The objective of this study is to evaluate in a 3 +3 design, the safety of escalating doses of Monalizumab given IV in combination with cetuximab in patients who have received prior systemic regimen(s) for recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Cohorts expansion will evaluate antitumor activity of monalizumab and cetuximab with or without anti-PD(L)1

Main Inclusion Criteria:

1. Age ≥ 18 years
2. Histologically or cytologically-confirmed, HPV (+) or HPV (-) squamous cell carcinoma of the nasopharynx (WHO Type 1), oropharynx, hypopharynx, larynx (supraglottis, glottis, subglottis) or oral cavity.
3. Recurrent or metastatic disease, documented by imaging (CT scan, MRI, X-ray) and/or physical examination with measurable disease as per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1

For phase II cohorts:

• Cohort #1: Patients who received a maximum of two prior systemic regimens for recurrent and/or metastatic disease and not amenable to further therapy with curative intent
• Cohort #2: Patients with R/M SCCHN not amenable to therapy of curative intent, who have received a maximum of two prior systemic regimens in the R/M setting and who have received prior PD-(L)1 blockers
• Cohort #3: Patients with R/M SCCHN who have not received prior systemic regimens in the R/M setting and who have not received prior PD-(L)1 inhibitors

Main Exclusion Criteria:

1. For phase II cohort #1 and cohort #2: Patients who received more than 2 prior systemic regimens for recurrent and/or metastatic disease (no restriction in the phase Ib part of the trial).
2. For phase II cohort #1 and cohort #2: Patients who received cetuximab or another inhibitor of epidermal growth factor receptor are excluded from the phase II of the trial, except if cetuximab was given as part of a primary treatment approach, with no progressive disease for at least 4 months following the end of prior cetuximab treatment.