Cadonilimab Plus Anlotinib for R/M/P Cervical Cancer

Study Overview
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Brief Summary
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The goal of this clinical trial is to test a new treatment combination including cadonilimab and anlotinib in recurrent, metastasis and persistent cervical cancer. The main questions it aims to answer are: The efficacy of this combination in R/M/P CC; The tolerance of this combination in R/M/P CC; Possible biomarker of treatment response for this combination. Participants will receive cadonilimab of 10mg/kg every three weeks at day 1 and take anlotinib (12mg) orally in day 1 to day 14, then take a 7 days break. This treatment will continue until progression or intolerable toxicity or withdraw of participants and it will last for no longer than 2 years.

Detailed Description
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The prognosis was poor for recurrent, metastasis and persistent cervical cancer especially for those who had multiple lesions and history of previous radiation therapy. KEYNOTE-826 Study demonstrated survival benefit of adding pembrolizumab into the standard first-line treatment for cervical cancer. Here we designed a exploratory clinical study to test a new treatment combination including cadonilimab and anlotinib in recurrent, metastasis and persistent cervical cancer. All Participants will receive cadonilimab of 10mg/kg every three weeks at day 1 and take anlotinib (12mg) orally in day 1 to day 14, then take a 7 days break. This treatment will continue until progression or intolerable toxicity or withdraw of participants and it will last for no longer than 2 years.

Official Title
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Cadonilimab Plus Anlotinib for Recurrent, Metastasis or Persistent Cervical Cancer

Conditions
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Cervical Cancer

Intervention / Treatment
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* Drug: Cadonilimab
* Drug: Anlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged ≥18 years and ≤75 years old; ECOG PS score 0-2 points; Cervical histological examination is clearly diagnosed as a malignant tumor, and the pathological type is not limited, except for blood system tumors involving the cervix; Expected survival period ≥ 6 months; At least one evaluable lesion that meets the requirements of RECIST 1.1; Previously received at least two lines of systemic therapy with definite progression, or intolerant to second-line or recent line treatment; Archived or freshly obtained tumor tissue samples can be provided for further testing; Sitting blood pressure in a resting state is lower than the normal high value (<140/90mmHg), or the average blood pressure of 24-hour ambulatory blood pressure monitoring is lower than the normal high value (<140/90mmHg), regardless of antihypertensive drugs usage; The hematological indicators are met (no blood transfusion, no hematopoietic stimulating factor drugs used to correct within 7 days before screening): white blood cell count (WBC) ≥ 3.5×109/L and ≤ 10×109/L, neutrophil count ( ANC)≥1.5×109/L, platelet (PLT)≥100×109/L, hemoglobin (Hb)≥90g/L; Liver function indicators meet: ALT and AST ≤ 2.5 times high normal value (ULN), bilirubin ≤ 1.5 × ULN, albumin ≥ 35g/L; Coagulation function indicators are met (not receiving anticoagulant or drug hemostasis): PT and APTT ≤ 1.5×ULN, while INR ≤ 1.5 ULN; Renal function indicators meet: blood urea nitrogen (BUN) and creatinine (Cr) ≤ 1.5 × ULN and creatinine clearance rate ≥ 60 mL/min (Cockcroft-Gault formula), urine protein < 2+ or 24-hour urine protein quantity < 1g ; Women of childbearing age must conduct a serum pregnancy study within 7 days before the first medication, and the result is negative, and they are not breastfeeding. Female subjects of childbearing age must agree to use effective methods of contraception during the study period and within 180 days after the last administration of the study drug; Obtain the informed consent signed by the patient or his legal representative; Have good compliance. Exclusion Criteria: Any unstable systemic disease, including but not limited to active infection within 4 weeks (defined as fever with body temperature over 38.5°C or clear evidence of bacteremia or evidence of heart, brain, kidney, lung, Infectious changes of the liver and intestinal tract), circulatory accidents within 6 months (malignant hypertension attack, myocardial infarction, severe/unstable angina, cardiac insufficiency above NYHA class 2, clinically significant supraventricular or Ventricular arrhythmia, cerebrovascular accident that has not recovered or caused serious sequelae), uncontrolled type 2 diabetes (fasting blood sugar> 11.1mmol/L or glycated hemoglobin> 8%), pulmonary insufficiency (lung function caused by any cause Decrease, defined as pulmonary function test FEV1/FVC<70%, FEV1<80% predicted value). Previous autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, autoimmune liver disease, autoimmune thyroiditis, systemic vasculitis, scleroderma, dermatomyositis, autoimmune immune hemolytic anemia; Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS); active hepatitis (hepatitis B, defined as HBV-DNA ≥ 500 IU/ml; hepatitis C, defined as HCV -RNA is higher than the detection limit of the analytical method) or co-infected with hepatitis B and hepatitis C; The history of live attenuated vaccine vaccination within 28 days before the first study medication or the expected live attenuated vaccine vaccination during the study period; Imaging examination show that the tumor invades large blood vessels or the investigator judges that the tumor is likely to invade important blood vessels during the follow-up study and cause fatal massive hemorrhage, or other diseases with serious bleeding risks (hemorrhage caused by simple cervical tumor rupture is not included) ; Previously received anlotinib combined with cardonirimab, if the two drugs are not used at the same time, it is not allowed to receive two drugs separately within the past 3 months; Evidence of active tuberculosis infection within 1 year before screening; Any other malignant tumors have been diagnosed within 5 years before entering the study, except for fully treated basal cell carcinoma or squamous cell skin cancer or carcinoma in situ of the cervix; Major surgery within 28 days before randomization (tissue biopsy and peripheral venous puncture into central venous catheter [PICC] are allowed for diagnosis); Arteriovenous thrombosis events that occurred within 6 months before randomization, such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis (venous thrombosis caused by venous catheterization due to previous chemotherapy, and the researchers judged that they have been cured except) and pulmonary embolism; Subjects who have previously received or are about to receive allogeneic bone marrow transplantation or solid organ transplantation; Intestinal obstruction with significant clinical significance, intestinal repair, intestinal anastomosis or intestinal fistula for any reason at any time; Subjects with hemoptysis symptoms within 2 months before entering the study and the maximum daily hemoptysis volume is about ≥ 2.5 mL. Have clinically significant bleeding symptoms or clear bleeding tendency within 3 months before entering the study, such as gastrointestinal bleeding, bleeding gastric ulcer, fecal occult blood ++ and above at baseline, or suffering from vasculitis; Known hereditary or acquired bleeding and thrombosis tendency, such as: hemophilia, coagulation disorder, thrombocytopenia, hypersplenism, etc.; Gross hematuria or other evidence of urinary bleeding; Are receiving thrombolysis or require long-term anticoagulant therapy with warfarin or heparin, or require long-term antiplatelet therapy (aspirin ≥ 300 mg/day or clopidogrel ≥ 75 mg/day) Long-term bed rest caused by any reason; Cachexia state; Known hypersensitivity to anlotinib, cardonirimab or any of their excipients; Those who have other anti-tumor treatment plans during treatment; Participated in any other drug clinical research within 4 weeks before randomization, or no more than 5 half-lives from the last study drug; The subject is known to have a history of psychotropic substance abuse, alcoholism or drug abuse; Those who are combined with mental diseases that seriously affect cognition and cannot achieve a stable mental state; According to the investigator's judgment, the patient may have other factors that may cause the study to be terminated midway, such as other serious diseases or serious laboratory test abnormalities or other conditions that will affect the safety of the subjects, or trial data and factors such as family or society for sample collection;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>This trial has a single treatment arm. All participants will receive small treatment including cadonilimab and anlotinib in this arm | Drug: Cadonilimab<br>* All Participants will receive cadonilimab of 10mg/kg every three weeks at day 1<br>* Other names: AK104;Drug: Anlotinib<br>* All Participants will take anlotinib (12mg) orally in day 1 to day 14, then take a 7 days break.<br>* Other names: AL001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Rate of participants with complete response plus partial response as best response in the intent to treatment group according to RECIST 1.1 | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate and grade of adverse events | The incidence of adverse events and severity graded according to CTCAE 5.0 | From enrollment to 90 days after last treatment of all subjects | 
| Disease control rate | Rate of participants with complete response plus partial response plus stable disease as best response in the intent to treatment group according to RECIST 1.1 | up to 2 years | 
| Duration of Response | Time period from first response to first progression | Up to 2 years | 
| Progression free survival rate | Proportion of participants without tumor recurrence or death | Up to 2 years | 
| Overall survival rate | Proportion of survival participants | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical Cancer, Cadonilimab, Anlotinib, Immunotherapy