Evaluation of Bintrafusp Alfa in Operable and Untreated Head and Neck Squamous Cell Carcinoma
Evaluation of Bintrafusp Alfa in Operable and Untreated Head and Neck Squamous Cell Carcinoma
This study is a prospective open label, multicenter, phase II, window-of-opportunity
 preoperative, single-agent trial.

 This study aims to evaluate the efficacy, the safety and tolerability profile of bintrafusp
 alfa in patients with histologically or cytologically confirmed squamous cell carcinoma of
 the oral cavity, oropharynx, larynx or hypopharynx, previously untreated, with indication of
 primary surgery. Patients with a diagnosis of head and neck squamous cell carcinoma (HNSCC)
 from unknown primary will not be enrolled.
The study plans to enrol up to 59 patients in total. Eligible patients who have provided
 their written informed consent for study participation will be assigned to one the 2 cohorts
 described below:

 Cohort A (43 patients): Non-oropharyngeal HNSCC, or Oropharyngeal squamous cell carcinoma
 (SCC) that are human papillomavirus (HPV) negative, or Oropharyngeal SCC that are HPV
 positive and smoker ≥20 pack year (PY).

 A Minimax two-stage Simon design will be used with an unacceptable rate of pathological
 response of 30% or less and a hypothesized actual pathological response rate of 50% or more.

 In the first stage, 28 patients will be accrued. If the observed number of patients with a
 pathological response is 7 or less, then the study for the cohort A will conclude to
 inefficacy and patient recruitment in this cohort will be stopped.

 Cohort B (16 patients): Oropharyngeal SCC that are HPV positive and non-smoker or smoker <20
 PY (former or active).

 The design for this cohort will be a single-stage design.

 All trial-related interventions will be strictly similar for these 2 cohorts.
Inclusion Criteria:

 1. Age ≥18 years

 2. Patients must have signed a written informed consent form prior to any trial specific
 procedures

 3. Histologically or cytologically confirmed HNSCC of the oral cavity, oropharynx, larynx
 or hypopharynx, previously untreated, with indication of primary surgery. Patients
 with a diagnosis of HNSCC of occult primary could not be enrolled.

 In order to avoid repeated biopsies procedures under general anesthesia, patients with
 clinically highly suspected squamous cell carcinoma could be registered before the
 histological or cytological proof. In these cases, the diagnosis will be confirmed
 rapidly after the endoscopy, either by using frozen sections or by reporting the
 results obtained on formalin-fixed paraffin-embedded (FFPE) within no more than 5
 working days.

 4. Absence of distant metastases determined by CT-scan or PET-CT that must be performed
 within 35 days prior to endoscopy.

 5. According to the 7th edition American Joint Committee on Cancer (AJCC) eligible stages
 are as follow:

 T2N1, T2N2, T2N3 T3 or T4 (any N)

 6. Baseline radiology studies evaluating primary tumor (MRI or CT-scan) must be performed
 within 28 days prior to endoscopy.

 7. Patients must have at least 1 lesion superior to 2 cm in larger axis

 8. Eastern Cooperative Oncology Group (ECOG) performance status ≤1

 9. Adequate organ and marrow function as defined by the following laboratory results
 obtained within 28 days prior to the baseline endoscopy:

 1. Hemoglobin (Hb) ≥9,0 g/dL;

 2. Absolute neutrophil count (ANC) ≥1,500/mm³;

 3. Platelet count ≥100,000/mm³;

 4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 ×
 institutional upper limit of normal (ULN);

 5. Total bilirubin ≤1.5 × ULN;

 6. Creatinine clearance >30 mL/min as determined by the Cockcroft-Gault equation
 (Cockcroft and Gault, 1976)

 10. Negative serology for hepatitis B and C

 11. Patients must be willing and able to comply with scheduled visits, treatment plan,
 laboratory tests and other study procedures

 12. Willing and able to provide tumor specimen and blood samples for translational
 research.

 13. Women of childbearing potential must have a negative serum β-human chorionic
 gonadotropin (β-HCG) pregnancy test within 7 days prior to the administration of the
 first study treatment and/or urine pregnancy 48 hours prior to the administration of
 the first study treatment.

 14. Both sexually active women of childbearing potential and males (and their female
 partners) patients must agree to use two methods of effective contraception, one of
 them being a barrier method, or to abstain from sexual activity during the study and
 for at least 2 months after last dose of study drugs.

 15. Absence of any psychological, familial, sociological or geographical condition
 potentially hampering compliance with the study protocol and follow-up schedule; those
 conditions should be discussed with the patient before registration in the trial

 16. Patients must be affiliated to the social security system or equivalent

 Exclusion Criteria:

 1. Primary site of head and neck carcinoma in nasopharynx, sinuses, or skin

 2. Patients receiving other anti-cancer medication such as, chemotherapy, immunotherapy,
 biologic therapy, targeted therapy, monoclonal antibodies, hormonal therapy (other
 than leuprolide or other gonadotropin releasing hormone (GnRH) agonists) or other
 investigational agent within 6 months prior to the first dose of study drug and while
 on study treatment.

 3. Patients receiving other anti-cancer non-drug therapies: radiation, or tumor
 embolization within 6 months prior to the first dose of study drug and while on study
 treatment.

 4. Previous or concurrent cancer within 2 years prior to study inclusion including
 symptomatic, untreated, or actively progressing central nervous system (CNS)
 metastases, with the exception of the following cancer types: in situ carcinomas of
 any location; skin basal cell carcinoma stage T1N0M0 or T2N0M0

 5. Any previous treatment with a PD-1, PD-L1 agent

 6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, active peptic ulcer disease or gastritis, active bleeding diatheses.

 7. Current or prior use of immunosuppressive medication within 28 days before the first
 dose of bintrafusp alfa, with the exceptions of intranasal, intraocular and inhaled
 corticosteroids or systemic corticosteroids at physiological doses, which are not to
 exceed 10 mg/day of prednisone or an equivalent corticosteroid.

 8. Receipt of live attenuated vaccination within 28 days prior to the first
 administration of bintrafusp alfa.

 9. History of (non-infectious) pneumonitis that required steroids within 28 days prior to
 the first administration of bintrafusp alfa or current pneumonitis.

 10. Major surgery within 28 days prior to the first administration of bintrafusp alfa and
 not recovered adequately from the toxicities and/or complications.

 11. Serious, non-healing or dehiscing, wound, active ulcer, or ongoing bone fracture.

 12. Active or prior documented autoimmune disease within the past 2 years. Note: Subjects
 with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
 the past 2 years) can be enrolled

 13. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
 ulcerative colitis)

 14. History of primary immunodeficiency

 15. History of allogenic organ transplant that requires the use of immunosuppressive drugs

 16. Pregnant or breast-feeding women

 17. Any condition that, in the opinion of the investigator, would interfere with
 evaluation of study treatment or interpretation of patient safety or study results

 18. Known positive HIV status

 19. Participation in another clinical study with an investigational product during the
 last 28 days.

 20. Known hypersensitivity to the study drug, study drug classes, or study drug
 excipients.

 21. Patients under guardianship or deprived of his liberty by a judicial or administrative
 decision or any condition (e.g., psychiatric illness/social/familial/geographical
 condition) that would limit compliance with study requirement or compromise the
 ability of the patients to give written informed consent