Zimberelimab Plus Lenvatinib After Progression on Prior Immune Checkpoint Inhibitors for Advanced Cervical Cancer

Inclusion Criteria:

1. Signed Informed Consent Form (ICF).

2. Has histologically confirmed diagnosis of metastatic, recurrent or persistentsquamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervixwhich is not amenable to curative treatment with surgery and/or radiation therapy.

3. Has progressed on at least one line of platinum-based systemic therapy. Note: Prioradjuvant therapy is NOT counted as a systemic chemotherapeutic regimen formanagement of recurrent, persistent or metastatic cervical cancer; adjuvant therapyincludes cisplatin given concurrent with primary radiation therapy and adjuvantchemotherapy given following the completion of concurrent chemotherapy and radiationtherapy. However, adjuvant chemotherapy could be counted as one prior regimen inpatients who had recurrence during or within 6 months of completion of therapy.

4. Has progressed on or after treatment of prior immune checkpoint inhibitors (ICIs).

5. Age ≥ 18 years and ≤ 75 years.

6. Has measurable disease per RECIST v1.1; measurable lesions are defined as those thatcan be accurately measured in at least one dimension (longest diameter to berecorded as ≥ 10 mm with computed tomography (CT) scan, magnetic resonance imaging (MRI); a lymph node must be ≥ 15 mm in short axis. Tumors within a previouslyirradiated field will be designated as "non-target" lesions unless progression isdocumented or a biopsy is obtained to confirm persistence at least 90 days followingcompletion of radiation therapy.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

8. Life expectancy exceeds 3 months.

9. Has adequate organ function as defined by the following criteria:

• Absolute neutrophil count (ANC) (≥1.5×109/L), hemoglobin of ≥90 g/L, platelets ≥100 ×109/L

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN (however, patients with known liver metastasis who have AST or ALT level ≤ 5 ×ULN may be enrolled)

• Serum creatinine ≤ 1.5 × ULN or creatinine clearance rate ≥ 60 ml/min (Cockcroft-Gault formula)

10. Females of childbearing potential should have a negative serum or urine pregnancytest prior to receiving the first dose of study treatment; and should be willing touse one acceptable contraception (i.e., oral contraceptives, condoms, intrauterinedevices [IUDs]) throughout the period of taking study treatment and for at least 6months after the last dose of study drug(s).

Exclusion Criteria:

1. Histologic types of carcinoma other than squamous cell carcinoma, adenosquamouscarcinoma, or adenocarcinoma.

2. Known or suspected allergy to any of study drugs.

3. Prior exposure to small molecule tyrosine kinase inhibitors within the past 6months.

4. Has an active autoimmune disease requiring systemic therapy (i.e., with use ofdisease modifying drugs, corticosteroids or immunosuppressive drugs) in past 2years. Subjects with vitiligo or resolved childhood asthma/atopy would be anexception to this rule. Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is permitted.

5. Concurrent medical condition requiring the use of systemic steroid therapy (dose > 10 mg/day of prednisone or equivalent) or any other form of immunosuppressivetherapy within 2 weeks prior to the first dose of study intervention.

6. Has an active infection requiring systemic therapy.

7. Any unresolved toxicities from prior therapy, greater than Common TerminologyCriteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment,with exception of alopecia and anemia.

8. Recieved major surgery with 28 days before the first medication or has seriousnonhealing wound, or ulcer.

9. Clinically significant cardiovascular diseases, including but not limited tocongestive heart failure (New York heart association [NYHA] class > 2), unstable orsevere angina, severe acute myocardial infarction within 6 months before enrollment,supraventricular or ventricular arrhythmia which need medical intervention, or QTinterval male ≥ 450 ms, female ≥ 470 ms.

10. Hypertension that can not be well controlled through antihypertensive drugs (systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg).

11. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures

12. Proteinuria ≥ (++) or 24 hours total urine protein > 1.0 g.

13. Coagulation abnormalities (INR > 2.0, PT > 16s), with bleeding tendency or arereceiving thrombolytic or anticoagulant therapy.

14. Has known active central nervous system metastases.

15. History of another malignancy in the previous 3 years, with a disease-free intervalof <3 years. Exceptions include basal cell carcinoma of the skin, squamous cellcarcinoma of the skin, or in situ cervical cancer that has undergone potentiallycurative therapy. Patients who have undergone a bone marrow or stem-cell transplantfor any malignancy are excluded.

16. Has a known history of immunodeficiency including human immunodeficiency virus (HIV), or other acquired or congenital immune-deficient disease.

17. Has known active hepatitis B disease (hepatitis B virus [HBV] DNA ≥ 1×104/ml) orhepatitis C disease (hepatitis C virus [HCV] RNA ≥ 1×103/ml).

18. Has received a live vaccine within 30 days prior to the first dose of trialtreatment. Note: Injection of inactivated viral vaccines against seasonal influenzaare allowed.

19. Any other medical, psychiatric, or social condition deemed by the investigator to belikely to interfere with a subject's rights, safety, welfare, or ability to signinformed consent, cooperate, and participate in the study or would interfere withthe interpretation of the results.