Cadonilimab/Anlotinib in Locally Advanced or Relapsed/Metastatic ESCC Patients After Failure of PD-1 Combined With Platinum-containing Chemotherapy

Inclusion Criteria:

1. Voluntarily sign a written informed consent form.
2. Age ≥18 and ≤80 years, both males and females are eligible.
3. ECOG performance status score of 0 or 1.
4. Expected survival≥3 months.
5. Patients with locally advanced or recurrent/metastatic esophageal squamous cellcarcinoma confirmed by histology and/or cytology that is incurable (including curativesurgery and curative radio/chemotherapy). Patients with locally advanced orrecurrent/metastatic esophageal squamous cell carcinoma who have failed of PD-1inhibitor combined with platinum-based chemotherapy , and are not allowed to receiveother systemic anti-tumor treatments. Note: For patients who have receivedadjuvant/neoadjuvant PD-1 inhibitor combined with platinum-based chemotherapy fornon-metastatic disease with curative intent, or curative platinum-basedradio/chemotherapy combined with PD-1 inhibitor for locally advanced orrecurrent/metastatic disease, if disease progression occurs within <6 months after theend of the last treatment, and the patients has not received other systemic anti-tumortreatments after disease progression, they are allowed to be enrolled.
6. According to RECIST v1.1, patients must have at least one measurable lesion. Forpatients who have received radiotherapy previously and have no other target lesionsavailable, when there is objective evidence of significant progression afterradiotherapy, the lesion treated with radiotherapy can be considered as a targetlesion.
7. The function of important organs meets the following requirements (excluding any bloodcomponents and growth factors used within 14 days):
8. Normal bone marrow function, neutrophils ≥1,500/mm3, platelet count ≥100,000/mm3,hemoglobin ≥5.6 mmol/L (9g/dL);
9. Normal renal function or serum creatinine ≤1.5 mg/dL and/or creatinine clearancerate ≥60 ml/min;
10. Normal liver function or bilirubin ≤1.5 times ULN, ASAT & ALST ≤1.5 times ULN.
11. Female patients of childbearing potential must undergo a urine or serum pregnancy testwithin the first 3 days before the first dose (if the urine pregnancy test resultcannot be confirmed as negative, a serum pregnancy test must be performed, and theserum pregnancy result will prevail), and the result must be negative. If a femalepatient of childbearing potential has sexual intercourse with an uncircumcised malepartner, the subject must take effective contraceptive measures from the beginning ofscreening and must agree to continue using contraceptive methods for 120 days afterthe last dose of study drug; whether to stop contraception after this time pointshould be discussed with the investigator.
12. If an uncircumcised male subject has sexual intercourse with a female partner ofchildbearing potential, the subject must take effective contraceptive measures fromthe beginning of screening until 120 days after the last dose; whether to stopcontraception after this time point should be discussed with the investigator.
13. The patient is willing and able to comply with the scheduled visits, treatment plan,laboratory tests, and other requirements of the study.

Exclusion Criteria: Subjects who meet any of the following criteria will be ineligible to participate in thisstudy:

1. Subjects who have had other malignant tumors within 3 years prior to enrollment,except those who have been cured by local treatment such as basal or squamous cellskin cancer, superficial bladder cancer, cervical or breast carcinoma in situ.
2. Subjects who are concurrently enrolled in another clinical study, unless it is anobservational, non-interventional clinical study or a follow-up period of aninterventional study.
3. Subjects who have received systemic anti-tumor therapy (chemotherapy, immunotherapy,etc.) for non-target lesions within 3 weeks before the first dose of study drug;palliative local therapy for non-target lesions within 2 weeks before the first doseof study drug; non-specific immunomodulatory therapy (such as interleukin, interferon,thymosin, tumor necrosis factor, etc., excluding IL-11 for thrombocytopenia) within 2weeks before the first dose of study drug; or Chinese herbal medicine or traditionalChinese medicine with anti-tumor indications within 1 week before the first dose ofstudy drug.
4. Subjects who have received any treatment targeting tumor immune mechanisms, such asimmunotherapy other than PD-1 inhibitors (including immune checkpoint inhibitors suchas anti-CTLA-4 antibodies, anti-CD47 antibodies, anti-SIRPα antibodies, anti-LAG-3antibodies, etc.), immune checkpoint agonists (such as ICOS, CD40, CD137, GITR, OX40antibodies, etc.), immune cell therapy, biologics, etc., other than PD-1 inhibitors.
5. Subjects who have experienced any of the following during previous PD-1 inhibitortreatment:
6. Grade 3 or higher irAE caused by PD-1 inhibitor treatment (excluding endocrinesystem-related irAEs), irAEs that led to permanent discontinuation of treatment,grade 2 immune-related cardiac toxicity or any grade of neurologic orophthalmologic irAE.
7. All adverse events during previous PD-1 inhibitor treatment have not beencompletely resolved or resolved to grade 1 before screening for this study. Forsubjects with grade ≥2 endocrine adverse events, if the condition is stable withappropriate alternative treatment and asymptomatic, enrollment is allowed.
8. Previous adverse events that required the use of immunosuppressive agents otherthan glucocorticoids or recurrence of adverse events during previousimmunotherapy that required systemic use of glucocorticoids.
9. Screening imaging shows that the tumor surrounds or invades important blood vessels ororgans (such as the heart and pericardium, trachea, aorta, superior vena cava, etc.),or there is obvious necrosis or cavity, and the investigator judges that entering thestudy would increase the risk of bleeding; there are subjects at risk of developingesophagotracheal fistula or esophageal pleural fistula.
10. Subjects who have had active autoimmune diseases requiring systemic treatment in thepast two years (such as use of disease-modifying drugs, corticosteroids,immunosuppressive therapy), and replacement therapy (such as thyroid hormone, insulin,or physiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered systemic treatment.
11. Subjects with non-infectious pneumonia/interstitial lung disease (including radiationpneumonitis) requiring systemic glucocorticoid therapy that is currently uncontrolled.
12. Presence of brainstem, meningeal metastasis, spinal cord metastasis or compression.
13. Presence of active central nervous system (CNS) metastatic lesions. Note: Subjectswith previously treated brain metastases (such as surgery or radiotherapy) are allowedto enroll if they are clinically stable for at least 2 weeks (from the time of firstadministration of study drug) and have discontinued corticosteroid hormones for 7 daysbefore administration of study drug; untreated asymptomatic brain metastases (i.e., noneurological symptoms, no need for corticosteroid hormones, no brain metastases with along axis >1.5 cm and no obvious peritumoral edema) are eligible to enroll.
14. Presence of pleural effusion, pericardial effusion or ascites with clinical symptomsor requiring repeated drainage.
15. Presence of uncontrolled comorbidities currently including but not limited todecompensated liver cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders,or psychiatric/social conditions that would limit compliance with study requirementsor affect the subject's ability to provide written informed consent.
16. History of myocarditis, cardiomyopathy or malignant arrhythmia. Unstable anginapectoris requiring hospitalization within 12 months before the first dose of studydrug, myocardial infarction, congestive heart failure (New York Heart Associationfunctional class II or higher), vascular disease (such as aortic aneurysm at risk ofrupture), or other cardiac damage that may affect the safety evaluation of the studydrug (such as poorly controlled arrhythmia or myocardial ischemia) within 12 monthsbefore the first dose of study drug.
17. Occurrence of any arterial thrombotic events within 6 months before the first dose ofstudy drug; grade 3 or higher venous thromboembolic events according to NCI CTCAE 5.0;transient ischemic attacks; cerebrovascular accidents; hypertensive crises orhypertensive encephalopathy; exacerbation of chronic obstructive pulmonary diseasewithin 1 month before the first dose of study drug; current hypertension with systolicblood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite oralantihypertensive therapy.
18. History of severe bleeding tendency or coagulation dysfunction; significant bleedingsymptoms within 1 month before the first dose of study drug, including but not limitedto gastrointestinal bleeding, bleeding peptic ulcer, hemoptysis (defined as coughingup or spitting out ≥1 teaspoon fresh blood or small clots or coughing up blood withoutsputum), which allows for inclusion if it is due to hemorrhoids and does not requireintervention.
19. Active or past history of confirmed inflammatory bowel disease (such as Crohn'sdisease, ulcerative colitis, or chronic diarrhea).
20. Severe infection occurring within 4 weeks prior to the first dose of study drug,including but not limited to complications requiring hospitalization, sepsis, orsevere pneumonia; active infection treated with systemic anti-infective therapy within 2 weeks prior to the first dose of study drug (excluding antiviral therapy forhepatitis B or C).
21. Known active tuberculosis (TB) or suspected active TB requiring clinical evaluation torule out; known active syphilis infection.
22. Participants with active hepatitis B (HBsAg-positive with HBV-DNA levels above 1000copies/mL (200 IU/mL) or higher than the lower limit of detection, whichever ishigher) must receive antiviral therapy for hepatitis B during the study treatmentperiod; active hepatitis C infection (HCV antibody-positive with HCV-RNA levels abovethe lower limit of detection).
23. History of immunodeficiency; positive HIV antibody test; current use of long-termsystemic corticosteroids or other immunosuppressive agents.
24. Known history of allogeneic organ transplantation or allogeneic hematopoietic stemcell transplantation.
25. Unresolved toxicities from prior anti-tumor therapy, defined as toxicities not yetresolved to NCI CTCAE version 5.0 grade 0 or 1, or at a level dictated in theinclusion/exclusion criteria, with the exception of alopecia. Participants withirreversible toxicities that are not expected to be exacerbated by study drug may beincluded in the study after consultation with the investigator (e.g., hearing loss).Participants with radiation-induced long-term toxicities judged by the investigator tobe irreversible may be included in the study.
26. Major surgery or serious injury within 30 days prior to the first dose of study drug,or planned major surgical procedure within 30 days after the first dose of study drug (at the discretion of the investigator); minor surgical procedure within 3 days priorto the first dose of study drug (excluding peripheral venous catheterization andplacement of venous infusion port).
27. Known hypersensitivity to any component of the study drug; history of serioushypersensitivity reaction to other monoclonal antibodies.
28. Receipt of live vaccine or attenuated live vaccine within 30 days prior to the firstdose of study drug, or planned receipt of live vaccine or attenuated live vaccineduring the study period; use of inactivated vaccine is allowed.
29. Known history of psychiatric illness, drug abuse, alcoholism, or drug addiction.
30. Pregnant or breastfeeding women.
31. Any past or current disease, treatment, or laboratory abnormality that may confoundthe study results, interfere with subject participation for the full duration of thestudy, or may not be in the best interest of the subject to participate in the study.
32. Local or systemic diseases caused by non-malignant tumors; or diseases or symptomssecondary to malignancy that may result in higher medical risk and/or uncertainty insurvival assessment, such as tumor leukemic reaction (white blood cell count >20×109/L), cachexia (known weight loss exceeding 10% in the 3 months prior toscreening), etc.