| Eligibility |
"Inclusion Criteria Subjects may be entered in the study only if they meet all of the
following criteria:
1. Fully understand the study and signed the Informed Consent Form (ICF) voluntarily;
2. Subjects with histologically and/or cytologically confirmed advanced and/or metastatic
gastric adenocarcinoma (including adenocarcinoma at esophageal-gastric conjunction),
esophageal squamous cell carcinoma, nasopharyngeal carcinoma, or head and neck
squamous cell carcinoma, who meet the following conditions (not applicable to cohort
5, 6, 7, and 8):
Subjects with gastric adenocarcinoma must have received at least one line of
anti-tumor treatment for advanced gastric adenocarcinoma and have documented tumor
progression or be intolerable to the current available chemotherapy regimen. Subjects
who have recurrence or metastasis within 6 months after completion of concomitant
adjuvant or neoadjuvant chemotherapy of radical operation are eligible to this study;
Subjects with esophageal squamous cell carcinoma must have received at least one line
of treatment for advanced esophageal squamous cell carcinoma (including but not
limited to anticancer drug treatment or radio-chemotherapy) and have documented tumor
progression or be intolerable to the current chemotherapy regimen. Subjects who have
recurrence or metastasis within 6 months after completion of concomitant adjuvant or
neoadjuvant therapy (including but not limited to chemotherapy or radio-chemotherapy)
of radical operation are eligible to this study;
Subjects with nasopharyngeal carcinoma or head and neck squamous cell carcinoma who
have received at least one line of treatment for advanced nasopharyngeal carcinoma or
head and neck squamous cell carcinoma (including but not limited to anticancer drug
treatment or radio-chemotherapy) and have documented tumor progression or be
intolerable to other current chemotherapy regimens. Subjects with recurrence or
metastasis within 6 months after completion of concomitant adjuvant or neoadjuvant
radio-chemotherapy of radical operation are eligible to this study (only applies for
Version 4.1 and the previous ones); while for the working protocol version 5.0,
subjects with nasopharyngeal carcinoma can be enrolled only if they meet the following
criteria:
subjects having received at least two lines of treatment for advanced nasopharyngeal
carcinoma (including but not limited to anticancer drug treatment and
radio-chemotherapy), who are confirmed to have tumor progression or be intolerable to
other current chemotherapy regimens; adjuvant or neoadjuvant radio-chemotherapy after
radical surgery can be considered as one line of treatment if tumor recurrence or
metastasis occurred within 6 months after the end of the radio-chemotherapy.
3. At least one measurable lesion (according to RECIST 1.1); Note: Any lesion which
received radiotherapy treatment previously cannot be regarded as a target lesion,
unless that it has definitely progressed after radiotherapy.
4. Agree to provide archived tumor tissue specimens or have biopsy to collect tumor
tissues for PD-L1 IHC measurement in the central laboratory;
5. Males or females aged between 18 and 75 years old;
6. ECOG score of 0-1;
7. Life expectancy = 3 months;
8. The results of laboratory tests performed within 7 days prior to enrollment must meet
the following criteria:
1. Neutrophils = 1.5×109/L (not applicable to cohort 5, 6, 7, and 8);
2. Platelets = 75×109/L (not applicable to cohort 5, 6, 7, and 8);
3. Hemoglobin = 90 g/L (without receiving infusion of concentrated red blood cells
within 2 weeks);
4. Serum creatinine = 1.5× upper limit of normal (ULN), or creatinine clearance > 50
mL/min (not applicable to cohort 5, 6, 7, and 8);
5. Serum total bilirubin = 1.5×ULN (total bilirubin = 3×ULN are acceptable for
subjects with Gilbert syndrome);
6. Both AST and ALT = 2.5×ULN; ALT and AST = 5×ULN are acceptable for subjects with
liver metastasis;
9. Serum pregnancy test result must be confirmed as negative for women of childbearing
potential within 28 days prior to enrollment and the subjects must agree to take
effective contraception measures throughout the study treatment period until 60 days
after the end of study treatment. Women of childbearing potential are defined as women
with sexual maturity, who meet any of the following conditions: 1) no hysterectomy or
bilateral oophorectomy; 2) without natural menopause for a consecutive 24 months
(patients with menopause after cancer treatment may also have childbearing potential)
(i.e. menstruation occurred at any time during the previous consecutive 24 months)
(not applicable to cohort 5, 6, 7, and 8).
Female partners of childbearing potential of the male subjects should also follow the
contraception requirements.
Other special inclusion criteria for cohort 5, 6, 7, and 8.
1. Subjects with histologically and/or cytologically confirmed advanced and/or metastatic
gastric adenocarcinoma (including adenocarcinoma at esophageal-gastric conjunction),
esophageal squamous cell carcinoma, nasopharyngeal carcinoma, or head and neck
squamous cell carcinoma, who meet any of the following conditions:
1. Subjects who have not received any systematic treatment.
2. Subjects who have received any neoadjuvant chemotherapy, adjuvant chemotherapy
for the purpose of curing must experience a period for at least 6 months from the
end of the last chemotherapy to tumor progression.
3. Subjects with head and neck squamous cell carcinoma must have received
radiotherapy for the purpose of curing, and the period from the end of
radiotherapy to tumor progression must be at least 1 year.
4. For subjects with gastric carcinoma, Her2 negative is required. HER2 positive is
defined as IHC 3+ or IHC 2+ combined with ISH+, and ISH positive is defined as
the ratio of the number of HER2 gene copies to the number of CEP17 signals = 2.0.
2. Results of laboratory test conducted within 7 days before enrollment must meet the
following criteria:
1. Neutrophils = 2×109/L; WBC count = 4×109L and < 15×109/L
2. Platelets = 100×109/L;
3. Hemoglobin = 90 g/L (no infusion of concentrated red blood cells within 2 weeks);
4. Creatinine clearance rate > 60 mL/min, based on the predicted value of
Cockcroft-Gault glomerular filtration rate:
(140 - age) × (weight, kg) × (0.85, if females) 72× (serum creatinine, mg/dL) Or:
(140 - age) × (weight, kg) × (0.85, if females) 0.818 × (serum creatinine,
µmol/L)
5. Serum total bilirubin = 1.5 × ULN (total bilirubin = 3 × ULN are acceptable for
subjects with Gilbert syndrome);
6. INR and aPTT = 1.5 × ULN, applies only to subjects who have not received
anticoagulation; and for subjects who are receiving anticoagulation, the dose for
anticoagulation must be stable.
3. Serum pregnancy test result must be confirmed as negative for women of childbearing
potential within 28 days prior to enrollment and the subjects must agree to take
effective contraception measures throughout the study treatment period until 6 months
after the end of chemotherapy or 60 days after the end of study treatment (whichever
comes last). Women of childbearing potential are defined as women with sexual
maturities, who meet any of the following conditions: 1) no hysterectomy or bilateral
oophorectomy; 2) without natural menopause for a consecutive 24 months (patients with
menopause after cancer treatment may also have childbearing potential) (i.e.
menstruation occurred at any time during the previous consecutive 24 months) .
Female partners of childbearing potential of the male subjects should also follow the
contraception requirements.
Subjects fulfilling any of the following conditions cannot be enrolled in the study:
1. Known hypersensitivity to citric acid monohydrate, dihydrate sodium citrate, mannitol
or polysorbate (components of the investigational drug);
2. Anti-tumor treatment with cytotoxic drugs, biological drugs (e.g. monoclonal
antibody), immunotherapy (e.g. interleukin 2 or interferon), or other investigational
drugs within 4 weeks prior to enrollment;
3. Tyrosine kinase inhibitor treatment within 2 weeks prior to enrollment;
4. Radiotherapy within 4 weeks prior to enrollment, or radioactive drugs within 8 weeks
prior to enrollment. However, patients receiving local palliative radiotherapy for
bone metastasis lesions can be included;
5. Subjects with any major surgical operation within 4 weeks prior to enrollment or who
have not completely recovered from the prior operation (for the definition of major
surgical operation, please refer to the Level 3 and Level 4 operations stipulated in
the Management of Clinical Application of Medical Technology enforced on May 1, 2009);
6. Toxicity due to any previous anticancer treatment has not recovered to CTCAE Grade
0-1, excluding the following conditions:
1. Alopecia;
2. Pigmentation;
3. Peripheral nerve toxicity recovered to < CTCAE Grade 2 (not applicable to cohort
5, 6, 7, and 8, subjects are not eligible if peripheral neurotoxicity does not
restore to normal);
4. Long-term toxicity related to radiotherapy, which will not fully recover as
judged by the investigator.
7. Central nervous system metastasis with clinical symptoms (e.g. brain edema, hormone
intervention required, or progression of brain metastasis) and/or carcinomatous
meningitis. Subjects with prior treatment for brain or meningeal metastasis can be
included if they have remained stable clinically for at least 2 months and systemic
hormone treatment (Prednisone at a dose of > 10 mg/day or other equivalent hormone
formulations) has been discontinued for more than 4 weeks;
8. Subjects with nasopharyngeal carcinoma or head and neck squamous cell carcinoma, who
are found to have necrotic lesions by examination within 4 weeks prior to enrollment,
for which there is a potential risk of massive hemorrhage as judged by the
investigator;
9. Previous or other concurrent malignant tumors (expect for effectively controlled
non-melanoma skin basal cell carcinoma, breast/cervix carcinoma in situ, and other
malignant tumors which were effectively controlled without treatment over the past 5
years);
10. Any active autoimmune disease or history of any autoimmune disease (including but are
not limited to interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis,
nephritis, hyperthyroidism or hypothyroidism. Patients with vitiligo or asthma (in
childhood) which was completely resolved and without need of any intervention in
adulthood can be included. However, subjects with asthma which needs bronchodilator
for medical intervention cannot be included);
11. Previous treatments with anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody
or anti-CTLA-4 antibody (or any other antibody which acts on T-cell co-stimulatory or
checkpoint pathway);
12. Subjects diagnosed with active tuberculosis (TB), who are receiving anti-tuberculosis
therapy or used to have anti-tuberculosis therapy within 1 year prior to screening;
13. Concomitant diseases requiring long-term treatment with immunosuppressive drugs, or
corticosteroids at an effective immunosuppressive dose (Prednisone at a dose of > 10
mg/day or other equivalent hormone formulations) for systemic or local treatment
purpose;
14. Subjects who have received any anti-infection vaccine (e.g. influenza vaccine,
varicella vaccine, etc.) within 4 weeks prior to enrollment;
15. Pregnant or lactating women
16. Positive test for HIV;
17. Positive test for HBsAg, with HBV DNA copies detected as positive (quantitative
measurements = 1000 cps/mL);
18. Positive test for chronic Hepatitis C in blood screening test (HCV antibody positive);
Any other clinical significant disease or condition, which as evaluated by the
investigator, may affect the protocol compliance, signing of inform consent form
(ICF), or not suitable to participate into this clinical trial.
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