REACTION (Radiation Enhanced Assessment of Combination Therapies in Immuno-ONcology) - Nivolumab or Nivolumab in Combination With Other Immuno-oncology (IO) Agents After Targeted Systemic Radiation in Patients With Advanced Esophagogastric Cancer

This is a Phase 1B study assessing the safety of immune checkpoint inhibition after SBRT in
patients with recurrent or metastatic gastroesophageal cancer (limited metastatic disease).
Arm A explores the safety and efficacy of nivolumab alone, and Arm B explores the safety and
efficacy of nivolumab plus Relatlimib. Patients with recurrent or metastatic esophagogastric
cancer are eligible for this study which will enroll patients with limited disease burden and
who are Programmed death-1(PD-1) therapy naïve. This will allow for us to assess if systemic
ablative radiation (SBRT to multiple metastatic sites plus PD-1/ anti-LAG3) is able to
enhance the effectiveness of nivolumab +/- anti-LAG3 or to overcome treatment resistance
mechanisms. Patients will be treated with targeted high dose radiation (SBRT) to metastatic
lesions as outlined below. One of the lesions which is considered the easiest to biopsy and
not causing symptoms will not be radiated so as to obtain tissue for correlative analysis.
This lesion will then be re-biopsied approx. 4 weeks after the completion of radiation to the
other metastatic sites. If a lesion is causing pain or other symptoms this site will not be
chosen as the biopsiable site. The chosen metastatic lesion can then be irradiated at a later
date if we do not see disease response in that region. Approximately 30 patients will be
enrolled on study with 15 enrolled on Arm A, and 15 enrolled on Arm B.

Inclusion Criteria:

- Men and women aged ≥ 18 years old.

- Histologically proven (squamous cell or adenocarcinoma) esophageal or
gastro-esophageal junction cancer or gastric cancer (core biopsy required)

- Either a formalin fixed paraffin block or a minimum of ten 5-micron tissue section's
(slides) of tumor biopsy sample must be available for biomarker evaluation.

- Recurrent disease or Stage IV disease as per American Joint Committee on Cancer (AJCC)
staging 8.0 - patients who decline systemic chemotherapy in the first line metastatic
setting are eligible.

- (Relatlimab arm only) LVEF assessment with documented left ventricular ejection
fraction ( LVEF) >/=50% by either echocardiogram TTE or multigated acquisition scan
(MUGA) (TTE preferred test) within 6 months from first study drug
administration,whichever is most recent.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Adequate organ function as follows:

- Leukocytes ≥ 2,000/mm3

- Absolute neutrophil count (ANC) ≥ 1000/mm3

- Platelet count ≥ 100,000/mm3

- Hemoglobin ≥ 9 g/dL

- Creatinine ≤ 2.0 mg/dL

- Bilirubin (total) within normal institutional limits (except subjects with
Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)

- Aspartate aminotransferase (AST) (SGOT), Alanine Aminotransferase (ALT) (SGPT),
and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal

- prothrombin time (PT) such that international normalized ratio (INR) is ≤ 1.5 (or
an in-range INR, usually between 2 and 3, if a patient is on a stable dose of
therapeutic warfarin) and a partial thromboplastin time (PTT) ≤ institutional
upper limit of normal

- Adequate cardiac function as defined by: no evidence of (PR) prolongation or
Atrioventricular block (AV block) on baseline electrocardiogram (ECG).

- The effects of nivolumab, relatlimab or BMS-986178, on the developing human fetus are
unknown. For this reason women of child-bearing potential (WOCBP) and men must agree
to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation and for 5
months after the last dose of nivolumab +/- IO therapy. Should a woman become pregnant
or suspect she is pregnant while she or her partner is participating in this study,
she should inform her treating physician immediately. Sexually active fertile men must
use effective barrier birth control if their partners are WOCBP for 7 months after the
last dose of nivolumab +/- IO therapy. WOCBP must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within two
weeks of registration.

- Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception (see Appendix 4) for the duration of treatment with study
treatment(s) plus 33 weeks after the last dose of the study treatment (ie, 90 days
[duration of sperm turnover] plus the time required for nivolumab and relatlimab to
undergo approximately 5 half-lives). In addition, male participants must be willing to
refrain from sperm donation during this time.

- Patient understands the study regimen, its requirements, risks and discomforts and is
able and willing to sign the informed consent form. Voluntary signed and dated
Institutional Review Board (IRB) approved written informed consent form in accordance
with regulatory and institutional guidelines must be obtained before the performance
of any protocol related procedures that are not part of normal patient care. Subjects
must be competent to report Adverse Events (AEs), understand the drug dosing schedule
and use of medications to control AEs.

Exclusion Criteria:

- Any active or history of autoimmune disease (including any history of inflammatory
bowel disease), or history of syndrome that required systemic steroids or
immune-suppressive medications, except for subjects with vitiligo or resolved
childhood asthma/atopy.

- (Relatlimab arm only) Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of
normal (ULN). Subjects with TnT or TnI levels between > 1 to 2 × ULN will be permitted
if repeat levels within 24 hours are ≤1 x ULN. If TnT or TnI levels are > 1 to 2 × ULN
within 24 hours, the subject may undergo a cardiac evaluation and be considered for
treatment, following a discussion with the BMS Medical Monitor or designee. When
repeat levels within 24 hours are not available, a repeat test should be conducted as
soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the
subject may undergo a cardiac evaluation and be considered for treatment, following a
discussion with the Bristol Myers Squibb (BMS) Medical Monitor or designee.

- (Relatlimab arm only) Participants must not have a history of myocarditis

- (Relatlimab arm only) Uncontrolled or significant cardiovascular disease including,
but not limited to, any of the following:

- Myocardial infarction (MI) 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,
poorly controlled atrial fibrillation, ventricular fibrillation, or torsades de
pointes)

- Corrected QT interval (QTc) prolongation > 480 msec

- History of other clinically significant cardiovascular disease (i.e., cardiomyopathy,
congestive heart failure with New York Heart Association (NYHA) functional
classification III-IV, pericarditis, significant pericardial effusion, significant
coronary stent occlusion, , poorly controlled venous thrombosis etc.)

- Cardiovascular disease-related requirement for daily supplemental oxygen

- History of two or more MIs OR two or more coronary revascularization procedures

- (Relatlimab arm only) LVEF (Left Ventricular Ejection Fraction) assessment with
documented LVEF ≥ 50% by either TTE or MUGA (TTE preferred test) within 6 months from
first study drug administration.

- Ongoing requirement for systemic corticosteroids. However, inhalational steroids are
allowed.

- Subjects with previous malignancies (except non-melanoma skin cancers, in situ
bladder, gastric, breast, colon or cervical cancers/dysplasia) are excluded unless a
complete remission was achieved at least 2 years prior to study entry and no
additional therapy is required or anticipated to be required during the study period.

- Subjects with known brain metastasis are excluded from this study. Patients with
suspected brain metastasis must have brain imaging (either MRI brain or CT brain with
contrast) prior to enrollment.

- Subjects with a history of interstitial lung disease. Patients requiring continuous
supplemental oxygen are excluded.

- Use of any vaccines against infectious diseases (e.g., influenza, varicella. etc.)
within 4 weeks (28 days) of initiation of study therapy.

- Active systemic infection requiring therapy, positive tests for Hepatitis B surface
antigen or Hepatitis C ribonucleic acid (RNA).

- Known positive history or positive test for Human Immunodeficiency Virus or Acquired
ImmunoDeficiency Syndrome (AIDS).

- History of allergy to study drug components.

- Women who are pregnant or nursing.

- Men with female partners (WOCBP) that are not willing to use contraception

- Underlying medical conditions that, in the Investigator's opinion, will make the
administration of study drug or radiation hazardous or obscure the interpretation of
toxicity or adverse events.

- Prior therapy with an anti-programmed death-1 (anti-PD-1), anti-programmed death
ligand-1 (anti-PD-L1), Anti-programmed cell death 1 ligand 2 (anti-PDL-2), or
Anti-Cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibody (or any other antibody
targeting T cell co-regulatory pathways).

- Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for
treatment of either a psychiatric or physical (e.g. infectious disease) illness.