Pembrolizumab and Lenvatinib in Advanced Cervical Cancer

Inclusion Criteria:

1. Female participants who are at least 18 years of age on the day of signing informedconsent with histologically confirmed diagnosis of locally advanced or metastaticcervical cancer will be enrolled in this study.

2. Patients with progression or intolerance to at least one line of therapy in thelocally advanced or metastatic setting will be eligible for this study.

3. A female participant is eligible to participate if she is not pregnant, notbreastfeeding, and at least one of the following conditions applies:

4. Not a woman of childbearing potential (WOCBP) as defined OR

5. A WOCBP who agrees to follow the contraceptive guidance during the treatmentperiod and for at least 120 days after the last dose of study treatment.

6. The participant (or legally acceptable representative if applicable) provideswritten informed consent for the trial.

7. Have measurable disease based on RECIST 1.1. Lesions situated in a previouslyirradiated area are considered measurable if progression has been demonstrated insuch lesions.

8. Have provided archival tumor tissue sample or newly obtained core or excisionalbiopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffinembedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies arepreferred to archived tissue. Note: If submitting unstained cut slides, newly cutslides should be submitted to the testing laboratory within 14 days from the dateslides are cut.

9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.Evaluation of ECOG is to be performed within 28 days prior to the date of treatmentinitiation.

10. Have adequate organ function as defined. Specimens must be collected within 28 daysprior to the start of study treatment.

11. Absolute neutrophil count (ANC) ≥1500/µL

12. Platelets ≥100 000/µL

13. Hemoglobin ≥9.0 g/dL

14. Creatinine OR Measured or calculated creatinine clearance (GFR can also be usedin place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant withcreatinine levels >1.5 × institutional ULN

15. Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with totalbilirubin levels >1.5 × ULN

16. AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with livermetastases)

17. International normalized ratio (INR) OR prothrombin time (PT), Activatedpartial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receivinganticoagulant therapy as long as PT or aPTT is within therapeutic range ofintended use of anticoagulants

Exclusion Criteria:

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatmentinitiation. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required.

2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent.

3. Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks Note: Participants must have recovered from all AEs due to previoustherapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may beeligible.Note: If participant received major surgery, they must have recoveredadequately from the toxicity and/or complications from the intervention prior tostarting study treatment.

4. Has received prior radiotherapy within 2 weeks of start of study treatment.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervoussystem (CNS) disease.

5. Has received a live vaccine or live attenuated vaccine within 30 days prior to thefirst dose of study drug. Administration of killed vaccines is allowed.

6. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study treatment.

7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

8. Has a known additional malignancy that is progressing or has required activetreatment within the past 3 years. Note: Participants with basal cell carcinoma ofthe skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breastcarcinoma) that have undergone potentially curative therapy are not excluded.

9. Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening),clinically stable and without requirement of steroid treatment for at least 14 daysprior to first dose of study treatment.

10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or lenvatinib and/or any oftheir excipients.

11. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

12. Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

13. Has an active infection requiring systemic therapy.

14. Has a known history of Human Immunodeficiency Virus (HIV).

15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] isdetected) infection. Note: no testing for Hepatitis B and Hepatitis C is requiredunless mandated by local health authority.

16. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

17. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

18. Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment.

19. Has uncontrolled blood pressure (BP) (Systolic BP>140 mmHg or diastolic BP>90 mmHg)in spite of an optimized regimen of antihypertensive medication.

20. Has electrolyte abnormalities that have not been corrected.

21. Has significant cardiovascular impairment: history of congestive heart failuregreater than New York Heart Association (NYHA) Class II, unstable angina, myocardialinfarction or stroke within 6 months of the first dose of study drug, or cardiacarrhythmia requiring medical treatment at Screening.

22. Has bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. Thedegree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery)should be considered because of the potential risk of severe hemorrhage associatedwith tumor shrinkage/necrosis following lenvatinib therapy.

23. Subjects having > 1+ proteinuria on urine dipstick testing unless a 24-hour urinecollection for quantitative assessment indicates that the urine protein is <1 g/24hours.

24. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any othercondition that might affect the absorption of lenvatinib.

25. Prolongation of QTc interval to >480 ms.