A Phase II Study of Balstilimab Independently or in Combination With Zalifrelimab in Advanced Cervical Cancer

Inclusion Criteria:

• Voluntarily agree to participate by giving written informed consent.
• Diagnosis:

1. Have a histologically or cytologically confirmed, locally advanced, inoperableand/or metastatic cervical squamous cell carcinoma, cervical adenosquamous cellcarcinoma or cervical adenocarcinoma. Note: A pathological report confirmed byhistology or cytology of the primary tumor is required for definitive diagnosis.The following cervical tumors are not eligible for inclusion: minimal deviationadenocarcinoma, gastric-type endocervical adenocarcinoma, clear celladenocarcinoma of the cervix, neuroendocrine carcinoma of the cervix andmesonephric adenocarcinoma.
2. Patients with recurrent/metastatic cervical cancer who have received at least 1platinum-based systemic therapy (excluding radiosensitizing chemotherapy) (withor without bevacizumab), and experienced recurrence or progression of cervicalcancer or were intolerable to chemotherapy toxicity during or after the systemictherapy and were unable to receive radiotherapy or radical surgery again. Note (definition of failure or intolerability of first-line platinum-basedchemotherapy):
3. Patients with recurrent or metastatic cervical cancer who have experienceddisease progression during platinum-based regimen or have experienceddisease progression after receiving ≥4 cycles of effective platinum-basedregimen (complete response/progressive disease/stable disease) or wereintolerable to toxicity caused by platinum during/after platinum-basedregimen and were not suitable for continuous platinum-based regimen. Or
4. Patients with cervical cancer progressed or relapsed during neoadjuvant oradjuvant chemotherapy with platinum-based regimen (≥4 cycles if theplatinum-based regimen is effective) or within 6 months after the end of thetreatment, are deemed to have failed first-line platinum-based chemotherapy.
5. Programmed death-ligand 1 (PD-L1) positive (combined positive score ≥1).

• Have at least 1 measurable lesion on imaging based on RECIST 1.1. Measurable lesionsshould have not been treated with topical treatment such as radiotherapy. If the onlyone measurable lesion has been treated with previous topical treatment (radiotherapy,ablation, vascular intervention, etc.), it is necessary to confirm that the lesion hasprogressed, otherwise it will be recorded as a non-target lesion.
• Have a life expectancy of at least 3 months.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Have satisfactory organ function as indicated by the following laboratory values:

1. Bone marrow: absolute neutrophil count >1.5 × 10^9/liter (L), platelet count >100 × 10^9/L, and hemoglobin >8 grams (g)/deciliter (80 g/deciliter) (withouttransfusions of blood or blood component within 2 weeks of test);
2. Liver: serum total bilirubin (TBIL) level ≤1.5 × upper limit of normal (ULN),aspartate aminotransferase (AST) level ≤2.5 × ULN, alanine aminotransferase (ALT)level ≤2.5 × ULN (TBIL ≤1.5 × ULN, AST ≤5 × ULN, ALT ≤5 × ULN in case of presenceof liver metastases);
3. Serum creatinine ≤1.5 × ULN; or endogenous creatinine clearance ≥50milliliters/minute for serum creatinine >1.5 × ULN;
4. Eligible coagulation function, defined as International Normalized Ratio andprothrombin time ≤1.5 x institutional upper limit of normal (IULN); and activatedpartial thromboplastin time ≤1.5 x IULN.

• No history of other malignancies within 5 years prior to first dose, except for basalcell carcinoma of the skin, superficial bladder cancer, and squamous cell carcinoma ofthe skin.
• Patient must provide an adequate amount of eligible formalin fixed paraffin-embeddedtumor tissue samples, preferably from a recent tumor focus biopsy, or tumor tissuesamples collected at or after the diagnosis of advanced or metastatic tumors from thesite that has not been previously treated with radiation. If tumor tissue is notavailable, a tumor biopsy is required.
• Female patients with or without childbearing potential, for the former, the serumpregnancy test should be negative at the time of screening (serum pregnancy test ispreferred within 7 days prior to first dose of the investigational drug, otherwiseurine pregnancy test is acceptable if serum pregnancy test is not available). Femalepatients without childbearing potential are defined as follows (for reasons other thanmedication): ≥45 years of age and menopause for more than 1 year; post hysterectomy,post oophorectomy or post tubal ligation.
• Females of potential pregnancy must use a highly effective method of contraception (e.g., oral contraceptives, intrauterine devices, abstinence or barrier contraceptioncombined with spermicide) throughout the study and continue contraception for 12months after the end of treatment.
• Is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a studyof an investigational agent and received study therapy or used an investigation devicewithin 4 weeks of the first dose of treatment.
• Has an inadequate washout period prior to first dose of study drug defined as:received systemic cytotoxic chemotherapy or biological therapy within 3 weeks beforefirst dose; received radiation therapy within 3 weeks before first dose; experiencedmajor surgical procedures within 4 weeks prior to the first dose.
• Has received prior therapy with any antibody/drug-targeting T-cell co-stimulatoryproteins (immune checkpoints), including but not limited to PD-1, PD-L1, CTLA-4,lymphocyte-activation gene 3, therapeutic vaccines, etc.
• Have not recovered from the toxicity of their last systemic antineoplastic therapy tograde 1 or below as defined by National Cancer Institute - Common Terminology Criteriafor Adverse Events (NCI-CTCAE) 5.0 prior to the first dose of the study. Note:Patients with sensory neuropathy or alopecia grade ≤2 are eligible.
• Is expected to require any other form of systemic or localized antineoplastic therapywhile on trial (including maintenance therapy with another agent, radiation therapy,and/or surgical resection).
• Has known severe hypersensitivity reactions to fully human monoclonal antibodies (NCI-CTCAE 5.0 Grade ≥3).
• Received hematopoietic stimulating factor treatment within 14 days (≤14 days) beforethe first dose of the study drug, such as granulocyte colony-stimulating factor,erythropoietin, etc.
• Central nervous system tumors, brain metastases, or meningeal metastases are foundprior to the first dose of the study drug. Note: Patients with brain metastases areeligible for the study when meeting the following requirements: brain metastases proveto be stable (patients are required to provide the most recent head imaging prior tothe first dose, with previous head imaging at least 4 weeks apart, for theinvestigator to determine whether the brain metastases are stable by comparing theresults of the two examinations); any neurological symptoms resulting from brainmetastases or their treatment must have resolved or be maintainable to a minimaldegree and the symptoms can be clinically determined to be sequelae of the treatedlesion; brain metastases treated with steroids must not be treated with steroids forat least 4 weeks prior to the first dose.
• Treatment with systemic corticosteroids or any other form of systemicimmunosuppression within 7 days (≤7 days) prior to the first dose of the study drug.Note: Combination with corticosteroids for the treatment of immune-related adverseevents and prophylactic use of anticontras allergy medications are permitted duringthe study period; patients requiring daily corticosteroid replacement therapy, e.g., 5to 7.5 milligrams daily doses of prednisone or equivalent doses of hydrocortisone andsteroid therapy (topical, intraocular, intranasal inhalation routes only) may beenrolled in this study. Note: Patients with type 1diabetes, vitiligo, psoriasis,hypothyroidism, or hyperthyroid disease not requiring immunosuppressive treatment areeligible.
• Active autoimmune disease requiring systemic therapy within the past 2 years orhistory of autoimmune disease or syndrome requiring systemicsteroids/immunosuppressive drugs, e.g., hypophysitis, colitis, hepatitis, nephritis,etc. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroidreplacement therapy for renal or pituitary insufficiency) is not considered systemicimmunosuppressive therapy. Note: Patients with type I diabetes, vitiligo, psoriasis,hypo- or hyperthyroidism who do not require immunosuppressive therapy are eligible forthe study.
• Has had an allogeneic tissue/solid organ transplant.
• History of interstitial lung disease or a history of pneumonia that has required oralor intravenous corticosteroids.
• Symptoms of an active infection requiring intravenous systemic therapy.
• Positive human immunodeficiency virus antibody or positive syphilis spirocheteantibody and positive syphilis spirochete antibody titer test result (i.e., activesyphilis infection).
• Presence of active hepatitis B, hepatitis C or tuberculosis. Active hepatitis B and Care defined as follows: active hepatitis B, positive for hepatitis B surface antigenwith the hepatitis B virus deoxyribonucleic acid quantification result greater thanthe ULN; active hepatitis C, positive for hepatitis C antibody with the hepatitis Cvirus ribonucleic acid quantification result greater than the ULN.
• Has clinically significant (i.e., active) cardiovascular disease. Note: The followingcases are observed within 6 months prior to the first dose: heart disease (ClassIII/IV congestive heart failure or heart block as defined by the New York HeartAssociation); deep vein thrombosis or pulmonary embolism; myocardial infarction;severe or unstable arrhythmias or angina pectoris; percutaneous coronary intervention,acute coronary syndromes, coronary artery bypass grafting; cerebrovascular accident,transient ischemic attack, cerebral embolism.
• Has a history or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the trial, interfere with the patient'sparticipation for the full duration of the trial, or is not in the best interest ofthe patient to participate, in the opinion of the treating investigator.
• Has known mental illness that would interfere with compliance with the requirements ofthe trial.
• Has a history of substance abuse, alcoholism or other addictions.
• Legal incapacity or legal limitation of capacity.