Table 4.

Inclusion and exclusion criteria for NANORAY-312.

Inclusion criteria		Exclusion criteria
1	Signed ICF	1	HNSCC categories T1, T2 N0, T2 N1, or M1 according to the 8th Edition of the AJCC Cancer Staging Manual
2	Men and women aged ≥60 years	2	Has received prior antineoplastic systemic therapy or intervention (including pharmacological – both marketed and investigational, RT, or surgery) for the treatment of HNSCC
3	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	3	Patients with known severe Grade 3 or 4 hypersensitivity reactions to cetuximab and patients with known prior or ongoing interstitial lung disease to be excluded as a candidate for cetuximab treatment as per the Investigator’s choice before randomization†
4	For participants with oropharyngeal cancer, HPV status must be known	4	Known history of HIV. Chronically ongoing active hepatitis B or C infection as defined in AASLD/EASL guidelines
5	Tumor categories T3–T4 any N or T2, if ≥N2 according to the 8th Edition of the AJCC Cancer Staging Manual	5	Locoregionally recurrent HNSCC that has been previously treated with surgery, chemotherapy, and/or RT are not eligible for the study
6	Has one primary tumor lesion that is amenable for IT injection, as determined by the Investigator	6	Ulceration or other characteristics (e.g., bleeding diathesis) that may, in the opinion of the Investigator, increase the risk of severe tumor bleeding
7	Ineligible to receive platinum based chemotherapy for the treatment of LA-HNSCC as defined by having at least one of the following: Estimated creatinine clearance ≥30 and <50 mL/min (calculated by Cockcroft and Gault) Hearing loss or tinnitus Grade ≥ 2 Grade ≥2 peripheral neuropathy ECOG PS = 2 New York Heart Association (NYHA) Class IIIOR aged 70–74 with Geriatric 8 (G8) score ≤ 14 or aged ≥75 years	7	SCC originating in the nasopharynx, paranasal sinus, salivary gland, or thyroid gland; or non-squamous histology (e.g., melanoma or neuroendocrine carcinoma), or SCC of unknown primary origin
8	Must be able to tolerate RT with curative intent as determined by the study Investigator.	8	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
9	Amenable to definitive treatment with RT. For patients with an oral cavity cancer, the decision for definitive treatment with RT requires consultation with the H&N surgeon and the site’s MDTB	9	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)
10	ECOG PS ≤ 2	10	Class IV congestive heart failure as defined by the NYHA functional classification system <6 months prior to screening
11	Adequate organ and bone marrow function at screening*	11	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)
12	Life expectancy ≥6 months	12	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 patient’s well-being) or that could prevent, limit, or confound the protocol/CIP-specified assessments, including patients under legal protection
		13	Patients participating in another clinical study, except for a non-interventional trial/registry, at the time of signing the ICF
		14	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

^†These patients can still be eligible for the study, only if RT alone or NBTXR3 + RT alone is chosen and documented by the Investigator before randomization. *Adequate organ and bone marrow function at screening, define as: (i) hemoglobin >9.0 g/dL; (ii) platelet count > 100,000 cells/mm³; (iii) leukocytes > 3000 cells/mm³; (iv) absolute neutrophil count > 1500 cells/mm³; (v) ALT ≤ 3 × ULN; (vi) AST ≤ 3 × ULN; (vi) total bilirubin ≤1.5 mg/dL (in patients 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 patient may be eligible); (vii) total serum magnesium within normal ranges if the patients is a candidate for cetuximab treatment as per the Investigator’s choice prior to randomization; and (vii) estimated creatinine clearance ≥30 mL/min (calculated by Cockcroft and Gault).

AASLD, American Association for the Study of Liver Diseases; AJCC, American Joint Committee on Cancer; EASL, European Association for the Study of the Liver; ECOG, Eastern Cooperative Oncology Group; H&N, head and neck; HNSCC, head and neck squamous cell carcinoma; HIV, human immunodeficiency virus; HPV, human papilloma virus; ICF, informed consent form; IT, intratumoral; LA, locally advanced; LN, lymph node; MDTB, multidisciplinary tumor board; NYHA, New York Heart Association; PS, performance status; RT, radiotherapy; SCC, squamous cell carcinoma; ULN, upper limit of normal.