NBTXR3 With or Without Cetuximab in LA-HNSCC

Study Overview
=================
Brief Summary
-----------------
This is a global, open-label, randomized, 2-arm, Investigator's choice Phase 3 (Pivotal Stage) study to investigate the efficacy/performance and safety of NBTXR3/RT±cetuximab versus RT±cetuximab in treatment-naïve, platinum-ineligible, elderly participants with LA-HNSCC.

Detailed Description
-----------------
This is a global, open-label, randomized, 2-arm, Investigator's choice Phase 3 (Pivotal Stage) study to investigate the efficacy/performance and safety of NBTXR3/RT±cetuximab versus RT±cetuximab in treatment-naïve, platinum-ineligible, elderly participants with LA-HNSCC. Participants will undergo a screening assessment over a period of ≤28 days to determine eligibility. One primary tumor lesion that is amenable for intratumoral injection, as determined by the Investigator Eligible participants will be treated by the Investigator's choice of RT alone or RT in combination with cetuximab. Following the Investigator's choice, participants will be randomized in a 1:1 ratio on Day: Arm A: NBTXR3, as an intratumoral/intranodal injection, activated by investigator's choice of RT alone or RT in combination with cetuximab Arm B: Investigator's choice of RT alone or RT in combination with cetuximab All participants (Arm A and Arm B) will receive 70 Gy in 35 fractions over a 7 week period. An EOT visit will be performed 4 weeks after the completion of RT. Follow-up visits will start at 12 weeks post-RT completion, and will continue every 12 weeks for 2 years, and then every 24 weeks thereafter until death; the participant is determined to be lost to follow up; withdrawal of consent; or the end of the study, whichever occurs first. Participants who have received further anti-cancer therapy for the study disease and/or have had disease progression/recurrence will be followed only for survival information

Official Title
-----------------
A Phase 3 Study of NBTXR3 Activated by Investigator's Choice of Radiotherapy Alone or Radiotherapy in Combination With Cetuximab for Platinum-based Chemotherapy-Ineligible Elderly Patients With LA-HNSCC

Conditions
-----------------
Locally Advanced Head and Neck Squamous Cell Carcinoma, Aged

Intervention / Treatment
-----------------
* Drug: NBTXR3
* Drug: Cetuximab
* Radiation: Radiation Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for the study, and is willing to participate in the study Age ≥65 years Biopsy-confirmed squamous cell carcinoma (SCC) of the oral cavity, oropharynx, supraglottic larynx, or hypopharynx (archived biopsies are allowed); if no biopsies are available, a new biopsy must be obtained to provide confirmation of SCC For participants with oropharyngeal cancer, human papilloma virus (HPV) p16 status must be known Tumor categories T3-T4 any N or T2, if ≥N2 according to the 8th edition of the American Joint Committee on Cancer Staging Manual (AJCC v8) Has one primary tumor lesion that is amenable for intratumoral injection, as determined by the Investigator Ineligible to receive platinum-based chemotherapy for the treatment of LA HNSCC as defined by having at least one of the following: Aged ≥75 years Estimated creatinine clearance ≥30 and <50 mL/min (calculated by Cockcroft and Gault) Hearing loss or tinnitus Grade ≥2 Grade ≥2 peripheral neuropathy ECOG = 2 New York Heart Association (NYHA) class III Must be able to tolerate RT with curative intent as determined by the study Investigator. Amenable to definitive treatment with RT. Participants with an oral cavity cancer, should not be eligible to the primary standard treatment, which is surgery, and the decision for definitive treatment with RT requires consultation with the head and neck surgeon and the site's multidisciplinary tumor board. ECOG performance status of 0 to 2 Life expectancy ≥6 months Adequate organ and bone marrow function at screening as defined by: Hemoglobin >9.0 g/dL Platelet count >100,000 cells/mm3 Leukocytes >3000 cells/mm3 Absolute neutrophil count >1500 cells/mm3 Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤3×ULN Total bilirubin ≤1.5 mg/dL (in participants with Gilbert's syndrome, if total bilirubin is >1.5×ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5×ULN, the participant may be eligible) Total serum magnesium within normal ranges (1.7-2.2 mg/dL or 0.85 to 1.10 mmol/L) if the participant is a candidate for cetuximab treatment as per the Investigator's choice prior to randomization Exclusion Criteria: HNSCC category T1, T2N0, T2N1 or M1 according to the 8th edition of the American Joint Committee on Cancer Staging Manual (AJCC v8) Has received prior antineoplastic systemic therapy or intervention (including pharmacological - both marketed and investigational, RT, or surgery) for the treatment of HNSCC Participants with known severe Grade 3 or 4 hypersensitivity reactions to cetuximab and participants with known prior or ongoing interstitial lung disease must be excluded as a candidate for cetuximab treatment as per the Investigator's choice before randomization (these participants can still be eligible for the study, only if RT alone is chosen by the Investigator before randomization) Known history of human immunodeficiency virus (HIV) Chronically ongoing active hepatitis B, or chronically ongoing active hepatitis C infection as defined in AASLD (American Association for the Study of Liver Diseases)/EASL (European Association for the Study of the Liver) guidelines Local regionally recurrent HNSCC that has been previously treated with chemotherapy and/or RT are not eligible for the study Ulceration or other characteristics that may, in the opinion of the Investigator, increase the risk of severe tumor bleeding SCC originating in the nasopharynx or paranasal sinus, from the salivary gland, or thyroid gland, or non-squamous histology (e.g., melanoma or neuroendocrine carcinoma), or SCC of unknown primary origin Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes, second- or third-degree atrioventricular heart block without a permanent pacemaker in place) Class IV congestive heart failure as defined by the New York Heart Association functional classification system <6 months prior to screening A pregnant or nursing woman, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception starting from signed ICF through 150 days after the last cetuximab dose/RT fraction. A woman who is ≥1 year postmenopausal or surgically sterile is not considered to be of childbearing potential. Ongoing areca nut (betel nut) consumption within 6 months prior to randomization Any condition for that, in the opinion of the Investigator, participation would not be in the best interest of the individual (e.g., compromises the participant's well-being) or that could prevent, limit, or confound the protocol/CIP specified assessments, including subjects under legal protection Subject participating in another clinical study at the time of signature of the informed consent form

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>NBTXR3, as an intratumoral/intranodal injection, activated by investigator's choice of RT alone or RT in combination with cetuximab. NBTXR3 is given as a single intratumoral injection as a dose of 33% of the Gross Tumor Volume | Drug: NBTXR3<br>* Suspension of inert, crystalline hafnium oxide particles, designed to generate oxygen free radicals to destroy cancer cells after activation by ionizing radiation.<br>* Other names: Functionalized hafnium oxide nanoparticles;Radiation: Radiation Therapy<br>* Intensity-modulated radiation therapy (IMRT): 70 Gray in 35 fractions over a 7-week period.<br>|
| Active Comparator: Arm B<br>Investigator's choice of RT alone or RT in combination with cetuximab | Drug: Cetuximab<br>* Solution for infusion<br>* Other names: Erbitux;Radiation: Radiation Therapy<br>* Intensity-modulated radiation therapy (IMRT): 70 Gray in 35 fractions over a 7-week period.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Time from randomization to local-regional recurrence, local-regional progression, distant progression, or death from any cause, whichever occurs first | 30 months following first randomized participant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from randomization to death from any cause | 48 months following first randomized participant | 
| Local-regional control | Time to local regional progression: time from Randomization to local-regional progression or death, whichever occurs first | 48 months following first randomized participant | 
| Distant control | Time to distant progression: time from Randomization to distant progression or death, whichever occurs first | 48 months following first randomized participant | 
| Objective Response Rate (ORR) | Rate of complete response (CR)+partial response (PR) [RESIST 1.1] | 48 months following first randomized participant | 
| Duration of Overall Response | Time from CR or PR to progression of disease, unequivocal clinical progression, or death, whichever occurs first | 48 months following first randomized participant | 
| Quality of Life over time - QLQ H&N35 | Change from baseline over time in symptoms, function, and health related QOL using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire-Head and Neck Cancer Module (QLQ H&N35) | 48 months following first randomized participant | 
| Quality of Life over time - EQ 5D 5L | Change from baseline over time in symptoms, function, and health related QOL using the 5 level EuroQol 5 dimension (EQ 5D 5L) instrument | 48 months following first randomized participant | 
| Safety across duration of study - AEs | Adverse events (AEs) | 48 months following first randomized participant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Radiotherapy, RT, HNSCC, LA-HNSCC, NBTXR3, hafnium oxide, radioenhancer