Sponsor R & D Strategy Adjustment

The study consists of the two parts, the first one is SHR7390 combined with SHR-1210, the second one is SHR7390 combined with SHR-1210 and SHR3162. Two parts of the study are separately to assess the safety and tolerability, to define dose limiting toxicity（DLT) and maximum tolerated dose (MTD),to evaluate the pharmacokinetics ,to assess the antitumor activity in patients with advanced solid tumors preliminarily and to recommend reasonable dosage regimen of SHR7390 for the follow-up clinical trial.

This is a phase I, open-label,two parts,dose escalation/expansion clinical study.The safety,tolerance,PK and preliminary efficacy of two-drug combination and three-drug combination were evaluated respectively in the patients with advanced solid tumors that have no any targeted agents as the standard therapies.

In the first study part, subjects receiving a single dose of SHR7390 (Run-in) are observed in 7-10 days, then accepted two drug combination therapy, SHR7390 is administered once daily orally for 28 days for a treatment cycle. At the same time, SHR-1210 was given intravenously per 2 weeks at the fixed dose of 200mg.

In the second study part, subjects accepted three drug combination therapy, SHR7390 is administered orally for 21 days and discontinued for 7 days in a 28-day treatment cycle,SHR3162 was administered orally twice a day for 28 days at a fixed dose of 100 mg. At the same time, SHR-1210 was given intravenously per 2 weeks at the fixed dose of 200mg.

Dose limiting toxicities (DLT) in the first study part will be assessed during the Run-in and first cycle of treatment. the dose escalation is designed by Accelerated Titration Designs during initial accelerated phase. when the significant toxicity or DLT is observed in the Run-in and first cycle of treatment,the accelerated titration trial terminates and subsequent dose escalations are become a conventional design of 3+3 patients. If one adverse event （AE） meets dose limiting toxicity (DLT) criteria at a given dose, 3 additional patients will be enrolled in this dose cohort. If 2 DLTs are determined at a given dose level, the previous dose will be designated as the MTD.

Based on preliminary determination of RP2D and sufficient safety data in the first part of the study, the second part of three-drug combination will be carried out. the preset dose of SHR7390 includes RP2D initially determined in the first part of the study and its previous low dose level (for example, RP2D is 0.5 mg/d, while the former low dose is 0.25 mg/d). Dose escalation is a conventional design of 3+3 patients.

Additional patients will be enrolled for pharmacokinetic (PK) evaluations at different dose levels based on preliminary safety and tolerability.Each dose level can expand at least 12 subjects , of which 9-12 subjects are PK subjects. Multiple blood samples at designated time points will be collected for PK evaluations (more than 12 subjects are determined by SMC).

The safety, tolerability and AEs will be closely monitored throughout the study duration. The preliminary effectiveness and clinical benefits of two-drug combination and three-drug combination will be evaluated.

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.