Cisplatin+Pembrolizumab+RT in Vulvar Cancer

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed unresectable,incompletely resected, recurrent, or metastatic squamous cell carcinoma of thevulva.Patients with unresectable disease are defined as T2 or T3 primary tumors (N0-3, M0) not amenable to surgical resection by standard radical vulvectomy.

• Participants must have measurable disease based on RECIST 1.1. Lesions situated in apreviously irradiated area are considered measurable if progression has beendemonstrated in such lesions.

• 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.

• Prior therapy: Participants with no prior therapy are eligible and patients withrecurrent disease must not have had more than two lines of cytotoxic therapy.Topical or hormonal therapy are not counted towards prior lines. Prior treatmentwith immunotherapy is allowed, provided treatment was not stopped for grade 2 orgreater adverse events.

• Time from prior therapy:

• Systemic anti-neoplastic therapy: 5 half-lives or 4 weeks, whichever isshorter.

• Hormonal therapy is not considered anti-neoplastic therapy.

• Radiotherapy: Any prior irradiation is acceptable provided the site beingconsidered for study has not been previously irradiated.

• Age ≥18 years. Because insufficient dosing or adverse event data are currentlyavailable on the use of pembrolizumab in combination with cisplatin-sensitizedradiation therapy participants <18 years of age, children are excluded. Vulva canceris rare in the pediatric population

• ECOG performance status of 0 or 1.

• Participants must have adequate organ and marrow function as defined below (Table 1):

• Table 1: Adequate Organ Function Laboratory Values

• Hematological

• Absolute neutrophil count (ANC) ≥1500/μL

• Platelets ≥100 000/μL

• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

• Renal

• Creatinine OR Measured or calculated b creatinine clearance (GFR canalso be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥50 mL/minfor participant with creatinine

• Hepatic

• Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participantswith total bilirubin levels >1.5 × ULN

• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants withliver metastases)

• Coagulation

• International normalized ratio (INR) OR prothrombin time (PT)Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unlessparticipant is receiving anticoagulant therapy as long as PT or aPTTis within therapeutic range of intended use of anticoagulants

• ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvictransaminase); AST (SGOT)=aspartate aminotransferase (serum glutamicoxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upperlimit of normal.

• Criteria must be met without erythropoietin dependency and withoutpacked red blood cell (pRBC) transfusion within last 2 weeks.

• Creatinine clearance (CrCl) should be calculated per institutionalstandard.

• Note: This table includes eligibility-defining laboratory valuerequirements for treatment; laboratory value requirements should beadapted according to local regulations and guidelines for theadministration of specific chemotherapies.

• Participant must be female, and is eligible to participate if she is not pregnant (see Appendix B), not breastfeeding, and at least one of the following conditionsapplies:

• Not a woman of childbearing potential (WOCBP) as defined in Appendix B OR

• A WOCBP must agree to use adequate contraception (hormonal or barrier method ofbirth control; abstinence) prior to study entry, during study treatment, andfor at least twelve weeks after the last dose of study treatment. Should awoman become pregnant or suspect she is pregnant while she is pregnant whileshe is participating in this study, she should inform her treating physicianimmediately.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Patients who in the opinion of the investigator cannot safely receive a minimum of 30 Gy in 10 fractions are not eligible for the trial.

• Participants who have received prior systemic anti-cancer therapy includinginvestigational agents within 4 weeks prior to first dose of study treatment. Note:If participant received major surgery, they must have recovered adequately from thetoxicity and/or complications from the intervention prior to starting studytreatment

• Participants must have recovered from all AEs due to previous therapies to ≤Grade 1or baseline.

• 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. Re-irradiation to apreviously treated site will not be permitted.

• Participants who have received a live vaccine within 30 days prior to the first doseof study drug. Examples of live vaccines include, but are not limited to, thefollowing: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever,rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenzavaccines for injection are generally killed virus vaccines and are allowed; however,intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and arenot allowed.

• Participants with vulvar melanomas, sarcomas, extramammary Paget's disease, or basalcell carcinoma

• Participants with a history of gastrointestinal or colovesicular fistulae

• 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.

• 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.

• Has a history of (non-infectious) pneumonitis that required steroids or has currentpneumonitis.

• Has an active infection requiring systemic therapy.

• Patients with a history of other invasive malignancies, with the exception ofnonmelanoma skin cancer, are excluded if there is any evidence of other malignancybeing present within the last five years. Patients are also excluded if theirprevious cancer treatment contraindicates this protocol therapy.

• Participants with uncontrolled intercurrent illness.

• Participants with psychiatric illness/social situations that would limit compliancewith study requirements.

• 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 required.

• Has a known history of active TB (Bacillus Tuberculosis).

• Pregnant or nursing women are excluded from this study because effects of agentsused in this study on infants or the developing human fetus are unknown.

• Presence of other malignancies unless they are considered cured by patient'soncologist.

• 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.

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