Cetuximab + Avelumab or Avelumab Alone for Unresectable, Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (SCCAC) Progressed After at Least One Line of Systemic Treatment (CARACAS)

Inclusion Criteria: * Histologically proven diagnosis of SCCAC; * Progression on or after first line systemic therapy for surgically unresectable or metastatic disease. Systemic radiosensitizing chemotherapy with curative intent in limited-stage disease should be considered equal to a first line for a patient experiencing progression during or within 6 months of completion; * Evaluable disease lesion according to RECIST v1.1 criteria; * Availability of tumor sample (primary and/or metastatic sites); * Age ≥ 18 years; * Eastern Cooperative Oncology Group - Performance Status (ECOG PS) ≤ 2; * Life expectancy of at least 12 weeks; * Laboratory Requirements: Neutrophils ≥ 1.5 x 109 /L; Platelets ≥ 100 x 109 /L; Hemoglobin ≥ 9 g/dL; Total bilirubin ≤ 1.5 time the upper-normal limits (UNL) of the normal values and ASAT (SGOT) and/or ALAT (SGPT) ≤ 2.5 x UNL (or \<5 x UNL in case of liver metastases); Alkaline phosphatase ≤ 2.5 x UNL (or \<5 x UNL in case of liver metastases); Creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) or serum creatinine ≤1.5 x UNL; * HIV-positive patients are eligible if their CD4+ cell count amounts to 300 cells per μL or more; HIV viral load has to be undetectable, and they have to be compliant with antiretroviral treatment; * Negative serum or urine pregnancy test at screening for women of childbearing potential. Female subjects, or male subjects with female partners of child-bearing potential must be willing to use highly effective contraception as approved by the investigator (i.e. barrier contraceptive measure or oral contraception, total abstinence) during the study and until 30 days after last study treatment; * Written informed consent to the study procedures and to molecular analyses before patients registration; * Will and ability to comply with the protocol. Exclusion Criteria: * Previous therapy with any drug targeting T-cell co-regulatory proteins (i.e., immune checkpoint inhibitors); * Concurrent anticancer treatment or use of any investigational drug within 28 days before the start of the trial treatment; * Major surgical procedure, open biopsy, or significant traumatic injury occurred within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study; * History or evidence upon physical examination of CNS disease unless adequately treated. Patients with treated brain metastases are eligible if their lesions were stable and asymptomatic for at least 3 months; * Neutrophils \< 1.5 x 109/L; Platelets \< 100 x 109/L; Hemoglobin \< 9 g/dL; * Active uncontrolled infections requiring systemic therapy or other clinically relevant concomitant illness contraindicating therapy administration or putting the patient at high risk for treatment-related toxicities; * Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive); * Patients with active autoimmune disease or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent or might potentially affect vital organ function, or require use of immunosuppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use for ≥ 1 month). Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible; * Current use of immunosuppressive medication, EXCEPT for the following: 1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); 2. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; 3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication); * Prior organ transplantation including allogenic stem-cell transplantation; * Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines; * Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma; * Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication; * Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonia, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study; * Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade \> 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable; * Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma of the skin or cervical cancer in situ; * Pregnant or lactating women; * Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.