Neo-adjuvant Nivolumab or Nivolumab With Ipilimumab in Advanced Cutaneous Squamous Cell Carcinoma Prior to Surgery

This is an investigator-initiated randomized non-comparative phase II trial consisting of 40 patients with resectable stage III-IVa CSCC randomized 1:1 to ARM A: 2 courses of nivolumab 3 mg/kg in week 0 and 2, or ARM B: 2 courses of nivolumab 3 mg/kg in week 0 and 2 plus 1 course of ipilimumab 1mg/kg in week 0. Both treatment arms are neo-adjuvant and applied prior to standard of care (consisting of surgery at week 4 with or without adjuvant radiotherapy).

Inclusion criteria

• Age 18 years or older.
• Patient is able to understand and comply with the protocol requirements and has signed the informed consent form.
• World Health Organization (WHO) Performance Status 0 or 1 (Appendix B).
• Patients with histologically or cytologically confirmed, primary or recurrent stage III-IVA CSCC of all body sites.

OR

Patients with histologically or cytologically proven stage I-II CSCC, only in the case of:

• Presence of multifocal disease for which extensive and/or mutilating surgery is necessary (e.g. near-total scalp resection).
• Situated in an anatomical localization that necessitates extensive and/or mutilating surgery (e.g. orbital exenteration).
• Eligible for standard-of-care, curatively intended surgery with or without adjuvant radiotherapy.
• Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109 /L, Neutrophils ≥1.5x109 /L, Platelets ≥100 x109 /L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN (except subjects with Gilbert Syndrome, who are eligible when total bilirubin < 3.0 mg/dL).
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. They should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of the investigational drug.
• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) prior to the start of nivolumab or nivolumab + ipilimumab.
• Men who are sexually active with WOCBP must use a contraceptive method with a failure rate of less than 1% per year and will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Surgically sterile or azoospermic men do not require aforementioned contraception.

Exclusion criteria

• Distantly metastasized (stadium IVb) CSCC.
• SCC localized in a mucosal surface (i.e. anus, vulva, penis or mucosal portion of lip).
• Patients for whom SOC consists of definitive (brachy)radiotherapy.
• Primary or recurrent CSCC appearing in an area that has been previously irradiated.
• Prior anti-CTLA4 or anti-PD1 immunotherapy.
• Active human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• A positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C antibody (HCV Ab).
• Subjects with any active autoimmune disease or a documented history of autoimmune disease, except for:

• Subjects with vitiligo
• Resolved childhood asthma/atopy
• Residual hypothyroidism due to an autoimmune condition requiring only hormone replacement
• Psoriasis not requiring systemic treatment
• Any condition not expected to recur in the absence of an external trigger.
• Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or AE.
• A concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
• Pregnant or nursing.
• A history of allergy to study drug components and/or a history of severe hypersensitivity to any monoclonal antibody.
• Use of other investigational drugs 30 days before study drug administration and 5 half times before study inclusion.
• Use of prohibited medication at start of study period