A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-Oncology Study in
Participants with Advanced Gastric Cancer (FRACTION-Gastric Cancer)

1) Participants must provide consent for 3 mandatory tumor biopsy samples (as
detailed in*J* below).
2) All participants must have inoperable, advanced, or metastatic GC or GEJ
carcinoma(including adenocarcinoma arising from the lower esophagus) and have
histologically confirmed predominant adenocarcinoma. The documentation of GEJ
involvement can include biopsy, endoscopy, or imaging.
3) Participants with human epidermal growth factor receptor 2 (HER2)
overexpressing tumor who progress after trastuzumab (or are ineligible for or
unwilling to be treated with trastuzumab) are eligible to be enrolled.
4) Prior adjuvant or neoadjuvant chemotherapy, radiotherapy, and/or
chemoradiotherapy are permitted as long as the last administration of the last
regimen (whichever was given last) occurred at least 4 weeks prior to
randomization.
5) Participants must have an Eastern Cooperative Oncology Group performance
status of <= 1 (see Appendix 7)., 6) Track-specific eligibility criteria
Track 1: anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment-naïve participants
1).Participants must not have received any anti-PD-1, anti-PD-L1, or
anti-CTLA-4 treatment prior to this study. Participants previously treated with
agents other than anti-PD-1, anti-PD-L1, or anti-CTLA-4 are eligible for Track
1.
2).Participants may have been offered platinum-based chemotherapy for
progressive or recurrent disease.
3).Participants must have documented PD-L1 tumor status following a required
pretreatment biopsy as described below.
After signing informed consent, participants will be required to submit a fresh
tumor biopsy meeting the criteria defined above for IHC staining to determine
PD-L1 status., Track 2: anti-PD-1, anti-PD-L1, or anti-CTLA-4
treatment-experienced participants
1).Participants must have had progressive or recurrent disease during or after
anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment. (Participants treated with any
study treatment targeting PD-1, PD-L1, or CTLA-4 will be considered anti-PD-1,
anti-PD-L1, or anti-CTLA-4 treatment experienced, respectively)
2).Participants may have been offered a platinum-based chemotherapy for GC or
GEJ.
The platinum-based chemotherapy may have been in the adjuvant,
neoadjuvant, or recurrent setting.
3).Participants who have had prior treatment with any 1 of the agents (or any
other agent targeting PD-1, PD-L1, or CTLA-4) in monotherapy or in any
combination regimen in a FRACTION-Gastric Cancer Sub-Protocol are eligible for
treatment on Track 2.
4).Participants who have had prior combination treatment with the same IO
combination agents (or IO agents directed against the same targets) as 1 of the
combination regimens in a FRACTION-Gastric Cancer Sub-Protocol are eligible for
study treatment on Track 2 but must be randomized to another combination
regimen.
5).After signing informed consent, participants will be required to submit a
fresh tumor biopsy for IHC staining to determine PD-L1 status., 7) At the time
of screening, participants must have a life expectancy of at least 3 months
following their most recent chemotherapy or immunotherapy for entry into all
Tracks.
a. Participants who wish to be re-randomized to a new study treatment
combination on Track 2 following progression on a prior study treatment in
Tracks 1 or 2 must have a life expectancy of at least 3 months following the
last study treatment.
8) Participants receiving prior palliative radiotherapy to a non-central
nervous system (CNS) lesion must have completed that treatment at least 2 weeks
prior to the first dose of study treatment.
9) Participants with symptomatic tumor lesions at baseline who may require
palliative radiotherapy within 4 weeks of the first dose of study treatment are
strongly encouraged to receive palliative radiotherapy prior to enrollment, and
they must complete that treatment at least 2 weeks prior to the first dose of
study treatment.
10) Participants must have at least 1 lesion with measurable disease as defined
by RECIST v1.1 criteria for solid tumors response assessment
a. Participants with lesions in a previously irradiated field as the sole site
of measurable disease will be permitted to enroll, provided that the lesion(s)
have demonstrated clear progression and can be measured accurately.
11) Participants with toxicity from any prior anti-cancer treatment must have
their toxicity returned to Grade <= 1 (NCI CTCAE Version 4.03) or baseline
before administration of study treatment.
12) Participants with Grade >= 2 toxicities attributed to prior anti-cancer
treatment that are not expected to resolve and result in long-lasting sequelae,
such as neuropathy after a platinum-based treatment, are eligible.
13) Participants must allow a tumor biopsy at the following time points: 1)
baseline (prior to study treatment); 2) on-study (Day 28 on-treatment); and 3)
EOT.
14) Participants who do not have accessible or suitable lesions are not
eligible.
a. ii).Baseline biopsies may be collected from participants with a single
measureable lesion (primary or metastatic), as long as it is not an excisional
biopsy.
b. iii) For participants whose pretreatment biopsy yields inadequate tissue
quantity or quality,(as determined by a pathologist in the central laboratory)
re-biopsy is permitted.
c. iv) The solid tumor tissue specimen must be a core-needle biopsy or an
excisional or incisional biopsy.
d. v) The biopsy at progression of disease after treatment on any Track may
function as the pretreatment biopsy for subsequent treatment on Track 2

a) Participants with overexpressing HER2 positive tumor and previously
untreated with trastuzumab are excluded; participants who are ineligible for or
unwilling to be treated with trastuzumab are still eligible.
b) Participants with ascites that cannot be controlled with appropriate
interventions.
c) Participants must not have suspected, known, or progressive CNS metastases;
have untreated CNS metastases; or have the CNS as the only site of disease.
i) Participants are eligible if CNS metastases are adequately treated and
participants neurologically return to baseline (except for residual signs or
symptoms related to the CNS treatment) for at least 2 weeks prior to study
entry. In addition, participants mus tbe either off corticosteroids or on a
stable or decreasing dose of prednisone <= 10 mg daily (or equivalent) for at
least 2 weeks prior to study entry.
ii) Participants must not have leptomeningeal disease or carcinomatous
meningitis.
d) Participants must not have prior malignancy active within the previous 3
years except for locally curable cancers that have been apparently cured, such
as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma
in situ of the prostate, cervix, or breast.
e) Participants must not have other active malignancy requiring concurrent
intervention.
f) Participants must not have received a prior organ allograft.
g) Participants must not have received any anti-cancer treatment (eg,
chemotherapy,
radiotherapy [except for palliative radiotherapy, which can be received at
least 2 weeks prior to study treatment]; biologics; or immunotherapies,
including investigational treatments) within 4 weeks prior to the first dose of
study treatment administration.
i) Participants who have received noncytotoxic anti-cancer therapies (eg, prior
use of targeted treatment) and who completed treatment at least 4 weeks or 5
half-lives (whichever is shorter) prior to the first dose of study treatment
are eligible to enroll.
h) Participants must not have active, known, or suspected autoimmune disease.
i) Participants with type I diabetes mellitus, hypothyroidism only requiring
hormone
replacement treatment, 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 must not have a condition requiring systemic treatment with either
corticosteroids (prednisone > 10 mg daily or equivalent) or other
immunosuppressive medications within 14 days of study treatment administration.
i) Inhaled or topical steroids and adrenal replacement steroid (prednisone > 10
mg daily or equivalent) are permitted in the absence of active autoimmune
disease.
j) Participants must not have a history of life-threatening toxicity related to
prior IO
treatment (eg, anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or
treatment specifically targeting T-cell co-stimulation or immune checkpoint
pathways).
k) Participants must not have interstitial lung disease that is symptomatic or
may interfere with the detection or management of suspected treatment-related
pulmonary toxicity.
l) Participants must not have uncontrolled or significant cardiovascular
disease including, but not limited to, any of the following:
i) Myocardial infarction or stroke/transient ischemic attack within the past 6
months
ii) Uncontrolled angina within the past 3 months
iii) Any history of clinically significant arrhythmias (such as ventricular
tachycardia,
ventricular fibrillation, or torsades de pointes)
iv) QT interval corrected with Fridericia*s formula > 480 ms
v) History of other clinically significant heart disease (eg, cardiomyopathy,
congestive
heart failure with New York Heart Association functional classification III to
IV,
myocarditis, pericarditis, or significant pericardial effusion)
m) Participants who require daily supplemental oxygen treatment are excluded.
n) Participants must not have any positive test result for hepatitis A,
hepatitis B virus or hepatitis C virus (HCV) indicating presence of virus, eg,
hepatitis B surface antigen (Australia antigen) positive, or hepatitis C
antibody (anti-HCV) positive (except if HCV-ribonucleic acid [RNA] negative).
i) Participants with a history of resolved hepatitis A virus infection are
eligible
o) Participants must not have evidence of active infection requiring
antibacterial, antifungal,or antiviral treatment * 7 days prior to initiation
of study treatment.
p) Participants must not have a known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
i) Testing for HIV must be performed at sites mandated by local requirements.
q) Participants must not have known or suspected active tuberculosis.
r) Participant must not have had any major surgery within 4 weeks of study
treatment
administration. Participants must have recovered from the effects of major
surgery or
significant traumatic injury at least 14 days before the first dose of study
treatment.
s) Participants must not have received nononcology vaccines containing live
virus for
prevention of infectious diseases within 12 weeks prior to the first dose of
study treatment.
t) Participants must not have received packed red blood cell or platelet
transfusion within 2 weeks prior to the first dose of study treatment.
u) Participants must not have a known or underlying serious or uncontrolled
medical condition that, in the opinion of the investigator or Sponsor, could
make the administration of study treatment hazardous to the participants or
could adversely affect the ability of the participant to comply with or
tolerate the study.