Pembrolizumab Combination With Lenvatinib in Pts With Recurrent,Persistent,Metastatic or Locally Advanced Vulvar Cancer Not Amenable to Curative Surgery or Radiotherapy

Inclusion Criteria:

1. Signed written informed consent obtained prior to initiation of any study-specificprocedures and treatment as confirmation of the patients awareness and willingnessto comply with the study requirements.

2. Female patients who are at least 18 years of age on the day signing informed consent

3. Histologically confirmed locally advanced, recurrent, persistent and/or metastaticVSCC not amenable for salvage surgery or definitive (chemo)radiation (additivepalliative radiotherapy for symptom control is allowed)

4. ≤2 previous lines of chemotherapy for recurrent or metastatic disease

5. Measurable disease (investigator assessed RECIST 1.1). Lesions situated in apreviously irradiated area are considered measurable if progression has beendemonstrated in such lesions.

6. Have an eastern cooperative oncology group (ECOG) performance status of 0-1.Evaluation of ECOG is to be performed within 7 days prior to the first dose of studyintervention.

7. No pregnancy (as documented by a positive beta-human chorionic gonadotropin [ß-hCG]or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L orequivalent units of ß-hCG [or hCG]), no breastfeeding, and at least one of thefollowing conditions applies:

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

9. A WOCBP who agrees to follow the contraception and pregnancy testingrecommendations for investigational medicinal products (IMPs) with demonstratedor suspected human teratogenicity/ fetotoxicity in early pregnancy of theCTFG-guideline in Appendix 4 during the treatment period and for at least 4months (corresponding to time needed to eliminate pembrolizumab) after the lastdose of study treatment. In addition to the described highly effectiveoral/transdermal contraception methods a barrier method must be used. A WOCBP should not become pregnant during the treatment and for at least fourmonths.

10. Available archival tumor tissue sample and/or newly obtained core or excisionalbiopsy of a tumor lesion ideally not previously irradiated. Formalin-fixed, paraffinembedded (FFPE) tissue blocks are preferred to slides.

11. Adequate organ function as defined in Table 3 of study protocol. Specimens must becollected within 10 days prior to the start of study treatment.

Exclusion Criteria:

1. Non squamous cell histology

2. Contraindications regarding treatment with pembrolizumab: allergy or hypersensitivity to pembrolizumab or one of the components.

3. Contraindications regarding treatment with lenvatinib: allergy or hypersensitivityto lenvatinib or one of the components or:

4. Pre-existing ≥Grade 3 gastrointestinal or nongastrointestinal fistula

5. Radiographic evidence of major blood vessel infiltration

6. Bradyarrhythmia

7. Arterial dissection/aneurysm

8. Long QT Syndrome

9. Significant cardiovascular impairment: history of congestive heart failure greaterthan New York Heart Association (NYHA) Class II, unstable angina, myocardialinfarction or stroke within 12 months of the first dose of study drug, or cardiacarrhythmia requiring medical treatment at screening.

10. History or evidence of major thrombotic (e.g. symptomatic pulmonary embolism) orhemorrhagic disorders within 6 months prior to day 1, cycle 1. The degree of tumorinvasion/infiltration of major blood vessels (e.g. carotid artery) should beconsidered because of the potential risk of severe haemorrhage associated with tumorshrinkage/necrosis following lenvatinib therapy.

11. Allogenic tissue/solid organ transplant.

12. Diagnosis of immunodeficiency

13. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considereda form of systemic treatment and is allowed.

14. History of a second malignancy, unless potentially curative treatment has beencompleted with no evidence of malignancy for 2 years (time requirement does notapply for definitively treated early endometrial cancer (FIGO IA/B), in-situcarcinomas [e.g. breast, cervix, bladder], or basal or squamous cell carcinoma ofthe skin).

15. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other conditionthat might affect the absorption of lenvatinib.

16. Active CNS metastases and/or carcinomatous meningitis. Patients with previouslytreated brain metastases may participate provided they are radiologically stable,i.e. without evidence of progression for at least 4 weeks by repeat imaging (notethat the repeat imaging should be performed during study screening), clinicallystable and without requirement of steroid treatment for at least 14 days prior tofirst dose of study intervention.

17. History of (non-infectious) pneumonitis/interstitial lung disease that requiredsteroids or has current pneumonitis/interstitial lung disease.

18. Active infection requiring systematic therapy.

19. Has active hemoptysis within 3 weeks prior to the first dose of study interventionor tumor bleeding within 2 weeks prior randomization.

20. Known history of Human Immunodeficiency Virus (HIV) infection

21. History of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) orknown active Hepatitis C virus (defined as HCV RNA [qualitative] is detected)infection.

22. Known history of active TB (Bacillus tuberculosis).

23. Known psychiatric or substance abuse disorders that would interfere with cooperationwith the requirements of the trial.

24. History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study, interfere with the subject'sparticipation for the full duration of the study, or is not in the best interest ofthe subject to participate, in the opinion of the treating investigator.

25. Pregnancy

26. Breastfeeding Prior/ Concomitant Therapy

27. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agentdirected to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40,CD137).

28. Systemic use of corticosteroids or immunosuppressive drugs within 7 days prior startof study treatment (see EC 11.)

• Systemic corticosteroids (at dose higher than 10 mg/day equivalent prednisone);if systemic corticoid use, corticoid must be stopped at least 7 days beforestudy treatment start

• Interferons

• Interleukins

• Live vaccine Note: Examples of live vaccines include, but are not limited to, the following:measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoidvaccine. Seasonal influenza vaccines for injection are generally killed virusvaccines and are allowed as other killed vaccines, if done at least 2 weeks priorthe first dose of study drug; however, intranasal influenza vaccines (e.g. FluMist®)are live attenuated vaccines and are not allowed.

27. Antiarrhythmics of classes Ia and III and other QT-interval prolongation drugs

28. Prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-lifedrugs] prior to allocation.

29. Prior radiotherapy within 2 weeks of start of study intervention. Patients must haverecovered from radiation-related toxicities, not require corticosteroids, and nothave had radiation pneumonitis. A 1-week washout is permitted for palliativeradiation (≤2 weeks of radiotherapy) to non-CNS disease.

30. Not recovered adequately from any toxicity from other anticancer treatment regimensand/or complications from major surgery prior to starting therapy. Note: Withholdlenvatinib for at least 1 week prior to elective surgery. Do not administer for atleast 2 weeks following major surgery and until adequate wound healing.

31. Administration of a live, attenuated vaccine within 30 days prior first dose ofstudy drug. Diagnostic Assessments

32. Uncontrolled blood pressure (Systolic BP >140 mmHg or diastolic BP >90 mmHg) inspite of an optimized regimen of antihypertensive medication.

33. Change of anti-HTN (hypertension) medical regimen within 1 week prior torandomization

34. Prolongation of corrected QT interval (QTc interval) >480 ms

35. Left ventricular ejection fraction (LVEF) below the institutional normal range asdetermined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).

36. Electrolyte abnormalities that have not been corrected.

37. 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. Prior/Concurrent Study Experience

38. Prior enrolment on a clinical study evaluating pembrolizumab and lenvatinib for acarcinoma, regardless of treatment received.

39. 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 intervention. Note: Patients who have entered the follow-up phase of aninvestigational study may participate as long as it has been 4 weeks after the lastdose of the previous investigational agent.