KN026 Plus Chemotherapy ± KN-046 in HER2 Positive Colorectal Cancer and Biliary Carcinoma

Inclusion Criteria:

1. Participants are able to comprehend the informed consent information and sign theinformed consent form.
2. Participants ≥ 18 years old, of any gender.
3. Cohorts A and B: Histologically confirmed unresectable HER2-positive metastaticcolorectal cancer, meeting the following criteria: a) Previously untreated withsystemic anti-tumor therapy, or the time from (neo)adjuvant chemotherapy completion todisease recurrence > 6 months; b) Gene sequencing shows wild-type RAS and BRAF (participants' previous KRAS and BRAF test results are acceptable).
4. Cohort C: Histologically confirmed unresectable HER2-positive biliary tract cancer,including intrahepatic or extrahepatic bile duct cancer or gallbladder cancer: a)Previously untreated with systemic anti-tumor therapy; b) If previously received (neo)adjuvant radiotherapy, the time from treatment completion to disease recurrenceis > 6 months.
5. HER-2 positive defined as a) HER2 IHC 3+; b) HER2 IHC 2+ with HER2 amplification (HER2/CEP17 > 2.0 by ISH method)； c) HER copy number > 6 by next-generation sequencingusing tumor tissue or circulating tumor DNA.
6. LVEF ≥ 50%

(9) Within 7 days before the first administration, hepatic function should meet thefollowing criteria:

• Total bilirubin ≤ 1.0 x ULN (≤ 1.5 x ULN for subjects with Gilbert's syndrome or livermetastases)
• Transaminases (ALT/AST) ≤ 1.5 x ULN (≤ 3 x ULN for subjects with liver metastases) (10) Within 7 days before the first administration, renal function should be asfollows:
• Serum creatinine ≤ 1.5 x ULN
• Creatinine clearance ≥ 60 mL/min (calculated using the Cockcroft-Gault formula) (11)Within 7 days before the first administration, bone marrow function should meet thefollowing criteria:
• Hemoglobin ≥ 90 g/L
• Absolute neutrophil count ≥ 1.5 x 10^9/L
• Platelet count ≥ 100 x 10^9/L (12) TSH within the normal range; if TSH is abnormal,free T3 and free T4 should be within the normal range. (13) Expected survival of ≥ 3 months. (14) Participants need to receive capecitabineand oxaliplatin regimen chemotherapy based on clinical assessment. (15) Female participants of childbearing potential or male participants with partnersof childbearing potential must agree to use effective contraception from 7 days beforethe first dose until 24 weeks after the last dose. Female participants of childbearingpotential must have a negative serum pregnancy test within 7 days before the firstdose. (16) Participants are capable and willing to comply with the study protocol, treatmentplan, laboratory tests, and other study-related procedures.

Exclusion Criteria:

1. Subjects with untreated active brain metastases or leptomeningeal metastases; ifsubjects have received treatment for brain metastases and the lesions are stable (stable brain imaging for at least 4 weeks before the first dose with no evidence ofnew or enlarging brain lesions and no new neurological symptoms or stable neurologicalsymptoms at baseline), they are allowed to be enrolled.
2. Ampullary carcinoma.
3. Previous history of receiving any systemic anticancer therapy for metastatic tumors orparticipation in interventional clinical trials.
4. Within 14 days before the first dose, the subject requires a continuous 7-daytreatment of systemic corticosteroids (≥10 mg/day prednisone or equivalent of othercorticosteroids) or immunosuppressive agents; exceptions are inhaled or locallyapplied corticosteroids or physiological replacement doses of corticosteroids foradrenal insufficiency. Short-term (≤7 days) corticosteroids are allowed for prevention (e.g., contrast dye allergy) or treatment of non-autoimmune conditions (e.g., delayedhypersensitivity reactions caused by exposure to allergens).
5. Received live vaccines (including attenuated live vaccines) within 28 days before thefirst dose.
6. Subjects with interstitial lung disease or requiring oral or intravenousadministration of corticosteroids.
7. History or current presence of autoimmune diseases, including but not limited toCrohn's disease, ulcerative colitis, systemic lupus erythematosus, sarcoidosis,Wegener's granulomatosis (granulomatosis with polyangiitis), Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, autoimmune hepatitis, systemic sclerosis (scleroderma), Hashimoto's thyroiditis (except under certain circumstances as outlinedbelow), autoimmune vasculitis, and autoimmune neurological disorders (such asGuillain-Barre syndrome). The following conditions are exempted: type 1 diabetes,stable hypothyroidism on hormone replacement therapy (including hypothyroidism causedby autoimmune thyroid disease), and psoriasis or vitiligo not requiring systemictreatment.
8. History of another malignant tumor within 5 years before the first dose, except forcured skin squamous cell carcinoma, basal cell carcinoma, non-muscle-invasive bladdercancer, localized low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6,and prostate-specific antigen (PSA) ≤10 ng/mL at diagnosis, and patients who receivedcurative treatment without PSA biochemical recurrence), and in situ cervical/breastcancer.
9. Has uncontrolled comorbidities, including but not limited to the following conditions:

• Active HBV or HCV infection.
• Subjects with positive HBsAg and/or HCV antibodies during screening must undergoHBV DNA and/or HCV RNA testing. Subjects with HBV DNA ≤ 500 IU/mL (or ≤ 2000copies/mL) and/or HCV RNA negative can be enrolled; during the trial, theinvestigator will decide on monitoring HBV DNA based on the subject's situation.
• Known HIV infection or history of AIDS.
• Active tuberculosis.
• Active infection or systemic use of antimicrobial drugs for more than 1 weekwithin 28 days before the first dose of this study; unexplained fever within 2weeks before dosing.
• Uncontrolled hypertension (resting blood pressure ≥ 160/100 mmHg), symptomaticheart failure (NYHA class II-IV), unstable angina or myocardial infarction withinthe past 6 months, or risk of QTc prolongation or arrhythmia (baseline QTc > 470msec corrected by Fridericia method, difficult-to-correct hypokalemia, long QTsyndrome, resting heart rate > 100 bpm with atrial fibrillation, or severevalvular heart disease).
• Active bleeding that cannot be controlled even with medical intervention.

10. History of allogeneic bone marrow or organ transplantation.
11. History of allergic reactions, hypersensitivity, or intolerance to antibody-baseddrugs; history of significant drug allergies (e.g., severe allergic reactions,immune-mediated hepatotoxicity, immune-mediated thrombocytopenia, or anemia).
12. Pregnant and/or lactating females.
13. Other conditions that, in the opinion of the investigator, may affect the safety orcompliance of the study drug treatment, including but not limited to moderate to largepleural/peritoneal/pericardial effusion, difficult-to-correctpleural/peritoneal/pericardial effusion, intestinal obstruction or subacute intestinalobstruction, psychiatric disorders, etc.