A First-in-Human Study of ALK-N001 for Injection in Patients With Advanced Solid Tumors

• Subjects meeting all of the following criteria may be enrolled in this study:

  1. Voluntarily sign the informed consent form, understand the study, agree to comply with, and be capable of completing all trial procedures;
  2. Male or female aged 18 years or older;
  3. Unresectable and/or metastatic advanced solid tumor confirmed histologically and/or cytologically;
  4. Dose escalation + rollover phase (Phase Ia): Patients with advanced solid tumors who have failed standard treatment, have no available standard treatment, or are intolerant to standard treatment (esophageal squamous cell carcinoma, small cell lung cancer, and gastric/gastroesophageal junction adenocarcinoma are prioritized); Cohort expansion phase (Phase Ib/II): Divided into 4 cohorts: ① Esophageal squamous cell carcinoma cohort: Failed at least one line of standard treatment; ② Small cell lung cancer cohort: Failed at least one line of standard treatment; ③ Gastric/gastroesophageal junction adenocarcinoma cohort: Failed at least one line of standard treatment; ④ Other solid tumor cohort (the Sponsor and Investigator will jointly decide whether to initiate Cohort 4 and which indications to enroll based on the safety, pharmacokinetics, and efficacy results of the investigational product). Documented radiologically confirmed disease progression after the last anti-tumor therapy;
  5. At least one measurable tumor lesion according to RECIST version 1.1 (lesions in previously irradiated or other locally treated areas are generally not considered measurable unless clear progression is observed);
  6. ECOG performance status 0-1;
  7. Life expectancy ≥ 3 months;

  8. Adequate organ function meeting the following criteria:

     **Hematologic system (no blood transfusion or hematopoietic growth factor therapy within 14 days)** Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L Platelet count (PLT) ≥ 90 × 10⁹/L Hemoglobin (Hb) ≥ 90 g/L **Hepatic function** Total bilirubin (TBIL) ≤ 1.5 × ULN Alanine aminotransferase (ALT) ≤ 3 × ULN;

     • 5 × ULN for patients with liver metastasis or hepatocellular carcinoma Aspartate aminotransferase (AST) ≤ 3 × ULN;
     • 5 × ULN for patients with liver metastasis or hepatocellular carcinoma **Renal function** Creatinine (Cr) ≤ 1.5 × ULN Creatinine clearance (Ccr) (calculated only if Cr > 1.5 × ULN) ≥ 50 mL/min (calculated using the Cockcroft-Gault formula) **Coagulation function** Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN International normalized ratio (INR) ≤ 1.5 × ULN
  9. Males and females of childbearing potential must agree to use non-pharmacological contraceptive measures from signing the informed consent form until 6 months after the last dose of study drug.

Exclusion Criteria:

- Subjects meeting **any** of the following criteria are **ineligible** for enrollment in this study:

1. Received chemotherapy, radiotherapy (local bone radiotherapy within 2 weeks), biotherapy, macromolecular targeted therapy, immunotherapy, TIL cell therapy, or other anti-tumor treatments within **4 weeks** prior to the first dose of study drug, **except**:

   • Received anti-cancer endocrine therapy (excluding GnRH agonists or antagonists, endocrine replacement therapy, or contraceptives), oral fluoropyrimidines, small-molecule targeted drugs, and traditional Chinese medicine with anti-tumor indications within **2 weeks or 5 half-lives** (whichever is longer) prior to the first study drug dose;
   • Received CAR-T, CAR-NK cell therapy, or tumor vaccine therapy within **3 months** prior to study drug administration;
   • Received inactivated viral vaccine within **2 weeks** or non-inactivated viral vaccine within **4 weeks** prior to study drug administration;
   • Received other uninvestigational investigational medicinal products within **4 weeks or 5 half-lives** (whichever is shorter) prior to study drug administration.
2. Used **strong CYP3A4 inducers or strong inhibitors** within 7 days before the first dose, or requires such agents during the study period.
3. Known **severe hypersensitivity** to any component of the investigational product (NCI-CTCAE v5.0 grade ≥ 3).

4. Presence of **central nervous system (CNS) metastases and/or leptomeningeal metastases**.

   Subjects with treated brain metastases may be enrolled if lesions are stable for at least 1 month with no new or enlarging lesions, and steroid therapy has been discontinued for **2 weeks** before the first dose.

5. Diagnosis of **another malignancy within 5 years** prior to enrollment, **except** cured carcinoma in situ of the cervix, squamous cell carcinoma of the skin, basal cell carcinoma, or papillary thyroid carcinoma.
6. Clinically **uncontrolled third-space fluid effusion** deemed inappropriate by the investigator.
7. History of severe gastrointestinal disorders including chronic inflammatory bowel disease, intestinal obstruction, or chronic diarrhea.

8. Severe cardiovascular disease, including but not limited to:

   1. Severe cardiac rhythm or conduction abnormalities requiring clinical intervention (e.g., ventricular arrhythmia, 2nd-3rd degree atrioventricular block);
   2. Acute coronary syndrome, congestive heart failure, stroke, or other cardiovascular events of **grade ≥3** within 6 months prior to first dose;
   3. New York Heart Association (NYHA) functional class **≥ II**, left ventricular ejection fraction (LVEF) \< 50%, or other structural heart disease at high risk as judged by the investigator;

   4. QTcF > 450 ms (males), > 470 ms (females) on ECG (calculated by Fridericia formula: QTcF = QT/(RR\^0.33)).

      *Note: If initial screening is abnormal, repeat twice within 48 hours; eligibility determined by the mean of three measurements.*

   5. Clinically uncontrolled hypertension (systolic BP ≥ 150 mmHg and/or diastolic BP ≥ 100 mmHg despite intervention);
   6. Poorly controlled diabetes defined as **HbA1c ≥ 8.0%**.
9. **Active infection** at screening, or systemic anti-infective treatment within 2 weeks before first dose (excluding biopsy prophylaxis and urological surgery prophylaxis).

10. Active hepatitis B (HBsAg positive and HBV-DNA > 500 IU/ml or above the local laboratory lower limit [if local LL > 500 IU/ml]); active hepatitis C (HCV antibody positive, but patients with HCV-RNA below local LL are eligible). Patients receiving prophylactic antiviral therapy **other than interferon** are allowed.

    Active syphilis or **positive HIV screening**.

11. Severe pulmonary disease (e.g., pulmonary embolism, interstitial lung disease) within **6 months** prior to first dose.

12. History of deep vein thrombosis or any **severe thromboembolism** within 6 months before first dose (implanted venous port/catheter-related thrombosis, superficial venous thrombosis, or lacunar infarction are **not** considered severe).

    Known familial and/or acquired thrombophilia (hereditary or acquired defects in anticoagulant proteins, coagulation factors, fibrinolytic proteins, or high thrombotic risk due to acquired risk factors).

13. Active hemorrhagic disease or bleeding history of **grade ≥3** within 4 weeks before first dose; high bleeding risk due to tumor invasion of large arteries.
14. Toxicity from prior anti-tumor therapy **not recovered to grade ≤1** (per NCI-CTCAE v5.0; exceptions include alopecia or other toxicities deemed safe by the investigator) or the level specified in inclusion criteria.
15. Receiving thrombolytic or anticoagulant therapy (**excluding prophylactic anticoagulation**).
16. History of allogeneic hematopoietic stem cell transplantation or organ transplantation.
17. History of psychiatric disorders (including epilepsy, dementia, etc.).
18. History of **substance abuse**, or any medical, psychological, or social condition that may interfere with study participation or outcome assessment.
19. Female subjects who are **breastfeeding** or have a positive blood/urine pregnancy test during screening.

Any other condition (medical, psychological, geographic, etc.) that prevents compliance with study and follow-up procedures, or any other situation in which the investigator deems the subject **unsuitable** for enrollment.