Overview

This is a prospective multicenter, open-label, Phase I clinical study designed to evaluate the safety, tolerability, and preliminary efficacy of propranolol hydrochloride in combination with adebrelimab and platinum-based chemotherapy in patients with small cell lung cancer (SCLC).The study includes two cohorts: patients with previously untreated extensive-stage SCLC and patients with resectable early-stage (T1-2N0M0) SCLC. Propranolol hydrochloride is a beta- adrenergic blocking agent which is associated with augment of immune cell responses. Propranolol hydrochloride may improve the responses of immune checkpoint inhibitors in treating patients with SCLC.

Eligibility

Inclusion Criteria:

1. Written informed consent must be obtained prior to any study-related procedures
2. Age ≥18 years and ≤75 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1
4. Life expectancy ≥12 weeks.
5. Histologically or cytologically confirmed extensive-stage (ES) SCLC or T1-2N0M0 stage SCLC patients(9th UICC/AJCC TNM staging). Extensive-stage patients not amenable to local therapy include both recurrent and treatment-naïve patients not suitable for local treatment (surgery and definitive concurrent chemoradiotherapy), who have not previously received systemic therapy for advanced/metastatic disease.
6. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Lesions located within prior radiation fields may be considered measurable if progression has been documented (within 28 days prior to first treatment).
7. Asymptomatic or symptomatic brain metastases that have been locally treated and are stable are allowed in ES-SCLC cohort, provided the subject meets the following conditions: Measurable disease outside the central nervous system (CNS) No CNS symptoms, or symptoms stable for at least 2 weeks No corticosteroid treatment required, or corticosteroids discontinued at least 7 days prior to first dose, or stable corticosteroid dose at ≤10 mg/day prednisone (or equivalent) for at least 7 days prior to first dose
8. Laboratory Parameters (within 14 days prior to first treatment) Hematologic: Absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count ≥100×10⁹/L; hemoglobin ≥9.0 g/dL (without transfusion or erythropoietin administration within 7 days). Hepatic: Total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (in absence of hepatic metastases). For patients with hepatic metastases: ALT or AST ≤5×ULN. Renal: Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance ≥60 mL/min (by Cockcroft-Gault formula), and urinalysis showing urine protein (UPRO) \<2+ or 24-hour urine protein \<1 g. Coagulation: Within 7 days prior to study treatment: International normalized ratio (INR) ≤1.5×ULN or prothrombin time (PT) ≤1.5×ULN; if subject is receiving anticoagulant therapy, PT within the intended therapeutic range of the anticoagulant is acceptable.
9. New York Heart Association (NYHA) Class \<3; left ventricular ejection fraction (LVEF) ≥50%; baseline electrocardiogram (ECG) showing no PR interval prolongation or atrioventricular block.
10. For women of childbearing potential (WOCBP), a negative urine or serum pregnancy test must be obtained within 3 days prior to first study drug administration (Cycle 1 Day 1). If urine pregnancy test results cannot be confirmed as negative, a serum pregnancy test is required. Non-childbearing potential is defined as postmenopausal for at least 1 year, or surgically sterile (bilateral oophorectomy, hysterectomy, or tubal ligation). All subjects (male and female) with reproductive potential must use highly effective contraception (failure rate \<1% per year) throughout the treatment period and for 120 days (or 180 days) after the last dose of study drug.

Exclusion Criteria:

1. Concurrent participation in another interventional clinical study or receiving other investigational drugs, unless participating in an observational clinical study.
2. Prior exposure to any anti-PD-1 or anti-PD-L1, PD-L2, CD137, CTLA-4 antibody therapy, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
3. Systemic treatment with Chinese patent medicines with anti-tumor indications or immunomodulatory drugs (including thymosin, interferon, and interleukins; except for local administration to control pleural effusion or ascites) within 2 weeks prior to first dose.
4. Current use of oral or intravenous beta-blockers (e.g., atenolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, sotalol, etc.) that cannot be safely switched to non-beta-blocker alternatives. Current subjects should have a washout period of at least 14 days with adequate transition period.
5. Contraindications to Beta-Blocker Use Hypersensitivity to any component of this product Bronchial asthma or risk of bronchospasm Ketoacidosis and metabolic acidosis Severe or symptomatic bradycardia, atrioventricular block (Grade II or III), sinoatrial block, sick sinus syndrome Cardiogenic shock Right heart dysfunction caused by pulmonary hypertension Congestive heart failure (NYHA Class III or IV) Hypotension (systolic blood pressure \<100 mmHg) Prolonged fasting state Severe peripheral circulatory failure (e.g., gangrene) Symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma Unstable angina or Prinzmetal's angina Concurrent use of rizatriptan benzoate Severe chronic obstructive pulmonary disease (COPD) Uncontrolled Type I or Type II diabetes mellitus (glycated hemoglobin \[HbA1C\] \>8.5 or fasting glucose \>160 mg/dL at screening)
6. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh Class B or more severe cirrhosis.
7. Malignant bowel obstruction (within 3 months prior to informed consent signing) or history of the following conditions: inflammatory bowel disease or extensive intestinal resection (partial colectomy or extensive small bowel resection with concurrent chronic diarrhea), Crohn's disease, or ulcerative colitis.
8. Completion of palliative radiotherapy within 7 days prior to first study drug administration.
9. Clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction.
10. History of psychoactive drug abuse or drug addiction.
11. Known hypersensitivity to active ingredients or excipients of the study drug.
12. Known history of primary immunodeficiency, or ongoing systemic corticosteroid therapy or any other form of immunosuppressive therapy.
13. Use of immunosuppressive drugs within 4 weeks prior to first study treatment, excluding intranasal, inhaled, or other routes of topical corticosteroids, or physiological doses of systemic corticosteroids (i.e., not exceeding 10 mg/day prednisone or equivalent dose of other corticosteroids), or corticosteroids used for prevention of contrast agent allergy.
14. Failure to recover adequately (i.e., to Grade ≤1 or baseline, excluding fatigue or alopecia) from any intervention-induced toxicities and/or complications prior to starting treatment.
15. Receipt of live attenuated vaccines within 4 weeks prior to first study treatment or planned vaccination during the study (inactivated influenza vaccine for seasonal influenza is allowed within 4 weeks prior to first dose; however, live attenuated influenza vaccine is not permitted).
16. Major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to first study treatment, or expectation of requiring major surgery during study treatment; laparoscopic exploratory surgery within 2 weeks prior to first study treatment.
17. Known symptomatic central nervous system metastases and/or carcinomatous meningitis. Exception may be made for subjects with previously treated brain metastases if the subject's condition is stable (no evidence of radiographic progression for at least 4 weeks prior to first dose of trial treatment, confirmed by repeat imaging showing no new brain metastases or enlargement of existing brain metastases), and no corticosteroid treatment is required for at least 14 days prior to first dose of trial treatment. This exception does not include carcinomatous meningitis, which should be excluded regardless of clinical stability.
18. Clinically uncontrolled pleural effusion or ascites (subjects who do not require drainage of effusion or in whom effusion does not significantly increase 3 days after stopping drainage may be enrolled).
19. Bone metastases with risk of paraplegia.
20. Known or suspected autoimmune disease or history of such disease within the past 2 years (subjects with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment within the past 2 years, hypothyroidism requiring only thyroid hormone replacement therapy, and Type 1 diabetes mellitus requiring only insulin replacement therapy may be enrolled).
21. Known active tuberculosis.
22. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
23. Known history of human immunodeficiency virus (HIV) infection (i.e., HIV antibody positive).
24. Known acute or chronic active hepatitis B virus (HBsAg positive with HBV DNA viral load ≥200 IU/mL or ≥10³ copies/mL) or acute or chronic active hepatitis C virus (HCV antibody positive with HCV RNA positive).
25. Active syphilis infection requiring treatment.
26. Interstitial lung disease requiring corticosteroid therapy.
27. Active or poorly controlled severe infection.
28. Severe cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism); angina requiring treatment; symptomatic peripheral vascular disease; NYHA Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite antihypertensive treatment.
29. History of other primary malignancies within 5 years, except for: Malignancies in complete remission for at least 2 years prior to enrollment with no other treatment required during the study Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence Adequately treated carcinoma in situ with no evidence of disease recurrence
30. Pregnant or lactating female patients.
31. Other acute or chronic medical conditions, psychiatric conditions, or laboratory abnormalities that may: increase the risk associated with study participation or study drug administration, or interfere with the interpretation of study results, and which, in the judgment of the investigator, render the patient ineligible for participation in this study.