of mass effect and no midline shift

- Patients must have no evidence of significant hematologic, renal, or hepatic
dysfunction; patients with underlying hepatocellular disease should be given
careful risk/benefit consideration prior to enrollment; patients with a history
of any chronic hepatitis as evidenced by the following are ineligible:

- 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

- Patients must be hepatitis C virus (HCV) negative (by quantitative PCR [qPCR])
and hepatitis B virus core antibody (HBcAb) negative (no prior hepatitis B
infection)

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, clinically
significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements, are ineligible

- Pregnant women are excluded from this study; breastfeeding should be discontinued
if the mother is treated with these agents

- Human immunodeficiency virus (HIV)-positive patients on combination
antiretroviral therapy are ineligible