Inclusion Criteria:
- - Age 18 to 75 years old (including boundary value), male or female;
- Voluntarily sign informed consent;
- Study population: advanced patients diagnosed by pathology and without effective
standard treatment or standard treatment failure or standard treatment intolerance or
refuse standard treatment.
Patients with malignant solid tumors. (the extended study
phase is mainly for patients with advanced melanoma);
- - According to recist1.1 standard, there is at least one measurable tumor focus;
- ECOG score shall be 0 or 1;
- The investigator assessed the expected survival ≥ 12 weeks;
- Have sufficient organ and bone marrow functions as below:Blood routine (no blood
transfusion, no hematopoietic stimulator, and no medication to correct blood count
within 14 days prior to first dosing),Neutrophil absolute count (ANC) ≥1.5×109 /L,
Platelet count ≥75×109/L, Hemoglobin ≥90g/L, Blood coagulation function Prothrombin
time (PT) or International standardized ratio (INR) and activated partial thrombin
time (APTT) ≤ 1.5×ULN, Liver function Total bilirubin (TBIL) ≤2×ULN ,Alanine
aminotransferase (ALT), aspartate aminotransferase (AST) -- ≤3×ULN,Serum Creatinine
≤1.5×ULN ，renal function Serum creatinine clearance rate & GT; 60ml/min
(Cockcroft-Gault formula, see appendix)
- Female patients with fertility must have negative serum pregnancy test during
screening, and agree to take effective birth control / contraception to prevent
pregnancy from the study period to 6 months after the last administration.
Male
patients must agree to take effective contraceptive methods from the study period to 6
months after the last administration.
Exclusion Criteria:
- - Have received experimental drug treatment or participated in clinical research of
medical devices within 4 weeks before the first administration of study drugs
Research;
- Received chemotherapy, radiotherapy, Biological therapy, endocrine therapy,
immunotherapy, and other anti-tumor treatments within 4 weeks before the first
administration of the study drug, except: 1.
Nitrosourea or mitomycin C within 6 weeks
prior to the first use of the study drug. 2. Oral fluorouracil and small molecule
targeted drugs within 2 weeks or 5 half lives,Whichever is longer, etc.). 3.
Traditional Chinese medicine/traditional Chinese patent medicines with definite
anti-tumor effect, and drugs with immunomodulatory effect (including but not limited
to thymosin Interferons, interleukins, etc.) within 2 weeks prior to the first use of
the study drug. 4. Palliative radiotherapy within 2 weeks prior to the first use of
the study drug.
- - Failure of CTLA-4 monoclonal antibody treatment in the past;
- Before the first administration of the study drug, the AE (ctcae5.0) caused by
previous antitumor treatment was still > grade 1, hair loss and menstrual stimulation
Except those with stable immune hypothyroidism controlled by hormone replacement
therapy;
- Received interventional therapy and major surgery (such as craniotomy, thoracotomy or
laparotomy) within 4 weeks before the first administration of the study drug;Surgery
is defined here as grade 3 and 4 surgery;
- Have a history of organ transplantation;
- Central nervous system or meningeal metastasis;
- If other malignant tumors have been diagnosed in recent 5 years, or the previous
malignant tumors have been cured for less than 5 years, the time of the first
pathological diagnosis shall prevail Subject to.
Except for radical skin basal cell
carcinoma, cutaneous squamous cell carcinoma or in situ carcinoma, such as in situ
breast cancer, Cervical carcinoma in situ);
- - Patients with ocular melanoma;
- Patients with esophageal or gastric variceal bleeding in the past 6 months, or the
investigator assessed the risk of bleeding;
- Serious cardiovascular disease occurred within 6 months before the first medication:
the New York Heart Association rating (NYHA) is 2 Heart failure of grade and above,
left ventricular ejection fraction (LVEF) < 50%, unstable arrhythmia or unstable heart
Colic and uncontrollable hypertension (this protocol is defined as contraction after
treatment despite optimal antihypertensive treatment Blood pressure > 150mmhg and / or
diastolic blood pressure > 100mmhg, and the investigator's evaluation is of clinical
significance);
- Patients with a history of autoimmune diseases; Had splenectomy or splenic
irradiation;
- Drugs with immunomodulatory effect (e.g. thymosin, interferon, interleukin) were used
within 2 weeks before the first administration of the study drug Hormone) or hormone
(equivalent dose > prednisone 10mg / day);
- Untreated or under treatment tuberculosis patients, including but not limited to
tuberculosis; Those who have received standardized anti-tuberculosis treatment and
have been confirmed by researchers as cured can be included;
- Patients who have experienced severe infections within 4 weeks prior to the first
medication use, including but not limited to infection complications requiring
hospitalization, bacteremia, severe pneumonia, etc; Exclude patients with active
infections before the first administration;
- Patients with a history of non infectious pneumonia requiring glucocorticoid treatment
or current interstitial lung disease within one year before the first administration;
- Patients with uncontrolled or requiring drainage of pleural effusion, pericardial
effusion, or abdominal effusion;
- Individuals with the following risks of thrombosis or bleeding:
1.
Have experienced myocardial infarction, unstable angina pectoris, cerebrovascular
accident, or transient ischemic attack within 6 months before the first
administration;
2. A history of deep venous thrombosis, pulmonary embolism, or any other severe
thromboembolism within 3 months prior to the first administration (implantable
venous infusion port or catheter derived thrombosis, or superficial venous
thrombosis is not considered "severe" thromboembolism);
3. Any life-threatening bleeding event or grade 3 or 4 gastrointestinal/variceal
bleeding event requiring blood transfusion, endoscopy, or surgical treatment
within 3 months prior to the first administration;
4. Investigator believe that other diseases with a higher risk of bleeding or
thrombosis in the future.
- - Patients with active tuberculosis; Active infections requiring intravenous antibiotic
treatment;
- People infected with the following diseases: human immunodeficiency virus (HIV)
infection; Treponema pallidum antibody positive; hepatitis B virus Infected persons
were positive for hepatitis B surface antigen (HBsAg) and hepatitis B virus
deoxyribonucleic acid (HBV DNA) detection > 2000iu / ml (or 1 × 104 copies / ml); HCV
infected persons [HCV antibody and disease];Viral RNA (HCV RNA) test results were
positive];
- Inoculated within 4 weeks before the first medication, or planned to receive live /
attenuated vaccine during the study period;
- Known hypersensitivity to any monoclonal antibody;
- Known history of psychotropic substance abuse or drug abuse;
- Pregnant or lactating women;
- Other patients considered by the investigator as unsuitable to participate in this
study.
