The purpose of this study is to evaluate the efficacy and safety of of anti-PD-1 antibody in
combination with chemotherapy as first-line treatment in patients with unresectable, locally
advanced recurrent or metastatic serum AFP-elevated gastric and gastroesophageal junction
AFP-elevated gastric adenocarcinoma is a special type of gastric cancer, with the
characteristics of high risk of liver and lymph node metastasis, poor therapeutic effect, and
This prospective study is a single-arm, multicenter phase II clinical study to evaluate the
efficacy and safety of anti-PD-1 antibody in combination with chemotherapy as first-line
treatment in patients with unresectable, locally advanced recurrent or metastatic serum
AFP-elevated gastric and gastroesophageal junction adenocarcinoma.
AFP elevation is defined as serum AFP > 20 ng/ml. In this prospective study, the objective
remission rate (ORR) will be used as primary outcome measures and 30 patients will be
recruited. Anti-PD-1 antibody in combination with chemotherapy will be administered. PD-L1
expression and tumor mutant burden (TMB) will be measured before treatment. In addition, the
dynamic changes of serum AFP levels, T lymphocyte in peripheral blood will be monitored
during treatment. In the course of treatment, safety evaluation will be carried out according
to the standard of adverse reaction classification (CTCAE) 4.0.
1. Patients must volunteer to participate in the study, signed informed consent, and were
able to comply with the program requirements of visits and related procedures.
2. Age and gender: ≥18 years old and≤75 years old, both men and women.
3. All subjects must have unresectable, local advanced recurrent or metastatic gastric
adenocarcinoma (GC) or gastroesophageal junction adenocarcinoma (GEC) confirmed by
4. No systematic treatment for advanced or metastatic GC/GEC has been received in the
past. For patients who have received adjuvant or neoadjuvant therapy (including
chemotherapy, radiotherapy and/or radiochemotherapy) for GC/GEC in the past, the last
treatment must be completed at least six months before the start of study drug.
Subjects are allowed to receive palliative radiotherapy, but it must be completed two
weeks before the start of study drug.
5. Serum AFP > 20 ng/ml.
6. All acute toxic reactions caused by previous medication or surgery were alleviated to
grade 0-1 (according to NCI-CTCAE version 5.0) or to the level specified by the
criteria for Inclusion/exclusion. The toxicities that do not pose a safety risk to
patients determined by investigators are excluded, such as hair loss , etc.
7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
8. Expected survival: ≥12 weeks.
9. Subject must have at least one measurable lesion or evaluable disease by CT or MRI per
RECIST 1.1 criteria.
10. The functions of important organs must meet the following
requirements:(1)Hematological system: Neutrophil count≥1.5×10^9/L; Platelet
count≥80×10^9/L; Hemoglobin≥90g/L;(2)Liver function: Serum albumin≥28g/L; Total
bilirubin (TBI)≤1.5×ULN; Alanine aminotransferase (ALT)≤2.5×ULN (or≤5×ULN if liver
metastases are present); Aspartate aminotransferase (AST)≤2.5×ULN (or≤5×ULN if liver
metastases are present); (3)Renal function: Serum creatinine≤1.5×ULN or calculated
creatinine clearance (CrCl) ≥40 mL/min (using the Cockcroft-Gault formula):Female CrCl
= (140- age in years) × weight in kg × 0.85/ 72 × serum creatinine in mg/ dL; Male
CrCl = (140- age in years) × weight in kg × 1.00/72 × serum creatinine in mg/
dL;(4)Coagulation function: Subjects not receiving anticoagulation therapy:
(International Normalized Ratio) INR or activeated partial thromboplastin time (APTT)
11. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test within 7 days prior to the start of study drug. WOCBP must agree to follow
instructions for method(s) of contraception (e.g. intrauterine devices,
contraceptives, condoms or abstinence) for the duration of study treatment and 6
months after the last dose of study treatment. Subjects must be non-lactating. Males
who are sexually active with WOCBP must agree to follow instructions for method(s) of
contraception for the duration of study treatment and 6 months after the last dose of
1. Known human epidermalgrowth factor receptor-2 (HER2) positive.
2. Currently participating in research and receiving research treatment, or participating
in the research of experimental drugs within four weeks before the start of study
drug, and having received research treatment or used experimental instruments.
3. Major surgery were performed within 4 weeks before the start of the study and
4. Existence of any active autoimmune disease or with a history of autoimmune disease (as
the following examples, but not limited to: autoimmune hepatitis, interstitial
pneumonia, uveitis, enteritis, hepatitis, pituitary, vasculitis, nephritis,
hyperthyroidism; patients with vitiligo; in childhood asthma has been completely
alleviated, adults without any intervention can be included; asthma with medical
intervention could not be included). Substitution therapy is not considered as
systemic therapy. Patients with the following diseases are not excluded and may
proceed to further screening: a. Controlled Type I diabetes; b. Hypothyroidism
(provided it is managed with hormone replacement therapy only).
5. Any condition that required systemic treatment with either corticosteroids (> 10 mg
daily of prednisone or equivalent) or other immunosuppressive medication ≤ 7 days
6. Any active malignancy ≤ 5 years before randomization except for the specific cancer
under investigation in this study and any cured limited tumors (eg, carcinoma in situ
of the cervix or prostate, basal cell skin cancer).
7. Patients with known central nervous system metastasis (suspected need to be excluded
by MRI scans) or a history of hepatic encephalopathy.
8. A history of pneumonia (non-infectious) requiring steroid therapy within 6 months or
currently suffering from pneumonia (pulmonary infectious).
9. With active infections, fever of unknown origin (≥38.5℃) within 7 days before the
start of study drug; or white blood cell count at baseline > 15×10^9/L); with severe
chronic or active infections (including tuberculosis infection, etc.) requiring
systemic antibacterial, antifungal or antiviral therapy during screening period,
excluding viral hepatitis.
10. With any other disease, metabolic abnormality, abnormal physical examination or
abnormal laboratory examination, according to the judgments of the investigators,
there is reason to suspect that the patient has a certain disease or condition that is
not suitable for the use of study drugs, or that it will affect the interpretation of
research results or put the patient at high risk.
11. Mental or drug abuse disorders known to have an impact on compliance with study
12. Congenital or acquired immunodeficiency (e.g. HIV-infected persons).
13. With active hepatitis B virus (HBV) or hepatitis C virus (HCV). Active hepatitis B is
defined as known positive HBsAg results, and HBV-DNA > 2000IU/ml. Active hepatitis C
is defined as known positive hepatitis C antibodies and the quantitative results of
HCV RNA are higher than the lower detection limit of analytical methods. Active HBV
will be allowed if they have HBV DNA < 500 IU/mL (or 2500 copies/mL) at screening.
Patients with HBV-DNA < 2000IU/ml through antiviral therapy can be considered
14. Was administered a live attenuated vaccine ≤ 4 weeks before randomization, or plan to
vaccinate during treatment with against PD-1 monoclonal antibody or within five months
after last administration.
15. More than a small amount of pericardial effusion, uncontrolled pleural effusion or
clinically obvious peritoneal effusion at screening. It is defined as meeting the
following criteria: physical examination at screening can detect pleural and
peritoneal effusion, or in screening process, pleural and peritoneal effusion needs
puncture and drainage.
16. With history of serious cardiovascular and cerebrovascular diseases: (1) Any history
of heart failure meeting New York Heart Association Classification III or IV or more
serious history of heart disease, myocardial infarction, or cerebrovascular accident
in 3 months before randomization；(2) Left ventricular ejection fraction < 50% by color
Doppler echocardiography；(3) Uncontrollable hypertension; (4) Uncontrolled
arrhythmias; (5) Acute coronary syndrome, congestive heart failure, stroke,
thromboembolism or other cardiovascular events above grade 3 within 6 months before
the start of study drug.
17. A history of allergy to anti-PD-1, anti-PD-L1 monoclonal antibody drugs or oxaliplatin
18. Known dihydropyrimidine dehydrogenase deficiency.
19. Pregnant or lactating women; or female subjects who are expected to conceive during
the planned trial period (from the start of screening visits to 120 days after the
last administration of the study) or male subjects whose spouses are pregnant.
20. Other situations that the researchers think should be excluded.