KN046 Plus Regorafenib or Apatinib in MSI-H Digestive System Cancers Resistant to PD-1/PD-L1 Blockade

Inclusion Criteria:

• Subjects are able to comprehend the informed consent form, voluntarily participate,and sign the informed consent form.
• Subjects are ≥18 years old on the day of signing the informed consent form, with nogender restrictions.
• Histologically confirmed digestive system cancers.
• According to RECIST 1.1 criteria, there should be at least one measurable or evaluablelesion at baseline. If the subject has only one measurable or evaluable lesion atbaseline, the lesion must not have been exposed to radiotherapy previously, or theremust be evidence of significant progression after radiotherapy treatment completion.
• ECOG performance status of 0 or 1.
• Expected survival ≥3 months.
• Archived tumor tissue samples or freshly obtained tumor tissue samples are available.
• Female subjects of childbearing potential or male subjects with partners ofchildbearing potential agree to use highly effective contraception from 7 days beforethe first dose until 120 days after the last dose. Female subjects of childbearingpotential must have a negative serum pregnancy test within 7 days before the firstdose.
• Subjects have the ability and willingness to comply with the study protocol's visits,treatment plan, laboratory tests, and other study-related procedures.
• Within the first 7 days of initial dosing, subjects should have good organ function:
• HGB ≥ 80g/L, NEU ≥ 1.010^9/L, PLT ≥ 7510^9/L, Cr≤1.5×ULN orCrCl≥50mL/min（Cockcroft-Gault method), TBiL ≤ 1.5×ULN, ALT and AST ≤3 ×ULN; forpatients with liver metastasis ALT and AST ≤5 ×ULN, urine protein <2+;,if urineprotein ≥ 2+, 24 hour urinary protein quantity <2g; INR, APTT, PT ≤ 1.5 ×ULN
• dMMR/MSI-H cancers resistant to PD1/PDL1 blockade. MSI status should be confirmed byPCR or NGS. If MSI status by PCR and NGS were not consistent, or no enough tissue wereavailable for PCR or NGS testing, whether to enroll this patient should be determineby investigators.

Exclusion Criteria:

• Subjects with untreated active brain metastases or meningeal metastases; if thesubject's brain metastases have been treated and the metastases are stable (brainimaging at least 4 weeks before the first dose shows stable lesions, and there is noevidence of new neurological symptoms or the neurological symptoms have returned tobaseline), then enrollment is allowed.
• Subjects with a history of gastrointestinal perforation or fistula within 6 monthsbefore the first dose. If the perforation or fistula has been treated with resectionor repair, and the disease is judged to be recovered or improved by the investigator,then enrollment is allowed.
• Subjects who have received any other interventional clinical trial or any otherantitumor treatment within 28 days or 5 half-lives before the first dose (whichever isshorter). Palliative radiotherapy for bone metastases to relieve symptoms ispermitted.
• Subjects who have undergone major surgery within 28 days before the first dose (e.g.,major abdominal or thoracic surgery; excluding drainage, diagnostic puncture, orperipheral vascular access replacement).
• Subjects who require systemic corticosteroids (≥10 mg/day prednisone or equivalent) orimmunosuppressive therapy for a continuous 7-day period within 14 days before thefirst dose. Inhaled or locally applied steroids and physiological replacement doses ofsteroids due to adrenal insufficiency are allowed. Short-term (≤7 days)corticosteroids for prophylaxis (e.g., contrast dye allergy) or treatment ofnon-autoimmune diseases (e.g., delayed hypersensitivity reaction caused by exposure toallergens) are allowed.
• Subjects who have received live vaccines (including attenuated live vaccines) within 28 days before the first dose.
• Subjects with interstitial lung disease or a history of non-infectious pneumoniarequiring oral or intravenous corticosteroid treatment.
• Subjects with active autoimmune diseases requiring systemic treatment within 2 yearsbefore the start of the study or those considered at risk of recurrence or plannedtreatment for autoimmune diseases as judged by the investigator. Exclusions include a)skin diseases that do not require systemic treatment (e.g., vitiligo, alopecia,psoriasis, or eczema); b) hypothyroidism caused by autoimmune thyroiditis, requiringstable doses of hormone replacement therapy; c) type 1 diabetes requiring stable dosesof insulin replacement therapy; d) childhood asthma fully resolved with no need forintervention in adulthood; e) the investigator judges that the disease will notrelapse without external triggering factors.
• Subjects with a history of other malignant tumors within 5 years, excluding cured skinsquamous cell carcinoma, basal cell carcinoma, non-invasive bladder carcinoma,localized low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, andprostate-specific antigen (PSA) ≤10 ng/mL (if measured) in patients who have undergonecurative treatment and have no biochemical recurrence of prostate-specific antigen (PSA)), in situ cervical/breast carcinoma, or Lynch syndrome.
• Subjects with uncontrolled comorbidities, including but not limited to: a) active HBVor HCV infection; b) subjects who are HBsAg positive and/or HCV antibody positiveduring screening must undergo HBV DNA and/or HCV RNA testing. Only subjects with HBVDNA ≤500 IU/mL (or ≤2000 copies/mL) and/or HCV RNA negative can be enrolled; HBV DNAmonitoring will be at the discretion of the investigator based on the subject'scondition during the trial; c) known HIV infection or AIDS history; d) activetuberculosis; e) active infection or systemic use of anti-infective drugs for morethan 1 week within 28 days before the first dose; fever of unknown cause within 2weeks before the first dose; f) uncontrolled hypertension (resting blood pressure ≥160/100 mmHg), symptomatic congestive heart failure (NYHA II-IV), unstable angina ormyocardial infarction within 6 months, or the presence of QTc prolongation or the riskof arrhythmia (baseline QTc >470 msec <Fridericia method correction>,difficult-to-correct hypokalemia, long QT syndrome, atrial fibrillation with restingheart rate >100 bpm, or severe valvular heart disease); g) active bleeding that cannotbe controlled after medical treatment.
• Toxicity from previous antitumor treatments has not recovered to Grade ≤2 (NCI-CTCAEv5.0) or baseline, except for alopecia, skin pigmentation (allowed at any level), andimmune-related adverse reactions requiring physiological replacement (e.g.,hypothyroidism, hypopituitarism, type 1 diabetes).
• History of allogeneic bone marrow or organ transplantation.
• Previous history of allergic reactions, hypersensitivity reactions, or intolerance toantibody drugs (e.g., severe allergic reactions, immune-mediated hepatotoxicity,immune-mediated thrombocytopenia, or anemia).
• Pregnant and/or lactating females.
• Other conditions that, in the investigator's opinion, may affect the safety orcompliance of the study drug treatment, including but not limited to moderate to largepleural/ascites/pericardial effusion, uncorrectable pleural/ascites/pericardialeffusion, intestinal obstruction or subacute intestinal obstruction, psychiatricdisorders, etc.
• Previous treatment with any immune checkpoint inhibitors in combination with anti-VEGFtyrosine kinase inhibitor, including but not limited to Regorafenib, Apatinib,Sulfatinib and Anlctinib.