Efficacy and Safety of AK104 Combined With Chemotherapy and Recombinant Human Adenovirus 5 Injection in Cervical Cancer

Inclusion Criteria:

• 1）Enrollees in this study will be voluntary participants who sign a written informedconsent form and are capable of adhering to scheduled visits and relatedprocedures.2) Ages between 18 and 75 years old.3) Histologically or cytologicallyconfirmed cases of persistent, recurrent, or metastatic cervical squamous cellcarcinoma, adenocarcinoma, or adenosquamous carcinoma. Note: A pathological reportis necessary for confirmation of the original primary tumor histology.4) Must haveexperienced failure with at least one standard systemic treatment and documenteddisease progression: Failure is defined as progression or recurrence within sixmonths after at least one cycle of standard systemic treatment. Patients who havedeveloped immune acquired resistance may also be included if they experienced PDafter achieving CR or PR with anti-PD-1/PD-L1 antibody treatment, or PD afterexperiencing SD≥6 months with anti-PD-1/PD-L1 antibody treatment.

5. Not suitable for local treatments such as unresectable surgery and/or definitiveconcurrent radiotherapy and chemotherapy.6) The interval between the end of previoussystemic treatment and the first dose of the study drug must be ≥2 weeks.Additionally, any treatment-related adverse events must have recovered to a grade ≤1according to Common Terminology Criteria for Adverse Events (CTCAE) V5.0 (excludinghair loss and fatigue).7) At least one measurable target lesion must be presentaccording to RECIST V1.1 criteria.8）At least one lesion that can receive localinjection therapy using recombinant human adenovirus type 5 should also meet RECISTV1.1 criteria as a measurable lesion.9) ECOG PS 0 or 1.10) The anticipated survivaltime should be ≥12 weeks.11) Female subjects of reproductive age are required to useeffective contraception throughout the treatment period and for at least 5 monthsafter their final dose of the investigational drug.12) Participants must consent toproviding an adequate amount of tumor tissue samples for PD-L1 expression detection,which may include archived tumor samples such as paraffin blocks or a sufficientnumber of unstained slides meeting the study's detection requirements. If noarchived tumor tissue samples are available, participants agree to undergo biopsy ofthe tumor lesion.13）With good organ and hematopoietic function.

Exclusion Criteria:

1. Diagnosed with other malignancies within the 5 years preceding initial dosing,excluding surgically cured basal cell carcinoma or squamous cell carcinoma ofthe skin, in situ carcinoma that has been surgically resected, and/or papillarythyroid carcinoma. Subjects with histologically confirmed small cell (neuroendocrine) cervical cancer, cervical sarcoma, and gastric-type cervicaladenocarcinoma.2) Infection at the injection site.3) Presence of ascites,pleural effusion, or pericardial effusion accompanied by clinical symptoms ornecessitating drainage. Subjects without clinical symptoms or requiringdrainage who have ceased drainage for a minimum of 3 days and show nosignificant increase in fluid accumulation may be included.4) Individualsscheduled for or having undergone organ or bone marrow transplantationpreviously.5) Acute or chronic active hepatitis B or C infection with HBV DNA >200IU/ml or 103 copies/ml; positive anti-HCV antibody and HCV-RNA level abovedetection limit. Those treated with nucleoside analog antiviral agentsresulting in HBV DNA/HCV-RNA levels below specified standards can be included.

2. Central nervous system (CNS) metastasis involving meningeal metastasis orsymptomatic CNS metastasis. Asymptomatic brain metastases patients showing stablesymptoms after treatment for at least 2 weeks may participate if they meet specificcriteria: measurable lesions outside the CNS; absence ofmeningeal/midbrain/pons/cerebellum/medulla oblongata/spinal cord metastases; nohistory of intracranial hemorrhage; cessation of hormone therapy 14 days beforefirst dose.7）Any life-threatening bleeding event within the past three monthsincluding need for blood transfusion，surgery，local treatment，or ongoing medicationtherapy.8）Arterial thrombosis，embolism，or ischemia within six months prior toenrollment including myocardial infarction，unstable angina pectoris ，cerebrovascularaccident etc。A history of deep vein thrombosis（DVT）or any other seriousthromboembolic events within three months prior to enrollment are not considered "serious" thromboembolic events.9）Hepatic vein thrombosis involving both hepaticportal trunk & left/right branches；hepatic portal trunk & mesentericsuperior/inferior veins；superior vena cava thrombosis/superior vena cavasyndrome.10）Tumor invasion into important surrounding organs/blood vessels such asgreat mediastinal vessels/superior vena cava/inferior vena cava/abdominalaorta/iliac vessels/trachea/esophagus；risk of tracheoesophageal fistula /mediastinalpleural fistula development.11）Uncontrollable hypertension defined as systolic bloodpressure ≥150mmHg/diastolic blood pressure ≥100mmHg/history hypertensioncrisis/hypertensive encephalopathy.12）Symptomatic congestive heart failure(NYHAclass II-IV)/symptomatic/poorly controlled arrhythmias/prolonged QTinterval(QTcF>470ms).13）Severe bleeding tendency/coagulation dysfunction/currentlyreceiving thrombolytic therapy.14）History gastrointestinal perforation/fistula lastsix months/bowel obstruction(including incomplete bowel obstruction requiringparenteral nutrition)/inflammatory bowel disease/extensive bowel resection(Crohn'sdisease/ulcerative colitis/chronic diarrhea).15 ) History interstitialpneumonitis/drug-induced pneumonitis/radiation pneumonitis/idopathic pneumonitis /active pneumonitis.16 ) Active tuberculosis(TB)，currently receiving anti-TBtherapy/or received study drug previous year.17 ) Human immunodeficiencyvirus(HIV)(HIV1/HIV2 antibody positive), known active syphilis infection.18 )Active/severely uncontrolled infections hospitalization severeinfections(infections/sepsis/severe pneumonia complications etc.)within four weeksprior to first dose.19 ) Oral/intravenous therapeutic antibiotics one week beforestarting study treatment.20 ) Systemic autoimmune diseases/requiring systemictreatment/two-year history(white vitiligo、psoriasis、alopecia、Graves' disease notrequiring systemic treatment/hypothyroidism only needing thyroid hormonereplacement/type1 diabetes only needing insulin replacement). Known primaryimmunodeficiency history Only patients with positive autoimmune antibodies needconfirmation by investigator presence autoimmune disease.21 ) Immunosuppressivedrugs use four weeks except nasal inhalant local corticosteroids/systemiccorticosteroids physiological doses(no more than prednisone equivalent daily dosesother cortico steroids temporary use relief breathing difficulties dueasthma/COPD).22 ) Live attenuated vaccine four weeks planned during study period.23 ) System immune stimulant treatments four weeks.24)Majorsurgery(craniotomy/thoracotomy/laparotomy)prior four weeks/unhealed wound ulcerfracture.25)Uncontrolled/metabolic disorder/non-malignant organ/systemicdiseases/cancer-related complications/higher medical risk uncertainty survivalperiod evaluation.26) Other acute chronic conditions psychiatric disorderslaboratory test abnormalities increasing risk participating study/receiving studydrug interfering interpretation results determined investigator patient eligibleparticipate thisstudy.27) Received oncolytic virus therapy past received anti-CTLA-4antibodytherapy past.28) Known allergic AK104,pemetrexed,cisplatin,and RecombinantHuman Adenovirus 5 Injection components/severe allergic reaction monoclonalantibodies past.29) Received investigational drug treatment previousfourweeksstarting studytreatment.30) No anticancer therapies received previousfourweeksstartingstudyoral chemotherapy(two-week washout oral fluoropyrimidine-based drugs),endocrine targeted therapies(small molecule targeted therapies two-week half-lifelonger),immunotherapy,tumor embolization Chinese herbal medicine indications.31)Pregnant breastfeeding femalepatients