Study of Cetuximab Plus/Minus Weekly Paclitaxel After Progression To First-Line Pembrolizumab Plus Platinum-5FU in Subjects With Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck.

Inclusion Criteria: \- Informed consent 1. Signed written and voluntary informed consent. 2. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. 3. Age \> 18 years old. Disease characteristics 4. Have histologically confirmed diagnosis of head and neck squamous cell carcinoma. 5. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. 6. Known Human papillomavirus (HPV) status in oropharyngeal primaries and tested by p16 and/or HPV DNA testing by ISH or PCR. Local testing is acceptable. 7. Have confirmed disease progression per RECIST 1.1 on or after receiving platinum / 5-FU and pembrolizumab as first-line therapy for recurrent/metastatic disease. Patients must have measurable disease assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI) based on RECIST 1.1 as assessed by the local site investigator/radiology. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 8. All patients should provide a tumor biopsy obtained prior to the start of cetuximab +/- paclitaxel. A newly obtained biopsy -after progression to pembrolizumab + platinum-based chemotherapy - of a tumor lesion not previously irradiated for central biomarker analysis prior to start of study treatment is strongly recommended, but an archival tumor biopsy sample may be acceptable upon discussion with the sponsor. A second tumor block (FFPE) sample will be strongly recommended to be collected between C2D1 and before C2D15 . Note: Fine needle aspirate \[FNA\] is not adequate. Repeat samples may be required if adequate (quality and quantity) tissue is not provided. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides Patient characteristics 9. Have a performance status of 0 or 1 on the ECOG Performance Scale 10. Patients must have adequate organ function as determined by the following. Screening labs should be performed within -7 days of treatment initiation: a. Hematology * Absolute neutrophils \> 1.5 x 109/L * Platelets \> 100 x 109/L * Hemoglobin \> 90 g/L * Biochemistry * Bilirubin \< 1.5 x upper limit of normal (ULN) * AST and ALT \< 2.5 x ULN * Creatinine or measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5xULN or ≥ 60 mL/min, respectively. 11. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: 1. Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). 2. Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). 12. Female subjects of childbearing potential should have a negative blood pregnancy test within 72 hours prior to receiving the first dose of study medication. A urine test can be considered if a blood test is not appropriate. 13. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication (6 months for paclitaxel). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \>1 year. Note: Abstinence is acceptable if this is the usual lifestyle and preferred method of contraception for the subject. 14. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 180 days after the last dose of study therapy (6 months for paclitaxel). Note: Abstinence is acceptable if this is the usual lifestyle and preferred method of contraception for the subject. Exclusion Criteria: 1. Patients with tumors of the head and neck region, arising from the nasopharynx, nasal cavity, paranasal sinuses, salivary glands, skin, unknown primary site. 2. Patients not treated or not progressing to pembrolizumab + platinum / 5-FU as the first line prior to their enrollment in the study. Progression to platinum / 5-FU plus pembrolizumab or other antiPD-(L)1 agents in combination with other immunotherapies including but not limited to other checkpoint regulatory monoclonal/bispecific antibodies such as anti CTLA-4, anti LAG-3 , anti TIGIT or anti TIM-3 may be allowed upon discussion with the sponsor. 3. Any previous treatment with paclitaxel and/or cetuximab in the recurrent or metastatic setting. 4. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging (using the identical imaging modality for each assessment, either MRI or CT scan) for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 5. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (e.g. tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator. 6. History of another primary malignancy, except for: 1. Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study drug and of low potential risk for recurrence, 2. Adequately treated non-melanoma skin cancer without evidence of disease, 3. Adequately treated carcinoma in situ without evidence of disease. 7. Any previous surgical treatment of the current cancer (except for a diagnostic biopsy) and no major surgery within 28 days prior to study treatment initiation. Performance of a tracheostomy or placement of a percutaneous gastrostomy tube within the 28 days prior to study treatment initiation will be allowed if the patient is clinically stable with no complications derived from those interventions. 8. Focal radiotherapy (RT) with palliative intent that is not completed 2 weeks prior to the first dose of Cetuximab +/- Paclitaxel. 9. History of allergic or hypersensitivity reactions to any study drugs or their excipients. 10. History of allogeneic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of study treatment initiation or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade ≥ 3 infusion reaction. 11. Any concurrent chemotherapy, biologic, immunologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. 12. Current or prior use of immunosuppressive medication within 7 days prior to starting dosing. The following are exceptions to these criteria: 1. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection). 2. Adrenal replacement steroid \> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. 3. Steroids as premedication for hypersensitivity reactions (eg, computed tomography scan premedication). 4. \< 10 mg prednisone or equivalent are permitted for the treatment of G1 IRAEs. 13. Any prior unresolved immune-related (ir) AE Grade \> 2 not properly controlled as described in the exclusion criteria 14 and considered limiting according to physician criteria. 14. History of primary immune deficiency. History of organ transplant that requires use of immunosuppressive medications. Subjects who are human immunodeficiency (HIV) positive. Participants under definitive treatment for HIV (HAART) with undetectable viral load and \>500 CD4+ T lymphocytes per μL at Screening Visit, are allowed. 15. History of stroke or transient ischemic attack within the previous 6 months. 16. Any of the following cardiac abnormalities: 1. Unstable angina pectoris, 2. Congestive heart failure ≥ NYHA Class 2, 3. QTc (Fridericia formula) \> 450 for males and \> 470 ms for females, 4. Known Left ventricular ejection fraction (LVEF) \< 50, 5. Unstable cardiac arrhythmia. 17. Pre-existing neuropathy ≥ Grade 2 per NCI CTCAE v5.0. 18. With history of interstitial lung disease, noninfectious pneumonitis, severe COPD, or uncontrolled lung diseases, including pulmonary fibrosis. However, specific cases may be allowed upon discussion with the sponsor. 19. Has a known history of or is positive for active hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (defined as HCV RNA \[qualitative\] is detected). Note: HBV DNA must be undetectable and HBsAg negative at Screening Visit. Active chronic hepatitis B on antiviral treatment with a negative viral load and preserved liver function is permitted upon consultation with the sponsor. Participants who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at Screening Visit. 20. Female patients who are pregnant or breast-feeding. 21. Uncontrolled intercurrent illness including, but not limited to, ongoing or active clinically significant infection requiring parenteral antibiotics 2 weeks before treatment start, 22. Uncontrolled intercurrent psychiatric illness/social situations that would limit compliance with study requirements. 23. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study regimen or interpretation of patient safety or study results.