A Clinical Study to Assess the Efficacy and Safety of Alpha DaRT224 for the Treatment of Patients With Recurrent Cutaneous Squamous Cell Carcinoma

This is a multi-center clinical study enrolling up to 86 participants. The primary objectives are to determine the objective response rate (ORR) established by the confirmed best overall response (BOR) following intratumoral administration of DaRT - Diffusing Alpha-Emitters Radiation Therapy, as well as to assess the Duration of Response (DOR) 6 months from initial response. Secondary objectives are to assess the safety of DaRT, and to assess the progression free survival (PFS), overall survival (OS), Overall Duration of Response (O-DOR), local control and quality of life (QOL) for patients treated with DaRT.

This study is a prospective multicenter, pivotal, single arm, open label clinical study to assess the efficacy and safety of intratumoral Alpha DaRT-224 for the treatment of patients with recurrent cutaneous squamous cell carcinoma.

The "Diffusing Alpha-emitter Radiation Therapy (DaRT)", based on the interstitial intratumoral placement of an encapsulated Radium-224 source (3.7 days half-life), is described in this study. These sources release short-lived alpha-emitting atoms into the tumor microenvironment by recoil. DaRT seeds will be inserted into recurrent Squamous Cell Carcinoma (SCC) tumors and will be removed following 14-21 days.

The Objective Response Rate (ORR) will be determined based on the confirmed Best Overall Response (BOR) following DaRT insertion. Duration of Response (DOR) will be assessed for up to 6 months from initial response is documented. Safety will be assessed based on the cumulative incidence rate, severity and outcome of device related Adverse Events (AEs). Classification of AEs will be done according to CTCAE v5.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with recurrent cutaneous SCC histologically confirmed who have failed at least first line standard of care therapy who are not indicated for surgery and standard radiation therapy, or non alpha radiation brachytherapy technologies, and for whom no curative systemic treatment is available
2. Central histopathological confirmation within 6 months of enrollment provided no tumor treatment occurred between the biopsy and enrollment
3. Measurable disease according to RECIST v 1.1.
4. Ability to undergo a CT scan
5. Tumor size ≤7 cm, at the longest diameter.
6. Single lesion per subject.
7. Targeted lesion must be technically amenable for complete coverage (including margins) by the DaRT seeds.Targets will be deemed technically amenable for complete coverage if there are entry and exit vectors for placement that are not hindered by bone or major vessels or other vital organs (eg. eye).
8. Interstitial implant indication validated by multidisciplinary team.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.
10. Life expectancy ≥12 months.
11. Subjects male/ female ≥18.
12. Willing and have the ability to provide signed Informed Consent.
13. Patients, male and female, with reproductive potential (including women who are menopausal for less than a year and not surgically sterilized), must practice acceptable effective methods of birth control, such as barrier methods, condom or diaphragm with spermicide or abstinence. Birth control should be continued for 3 months after the DaRT insertion visit.
14. Women with childbearing potential must provide a negative pregnancy test during the screening period and up to V1, prior to the DaRT insertion procedure.
15. Blood tests values:

    * Leucocytes ≥3000mm3,
    * Absolute neutrophil count ≥1500mm3,
    * Platelets ≥100,000 mm3,
    * Total bilirubin ≤ 1.5xULN (upper limit of normal)
    * Aspartate Aminotransferase (AST) ≤2.5xULN,
    * Serum Glutamic-Oxaloacetic Transaminase (SGOT) ≤2.5xULN,
    * Serum Glutamic-Pyruvic Transaminase (SGPT) ≤2.5xULN,
    * Alkaline Phosphatase ≤2.5xULN.
    * Creatinine ≤ 2.0xULN or Creatinine Clearance ≥60 ml/min.
    * INR (International Normalized Ratio) or Prothrombin time ≤1.5xULN.

Exclusion Criteria:

1. Distant or nodal metastatic disease (according to the TNM \[tumor, nodes , and metastases\] staging system - N+ or M1 patients are excluded).
2. T4 disease or perineural spread of disease
3. Previously untreated cutaneous SCC indicated for surgery or radiation.
4. Mucosal, vulvar, anal and penile SCC.
5. Inability to fully cover the entire volume with DaRT seeds
6. Inability to place DaRT seeds into tumor due to inaccessibility by presence of bones or major vessels or vital organs
7. Inability to undergo a CT scan
8. Patients undergoing systemic immunosuppressive therapy excepting intermittent, brief use of systemic corticosteroids.
9. Patients receiving any of the following within 4 weeks of enrollment:

   1. Antineoplastic systemic chemotherapy or biological therapy
   2. Immunotherapy
   3. Investigational agents other than the study intervention
   4. Radiation therapy
   5. Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial.
10. Longest tumor diameter \>7 cm.
11. Tumor with keratoacanthoma histology.
12. Known hypersensitivity to any component of treatment.
13. Clinically significant cardiovascular disease e.g., cardiac failure of New York Heart Association class III-IV, uncontrolled coronary artery disease, cardiomyopathy, uncontrolled arrhythmia, uncontrolled hypertension, history of myocardial infarction in the last 12 months.
14. Any medical or Psychiatric illness, which in the opinion of the investigator would compromise the patient's ability to tolerate treatment and to adhere to the clinical trial protocol.
15. Serious medical comorbidities that, in the opinion of the investigator, may affect subject compliance and/or interpretation of treatment safety or effectiveness.
16. High probability of protocol non-compliance (in opinion of investigator).
17. Volunteers participating in another interventional study in the past 30 days which might conflict with the endpoints of this study or the evaluation of response or toxicity of DaRT.
18. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
19. Patients do not agree to use adequate contraception (vasectomy or barrier method of birth control) prior to study entry and for 3 months after the DaRT insertion visit.
20. Breastfeeding or pregnant women
21. Tattoos or other identifying marks which can not be adequately hidden on digital photos