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

Inclusion criteria

• Voluntarily sign informed consent, understand the study and be willing and able to comply with all study procedures.
• Age ≥18 years (male or female) at the time of signing informed consent.
• Histologically or cytologically confirmed locally advanced or metastatic esophageal squamous cell carcinoma, colorectal adenocarcinoma, or other gastrointestinal tumors.
• Disease progression or intolerance after prior standard-of-care (SoC) treatment:

• 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.
• 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.
• Cohort3 (Other GI tumors): Not curable by surgery; disease progression/intolerance after standard-of-care therapy, or no available effective treatment.
• At least one measurable lesion per RECIST V1.1 (lesions in prior radiation field generally not measurable unless clear progression).
• ECOG performance status 0 or 1.
• Expected survival ≥3 months.
• 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
• 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.

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

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

• 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.

• 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).

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

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

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

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

• Severe cardiovascular disease:

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

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

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

• 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.