Vulvar Cancer Clinical Trials

⁃ Target subject population Inclusion Criteria

• Signed informed consent prior to any study specific procedure;

• Female, age ≥ 18 years at time of signing informed consent;

• Patients with histologically or cytologically confirmed unresectable squamous cell carcinoma, adenocarcinoma and mixed histology (adenosquamous) of the vulva, defined as:

∙ T2 or T3 primary tumors (N0-3, M0) not amenable to surgical resection by standard radical vulvectomy (Cohort A) OR

‣ recurrent or de novo metastatic chemotherapy-naive vulvar squamous cell carcinoma, adenocarcinoma and mixed histology (adenosquamous) of the vulva, (Cohort B) OR

‣ recurrent squamous cell carcinoma of the vulva after primary chemoradiation or patients with metastatic squamous cell carcinoma, adenocarcinoma and mixed histology (adenosquamous) of the vulva in progression to a chemotherapy-based treatment (Cohort C)

• At least 1 measurable target lesion according to RECIST 1.1;

• Patients must have a life expectancy ≥ 16 weeks;

• ECOG performance status of 0 to 1;

• Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤140/90 mmHg at Screening and no change in antihypertensive medications within 1 week before the Cycle 1/Day 1;

• Patient must provide formalin fixed paraffin embedded (FFPE), archival tumor samples, from primary tumor surgery or biopsy of primary tumor or metastases. The samples must be collected before any systemic treatment. (chemotherapy-naïve patients). A quality control analysis of samples will be performed before patient's enrollment. Only patients with adequate tumor samples will be enrolled.

• Patient must be able to take oral medications;

⁃ Patients must have normal organ and bone marrow function measured as defined below:

∙ Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

‣ Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

‣ Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN

‣ Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine clearance = (140-age \[years\]) x weight (kg)(x F)a serum creatinine (mg/dL) x 72 (a where F=0.85 for females)

⁃ INR or PT aPTT/PTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants;

⁃ Patient is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

• Is not a Women of Childbearing Potential (WOCBP) or

∙ Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix 1 during the intervention period and for at least 4 months post pembrolizumab or 30 days post lenvatinib, whichever occurs last. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention

⁃ A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention; Note: If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive;

⁃ Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.