A Phase I Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of HLX3901 in Patients With Advanced SCLC or NEC

phase Ia is the dose escalation and backfill stage, accelerated titration and 3 + 3 dose escalation method will be adopted in the dose escalation stag, and the patients will be administered with HLX3901 at different doses via intravenous infusion. The DLT observation period lasts for 4 weeks after the first administration of HLX3901. The backfill cohort will enrolls 2 to 3 dose groups.

Part Ib is a dose-expansion study of HLX3901, designed to explore and confirm the efficacy and safety of HLX3901 monotherapy in advanced small-cell lung cancer or neuroendocrine carcinoma.The Safety Review Committee will recommend dose groups for expansion based on the safety, efficacy and PK data of the dose escalation phase.

Inclusion criteria

• Have a full understanding of the study content, process, and possible adverse reactions before the study, and sign the informed consent form (ICF); voluntarily participate in the study; be able to complete the study as per protocol requirements;
• Aged ≥ 18 years and ≤ 75 years at the time of signing the ICF, male or female;
• Histologically or cytologically confirmed advanced small cell lung cancer or neuroendocrine carcinoma; patients with advanced small cell lung cancer must have experienced intolerance, recurrence, or disease progression following prior treatment with a platinum-based therapy combined with immune checkpoint inhibitors, while patients with neuroendocrine carcinoma must have experienced intolerance, recurrence, or disease progression following prior platinum-based therapy; allowed histological subtypes include combined small cell lung cancer and mixed neuroendocrine-non-neuroendocrine neoplasms.
• At least one measurable lesion as per RECIST 1.1 within 4 weeks prior to the first administration;
• An ECOG performance status score of 0-1 within 7 days prior to the first administration;
• Expected survival > 3 months;
• The following conditions must be met in terms of the time of the first administration of the investigational product: at least 28 days from the previous major surgery, medical device treatment, locoregional radiotherapy (except for palliative radiotherapy for bone lesions), cytotoxic chemotherapy, immunotherapy, or biological product therapy; at least 14 days from the previous small molecule targeted drug therapy and previous hormone therapy; at least 7 days from the previous administration of the traditional Chinese medicine for anti-tumor indications or minor surgery; recovery of treatment-induced AEs to Grade ≤ 1 (CTCAE v6.0, except for alopecia);
• Participants who agree to provide archived tumor tissue specimens that meet the testing requirements (either from the most recent surgery or biopsy, preferably within 2 years) or agree to undergo a biopsy to collect tumor tissue for DLL3 expression testing; Note: Formalin-fixed paraffin-embedded (FFPE) tumor samples (paraffin blocks or unstained sections, which must meet the quality control criteria for testing) collected from non-radiotherapy sites during the most recent surgery or biopsy at or after the diagnosis of malignant tumor and pathological reports of such specimens shall also be provided.
• Adequate organ function as confirmed by laboratory tests within 7 days prior to the first administration of the investigational product, with no therapies such as blood transfusion, albumin infusion, renal replacement therapy, granulocyte colony-stimulating factor (G-CSF), thrombopoietin, or erythropoietin administered within 14 days prior to the first administration:
• Male and female participants with child-bearing potential must agree to use at least one highly effective contraception method during the study and within at least 6 months after the last dose of the investigational product; female participants of childbearing age must be negative for pregnancy test within 7 days prior to enrollment.

Exclusion criteria

• History of other malignant tumors within 2 years prior to the first administration, except cured cervical carcinoma in situ or cutaneous basal cell carcinoma;
• Presence of Grade ≥ 2 immune-related pneumonitis or immune-related myocarditis, or severe, life-threatening immune-mediated AEs or infusion-related reactions, including those leading to permanent discontinuation, when receiving previous anti-tumor immunotherapy;
• History or presence of clinically significant pulmonary impairment due to concurrent lung disease, including but not limited to any underlying lung disease (e.g., pulmonary embolism within 3 months prior to the first administration, severe asthma, severe chronic obstructive pulmonary disease, restrictive pulmonary disease, interstitial pneumonia, pneumoconiosis, drug-related pneumonitis, and pleural effusion), any autoimmune, connective tissue, or inflammatory disease that may involve the lungs (i.e., rheumatoid arthritis, Sicca syndrome, and sarcoidosis), prior pneumonectomy that may interfere with the detection and management of suspected drug-related pulmonary toxicity, or history of radiation pneumonitis within the past 6 months;
• With central nervous system diseases within 12 months prior to enrollment, such as seizures, cerebral hemorrhage, paralysis, aphasia, cerebral infarction (except for old cerebral infarction), severe brain injury, dementia, Parkinson's disease, cerebellar disease, mental illness, or any autoimmune disease involving the central nervous system;
• Active paraneoplastic syndrome;
• History of hypophysitis or pituitary dysfunction;
• Presence of uncontrolled third-space effusions (e.g., massive pleural effusion, ascites, or pericardial effusion) requiring repeated drainage and considered by the investigator to be unsuitable for enrollment;
• Prior allogeneic stem cell or solid organ transplantation;
• Prior exposure to any of the following: (1) combination or sequential therapy targeting DLL3, CD3, or CD28; (2) treatment with antibody-drug conjugates (ADCs); (3) major surgery, chemotherapy, biologic therapy, endocrine therapy, or macromolecular targeted therapy within 4 weeks prior to the first administration. Traditional Chinese medicine and small molecule targeted therapy with anti-tumor indications ≤ 2 weeks from the first administration of the investigational product;
• Known history of severe allergic reactions, anaphylactoid reactions, or other hypersensitivity reactions to humanized antibodies or fusion proteins, severe allergic reactions to macromolecular protein preparations/monoclonal antibodies, or allergy to components of the investigational product preparations;
• Active systemic infectious diseases requiring intravenous antibiotics within 2 weeks prior to the first administration of the investigational product;
• Any poorly-controlled cardiovascular and cerebrovascular clinical symptoms or diseases, including but not limited to: (1) NYHA Class II or greater heart failure or left ventricular ejection fraction (LVEF) < 50%; (2) unstable angina pectoris; (3) myocardial infarction or cerebrovascular accident within 6 months (except lacunar infarction, slight cerebral ischemia, or transient ischemic attack); (4) poorly controlled arrhythmia (including QTc intervals ≥ 450 ms for males and ≥ 470 ms for females) (QTc intervals are calculated by Fridericia's formula); (5) poorly-controlled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg after active treatment);
• Active central nervous system (CNS) metastases and/or carcinomatous meningitis known or diagnosed at screening. However, the following participants are allowed to be enrolled: 1) Patients with asymptomatic brain metastases (i.e., no progressive central nervous system symptoms caused by brain metastases, no requirement for corticosteroids, and lesion size ≤ 1.5 cm) may be included, but are required to receive regular brain imaging as a site of disease. 2) Participants with treated brain metastases that have been stable for at least 2 months (confirmed by 2 imaging assessments at least 4 weeks apart following brain metastasis treatment), with no evidence of new or enlarging brain metastases and discontinued steroids at least 3 days prior to administration (stable brain metastases here should be confirmed before the first administration of the investigational product).
• Patients with known active or suspected autoimmune diseases. Patients with autoimmune-related hypothyroidism who are receiving thyroid hormone replacement therapy and those with type 1 diabetes mellitus controlled with insulin therapy are eligible to be enrolled;
• Patients who have received systemic corticosteroids (prednisone > 10 mg/day or equivalent dose of a similar drug) or other immunosuppressive agents within 14 days prior to the first administration; Except: patients treated with topical, ocular, intra-articular, intranasal, and inhaled corticosteroids; those with short-term use of corticosteroids for prophylaxis if a contrast agent is used;
• Patients with active tuberculosis;
• Patients with a history of immunodeficiency, including human immunodeficiency virus (HIV)-positive or other acquired or congenital immunodeficiencies, or a history of organ transplantation;
• Patients with active HBV or HCV infection or HBV/HCV co-infection; Note: Patients who are HBsAg (+) and/or HBcAb (+) must undergo an HBV-DNA test and have a result < 500 IU/mL, < 2500 copies/mL, or < ULN to be enrolled. Enrolled participants with detectable HBV-DNA must consent to receive antiviral nucleoside/nucleotide therapy.

If HCV antibody (+), HCV-RNA must be tested, and the result must be < ULN for the participant to be eligible.

Participants with HBV/HCV co-infection shall be excluded (positive for HBsAg or HBcAb and positive for HCV antibody).

• Have received live vaccines within 28 days prior to the first administration;
• Pregnant or lactating women;
• Participants who are not suitable for participating in this clinical study due to any clinical or laboratory abnormalities or other reasons as assessed by the investigator.