Phase I Study of SHR9146 + SHR-1210 +/- Apatinib in Patients With Advanced Solid Tumors

Inclusion Criteria:

1. Subjects with histologically or cytologically confirmed advanced or metastatic solid tumors that have failed prior standard therapy (including subject refusal or intolerance).
2. At least one measurable parameter according to RECIST 1.1.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
4. Life expectancy of at least 12 weeks.
5. Subjects must have normal organ and marrow function as defined below:

   1. Absolute neutrophil count \> 1,500/mcL
   2. Platelets \> 100,000/mcL
   3. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN); for subjects with liver metastases, Total bilirubin≤ 2 x ULN,
   4. AST/ALT (SGOT/SGPT) ≤ 2.5 times institutional normal limits; for subjects with liver metastases, ALT and AST ≤ 5 × ULN
   5. Creatinine ≤ 1.5 times the ULN
6. Subjects with known brain metastases will only be eligible after their tumors have been treated with definitive resection and/or radiotherapy and they are neurologically stable for at least two months apart and at least 1 month off steroids.
7. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Known history of hypersensitivity to any components of SHR9146 and SHR-1210 formulation, or other antibody formulation.
2. Prior exposure to any T cell co-stimulatory therapy or immune checkpoint inhibitors, including but not limited to other anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies.
3. Prior systemic chemotherapy, radiotherapy, immunotherapy, hormone therapy, surgery or target therapy within 4 weeks (Or 5 half-life of the drug, calculate the longer ) before the study drug administration, or any unresolved AEs \> Common Terminology Criteria for Adverse Events (CTCAE) Grade 1.
4. Patients with any active autoimmune disease or history of autoimmune disease, including but not limited to the following: hepatitis, pneumonitis, uveitis, colitis (inflammatory bowel disease), hypophysitis, vasculitis, nephritis, hyperthyroidism, and hypothyroidism, except for subjects with vitiligo or resolved childhood asthma/atopy. Asthma that requires intermittent use of bronchodilators or other medical intervention should also be excluded.
5. Active brain metastasis or meningeal metastasis.
6. Clinically significant cardiovascular and cerebrovascular diseases, including but not limited to severe acute myocardial infarction within 6 months before enrollment, unstable or severe angina, or coronary artery bypass surgery, Congestive heart failure (New York heart association (NYHA) class \> 2), ventricular arrhythmia which need medical intervention.
7. Any other medical, psychiatric, or social condition deemed by the investigator to be likely to interfere with a subject's rights, safety, welfare, or ability to sign informed consent, cooperate, and participate in the study or would interfere with the interpretation of the results.
8. Severe or uncontrolled systemic disease such as clinically significant hypertension(systolic pressure \>/= 140 mm Hg and/or diastolic pressure \>/= 90 mm Hg). (group 2)
9. Previous digestive tract bleeding history within 3 months or evident gastrointestinal bleeding tendency, such as: esophageal varices, local active ulcerative lesions, gastric ulcer and duodenal ulcer, the ulcerous colitis, gastrointestinal diseases such as portal hypertension or resection of tumor with bleeding risk, etc. (group 2)
10. Previous Arterial/venous thrombosis events within 3 months. (group 2)
11. Proteinuria ≥ (++) or 24 hours total urine protein \> 1.0 g. (group 2)