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)
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)
Chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma is palliative
 and usually platinum based, and the patients often present with poor physical condition.
 Consequently, many of them are not able to withstand a platinum-based chemotherapy. The
 addition of taxanes to the armamentarium of drugs improve the outcome in this group of
 patients. An alternative and better tolerated regimen for these patients is paclitaxel in
 combination with cetuximab, included the in guidelines of the Spanish Society of Medical
 Oncology.

 Recently, new treatments such as immune-checkpoint inhibitors have shown promising activity
 and good tolerability in patients with recurrent or metastatic head and neck squamous cell
 carcinoma and has been included in the recently published guidelines from the Society for
 Immunotherapy of Cancer. Nivolumab (anti-PD1) has been approved for patients progressing on
 or after platinum-based therapy, as it clearly impacts on overall survival.

 This randomized phase II study will evaluate the efficacy of nivolumab plus paclitaxel for
 first-line treatment of recurrent or metastatic HNSCC in the platinum ineligible and platinum
 refractory settings. Control arm will be paclitaxel in combination with cetuximab, treatment
 included in the guidelines of the Spanish Society of Medical Oncology.
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.