This is a multi-center clinical study enrolling up to 30 participants (15 patients in each cohort). The primary objective of the study is to evaluate the safety of Alpha DaRT in combination with chemotherapy, based on the cumulative incidence rate, severity and outcome of device related AEs. Classification of AEs will be done according to CTCAE V5. The secondary objectives of the study are to:

• Assess efficacy of the Alpha DaRT sources in combination with chemotherapy, determined by overall and progression-free survival.
• Assess pain control
• Assess rate of surgical resection in Cohort 1.

This study will be a prospective, interventional, open label, two cohort, multiple center study to assess the efficacy of Alpha DaRT in combination with chemotherapy. Eligible patients with newly diagnosed pancreatic cancer will be categorized into one of the following two cohorts according to their disease state at baseline and the chemotherapy choice at the physician's discretion:

1. Cohort 1: Locally advanced pancreatic cancer treated with mFOLFIRINOX or Gemcitabine/Abraxane
2. Cohort 2: Metastatic pancreatic cancer treated with mFOLFIRINOX or Gemcitabine/Abraxane

Patients will begin mFOLFIRINOX or Gemcitabine/Abraxane treatment depending on their assigned cohort and will undergo DaRT placement during the first 4 cycles of chemotherapy.

Inclusion Criteria:

• Histologically and/or cytologically proven newly diagnosed locally advanced inoperable pancreatic adenocarcinoma (Cohort 1) OR histologically and/or cytologically proven newly diagnosed metastatic pancreatic adenocarcinoma (Cohort 2).
• Patients will start treatment with mFOLFIRINOX (up to 4 cycles) before DaRT insertion
• Target lesion is technically amenable for Alpha DaRT sources implantation.
• Measurable lesion per RECIST (version 1.1) criteria
• Lesion size ≤ 5 cm in the longest diameter
• Interstitial radiation indication validated by a multidisciplinary team.
• ECOG Performance Status Scale 0 -2
• Life expectancy is more than 6 months
• WBC ≥ 3500/μl, granulocyte ≥ 1500/μl
• Platelet count ≥60,000/μl
• Creatinine ≤1.9 mg/dL
• AST and ALT ≤ 2.5 X upper limit of normal (ULN)
• INR < 1.4 for patients not on Warfarin
• Age ≥18 years old
• Subjects are willing and able to sign an informed consent form
• Women of childbearing potential (WOCBP) will have evidence of negative pregnancy test before the Ra-224 implantation and are required to use an acceptable contraceptive method to prevent pregnancy for 3 months after initiation of Alpha DaRT therapy.
• Patients must agree to use adequate contraception (vasectomy or barrier method of birth control) prior to study entry, for the duration of study participation and for 3 months after DaRT insertion.

Exclusion Criteria:

• For Cohort 1 only: Borderline unresectable pancreatic cancer, and/or fit for surgical exploration unless patient refuses surgery.
• For Cohort 1 and Cohort 2: Prior treatment for pancreatic cancer, including chemotherapy except for 1 - 4 cycles of mFOLFIRINOX, radiation therapy, immunotherapy, etc.
• Known hypersensitivity to any of the components of the treatment.
• Patients undergoing systemic immunosuppressive therapy excepting intermittent, brief use of systemic corticosteroids.
• Clinically significant cardiovascular disease, e.g. cardiac failure of New York Heart Association classes III-IV, uncontrolled coronary artery disease, cardiomyopathy, uncontrolled arrhythmia, uncontrolled hypertension, or history of myocardial infarction in the last 12 months.
• Patients with uncontrolled intercurrent illnesses including, but not limited to an active infection requiring systemic therapy or a known psychiatric or substance abuse disorder(s) that would interfere with cooperation with the requirements of the trial or interfere with the study endpoints.
• Has a known additional malignancy that is progressing or requires active treatment.

Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, low risk prostate cancer, or in situ cervical cancer.

• Patient requires treatment not specified in this protocol which may conflict with the endpoints of this study including evaluation of response or toxicity of DaRT.
• Patients do not agree to use adequate contraception (vasectomy or barrier method of birth control) prior to study entry, for the duration of study participation and for 3 months after DaRT insertion.
• 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.
• High probability of protocol non-compliance (in opinion of investigator).
• Breastfeeding women or women of childbearing potential unwilling or unable to use an acceptable contraceptive method to prevent pregnancy for 3 months after DaRT insertion
• Patients who are at high risk of complications from radiation due to genetic conditions/mutations, inflammatory bowel disease, or connective tissue disease.