A Phase IIa Study Evaluating Injectable ALK-N001 in Patients With Advanced Gastrointestinal Tumors

Inclusion Criteria:

1. Voluntarily sign informed consent, understand the study and be willing and able to comply with all study procedures.
2. Age ≥18 years (male or female) at the time of signing informed consent.
3. Histologically or cytologically confirmed locally advanced or metastatic esophageal squamous cell carcinoma, colorectal adenocarcinoma, or other gastrointestinal tumors.

4. Disease progression or intolerance after prior standard-of-care (SoC) treatment:

   1. Cohort1 (ESCC): Not eligible for curative surgery/radiochemotherapy; progressed or intolerant after at least 1st-line platinum-based chemotherapy plus PD-(L)1 inhibitor. If immunotherapy is declined/ineligible, progressed after ≥2 lines of systemic therapy.
   2. Cohort2 (CRC): Received standard systemic therapy for metastatic colorectal cancer and experienced progression or intolerance. Must have received fluoropyrimidine, oxaliplatin and irinotecan-based chemotherapy (±bevacizumab/cetuximab), unless contraindicated. For MSI-H/dMMR tumors, prior PD-(L)1 inhibitor is required.
   3. Cohort3 (Other GI tumors): Not curable by surgery; disease progression/intolerance after standard-of-care therapy, or no available effective treatment.
5. At least one measurable lesion per RECIST V1.1 (lesions in prior radiation field generally not measurable unless clear progression).
6. ECOG performance status 0 or 1.
7. Expected survival ≥3 months.

8. Adequate organ function:

   • Bone marrow (no transfusion/growth factors within prior 14 days): ANC ≥1.5×10⁹/L; PLT ≥90×10⁹/L; Hb ≥90 g/L
   • Liver: TBIL ≤1.5×ULN; ALT ≤3×ULN (≤5×ULN for liver metastasis); AST ≤3×ULN (≤5×ULN for liver metastasis); ALB ≥35 g/L
   • Renal: Cr ≤1.5×ULN; if Cr>1.5×ULN, CrCl ≥50 mL/min (Cockcroft-Gault formula)
   • Coagulation: APTT ≤1.5×ULN; INR ≤1.5×ULN
9. Women of childbearing potential must have negative pregnancy test at screening and agree to effective contraception or abstinence from consent until 6 months after last dose. Male participants must use effective contraception or abstinence from consent until 6 months after last dose; no sperm donation.

Exclusion Criteria:

• 1. Received chemotherapy, radiotherapy (palliative local radiotherapy within prior 2 weeks), biotherapy, targeted therapy, immunotherapy, TIL or other anti-tumor therapies within 4 weeks before first dose.

  1. Anti-endocrine therapy within 2 weeks or 5 half-lives; oral CDK4/6i, small molecule targeted agents, anti-tumor Chinese medicine.
  2. CAR-T, CAR-NK or tumor vaccine within prior 3 months.
  3. Live vaccine within 2 weeks; non-live vaccine within 4 weeks before first dose.

  4. Investigational drug within 4 weeks or 5 half-lives before first dose (whichever shorter).

     2. Use of strong CYP3A4 inducer/inhibitor within 7 days before first dose or planned during study.

     3. Prior treatment with DXD-containing ADC or PDC. 4. Active infection at screening requiring systemic anti-infective therapy within 2 weeks prior to first dose.

     5. Known BRAF mutation or NTRK fusion positive colorectal cancer (Cohort2). 6. Unstable or progressive CNS/leptomeningeal metastases (stable brain metastases ≥1 month, no new/enlarging lesions and off steroids ≥4 weeks may enroll).

     7. Clinically uncontrolled third-space effusion requiring therapeutic paracentesis/drainage within prior 14 days.

     8. Prior or current interstitial lung disease (ILD), non-infectious pneumonitis requiring steroids, suspected ILD or severely impaired pulmonary function.

     9. Severe GI disease including chronic inflammatory bowel disease, bowel obstruction or chronic diarrhea.

     10. Esophageal stent placement, tracheal stent or esophageal stricture (Cohort1).

     11. Severe cardiovascular disease:

  1. Clinically significant cardiac arrhythmias or 2nd/3rd degree AV block requiring intervention.
  2. Acute coronary syndrome, heart failure, stroke or grade ≥3 cardiovascular event within 6 months.
  3. NYHA Class ≥II heart failure (exception: stable NYHA II, LVEF≥50%, no exacerbation ≥6 months after optimized medical treatment, confirmed by cardiologist).

  4. Uncontrolled hypertension: SBP≥150 mmHg and/or DBP≥100 mmHg. 12. History of GI perforation/fistula within 6 months before first dose, or tumor invading adjacent organs (great vessel/trachea) with high risk of bleeding/fistula.

     13. History of severe thromboembolism within prior 6 months; known inherited/acquired thrombophilia.

     14. Other malignancy within past 5 years (exception: cured cervical carcinoma in situ, cutaneous squamous cell carcinoma, basal cell carcinoma, papillary thyroid carcinoma).

     15. Prior allogeneic hematopoietic stem cell or solid organ transplantation. 16. Prior anti-tumor adverse events not recovered to ≤ Grade1 (NCI-CTCAE v6.0, alopecia and investigator-assessed non-risk toxicities excluded) or not meeting eligibility lab criteria.