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

Korábbi kezelés

• Prior Anti-Tumor Therapy:
  • 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.).
  • Treatment with any other investigational drug within 28 days prior to the first dose in this study.
  • 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.).
• Recent Surgery: Any surgery within 4 weeks prior to screening examinations.
• 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.).
• Recent Trial Participation: Participation in any drug clinical trial within 6 months prior to screening.
• Central Nervous System (CNS) Metastases:
  • Symptomatic or progressive CNS metastases or carcinomatous meningitis.
  • 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.
  • Asymptomatic CNS metastases newly discovered during screening are allowed.
  • Subjects with a history of asymptomatic CNS metastases require confirmation of no progression via imaging scans performed at least 2 weeks apart.
  • Subjects with symptomatic CNS metastases may be considered if clinically stable after radiotherapy and/or surgery.
  • Subjects who underwent surgery for CNS metastases must have an interval of at least 4 weeks before the first study dose.
  • Asymptomatic subjects after CNS radiotherapy must have discontinued corticosteroids for at least 2 weeks prior to the first dose.
• History of Epilepsy: Previous history of epilepsy.
• 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.
• Recent Live Vaccination: Administration of a live attenuated vaccine within 4 weeks before the first dose.
• Immunosuppressive Therapy: Receiving systemic corticosteroids or other immunosuppressive therapy.
• Recent Major Surgery/Trauma: Major surgery or significant trauma within 4 weeks before the first dose.
• Recent Radiotherapy: Palliative radiotherapy within 2 weeks before the first dose.
• Residual Toxicity from Prior Therapy: Toxicities from previous anti-cancer therapy not recovered to Grade ≤1.

Más betegség

• 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.
• Conditions Affecting Compliance: Any history of conditions that may affect protocol compliance (e.g., severe psychiatric disorders, cognitive dysfunction, drug abuse or addiction).
• Allergy: Known allergy to any component of the study drug(s).
• Investigator's Discretion: Any condition considered by the investigator as unsuitable for study participation.
• Superior Vena Cava Syndrome: Presence of superior vena cava syndrome.
• 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.
• Active Infection: Active or uncontrolled severe infection, or unexplained fever > 38.5°C.
• Gastrointestinal Diseases: Known GI impairment or diseases significantly affecting drug absorption/metabolism, or major GI surgery affecting absorption.
• Severe Hypersensitivity to mAbs: History of severe hypersensitivity reaction to other monoclonal antibodies.
• Autoimmune Disease: Active autoimmune disease requiring systemic treatment within 2 years before the first dose.
• Viral Infections: Positive HIV antibody, or active viral hepatitis.
  • Active Hepatitis B or active Hepatitis C.
  • Carriers require antiviral therapy and monitoring during the study.
• Renal Failure: Requiring hemodialysis or peritoneal dialysis.
• Organ Transplant: History of or planned organ transplantation.
• Other: Any other clinically significant abnormality or disease deemed by the investigator to pose risk or interfere with the study.

Laborértékek

• Abnormal Organ Function: Meeting any of the following at screening:
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 1.5 times the upper limit of normal (ULN).
  • Creatinine clearance rate (CrCl) > ULN.
• Hematological Abnormalities: Total white blood cell (WBC) count > 10.0 × 10\^9/L or < 1.0 × 10\^9/L at screening.
• 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).
• Cardiovascular Disease: Any of the following:
  • Congestive heart failure of New York Heart Association Class II or above.
  • Severe arrhythmia requiring medication.
  • Acute myocardial infarction, severe or unstable angina, coronary or peripheral artery bypass graft within 6 months prior to enrollment.
  • Left ventricular ejection fraction (LVEF) < 50%.
  • Prolonged QTcF interval ( > 470 ms for females, > 450 ms for males) or risk factors for Torsades de Pointes.
  • Uncontrolled hypertension (systolic BP ≥ 150 mmHg and/or diastolic BP ≥ 100 mmHg after antihypertensive therapy).
• Poorly Controlled Diabetes: Fasting blood glucose > 10 mmol/L.

Egyéb

• Pregnancy, Lactation, and Contraception: Pregnant or lactating women, or subjects of childbearing potential unwilling or unable to use effective contraception.
• Thromboembolic Events: Arterial/venous thrombotic events within 6 months, hypertensive crisis, or hypertensive encephalopathy.
• Severe Bone Lesions: Existing or potential severe bone damage from metastases, or uncontrolled bone pain.
• Third-Space Fluid: Poorly controlled or drainage-requiring pleural effusion, ascites, or pericardial effusion. Subjects stabilized after treatment may be enrolled.
• Tumor Invading Major Vessels: Imaging shows tumor invading or with unclear boundaries to major blood vessels.
• Active Syphilis.

• Age Range: Males or females aged 18 years or older.
• Diagnosis and Stage: Patients with histologically or cytologically confirmed resectable IB-IIIB NSCLC, staged according to the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology, 9th Edition.
• Informed Consent: Patients must voluntarily participate in the study, provide written informed consent, and be willing to comply with follow-up procedures.
• Prior Therapy: No prior systemic therapy for locally advanced or metastatic NSCLC (including adjuvant chemo/radiotherapy, neoadjuvant chemo/radiotherapy, definitive chemoradiotherapy, chemotherapy, radiotherapy, immune checkpoint inhibitors, targeted therapy, or anti-angiogenic therapy for locally advanced disease).
• Mutation Status: KRAS G12C mutation positivity must be confirmed by next-generation sequencing (NGS) or polymerase chain reaction (PCR) testing.
• Measurable Disease: At least one measurable target lesion as per RECIST v1.1. Lesions previously treated with radiotherapy or other local-regional therapies cannot be considered target lesions unless clear progression has been documented post-radiotherapy. At baseline, the lesion must be ≥10mm in the longest diameter (≥15mm in short axis for lymph nodes) on CT or MRI and be suitable for accurate repeated measurement per RECIST v1.1.
• Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Adequate Organ Function: Must meet the following criteria within 14 days prior to relevant tests, without transfusion or use of hematopoietic growth factors:
  • Platelets (PLT) ≥90 × 10\^9/L
  • Hemoglobin (HGB) ≥90 g/L
  • Absolute Neutrophil Count (ANC) ≥1.5 × 10\^9/L
  • Serum creatinine ≤1.5 × ULN or Creatinine Clearance (CrCl) ≥50 mL/min (calculated using the Cockcroft-Gault formula)
  • Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if liver metastases are present)
  • Total Bilirubin (TBIL) ≤1.5 × ULN (≤3 × ULN for patients with Gilbert's syndrome)
  • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN, and Activated Partial Thromboplastin Time (APTT) ≤1.5 × ULN, or patients assessed by the investigator as having controlled bleeding tendency.
  • Urinalysis showing urine protein <2+ or 24-hour urinary protein quantification <1g.
• Life Expectancy: Expected survival time ≥3 months.
• Contraception: Fertile female subjects must agree to use effective contraception (e.g., IUD, oral contraceptives, condoms) during the study and for 6 months after study completion; have a negative serum pregnancy test within 7 days before enrollment; and must not be breastfeeding. Male subjects must agree to use effective contraception during the study and for 6 months after study completion.