Targeting the Tumor Microenvironment in R/M SCCHN

Inclusion Criteria: 1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for the translational study. 2. Be 18 years of age on day of signing informed consent. 3. ECOG Performance Status 0-2. 4. Have histologically or cytologically-confirmed recurrent or metastatic (disseminated) head and neck squamous cell carcinoma 5. Have a disease progression after treatment with at least one line of therapy including at least Cisplatin, Fluorouracil and Cetuximab for recurrent (disease not amenable to curative treatment)/metastatic disease. 6. Measurable disease by RECIST criteria. 7. At least one metastatic site suitable for irradiation 8. Life expectancy \> 3 months. 9. Adequate bone marrow function: neutrophils 1.5 x 109/L, platelets 100 x 109/L, hemoglobin 9 g/dL. 10. Adequate liver function: AST and ALT levels 2.5 × ULN; bilirubin 1.5 x ULN. 11. Adequate renal function: creatinine clearance 30 mL/min (Cockroft-Gault). 12. Fertil men must be using adequate contraceptive measures throughout the study period if their partner are women of childbearing potential. 13. If of childbearing potential, women must use effective contraceptive method (Pearl Index \< 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant, transdermal patch, a combination of two barrier methods (condom and diaphragm), sterilisation, sexual abstinence) for the study duration and for at least 6 months after last avelumab treatment administration if the risk of conception exists. Exclusion Criteria: 1. History of malignant disease (with the exception of non-melanoma skin tumours and/or in situ cervical cancer) in the preceding five years. 2. Brain metastases. 3. Autoimmune disorders. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. 4. Allergic disorders. 5. Cyclophosphamide treatment contraindications: 1. Cystitis. 2. Urinary Obstruction. 3. Inadequate bone marrow function: WBC \<2900 mm3 and/or HCT \<30% and/or platelets count \<90000 mm3. 4. Active infections. 5. Pregnancy or breast feeding. 6. Prior treatment with inhibitors of the PD-L1 - PD - 1 axis or inhibitors of CTLA-4 (immune check point inhibitors) 7. Previous HBV or HCV infections. 8. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). 9. Any active infection requiring specific treatment (Antibiotics, antimicotic, antiviral). 10. Radiotherapy within 6 weeks before enrolment 11. Other non-malignant uncontrolled systemic diseases or social conditions that would preclude trial entry in the opinion of the investigator. 12. Prior organ transplantation including allogenic stem-cell transplantation. 13. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines. 14. 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. 15. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; 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. 16. Avelumab treatment contraindications: 1. Hypersensitivity to the active ingredient or to any excipient. 2. Inadequate bone marrow function: WBC \<2900 mm3 and/or HCT \<30% and/or platelets count \<90000 mm3. 3. Uncontrolled serous effusions (pleural, pericardic or peritoneal) 4. Blood Pressure \<60 mmHg. 5. Pregnancy or breast feeding. 6. Active infections. Known history of testing positive for HIV or known acquired immunodeficiency syndrome. 7. Brain metastases. 8. 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. 17. Participation to other concomitant experimental study.