Phase 3 Study of NBTXR3 with Radiotherapy ± Cetuximab in Elderly Patients Ineligible for Platinum-Based Chemotherapy with Locally Advanced Head and Neck SCC

Trial ID: 2024-513082-39-00
Protocol: NANORAY-312
Sponsor: Nanobiotix

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Diseases & Conditions

Head and neck cancer

Objectives

The primary objective of this Phase 3 study is to evaluate **survival outcomes** in patients with **Locally Advanced Head & Neck Squamous Cell Carcinoma** who are treated with intratumorally injected NBTXR3 activated by the investigator's choice of radiotherapy (RT) alone or RT in combination with **cetuximab**, compared to the investigator's choice of RT alone or RT with cetuximab. This evaluation is clinically relevant as it aims to determine the efficacy of NBTXR3 in enhancing the therapeutic effects of RT, potentially improving survival rates in a population that is ineligible for platinum-based chemotherapy.

Secondary objectives include evaluating long-term survival outcomes of NBTXR3/RT±cetuximab versus RT±cetuximab. This assessment will provide insights into the sustained benefits of the treatment regimen over an extended period, which is crucial for understanding the long-term impact on patient prognosis and quality of life.

Participants

The clinical trial involves a total of **275 participants** diagnosed with **Locally Advanced Head & Neck Squamous Cell Carcinoma**. The study population includes both male and female subjects, with an age range starting from **60 years** and above. Participants were selected based on specific inclusion criteria, including a biopsy-confirmed diagnosis of squamous cell carcinoma in specified regions such as the oral cavity, oropharynx, hypopharynx, or supraglottic larynx. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and a life expectancy of at least six months. They must also demonstrate adequate organ and bone marrow function. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial excludes individuals eligible for platinum-based chemotherapy and those unable to tolerate radiotherapy with curative intent. The selection process ensures that participants have a primary tumor lesion suitable for intratumoral injection, as determined by the investigator.

Plans and Procedures

The clinical trial is designed to evaluate the **survival outcomes** in elderly patients with **locally advanced head and neck squamous cell carcinoma** who are ineligible for platinum-based chemotherapy. This is a Phase 3, randomized, double-blind, controlled study comparing the efficacy of intratumorally injected NBTXR3 activated by radiotherapy (RT) alone or in combination with **cetuximab** against RT alone or in combination with cetuximab. The trial is expected to run from September 2022 to April 2027, with the primary endpoint being progression-free survival (PFS) and the secondary endpoint being overall survival (OS).

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment. The expected length of participant involvement is approximately five years, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

Key elements of the research methodology include the use of a double-blind design to minimize bias, and the control group receiving standard RT with or without cetuximab. The trial will ensure rigorous monitoring of safety and efficacy, with data collected at each visit to assess the impact of the investigational treatment. Participants will be closely monitored for any adverse reactions, particularly those related to the investigational product and the combination therapy. The study aims to provide valuable insights into the potential benefits of NBTXR3 in enhancing the effects of radiotherapy in this patient population.

Treatment

The clinical trial involves the administration of **Erbitux**, a **solution for infusion** containing the active substance **cetuximab**. Erbitux is provided in a concentration of 5 mg/mL and is administered via **intravenous use**. The dosing regimen for cetuximab involves a maximum daily dose of 400 mg/m², with a total maximum dose not exceeding 1900 mg/m² over a treatment period of up to 7 days. Cetuximab is a protein of biological origin, specifically classified as "Protein - Other," and is manufactured by Merck Europe B.V. The pharmaceutical form of Erbitux is a solution for infusion, and it is not formulated for pediatric use.

In addition to the experimental treatment with Erbitux, the study also involves the use of NBTXR3, a sterile implantable nanomaterial. NBTXR3 is an aqueous suspension comprising crystalline metal oxide or metal nanoparticles, designed to be administered directly into a tumor. This administration is intended to enhance the absorption of therapeutic ionizing radiation. The use of NBTXR3 is activated by the investigator's choice of radiotherapy, either alone or in combination with cetuximab, depending on the treatment arm of the study. The device associated with NBTXR3 has been certified with a CE mark by GMED Groupe LNE, France.

Efficacy

Efficacy in this clinical trial will be assessed using specific endpoints to evaluate the treatment outcomes for elderly patients with locally advanced head and neck squamous cell carcinoma. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization to loco-regional recurrence, loco-regional progression, distant progression, or death from any cause, whichever occurs first. The secondary endpoint is **Overall Survival (OS)**, which measures the time from randomization to death from any cause.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent form (ICF) indicating that the subject understands the purpose of, and procedures required for the study, and is willing to participate in the study
Age ≥60 years
Biopsy-confirmed SCC of the oral cavity, oropharynx, hypopharynx or supraglottic larynx (archived biopsies are allowed); if no biopsies are available, a new biopsy must be obtained to provide confirmation of SCC
For subjects with oropharyngeal cancer, HPV status must be known
Tumor categories T3-T4 any N or T2, if ≥N2 according to the 8th Edition of the AJCC Cancer Staging Manual
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: a. Estimated creatinine clearance ≥30 and <50 mL/min (calculated by Cockcroft and Gault) b. Hearing loss or tinnitus Grade ≥2 c. Grade ≥2 peripheral neuropathy d. ECOG performance status=2 e. New York Heart Association (NYHA) Class III OR Aged 70-74 with Geriatric 8 (G8) score ≤14 or aged ≥75 years
Must be able to tolerate RT with curative intent as determined by the study Investigator.
Amenable to definitive treatment with RT. Subjects 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: a. Hemoglobin >9.0 g/dL b. Platelet count ≥100,000 cells/mm3 c. Leukocytes >3000 cells/mm3 d. Absolute neutrophil count >1500 cells/mm3 e. Alanine aminotransferase (ALT) ≤3×upper limit of normal (ULN) f. Aspartate aminotransferase (AST) ≤3×ULN g. Total bilirubin ≤1.5 ULN (in subjects 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 subject may be eligible) h. Total serum magnesium within normal ranges if the subject is a candidate for cetuximab treatment as per the Investigator's choice prior to randomization. i. Estimated creatinine clearance ≥30 mL/min (calculated by Cockcroft and Gault)

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Exclusion Criteria

HNSCC category T1, T2 N0, T2 N1, or M1 according to the 8th Edition of AJCC Cancer Staging Manual.
Has received prior antineoplastic systemic therapy or intervention (including pharmacological - both marketed and investigational, RT, or surgery) for the treatment of HNSCC
Subjects with known severe Grade 3 or 4 hypersensitivity reactions to cetuximab and subjects 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 subjects can still be eligible for the study, only if RT alone or NBTXR3+RT alone is chosen and documented by the Investigator before randomization)
Known history of HIV, Chronically ongoing active hepatitis B, or chronically ongoing active hepatitis C infection as defined in AASLD/EASL guidelines
Loco-regionally recurrent HNSCC that has been previously treated with surgery, chemotherapy and/ or RT are not eligible for the study.5. Loco-regionally recurrent HNSCC that has been previously treated with surgery, chemotherapy and/ or RT are not eligible for the study.
Ulceration or other characteristics (e.g. bleeding diathesis) that may, in the opinion of the Investigator, increase the risk of severe tumor bleeding
SCC originating in the nasopharynx, paranasal sinus, salivary gland, or thyroid gland; non-squamous histology (e.g., melanoma or neuroendocrine carcinoma), or SCC of unknown primary origin
Prior or concurrent malignancy (including a second synchronous HNSCC) whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen except when: • The risk of the prior malignancy interfering with either safety or efficacy endpoints is very low; and if all treatment of that malignancy was completed at least 2 years before randomization and the subject has no clinical evidence of disease recurrence • This exception includes completely resected/treated non-melanoma skin cancer, cervical uterine cancer, T1 N0 M0 invasive hormone-sensitive breast cancer, hormone- sensitive prostate cancer with a Gleason score of 6, and completely resected non muscle invasive bladder cancer
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 NYHA 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 the time that the ICF is signed through 150 days (18 months for South Korean subjects) after the last cetuximab dose/RT fraction. A woman who is ≥ 1 year postmenopausal or who is surgically sterile is not considered to be of childbearing potential (pregnancy test is not required).
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 subject's well-being) or that could prevent, limit, or confound the protocol/CIP specified assessments, including subjects under legal protection.
Ongoing or active bacterial or fungal infection (includes infection requiring treatment with antimicrobial therapy for which participants will be required to complete 2 weeks before randomization), symptomatic viral infection, any other clinically significant infection, or use of immune suppressive agents.
Subject participating in another clinical study, except for a non interventional trial/registry at the time of signing the ICF