Cyclophosphamide and IRX-2 in Treating Women with Cervical Squamous Intraepithelial Neoplasia 3 or Squamous Vulvar Intraepithelial Neoplasia 3

Inclusion Criteria

• Histologically confirmed squamous CIN 3, or VIN 3 (usual type only)
• Female aged >= 25 years
• The subject is either surgically sterile, postmenopausal, or agrees to practice an effective method of birth control as determined by the investigator (to be continued for one year following last dose of study medication), except that subjects with CIN 3 are not permitted to use a cervical cap or diaphragm for contraception
• White blood cell > 2,500/ mcL (> 2.5 x 10^9/L)
• Absolute neutrophil count > 1,000/ mcL (> 1 x 10^9/L)
• Platelet count > 75,000/ mcL (> 75 x 10^9/L)
• Hemoglobin >= 8 g/dL (>= 80 g/L) (subjects who have received a transfusion or erythropoietin up to one week prior to receiving the first dose of cyclophosphamide are eligible for the study)
• International normalized ration (INR) or prothrombin time (PT) =< 1.5 x ULN (upper limit of normal)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN
• Serum creatinine =< 1.5 x ULN
• Total bilirubin =< 2.0 x ULN unless thought to be related to inherited bilirubin conjugation disorder (ie Gilbert’s disease)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
• The subject is geographically accessible for ongoing follow-up and is committed to comply with the designated visits
• The subject is capable of understanding and complying with the protocol and has signed the enrollment informed consent form at screening

Exclusion Criteria

• For subjects with cervical dysplasia: evidence of atypical glandular cells or adenocarcinoma in situ (ACIS) based on cervical cytology, colposcopy or biopsy
• For subjects with either cervical or vulvar squamous dysplasia: evidence of microinvasive squamous carcinoma based on cytology, colposcopy or biopsy
• For VIN subjects, those with > 2 vulvar lesions
• Pregnancy or lactation
• Allergy to ciprofloxacin or other quinolones (because ciprofloxacin is used in preparation of IRX-2)
• Allergy to indomethacin (a necessary component of the regimen) or to acetylsalicylic acid (aspirin) due to likely allergy cross-reaction
• Aldara (imiquimod) for the topical treatment of lower genital tract warts or dysplasia within 3 months of study enrollment
• Known to be positive for human immunodeficiency virus-1 (HIV-1) antibody, human immunodeficiency virus-2 (HIV-2) antibody, hepatitis B surface antigen, or hepatitis C virus antibody
• Known to have other immunodeficiency diseases, including cellular immunodeficiencies, hypogammaglobulinemia, or dysgammaglobulinemia
• Immunotherapy (eg, interferons, tumor necrosis factor, interleukins) or biological response modifiers (granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor) or any investigational drug within 3 months of study enrollment
• Concurrent treatment with systemic corticosteroids at a dose of >= 5 mg/day of prednisone (or equivalent)
• Subjects should not take aspirin (except for low-dose aspirin as prescribed for vascular disease) or other non-prescribed, non-steroidal anti-inflammatory agents from start of treatment to surgery
• An infectious process or any other significant illness such as an autoimmune disease or advanced age that in the opinion of the investigator would compromise the subject’s ability to mount an immune response
• Active SARS-CoV2 infection or coronavirus disease 2019 (COVID-19) disease
• Impaired hepatic, renal or hematological function, evidenced by: * Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin > 2 times upper limit of normal (ULN), * Serum creatinine > 2 times ULN, or
• Clinically significant active cardiovascular disease, including a history of myocardial infarction within the past 6 months, heart failure as defined by New York Heart Association classes III or IV, and/or blood pressure greater than 160/90 mm Hg (1 repeat measure allowed no more than 5 minutes after the first measurement)
• History of severe allergic reaction to insect bites or stings, or to any biologic pharmaceutical product, including compounds similar to the test article
• Any medical contraindications, allergies or previous therapy that would preclude treatment with the components of the IRX-2 regimen, i.e., cyclophosphamide, indomethacin, zinc-containing multivitamins or omeprazole
• Donation or loss of > 450 mL of blood or plasma within 30 days of start of treatment