A unique approach for cancer treatment employing intratumoral diffusing alpha radiation emitter device (DaRT) as a treatment prior to additional radiation or chemo therapy.

The study is planned as a phase II, single arm interventional, open-label, multi-center, prospective study evaluating DaRT as a neoadjuvant therapy in patients with advanced oral cavity Squamous Cell Carcinoma.

The study will enroll 79 subjects with pathologically confirmed, previously untreated, resectable squamous cell carcinoma of the oral cavity above the age of 18.

This approach combines the advantages of local intratumoral irradiation of the tumor, as used in conventional brachytherapy, with the power of the alpha radiation emitting atoms, that will be introduced in quantities considerably lower than radiation therapy already used in patients.

The target lesion will be inserted with DaRT in a neo-adjuvant setting. DaRT seeds will be removed 15 days following the insertion. Surgery will follow 15 to 20 days after removal of the DaRT seeds followed by standard chemoradiotherapy or radiotherapy alone based on histopathology.

The primary outcome of the study will be the assessment of the major pathological response.

Inclusion Criteria:

1. Pathologically confirmed, previously untreated, resectable squamous cell carcinoma of the oral cavity (no involvement of the lips);

2. T1-T2, N1-N2; T3 N0-2 with T3 <5 cm, depth of infiltration <15 mm, (AJCC version 8 oral cavity);

3. Tumor must be potentially curable by conventional methods;

4. Primary tumor must be amenable for complete coverage (including margins) by the DaRT seeds;

5. Assessment by a Multi-Disciplinary Team (MDT) of the treatment naïve patient and suitable for DaRT based on diagnostic, contrast enhanced whole body PET-CT - and MRI at the discretion of the investigator - within 2 weeks prior to enrolment. MDT preferably composed of a head and neck/ear, nose, and throat (ENT) surgeon, medical oncologist, radiologist, radiotherapist, and pathologist but at least a surgeon and a radiotherapist;

6. Age 18 and older;

7. Eastern Cooperative Oncology Group (ECOG)/ World Health Organization (WHO) Performance status 0-2;

8. Adequate bone marrow function as demonstrated by neutrophils (ANC) ≥ 1,5 109 /L, platelet count ≥ 100 109 /L, leukocytes (WBC) ≥ 3.0 109 /L;

9. Hemoglobin ≥ 9.0 g/dL

10. Calculated creatinine clearance (CL) > 60 mL/min by the Cockcroft-Gault formula;

11. Coagulation parameter (as per institution's standard international normalized ratio (INR), PT or Quick PT) is within the normal ranges, or within the expected target range of their current dose for those patients receiving anticoagulant therapy.

12. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test within 21 days prior to the DaRT insertion.

    Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antioestrogens, low body weight, ovarian suppression or other reasons.

13. Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last dose of treatment.

    Note: A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:

    • Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
    • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
    • Intrauterine device (IUD)
    • Intrauterine hormone-releasing system (IUS)
    • Bilateral tubal occlusion
    • Vasectomized partner
    • Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)

14. Female subjects who are breast-feeding should discontinue nursing prior to starting treatment and until 6 months after the last dose of study treatment;

15. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up;

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

17. Before patient registration/randomization, written informed consent must be given according to International Conference on Harmonization (ICH)/ Good Clinical Practice (GCP), and national/local regulations.

Exclusion Criteria:

1. Floor-of-mouth primaries or extension onto the floor-of-mouth;

2. Documented evidence of distant metastases (M1) based on a diagnostic, contrast-enhanced whole-body PET-CT scan ;

3. Any previous anti-cancer therapy for HNSCC (surgery, chemo, radiotherapy or molecularly targeted therapy);

4. History of another primary malignancy with the exception of:

   • Malignancy treated with curative intent and with no known active disease ≥2 years before enrolment and of low potential risk for recurrence
   • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
   • Adequately treated carcinoma in situ without evidence of disease;

5. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study;

6. 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 enrolment in the trial;

7. Known contraindication to imaging tracer or nay product of contrast media, or MRI contraindications.