First Line Sintilimab Combined With Anlotinib and Platinum Doublet Chemotherapy in Malignant Pleural Mesothelioma

Inclusion Criteria:

• Sign written informed consent before implementing any trial-related procedures;

• Age ≥ 18 years old.

• Histologically confirmed, unresectable or inoperable or locally advanced (IIIBstage), recurrent or metastatic (IV stage) malignant pleural mesothelioma.

• According to the modified version of the evaluation criteria for the efficacy ofsolid tumor (mRECIST1.1 ), patients have at least one imaging lesion can bemeasured;

• Patients have not received any systemic anti-tumor therapy for advanced/metastaticdiseases in the past. Patients who have previously received platinum-containingadjuvant / neoadjuvant chemotherapy, or radical radiotherapy and chemotherapy foradvanced diseases, such as the interval between disease progression or recurrenceand the end of the last chemotherapeutic drug treatment at least 6 months, areallowed to be enrolled in this study.

• Patients with brain metastasis who are asymptomatic or stable after local treatmentare allowed to be included in this study, as long as they meet the followingconditions:

1. There are measurable lesions outside the central nervous system.

2. No central nervous system symptoms or no aggravation within at least 2 weeks.

3. Those who do not need glucocorticoid therapy or stop glucocorticoid therapywithin 7 days before the first study drug administration.

• Patients are allowed to receive palliative radiotherapy, but the end of radiotherapyis within 7 days before the administration of the first study drug.

• ECOG score 0-1 points;

• The expected survival time was > 3 months,

• For adequate organ function, the patients need to meet the following laboratoryindexes:

1. the absolute value of neutrophils (ANC) ≥ 1.5x109/L without granulocyte colonystimulating factor in the past 14 days.

2. in the last 14 days without blood transfusion, the platelet count was ≥ 100x109/L.

3. in the absence of blood transfusion or the use of erythropoietin in the past 14days, hemoglobin > 9g/dL;

4. Total bilirubin ≤ 1.5 × normal upper limit (ULN); for example,if totalbilirubin > 1.5 × ULN but direct bilirubin ≤ ULN is also allowed to enter thegroup

5. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (patients with liver metastasis allow ALT or AST ≤ 5 × ULN).

6. Serum creatinine ≤ 1.5 × ULN and creatinine clearance (calculated byCockcroft-Gault formula) ≥ 60ml;

7. Coagulation function is good, defined as international standardized ratio (INR)or prothrombin time (PT) ≤ 1.5 times ULN;

8. Normal thyroid function is defined as thyroid stimulating hormone (TSH) withinthe normal range. If the baseline TSH is beyond the normal range, subjects withtotal T3 (or FT3) and FT4 within the normal range can also be enrolled.

9. Myocardial enzyme spectrum is within the normal range (if the researcherscomprehensively judge that there is no clinical significance of simplelaboratory abnormalities can also be included in the group); (optional)

• For female patients at childbearing age, they should undergo a urine or serumpregnancy test within 3 days before receiving the first study drug administration (day 1 of cycle 1) and the results be negative. If the urine pregnancy test resultscannot be confirmed as negative, a blood pregnancy test is required. Women ofnon-childbearing age are defined as at least 1 year after menopause or haveundergone surgical sterilization or hysterectomy.

• If there is a risk of pregnancy, all patient (male or female) are required to usecontraception with an annual failure rate of less than 1% during the entiretreatment period until 120 days after the last study drug administration (or 180days after the last chemotherapy drug administration).

Exclusion Criteria:

• Diagnosis of malignant diseases other than malignant pleural mesothelioma (excludingradical skin basal cell carcinoma, skin squamous cell carcinoma, and / or radicalresection of carcinoma in situ) within 5 years before the first administration

• Currently participating in interventional clinical research treatment, or receivingother research drugs or using research instruments within 4 weeks before the firstadministration;

• Previous usage of the following treatments: anti-PD-1, anti-PD-L1 or anti-PD-L2drugs, for another stimulating or synergistic inhibition of T cell receptors (forexample, CTLA-4, OX-40, CD137) drug;

• Within 2 weeks before the first administration, they received systemic systemictherapy with anti-tumor indications of proprietary Chinese medicine orimmunomodulatory drugs (including thymosin, interferon, interleukin, except forcontrolling local use of pleural effusion)

• Active autoimmune diseases requiring systemic treatment (such as the use ofdisease-relieving drugs, glucocorticoids or immunosuppressants) occurred within 2years before the first administration. Alternative therapy (such as thyroxine,insulin or physiological glucocorticoids for adrenal or pituitary insufficiency) arenot considered systemic therapy.

• The patients are received systemic glucocorticoid therapy (excluding nasal, inhaledor other topical glucocorticoids) or any other form of immunosuppressive therapywithin 7 days before the first administration.

Note: The use of physiological doses of glucocorticoids (≤10 mg/day prednisone or equivalent drugs) is allowed;

• There are clinically uncontrollable pleural effusion / ascites (patients who do notneed drainage or stop drainage for 3 days without a significant increase in effusioncan be enrolled in the group)

• Known allogeneic organ transplantation (except corneal transplantation) orallogeneic hematopoietic stem cell transplantation;

• Those who are known to be allergic to the active ingredients or excipients ofSintilimab in this study.

• Patients with multiple factors affecting oral drugs (such as inability to swallow,gastrointestinal resection, chronic diarrhea and intestinal obstruction, etc.)

• Symptomatic or uncontrolled brain metastasis;

• Active hemoptysis (at least 2.5ml or 1/2 teaspoon of blood was spit out at a time) 3months before the first study drug administration;

• Imaging showed that there were tumors invading / infiltrating large blood vessels orbleeding tendency assessed by researchers or radiologists;

• Received major surgery (except for surgery for the purpose of biopsy) within 4 weeksbefore the first study drug administration, or is expected to undergo major surgeryduring the study period;

• Severe unhealed wound ulcers or fractures;

• Minor surgery was performed within 48 hours before first receiving the study drug (outpatient / inpatient surgery requiring local anesthesia, including central venouscatheterization);

• Use aspirin (>325 mg/day) or other non-steroidal anti-inflammatory drugs that areknown to inhibit platelet function for 10 consecutive days (within 10 days beforereceiving the first dose of study drug) at present or in the near future;

• Current or recent treatment with full-dose oral or parenteral anticoagulants orthrombolytic agents for 10 consecutive days (within 10 days before receiving thefirst study drug) Note: Prophylactic use of low-dose anticoagulants is permitted:low-dose warfarin (≤ 1mg/d) is allowed for preventive purposes on the premise thatthe international standardized ratio of prothrombin time (INR) ≤ 1.5. Low-doseheparin (≤ 12000 U/e d) or low-dose aspirin (≤ 100mg/d).

• Hereditary bleeding tendency or coagulation dysfunction, or history of thrombosis;

• Did not fully recover from toxicity and / or complications caused by anyintervention (i.e., ≤ level 1 or reached baseline, excluding fatigue or hair loss)before starting treatment;

• Known human immunodeficiency virus (HIV) infection history (i.e. HIV 1/2 antibodypositive)

• Untreated active hepatitis B (defined as HBsAg positive and the number of HBV-DNAcopies detected is greater than the upper limit of the normal value of thelaboratory in the research center).

Note: hepatitis B subjects who meet the following criteria can also be enrolled in the group:

1. Before the first administration, the HBV viral load is less than 1000 copies/ml (200IU/ml), and the patients should receive anti-HBV treatment during the entire studydrug treatment period to avoid viral reactivation;

2. For patients with anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load (-),there is no need to receive preventive anti-HBV therapy. However, the virus needs tobe closely monitored for reactivation

• Active HCV infection subjects (HCV antibody positive and HCV-RNA level higherthan the lower limit of detection)

• Live vaccine is given within 30 days before the first administration (cycle 1,day 1).

Note: It is allowed to receive inactivated virus vaccine for seasonal influenza within 30 days before the first administration; however, it is not allowed to receive live attenuated influenza vaccine for intranasal administration..

• Pregnant or lactating women;

• There are any serious or uncontrollable systemic diseases, such as

1. significant abnormalities in rhythm, conduction, or morphology of restingelectrocardiogram and serious and uncontrollable symptoms, such as completeleft bundle branch block, second-degree cardiac block, ventricular arrhythmiaor atrial fibrillation.

2. unstable angina pectoris, congestive heart failure, chronic heart failure withNew York Heart Association (NYHA) grade ≥ 2;

3. any arterial thrombosis, embolism or ischemia occurred within 6 months beforetreatment, such as myocardial infarction, unstable angina pectoris,cerebrovascular accident or transient ischemic attack;

4. Blood pressure control is not satisfactory (systolic blood pressure > 140mmHg,diastolic blood pressure > 90mmHg).

5. within 1 year before the first administration, there is a history ofnon-infectious pneumonia requiring glucocorticoid treatment, or currently thereis clinically active interstitial lung disease;

6. active pulmonary tuberculosis;

7. active or uncontrolled infections requiring systemic treatment;

8. clinically active diverticulitis, abdominal abscess, gastrointestinalobstruction.

9. liver diseases such as liver cirrhosis, decompensated liver disease, acute orchronic active hepatitis;

10. poorly controlled diabetes (fasting blood glucose (FBG) > 10mmol/L);

11. patients with urinary protein ≥ + + and confirmed 24-hour urinary proteinquantity > 1.0g;

12. patients with mental disorders and unable to cooperate with treatment

• At the discretion of the investigator, there are patients with serious concomitantdisease that compromises patient safety or affects the patient's completion of thestudy; The investigator believes that there are other potential risks and is notsuitable for participation this research.