AMT-116 in Combination With Ivosidan in Patients With Lung Cancer

Key Inclusion Criteria:

• Willing and able to provide written informed consent for this trial.
• At the time of screening, aged ≥18 years and ≤75 years.
• Histologically or cytologically confirmed locally advanced (Stage IIIB/III C) or metastatic (Stage IV) NSCLC that is not amenable to complete surgical resection and cannot be treated with curative concurrent or sequential chemoradiotherapy (according to the 8th edition of the International Union Against Cancer and the American Joint Committee on Cancer TNM staging for lung cancer).
• Stage Ib: Locally advanced/metastatic NSCLC; both subjects who have previously received systemic therapy and those who have not may be enrolled;

Phase II: Each cohort must meet the following requirements:

Cohort 1: Histologically or cytologically diagnosed with non-squamous NSCLC, EGFR wild-type, and ALK fusion-negative.

Co-hort 2: Histologically or cytologically diagnosed with squamous-cell NSCLC, known to be EGFR wild-type and ALK fusion gene-negative.

Co-hort 3: Histologically or cytologically diagnosed with non-squamous NSCLC and harboring an EGFR mutation.

• Subjects must have at least one measurable lesion (as defined by RECIST 1.1 criteria).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Expected survival of ≥12 weeks.
• Subjects' laboratory test results must meet the requirements.
• Women of child-bearing potential (WCBP) must consent to the use of two effective contraceptive methods during the study treatment period and for at least 12 weeks after the final administration of IMP
• Women of child-bearing potential (WCBP) must have a negative serum pregnancy test within seven days preceding the initial administration of the investigational medicinal product (IMP).
• Male patients must agree to use a latex condom, even if they had a successful vasectomy, while on study treatment and for at least 12 weeks after the last dose of the IMP.
• Male patients must agree not to donate sperm, and female patients must agree not to donate eggs, while on study treatment and for at least 12 weeks after the last dose of the IMP.

Key Exclusion Criteria:

• Histopathological evidence of small cell lung cancer.
• For Cohort 1 and Cohort 2 of Phase II, patients must not have non-small cell lung cancer with known EGFR-sensitive mutations, ALK fusions, BRAF V600E mutations, ROS1 fusions, MET exon 14 skipping mutations, NTRK fusions, or RET fusions.
• Prior treatment with any CD44v9-targeted therapy or an antibody-drug conjugate (ADC) based on a topoisomerase I inhibitor as the toxin.
• Received the following treatments or medications prior to the start of the study:

i. Systemic anticancer therapy, including chemotherapy and biologics, within 3 weeks prior to the first dose; hormonal anticancer therapy or small-molecule targeted therapy within 2 weeks prior to the first dose; or Chinese herbal medicines or proprietary Chinese herbal preparations with anticancer indications within 2 weeks prior to the first dose. Received nonspecific immunomodulatory therapy (e.g., interleukins, interferons, thymosin, tumor necrosis factor, etc.) within 2 weeks prior to the first dose.

ii. Received a live or attenuated vaccine within 4 weeks prior to the first dose.

iii. Received radiation therapy within 3 weeks prior to the first dose. Palliative radiation therapy administered for symptom control at least 2 weeks prior to the first dose is permitted.

• Received systemic immunosuppressive therapy (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to the first dose.
• Adverse reactions from prior treatment have not yet resolved to Grade 1 or less.
• Subjects who have experienced an immune-related adverse event (irAE) requiring permanent discontinuation of treatment, or a Grade 3 or higher irAE, or a cardiac, neurological, or ocular irAE of any grade (including Grade 2 immune-related pneumonia, but excluding Grade 3 hypothyroidism that can be controlled with hormone replacement therapy).
• Known symptomatic brain metastases or other central nervous system (CNS) metastases, or brain metastases or other CNS metastases that the investigator deems to require treatment but have not been treated. Subjects with asymptomatic brain metastases or a history of brain metastases that have been stable for ≥2 weeks prior to the first dose may be eligible for this study, provided they meet all of the following criteria: no metastases to the meninges, midbrain, pons, cerebellum, medulla oblongata, or spinal cord, or spinal cord compression; discontinuation of hormonal therapy for more than 2 weeks prior to the first dose; imaging studies performed within at least 4 weeks show no evidence of new or enlarged brain metastases.
• History of malignancy other than the enrollment diagnosis within 5 years prior to the first administration of the study drug.
• Underwent major surgery within 4 weeks prior to the first administration of the study drug, or has not fully recovered from surgery; or sustained a major traumatic injury within 4 weeks prior to the first administration; or is scheduled to undergo surgery during the anticipated duration of study participation or within 4 weeks after the last administration.
• History of interstitial lung disease (ILD) or non-infectious pneumonia requiring steroid therapy; current ILD/pneumonia; suspected ILD/pneumonia (e.g., idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonia, idiopathic pneumonia, etc.); or other pulmonary diseases that significantly impair lung function at baseline.
• History of active autoimmune disease or a history of autoimmune disease requiring systemic treatment within the past 2 years.
• Current or past history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or chronic diarrhea).
• History of hypertensive crisis or hypertensive encephalopathy.
• Subjects with severe coagulation disorders or other evidence of significant bleeding risk.
• Uncontrolled pleural effusion or ascites requiring repeated drainage within 4 weeks prior to the first dose.
• Active infection treated with systemic antimicrobial therapy within 2 weeks prior to the first dose. Severe infection occurring within 4 weeks prior to the first dose, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia.
• History of abdominal fistula, tracheoesophageal fistula, or female genital fistula (e.g., vesicovaginal fistula, ureterovaginal fistula, and vesicovaginal fistula), gastrointestinal perforation, or abdominal abscess; or if the investigator considers the subject to have risk factors for gastrointestinal obstruction. If the fistula or perforation has been treated by resection or repair, and the investigator assesses that the condition has fully resolved, the subject may be enrolled.
• The subject has uncontrolled comorbidities, including but not limited to poorly controlled hypertension or diabetes, psychiatric disorders, or conditions that may limit study compliance, or other comorbidities or conditions that the investigator believes may affect study judgment or interfere with the completion of study procedures and follow-up examinations.
• Known immunosuppressive disease or human immunodeficiency virus (HIV) infection.
• Patients who are positive for hepatitis B surface antigen (HBsAg) and/or hepatitis C virus (HCV) antibodies at screening are ineligible for enrollment, unless hepatitis B virus (HBV) DNA levels and HCV RNA testing clearly rule out active infection requiring antiviral treatment for hepatitis B or C (HBV DNA ≥ 1000 cps/mL or 200 IU/mL).
• Known active tuberculosis (TB); suspected active tuberculosis must be ruled out by clinical examination.
• History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation, excluding corneal transplantation.
• Known immediate-type or delayed-type hypersensitivity to the study drug, a history of allergic reactions, or allergy to any component of the study drug or excipients.
• Pregnancy (positive β-human chorionic gonadotropin [β-hCG] test) and lactating women.
• The subject is unwilling or unable to comply with the protocol.
• The subject requires the use of a potent CYP3A4 inhibitor within one week prior to dosing or during the study.
• Any other disease, metabolic disorder, physical examination findings, or clinical laboratory results that raise suspicion of contraindications to the study drug, or that may affect the subject's safety, the interpretation of study results, or place the subject at high risk of complications.

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