A Study of LM-168 Combined With Other Anti-tumor Treatments in Participants With Advanced Solid Tumors

A Phase II，Open Label,Multicenter Study to Evaluate the Efficacy,Safety,and Tolerability of LM-168 Combined With Other Anti-tumor Therapies in Participants With Advanced Solid Tumor Trials

For Safety introduction phase，this study is to evaluate the safety and tolerability of LM-168 in combination with other anti-tumor treatment regimens in participants of advanced solid tumor trials, determine the maximum tolerated dose (MTD), and explore the recommended phase II dose (RP2D).

For Dose expansion phase，this study is to evaluate the preliminary antitumor activity of LM-168 in combination with other antitumor treatment regimens in participants of advanced solid tumor trials, measured by objective response rate (ORR)

Inclusion Criteria:

• Participants who are fully informed of the purpose, nature, method and possible adverse reactions of the study, and are willing to participate in the study and sign the informed consent document prior to any procedure.
• Aged ≥18 years old, male or female when sign the Informed consent form (ICF).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no deterioration within 2 weeks prior to the first dose.
• Life expectancy ≥ 3 months.
• In dose escalation stage, participants must have histological or cytological confirmation of recurrent or refractory advanced solid tumours, and have progressed on standard therapy, or are intolerable for available standard therapy, or there is no available standard therapy.
• In dose expansion stage, participants must have histological or cytological confirmation of selected advanced solid tumors.
• Pre-treatment archived tumour tissue (within 5 years) or on treatment could be provided for biomarker analysis optionally.
• At least one measurable disease for expansion cohorts per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.
• Participants must show appropriate organ and marrow function in laboratory examinations within 7 days prior to the first dose.
• Participants who are able to communicate well with investigators and understand and adhere to the requirements of this study

Exclusion Criteria:

• Received any other investigational product or treatment within 28 days prior to the first dose of LM-168.

• Received anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agents, any other immunotherapy or oncology immune-oncology (IO) drugs within 28 days prior to the first dose of LM-168; or permanently discontinued prior immunotherapy due to immune-related adverse events (irAEs). All adverse events (AEs) from previous anti-tumor treatments have not fully resolved or resolved to Grade 1 prior to screening. Requirement for additional immunosuppressants (other than low-dose corticosteroids) to control irAEs.

• Received other anti-tumor treatments prior to the first dose of LM-168, as specified below:

  1. Received limited-field palliative radiotherapy within 14 days prior to the first dose (excluding radiotherapy solely for pain control of bone metastases).
  2. Received chemotherapy, small-molecule targeted agents (e.g., tyrosine kinase inhibitors) or hormonal therapies within 14 days prior to the first dose or within 5 half-lives of the respective agent (whichever is longer).
  3. Received biologic therapy or immunotherapy within 28 days prior to the first dose or within 5 half-lives of the respective agent (whichever is shorter).
  4. Received traditional Chinese medicines with anti-tumor indications within 14 days prior to the first dose.
  5. Received nitrosoureas or mitomycin C within 42 days prior to the first dose.

• AEs from prior anti-tumor treatments have not recovered to Grade ≤ 1 per NCI CTCAE Version 6.0. Exceptions include: toxicities assessed by the Investigator to pose no safety risks (e.g., alopecia), long-term radiation-related toxicities with Grade ≤ 2, and hypothyroidism stabilized with hormonal replacement therapy.

• Uncontrolled tumor-related pain. Participants requiring analgesic treatment must have been on a stable analgesic dose prior to study entry.

• Known active brain metastases or leptomeningeal metastases.

• Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage.

• Esophageal or gastric varices requiring immediate clinical intervention, or a history of variceal bleeding; except for participants with stable conditions confirmed by endoscopic evaluation within 3 months prior to the first study drug administration.

• History of hepatic encephalopathy, hepatorenal syndrome, or cirrhosis classified as Child-Pugh Class B or higher.

• Tumor invasion into adjacent vital organs (e.g., aorta, heart, pericardium, superior vena cava, trachea, esophagus, etc.), or at risk of developing esophagotracheal fistula or esophagopleural fistula.

• Active or prior history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, chronic diarrhea).

• History of Grade ≥ 3 hypersensitivity reactions to monoclonal antibody-based therapies.

• Experienced Grade ≥ 3 irAEs during prior immunotherapy, or discontinued prior immunotherapy due to severe or life-threatening irAEs.

• Received systemic corticosteroids (prednisone equivalent > 10 mg daily) or other systemic immunosuppressive agents (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, anti-tumor necrosis factor agents) within 2 weeks prior to the first dose of LM-168. Topical, ophthalmic, intra-articular, intranasal and inhaled corticosteroids are permitted.

• Known history of autoimmune diseases, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, Guillain-Barré syndrome, multiple sclerosis and glomerulonephritis (see Appendix 3 for the complete list of autoimmune diseases). Exception: participants with autoimmune hypothyroidism maintained on a stable dose of thyroid replacement hormones.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonia, interstitial lung disease or severe radiation pneumonitis; or evidence of active pneumonia on chest CT scan during the screening period.

• Received any live vaccine within 28 days prior to the first dose.

• Underwent major surgery or interventional procedures within 28 days prior to the first dose of LM-168 (excluding tumor biopsy, puncture and other minor procedures).

• Severe cardiovascular and cerebrovascular diseases,

• Uncontrolled or severe concomitant diseases, including ongoing or active infections (e.g., active COVID-19/SARS-CoV-2 infection, syphilis) requiring therapeutic antibiotics and/or other medications. SARS-CoV-2 testing is not mandatory for study enrollment but shall comply with local clinical practice guidelines and standards.

• History of immunodeficiency disorders, including other acquired or congenital immunodeficiencies; or history of solid organ transplantation, allogeneic bone marrow transplantation or autologous hematopoietic stem cell transplantation.

• Human Immunodeficiency Virus (HIV) infection, or active hepatitis infection (including tuberculosis, Hepatitis B Virus [HBV] and Hepatitis C Virus [HCV] infection),

• History of other malignancies within 5 years prior to the first study drug administration. Exceptions include cured cutaneous squamous cell carcinoma, basal cell carcinoma, non-muscle invasive bladder cancer, localized low-risk prostate cancer (defined as Stage ≤ T2a, Gleason score ≤ 6, curatively treated at diagnosis with no biochemical recurrence of prostate-specific antigen [PSA; PSA ≤ 10 ng/mL if tested]), carcinoma in situ of cervix or breast, and other malignancies deemed appropriate for study participation by the Investigator.

• Females of childbearing potential with a positive pregnancy test or who are breastfeeding.

• Psychiatric illnesses or disorders that may interfere with study compliance.

• Any other conditions that render the participants unsuitable for study participation, as determined by the Investigator.

Exclusion Criteria for the Combination cohort with Docetaxel

1. Prior exposure to taxane-based therapies.
2. Received strong CYP3A4 inhibitors or strong CYP3A4 inducers within 14 days prior to the first dose (see Appendix 5).