The Study of SHR7390 in Combination With SHR-1210 and SHR3162 in Patients With Advanced Solid Tumors

Inclusion Criteria:

The study is open to all males and females who meet the following inclusion criteria at screening and baseline to participate in the study.

To be included to participate in this study each patient must:

1. 18-70 years of age, both male and female;
2. The invalid standard treatment or non standard and effective treatment in patients with advanced solid tumors diagnosed by pathology;

（1) in the phase of dose escalation , the subjects with RAS or BRAF mutation status and microsatellite stability （MSS）are not restricted.

（2）in the phase of dose expansion，the subjects with RAS or BRAF mutations and microsatellite stability (MSS) are included necessarily.

（3) the subjects included in the phase of dose expansion must have at least one measurable target lesion with RECIST V 1.1.

(4) If they in the phase of dose expansion are unable to provide the results of previous RAS/BRAF mutation and microsatellite stability,subjects must provide previous cancer tissues（paraffin blocks or pathological 8-10 white sections）, or fresh biopsy specimens.

3\. The Eastern Cooperative Oncology Group （ECOG） General status (performance status, PS) of 0-1;

4\. The expected lifetime ≥ 3 months;

5\. The organ function must meet the following requirements:

1. Adequate bone marrow reserve: including neutrophil absolute count,platelets and hemoglobin;
2. Liver: serum albumin ≥ 2.8 g/dl; bilirubin≤1.5 upper limit of normal value (ULN), Alanine aminotransferase（ALT）and aspartate aminotransferase（AST）≤ 2.5 upper limit of normal value (ULN),if there is liver metastasis, the ALT or AST≤5xULN;
3. Kidneys: creatinine clearance ≥ 50 mL/min (Cockcroft-Gault of the standard formula）；
4. Heart: left ventricular ejection fraction ≥ 50%; normal Electrocardiograph (ECG) and corrected QT interval（QTc）;male QTc\<450ms，female QTc\<470ms

6\. The lesion of the patients caused by other treatments has been restored(≤1 grade，except alopecia and other adverse events that the investigators judged to be tolerable）。The time interval between previous treatment and the first use of study drugs：nitrosourea or mitomycin\> 6 weeks; cytotoxic drugs, monoclonal antibodies, radiotherapy or surgery\> 4 weeks; TKI targeted drugs\> 2 weeks;endocrine therapy\> 1 week；

7\. A agreement to use a highly effective, non-hormonal form of contraception is required for women of childbearing potential and men with partners of childbearing potential, who were not sterilized surgically, for duration of the study treatment and after the last dose of study treatment; For female patients of child bearing potential,who was not sterilized surgically,the serum human chorionic gonadotropin （HCG） pregnancy test must be the negative

8\. Voluntary ability to follow the procedures of clinical study. Written informed consent is provided by signing the informed consent form.

Exclusion Criteria:

1. Previous treatment with any other tumor immune checkpoint inhibitors within 2 months before the first use of study drugs；previous treatment with other MEK inhibitors or PARP inhibitors (the previous treatment of PARP inhibitors is only excluded in the second part of the study).
2. Use of other investigational anti-cancer drugs or the termination of the investigational drugs within the last four weeks.
3. The subjects had active autoimmune diseases, a history of immunodeficiency disease and autoimmune diseases, or a history of disease or syndrome with systemic steroid hormones or immunosuppressive drugs(such as asthma, idiopathic pulmonary fibrosis, institutional pneumonia, bronchiolitis obliterans, and drug pneumonia,idiopathic pneumonia or interstitial pneumonia, colitis, hepatitis, pituitary inflammation, vasculitis, nephritis,hyperthyroidism, hypothyroidism, but not limited to these diseases or syndromes），or other acquired (HIV) and congenital immunodeficiency diseases, or a history of organ transplantation (including allogeneic bone marrow transplantation).
4. Known severe hypersensitivity or other hypersensitivity to chimeric or humanized antibodies or fusion proteins; known to be allergic or hypersensitive to components of SHR-1210，SHR7390 or SHR3162.
5. The subjects were known to have tumor metastases of central nervous system or meningeal metastases, or a history of primary tumors of CNS.
6. Presence of a factor that influences the oral drug (such as inability to swallow) or presence of active gastrointestinal disease or other diseases that will interfere significantly with the absorption, distribution, metabolism, or excretion of drug.
7. History of the retinopathy or the sensory retinal detachment. As assessed by ophthalmologist, presence of the risk factors of study treatment that may cause retinal vein thrombosis/occlusion (RVO), central serous chorioretinopathy (CSCR),or neovascular and macular degeneration.
8. The intraocular pressure \> 21mmHg or glaucoma was diagnosed within 4 weeks
9. The evidence of severe or uncontrollable pleural effusion, peritoneal effusion or pericardial effusion. The clinical treatment is required, such as periodic drainage.
10. The evidence of severe or uncontrolled systemic diseases (e.g. chronic lung, liver, kidney, or heart diseases).
11. Unstable angina pectoris or new angina pectoris within recent three months.Presence of arrhythmia, myocardial ischemia with long-term drug treatment.III-IV stage heart failure as defined by the New York Heart Association (NYHA). Presence of acute myocardial infarction events and congestive heart failure within the first six months before screening.
12. Medical treatment for an acute stage of infection or active TB.
13. Hepatitis B virus（HBV) or hepatitis C virus (HCV) infection stage with abnormal liver function.
14. Pregnant or lactating women or intending to become pregnant during the study period.
15. Living attenuated vaccines within one months of the initial use of the drug, or a living attenuated vaccine is expected during the study period.
16. A history of neurological or psychiatric disorders, and a history of psychotropic substance or drug abuse.
17. According to the judgement of the investigators, presence of serious hazards to the safety of the subjects, the concomitant diseases confusing to analyze the study data or influencing to complete this study (such as severe hypertension, diabetes, thyroid disease, etc.),or any other situation.