Study of Monalizumab and Cetuximab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

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. In phase II, measurable disease as per Response Evaluation
Criteria in Solid Tumors [RECIST] 1.1 is mandated. In phase Ib, patients with or
without measurable disease are eligible.

4. Progression after platinum-based chemotherapy

5. For phase Ib only: Pretreated patients, and not amenable to further therapy with
curative intent.

This part is open to pretreated patients regardless of the number of previous
treatment lines.

For phase II 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

For phase II cohort #2: Patients with R/M SCCHN:

1. not amenable to therapy of curative intent,

2. who have received a maximum of two prior systemic regimens in the R/M setting and

3. who have received prior PD-(L)1 blockers

6. No prior treatment with cetuximab except if given for primary treatment (i.e., with
radiation in locally advanced disease) with no progressive disease for at least 4
months following the end of prior cetuximab treatment

7. Recovery from prior surgery and recovery from adverse events to grade 1 or less
(except alopecia) due to prior radiation therapy and any systemic therapy.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

9. Life expectancy of ≥ 3 months

10. Patients with treated brain metastases are eligible if they are > 4 weeks from therapy
completion (including radiation and/or surgery), are clinically stable at the time of
study entry and are not receiving corticosteroid therapy at the time of study entry

11. Adequate hematologic, immunologic, liver and renal function, defined as a. hemoglobin
≥ 9.0 g/dL, b. absolute neutrophil count ≥ 1,500/mm3, c. platelets ≥ 100,000/mm3, d.
total bilirubin ≤ 1.5 X institutional upper normal limit (UNL), e. AST and ALT ≤ 2.5 X
institutional UNL, f. serum creatinine ≤1.5 X institutional UNL or estimated
(Cockroft-Gault formula) or measured creatinine clearance ≥ 50 mL/min

12. Negative serum pregnancy test within 72 hours before starting study treatment for
women of childbearing potential. Women of childbearing potential and all men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of monalizumab administration and
for up to 5 months after the last dose of monalizumab.

13. Ability to understand a written informed consent document

14. Signed informed consent prior to any protocol-specific procedures

Exclusion Criteria:

Patients will not be eligible for the study if they fulfil one or more of the following
exclusion criteria:

1. For phase II only: 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 only: 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 a component of the primary treatment with no progressive
disease for at least 4 months following the end of prior cetuximab treatment

3. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cetuximab; history of severe or unresolved toxicity to prior treatment
with PD-(L)1 blockers (severe AE must have completely resolved or resolved to baseline
prior to screening for this study).

4. Patients with known untreated and uncontrolled brain metastases are excluded. However,
brain-imaging studies are not required for eligibility if the patient has no
neurological signs or symptoms.

5. Serious concurrent uncontrolled medical disorder

6. Auto-immune disease, which

1. currently or previously required systemic immunosuppressive or immunomodulatory
therapy (including corticosteroids administered by systemic route) and/or

2. has a substantial probability to cause an irreversible injury to any tissue
and/or

3. has been diagnosed less than 3 months before study entry and/or

4. is clinically unstable and/or

5. has a substantial risk to progress and cause severe complications

7. Abnormal cardiac status with any of the following:

1. Unstable angina

2. Arrhythmia requiring treatment which is not stabilized by the treatment

3. QTc > 450 ms (M) or 470 ms (F) (Bazett formula -QT Interval / √ (RR interval)
where RR Interval = 60/HR)

8. History of cardiac dysfunction including any of the following:

1. Myocardial infarction within the last 6 months

2. History of documented congestive heart failure (New York Heart Association
functional classification III-IV)

9. Known interstitial lung disease

10. Pregnant women are excluded from this study; breastfeeding must be discontinued

11. Other active invasive malignancy (except for treated basal or squamous cell skin
carcinoma, or in situ cervix carcinoma)

12. Treatment with other investigational agents less than 14 days prior to study entry

13. Systemic treatment with steroids or other immunosuppressive agents within 30 days
prior to entry. Physiological replacement with hydrocortisone or equivalent is
acceptable

14. Current active infection

15. Positive serology for HIV

16. Positive HBs Ag or positive HBV viremia, Positive HCV viremia

17. Psychological, familial, sociological, or geographical conditions that do not permit
medical follow-up and compliance with study protocol.