Study to Assess the Efficacy and Safety of Nivolumab in Combination With Paclitaxel in Subjects With Head and Neck Cancer Unable for Cisplatin-based Chemotherapy (NIVOTAX)

Inclusion Criteria:

1. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care.
2. Histologically confirmed HNSCC (oral cavity, oropharynx, hypopharynx, larynx) not amenable to therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
3. Patients not previously treated for recurrent/metastatic disease.
4. Radiographically measurable disease as defined by RECIST version 1.1. Previously irradiated lesions can only be considered as measurable disease if disease progression according to RECIST version 1.1.
5. Patients unable for cisplatin-based chemotherapy, defined "unable" by:

   1. Karnofsky 70% or
   2. Karnofsky 80-100% and amenable to chemotherapy, but:

   i. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine (see annex 5), or

   ii. grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or

   iii. Class III heart failure according to the New York Heart Association (annex 9), or

   iv. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds or

   v. Prior dose of cisplatin ≥225 mg/m² for locally advanced disease (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer can be included), or

   vi. Disease progression or relapse during or within 6 months of receiving platinum-based therapy administered as neoadjuvant, adjuvant therapy or as concomitant chemotherapy with radiotherapy and have received at least 200 mg/m2 of cisplatin.
6. Male or female patients aged ≥18 years. Patients aged ≥70 years old can only be included with a G8 (Geriatric 8) health status screening score ≥ 14.
7. Clinical laboratory values as specified below within 28 days before the first dose of study drug:

   1. Total bilirubin must be ≤2 × the upper limit of normal (ULN).
   2. Magnesium ≥ lower limit of normal.
   3. Calcium ≥ lower limit of normal.
   4. ALT and AST must be ≤3 × ULN unless liver metastases are present, in which case they must be ≤5x ULN.
   5. Hemoglobin must be ≥9 g/dL, absolute neutrophil count (ANC) must be ≥1.500/µL, WBC must be ≥2.000/µL and platelet count must be ≥100.000/µL.
8. Subjects who have received radiation as primary therapy are eligible if radiation therapy treatment was completed \> 4 weeks prior to inclusion.
9. Documentation of PD-L1 status by IHC performed by the central lab at randomization. A pre-treatment tumor tissue sample should be sent. A newly obtained biopsy (within 6 months prior to start of study treatment) is preferred but an archival sample is acceptable, if several tumor samples are available, testing should be performed on the most recently obtained tumor sample.
10. Documentation of HPV p16 status (OPC) is required for HNSCC tumor of the oropharynx. For subjects with oropharyngeal cancer, sites are defined in annex 8. HPV status of tumor tissue has to be locally determined at screening by any of the following methods: p16 IHC, in situ hybridization, or polymerase chain reaction based assay. If HPV status by p16 IHC is positive result confirmation by PCR is mandatory.

Exclusion Criteria:

1. Male or female patients aged \<18 years. Patients aged ≥ 70 years old should not be included with a G8 (Geriatric 8) health status screening score \< 14.
2. Karnofsky \<70%.
3. Patients that meets more than one of the following criteria:

   1. Karnofsky 70%,
   2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine (see annex 5),
   3. Class III heart failure according to the New York Heart Association (annex 9).
4. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy except for alopecia, vitiligo, hear loss and the laboratory values defined in the inclusion criteria.
5. Histologically confirmed recurrent or metastatic squamous cell carcinoma of unknown primary, of the nasopharynx or non-squamous histologies (eg, mucosal melanoma).
6. Active brain metastases or leptomeningeal metastases.
7. Carcinomatous meningitis.
8. Active, known, or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or unexpected conditions of recurrence in the absence of an external trigger are allowed to be included.
9. Diagnosis of immunodeficiency or any condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment.
10. History of pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
11. Patients with a history of interstitial lung disease cannot be included if they have symptomatic ILD (Grade 3-4) and/or poor lung function.
12. Prior therapy with experimental antitumor vaccines; any T-cell co-stimulation agents or inhibitors of checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody; or other agents specifically targeting T cells are prohibited.
13. Any serious medical or psychiatric illness, including drug or alcohol abuse, that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
14. Life-threatening illness unrelated to cancer.
15. Female patients who are lactating and breast-feeding or a positive serum pregnancy test during the screening period.
16. Systemic anticancer treatment or radiotherapy less than 4 weeks or 5 half-lives, whichever is longer, before the first dose of study treatment or not recovered from acute toxic effects from prior chemotherapy and radiotherapy.
17. Prior treatment with investigational agents ≤21 days (≤4 weeks for monoclonal antibodies with evidence of PD) or ≤5 their half-lives (whichever is shorter) before the first dose of study treatment. A minimum of 10 days should elapse from prior therapy to initiating protocol therapy.
18. Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications from surgery.
19. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
20. Known human immunodeficiency virus (HIV) positive (testing not required), or known acquired immunodeficiency syndrome (AIDS).
21. Patients with positive test for hepatitis B virus or hepatitis C virus indicating presence of virus, eg, Hepatitis B surface antigen (HBsAg) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative).
22. Active secondary malignancy that requires treatment. Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required during the study period
23. Any clinically significant co-morbidities, such as uncontrolled pulmonary disease, known impaired cardiac function or clinically significant cardiac disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study.
24. Patients with history of hypersensitivity reactions to study drugs (nivolumab, cetuximab or paclitaxel) or any of their excipients.
25. Symptomatic peripheral neuropathy of Grade ≥ 2 based on the CTCAE v5.0
26. Pulmonary embolism, deep vein thrombosis, or other significant thromboembolic event ≤ 8 weeks prior to starting the study treatment.
27. History of severe skin disorder that in the opinion of the investigator may interfere with study conduct.