Sponsor decision following information on cases of hyperprogression and early toxicities with bintrafusp alfa in other studies

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

Individual Participant Data will not be shared at an individual level. Those data will be part of the study database including all enrolled patients.