Cisplatin, Pembrolizumab and Radiation Therapy for the Treatment of Unresectable, Recurrent or Metastatic Vulvar Squamous Cell Cancer

Inclusion Criteria

• Participants must have histologically or cytologically confirmed unresectable, incompletely resected, recurrent, or metastatic squamous cell carcinoma of the vulva. Patients with unresectable disease are defined as T2 or T3 primary tumors (N0-3, M0) not amenable to surgical resection by standard radical vulvectomy. The staging can be confirmed by the referring physician, the treating physician or the overall trial principal investigator (PI)
• Participants must have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Availability of archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. A total of 8-10 unstained slides will be required if FFPE tissue block cannot be provided
• Documented microsatellite stability status by routine methods including MMR immunohistochemistry (IHC), MSI polymerase chain reaction (PCR) or MSI by next generation sequencing (NGS). This assay must be ordered or in process prior to cycle 1 day 1, the results do not need to back prior to registration or start of treatment
• Participants with no prior therapy are eligible. Participants with recurrent disease must not have had more than two lines of cytotoxic therapy. Topical or hormonal therapy are not counted towards prior lines. Prior treatment with immunotherapy is allowed, provided treatment was not stopped for grade 2 or greater adverse events
• Time from prior therapy: * Systemic anti-neoplastic therapy: 5 half-lives or 4 weeks, whichever is shorter. Hormonal therapy is not considered anti-neoplastic therapy * Radiotherapy: Any prior irradiation is acceptable provided the site being considered for study has not been previously irradiated
• Age >= 18 years. Because insufficient dosing or adverse event data are currently available on the use of pembrolizumab in combination with cisplatin-sensitized radiation therapy participants < 18 years of age, children are excluded. Vulva cancer is rare in the pediatric population
• Participants must have a documented Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 obtained during screening. ECOG performance status must re-meet criteria on cycle 1, day 1 (C1D1)
• Absolute neutrophil count (ANC) >= 1500/uL (must be obtained within 28 days prior to first dose of study drug and must re-meet criteria on C1D1)
• Platelets >= 100 000/uL (must be obtained within 28 days prior to first dose of study drug and must re-meet criteria on C1D1)
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (must be obtained within 28 days prior to first dose of study drug and must re-meet criteria on C1D1)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 50 mL/min for participant with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) (must be obtained within 28 days prior to first dose of study drug and must re-meet criteria on C1D1) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (must be obtained within 28 days prior to first dose of study drug and must re-meet criteria on C1D1)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (must be obtained within 28 days prior to first dose of study drug and must re-meet criteria on C1D1)
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (must be obtained within 28 days prior to first dose of study drug and must re-meet criteria on C1D1)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (must be obtained within 28 days prior to first dose of study drug and must re-meet criteria on C1D1)
• Participant must be female, and is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during study treatment, and for at least twelve weeks after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

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 including investigational agents within 4 weeks prior to first dose of study treatment * Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
• Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Re-irradiation to a previously treated site will not be permitted
• Participants who have received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• Participants with vulvar melanomas, sarcomas, extramammary Paget's disease, or basal cell carcinoma
• Participants with a history of gastrointestinal or colovesicular fistulae
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, 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 days prior to first dose of study treatment
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Patients with a history of other invasive malignancies are eligible if they are considered cured by their treating oncologist or the principal investigator (PI) based on chart review. Patients are excluded if their previous cancer treatment contraindicates this protocol therapy
• Participants with uncontrolled intercurrent illness
• Participants with psychiatric illness/social situations that would limit compliance with 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 hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection. Note: no testing for hepatitis B and hepatitis C is required
• Has a known history of active TB (Bacillus tuberculosis)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Participants with a history of allogeneic stem cell transplant or solid organ transplants are excluded
• Has a known history of human immunodeficiency virus (HIV). Note: no testing for human immunodeficiency virus (HIV) is required