Phase II Neoadjuvant Study of Garsorasib Followed by Ivonescimab Plus Chemotherapy in Resectable Stage IIA-IIIB KRAS G12C-Mutant NSCLC (GIVEN Study)

Exclusion Criteria

• •1. Prior Anti-Tumor Therapy:
• •1. Previous receipt of any anti-tumor therapy for lung cancer (including adjuvant chemoradiotherapy, neoadjuvant chemoradiotherapy, chemotherapy, radiotherapy, immune checkpoint inhibitors, targeted therapy, anti-angiogenic therapy, etc.).
• •2. Treatment with any other investigational drug within 28 days prior to the first dose in this study.
• •3. Treatment within 2 weeks prior to the first dose with NMPA-approved Chinese patent medicines explicitly indicated for anti-tumor purposes in their drug说明书 (e.g., Compound Banmao Capsules, Kang'ai Injection, Kanglaite Capsules/Injection, Aidi Injection, Yadanzi Oil Injection/Capsules, Xiaoaiping Tablets/Injection, Huachansu Capsules, etc.).
• •2. Recent Surgery: Any surgery within 4 weeks prior to screening examinations.
• •3. Concurrent Primary Malignancy: Patients with a concurrent primary malignancy (except for adequately treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, etc.).
• •4. Abnormal Organ Function: Meeting any of the following at screening:
• •1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 1.5 times the upper limit of normal (ULN).
• •2. Creatinine clearance rate (CrCl) \> ULN.
• •5. Hematological Abnormalities: Total white blood cell (WBC) count \> 10.0 × 10\^9/L or \< 1.0 × 10\^9/L at screening.
• •6. Significant Comorbidities: History of immunodeficiency diseases (e.g., HIV), other active cancers or malignancy history, autoimmune diseases, severe cardiovascular or cerebrovascular diseases, or any other diseases that may significantly reduce life expectancy.
• •7. Conditions Affecting Compliance: Any history of conditions that may affect protocol compliance (e.g., severe psychiatric disorders, cognitive dysfunction, drug abuse or addiction).
• •8. Pregnancy, Lactation, and Contraception: Pregnant or lactating women, or subjects of childbearing potential unwilling or unable to use effective contraception.
• •9. Allergy: Known allergy to any component of the study drug(s).
• •10. Recent Trial Participation: Participation in any drug clinical trial within 6 months prior to screening.
• •11. Investigator's Discretion: Any condition considered by the investigator as unsuitable for study participation.
• •12. Other Driver Mutations: Non-small cell lung cancer with other standard-therapy-eligible driver gene mutations (e.g., EGFR, ALK, BRAF V600E, HER-2, MET Exon 14, ROS1, RET, or NTRK1/2/3).
• •13. Central Nervous System (CNS) Metastases:
• •1. Symptomatic or progressive CNS metastases or carcinomatous meningitis.
• •2. Subjects with a history of brain metastases may be considered if they are clinically stable: no neurological symptoms, no corticosteroid treatment required, no indication for radiotherapy, and the largest diameter of the largest metastatic lesion on recent imaging is ≤ 1.5 cm.
• •3. Asymptomatic CNS metastases newly discovered during screening are allowed.
• •4. Subjects with a history of asymptomatic CNS metastases require confirmation of no progression via imaging scans performed at least 2 weeks apart.
• •5. Subjects with symptomatic CNS metastases may be considered if clinically stable after radiotherapy and/or surgery.
• •6. Subjects who underwent surgery for CNS metastases must have an interval of at least 4 weeks before the first study dose.
• •7. Asymptomatic subjects after CNS radiotherapy must have discontinued corticosteroids for at least 2 weeks prior to the first dose.
• •14. Cardiovascular Disease: Any of the following:
• •1. Congestive heart failure of New York Heart Association Class II or above.
• •2. Severe arrhythmia requiring medication.
• •3. Acute myocardial infarction, severe or unstable angina, coronary or peripheral artery bypass graft within 6 months prior to enrollment.
• •4. Left ventricular ejection fraction (LVEF) \< 50%.
• •5. Prolonged QTcF interval ( \> 470 ms for females, \> 450 ms for males) or risk factors for Torsades de Pointes.
• •6. Uncontrolled hypertension (systolic BP ≥ 150 mmHg and/or diastolic BP ≥ 100 mmHg after antihypertensive therapy).
• •15. Thromboembolic Events: Arterial/venous thrombotic events within 6 months, hypertensive crisis, or hypertensive encephalopathy.
• •16. History of Epilepsy: Previous history of epilepsy.
• •17. Superior Vena Cava Syndrome: Presence of superior vena cava syndrome.
• •18. Pulmonary Disease: Active non-infectious interstitial lung disease, radiation pneumonitis, etc., active tuberculosis, pneumoconiosis, ≥ Grade 2 other pneumonias, or severely impaired pulmonary function at screening.
• •19. Severe Bone Lesions: Existing or potential severe bone damage from metastases, or uncontrolled bone pain.
• •20. Active Infection: Active or uncontrolled severe infection, or unexplained fever \> 38.5°C.
• •21. Third-Space Fluid: Poorly controlled or drainage-requiring pleural effusion, ascites, or pericardial effusion. Subjects stabilized after treatment may be enrolled.
• •22. Tumor Invading Major Vessels: Imaging shows tumor invading or with unclear boundaries to major blood vessels.
• •23. Bleeding Risk: Evidence or history of bleeding tendency within 2 months before the first dose; history of hemoptysis, or unhealed wounds/ulcers/fractures within 2 weeks before the first dose.
• •24. Gastrointestinal Diseases: Known GI impairment or diseases significantly affecting drug absorption/metabolism, or major GI surgery affecting absorption.
• •25. Recent Live Vaccination: Administration of a live attenuated vaccine within 4 weeks before the first dose.
• •26. Severe Hypersensitivity to mAbs: History of severe hypersensitivity reaction to other monoclonal antibodies.
• •27. Autoimmune Disease: Active autoimmune disease requiring systemic treatment within 2 years before the first dose.
• •28. Immunosuppressive Therapy: Receiving systemic corticosteroids or other immunosuppressive therapy.
• •29. Viral Infections: Positive HIV antibody, or active viral hepatitis.
• •1. Active Hepatitis B or active Hepatitis C.
• •2. Carriers require antiviral therapy and monitoring during the study.
• •30. Active Syphilis.
• •31. Renal Failure: Requiring hemodialysis or peritoneal dialysis.
• •32. Poorly Controlled Diabetes: Fasting blood glucose \> 10 mmol/L.
• •33. Organ Transplant: History of or planned organ transplantation.
• •34. Recent Major Surgery/Trauma: Major surgery or significant trauma within 4 weeks before the first dose.
• •35. Recent Radiotherapy: Palliative radiotherapy within 2 weeks before the first dose.
• •36. Residual Toxicity from Prior Therapy: Toxicities from previous anti-cancer therapy not recovered to Grade ≤1.
• •37. Other: Any other clinically significant abnormality or disease deemed by the investigator to pose risk or interfere with the study.