Propranolol Hydrochloride in Combination With Sintilimab and Platinum-based Chemotherapy for Treatment of Advanced Non-small Cell Lung Cancer

Inclusion Criteria:

• Sign a written informed consent prior to any research-related procedure

• Age ≥18 years and ≤ 75 years old

• ECOG PS score of 0-1

• Expected survival time ≥ 12 weeks

• Patients with histologically or cytologically confirmed non-localizable stageIIIB-IIIC, stage IV non-small cell lung cancer (International Association for theStudy of Lung Cancer and the Joint Committee on the American Classification ofCancers, 8th edition). Patients with unresectable IIIB-IIIC include recurrent andprimary unresectable (surgery and radical concurrent chemoradiotherapy), and stageIV includes primary or recurrent stage IV but without prior systemic therapy foradvanced/metastatic disease.

• Chemotherapy and chemoradiotherapy are permitted as neoadjuvant/adjuvant treatmentas long as the treatment is completed at least 12 months prior to the diagnosis ofadvanced or metastatic disease

• There must be no EGFR gene-sensitive mutation, ALK gene fusion or ROS1 gene fusionin non-squamous carcinoma

• At least one imaging measurable lesion according to the criteria for the evaluationof the efficacy of solid tumors (RECIST version 1.1). A lesion located in the fieldof exposure to previous radiotherapy is considered measurable if progression isconfirmed (within 28 days prior to the first treatment)

• Subjects with brain metastases who are asymptomatic or whose symptoms havestabilized with local treatment are permitted to be enrolled, provided that thesubject meets the following criteria:

1. Have a measurable lesion outside the CNS.

2. No CNS symptoms or no worsening of symptoms for at least 2 weeks.

3. No glucocorticoid therapy is required, or glucocorticoid therapy has beendiscontinued within 7 days prior to the first dose, or the glucocorticoiddosage has been stable and reduced to less than 10 mg/day of prednisone (orequivalent dose) within 7 days prior to the first dose

• Meet the following laboratory indicators (within 14 days before the firsttreatment):

1. Blood routine examination: absolute neutrophil count ≥ 1.5 x 10^9/L; plateletcount ≥ 100 x 10^9/L; hemoglobin level ≥ 9.0 g/dL (no blood transfusion orerythropoietin-dependent administration within 7 days).

2. Liver function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN);alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULNin the absence of hepatic metastases; ALT or AST ≤ 5 × ULN in the case ofpatients with hepatic metastases.

3. Renal function: serum creatinine (Cr) ≤1.5 times ULN or Cr clearance ≥60 mL/min (Cockcroft-Gault formula), and urine routine test results show urine protein (UPRO) <2+ or 24-hour urine protein quantification <1g.

4. Coagulation: International Normalized Ratio (INR) ≤ 1.5 times ULN orProthrombin Time (PT) ≤ 1.5 times ULN within 7 days prior to study treatment;if the subject is receiving anticoagulant therapy, as long as the PT is withinthe range of the anticoagulant drug

• Heart function: the New York heart association (NYHA) classification < 3;Leftventricular ejection fraction（LVEF）≥ 50%; Baseline ECG showed no PR intervallengthened or atrioventricular block

• For female subjects of childbearing potential, a negative urine or serum pregnancytest should be obtained within 3 days prior to receiving the first dose of studydrug (Day 1 of Cycle 1). If a negative urine pregnancy test result cannot beconfirmed, a blood pregnancy test will be requested. Females not of childbearingpotential are defined as being at least 1 year postmenopausal or having undergonesurgical sterilization or hysterectomy; if conception is at risk, all subjects (maleor female) are required to use contraception with an annual failure rate of lessthan 1% throughout the treatment period up to 120 days after the end-of-treatmentadministration of study drug (or 180 days after the end-of-study drugadministration)

Exclusion Criteria:

• Concurrent participation in another interventional clinical study or receipt ofanother investigational drug, unless participating in an observational clinicalstudy

• Prior exposure to any anti-PD-1 or anti-PD-L1, PD-L2, CD137, CTLA-4 antibodytherapy, or any other antibody or drug specifically targeting T-cell co-stimulationor checkpoint pathways

• Systemic therapy with proprietary Chinese medicines with anti-tumor indications orimmunomodulatory drugs (including thiopeptides, interferons, interleukins, exceptthose used locally for the control of hydrothorax or ascites) within 2 weeks priorto the first dose

• Current use of oral or intravenous beta-blockers (e.g., atenolol, bisoprolol,carvedilol, labetalol, metoprolol, nadolol, sotalol, etc.) cannot be safely switchedto a non-beta-blocker

• There are contraindications to the use of beta-blockers:

1. Hypersensitivity to any of the components of the product.

2. Bronchial asthma or risk of bronchospasm.

3. Ketoacidosis and metabolic acidosis.

4. Severe or symptomatic bradycardia (resting heart rate ≤55bpm), atrioventricularblock (degrees II and III), sinus block, sick sinus node syndrome.

5. Cardiogenic shock

6. Right heart insufficiency due to pulmonary hypertension.

7. Congestive heart failure (class III or IV).

8. Hypotension (systolic blood pressure < 100 mmHg).

9. Prolonged fasting.

10. Severe peripheral circulatory failure (e.g., gangrene).

11. Symptomatic peripheral arterial disease or Raynaud's syndrome, untreatedpheochromocytoma.

12. Unstable angina or variant angina.

13. Patients on rizatriptan benzoate.

14. Severe asthma or chronic obstructive pulmonary disease (COPD)

15. Uncontrolled type I or type II diabetes mellitus (glycosylated hemoglobin [HbA1C] > 8.5 or fasting blood glucose > 160 mg/dl at screening).

16. Current use or within the last 2 years of a non-dihydropyridine calcium channelblocker (NDCCB)

• Hepatic encephalopathy, hepatorenal syndrome or Child-Pugh class B or more severecirrhosis

• Tumor-related intestinal obstruction (within 3 months prior to the signing of theinformed consent) or history of inflammatory bowel disease or extensive bowelresection (partial colectomy or extensive small bowel resection with chronicdiarrhea), Crohn's disease, ulcerative colitis

• Completion of palliative radiotherapy within 7 days prior to the first dose of studydrug

• With clinically active diverticulitis, abdominal abscess, gastrointestinalobstruction

• History of psychotropic substance abuse or addiction

• Known hypersensitivity to the active ingredients or excipients of the study drug

• Known history of primary immunodeficiency or undergoing systemic glucocorticoidtherapy or any other form of immunosuppressive therapy

• Use of immunosuppressive drugs, excluding topical glucocorticoids by nasal,inhalational or other routes or physiological doses of systemic glucocorticoids (i.e., no more than 10 mg/day of prednisone or an equivalent dose of otherglucocorticoids), or use of hormones for the prevention of contrast sensitization,within 4 weeks prior to the first dose of study treatment

• Failure to recover adequately from any intervention-induced toxicity and/orcomplications (≤ grade 1 or baseline, excluding weakness or alopecia) prior toinitiation of treatment

• Receipt of live attenuated influenza vaccine within 4 weeks prior to the first doseof study treatment or planned for the duration of the study (inactivated injectableviral vaccine against seasonal influenza is permitted up to 4 weeks prior to thefirst dose; however, live attenuated influenza vaccine is not permitted)

• Major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to thefirst dose of study treatment or anticipation of major surgery during studytreatment; laparoscopic exploratory surgery within 2 weeks prior to the first doseof study treatment

• Known symptomatic CNS metastases and/or carcinomatous meningitis. Subjects withpreviously treated brain metastases may be enrolled in the trial if they areclinically stable (no evidence of imaging progression for at least 4 weeks prior tothe first dose of the experimental treatment, no evidence of new brain metastases orincrease in size of pre-existing brain metastases as confirmed by repeat imaging)and do not require steroid therapy for at least 14 days prior to the first dose ofthe experimental treatment. This exception does not include carcinomatousmeningitis, which should be excluded regardless of whether it is clinically stable.

• Presence of clinically uncontrolled pleural effusion or ascites (subjects may berecruited who do not require drainage of the effusion or who do not have asignificant increase in the effusion after 3 days of cessation of drainage)

• Patients with bone metastases at risk of paraplegia

• Known or suspected autoimmune disease or history of such disease within the last 2years (patients with vitiligo, psoriasis, alopecia areata or Graves' disease notrequiring systemic treatment within the last 2 years, hypothyroidism requiring onlythyroid hormone replacement therapy, and type I diabetes mellitus requiring onlyinsulin replacement therapy may be enrolled)

• Known to have active tuberculosis.

• A history of allogeneic organ transplants and allogeneic hematopoietic stem celltransplants is known

• Known history of human immunodeficiency virus (HIV) infection (HIV-positive)

• Known acute or chronic active hepatitis B virus (HBsAg-positive and HBVDNA viralload ≥200 IU/mL or ≥10^3 copies/mL) or acute or chronic active hepatitis C virus (HCV antibody-positive and HCV RNA-positive)

• Active syphilis infection requiring treatment

• Suffer from interstitial lung disease requiring steroid hormone therapy

• Serious infections that are active or poorly controlled clinically

• Severe cardiovascular disease (e.g., myocardial infarction, arterialthromboembolism, cerebrovascular thromboembolism); angina pectoris requiringtreatment; symptomatic peripheral vascular disease; NYHA cardiac class 3 or 4congestive heart failure; or uncontrolled ≥class 3 hypertension (diastolic bloodpressure ≥100 mm Hg or systolic blood pressure ≥160 mm Hg) despite antihypertensivetreatment

• History of other primary malignancies within 5 years, except：

1. malignancies that have been in complete remission for at least 2 years prior toenrolment and for which no other treatment was required during the studyperiod.

2. adequately treated non-melanoma skin cancer or malignant nevus with no evidenceof disease recurrence.

3. adequately treated carcinoma in situ without evidence of disease recurrence

• Female patients who are pregnant or breastfeeding

• Other acute or chronic medical conditions, psychiatric disorders, or abnormallaboratory test values that may result in increased risk associated with studyparticipation or administration of study medication, or interfere with theinterpretation of study results, and that, in the investigator's judgement, classifythe patient as ineligible for participation in this study.