The purpose of this study is to perform a pilot phase II trial to evaluate the safety and efficacy of combined EUS-RFA, chemotherapy, and systemic immunotherapy (pembrolizumab) for the treatment of locally advanced unresectable and metastatic Pancreatic ductal adenocarcinoma (mPDAC).

Inclusion Criteria:

• 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

• Biopsy-proven locally advanced unresectable or metastatic PDAC

  1. Patients who have undergone prior resection will be excluded unless there is recurrent pancreatic tumor that is amenable to EUS-RFA.
  2. If biliary metal stent is placed, during procedure of EUS-RFA, indwelling biliary metal stent will be removed during initial EUS-RFA and then replaced with plastic stent.

• Mental capacity to provide informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

• Eastern Cooperative Oncology Group (ECOG) Performance status 0-2

• At least one measurable metastatic lesion on axial imaging per Response Evaluation Criteria in Solid Tumors (RECIST) v1.

• No prior systemic therapy, including chemotherapy or chemoradiation is permitted with the following exceptions:

  1. Prior adjuvant therapy (including chemotherapy and/or radiotherapy) for pancreatic adenocarcinoma is permitted if standard of care neoadjuvant or adjuvant therapy was completed at least 3 months prior to study enrollment. Prior adjuvant therapy may include mFFX, NALIRIFOX, GA or Capecitabine (Xeloda).
  2. If started on first-line treatment for mPDAC elsewhere (i.e., not at our study site), eligible participants can have undergone 3 months of chemotherapy with stable disease before study entry. Note: Imaging done outside the site will need to be reviewed for a 2nd opinion to confirm stable disease.

  i. For patients who had prior treatment and stable disease up to 3 months and confirmed radiographically by our radiology investigators, then patients can proceed with EUS-RFA within 6-8 weeks of enrollment of study.

  c. Patients who have started chemotherapy within a 3-month timeframe are allowed.

• Absolute neutrophil count (ANC) ≥1 x 109/L

• Platelet count ≥75 x 109/L

• Albumin levels ≥3 g/dL

• Total serum bilirubin <2× upper limit of normal (ULN) unless secondary to Gilbert's Syndrome

  a. Subjects requiring biliary decompression, biliary stent, or drainage using percutaneous trans-hepatic cholangiogram are allowed (patients with a declining bilirubin status post stent placement are eligible with serum bilirubin ≤2.5 x ULN)

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤3× ULN, or ≤5× ULN in cases of documented liver involvement

• Serum creatinine clearance must be ≥30 mL/minute either measured or calculated using a standard Cockcroft and Gault formula

• Prior surgery that required general anesthesia or other major surgery as defined by the Investigator must be completed at least 4 weeks before immunotherapy.

Exclusion Criteria:

• No telephone number and permanent street address

• Pregnant or breastfeeding patients; or is a male or female patient of reproductive potential who is not willing to employ effective birth control from time of screening to 90 days after the last dose

• Inmates or prisoners

• Unable to provide informed consent

• Resectable, borderline resectable PDAC.

• Known history of central nervous system (CNS) metastases

• Has a history of another primary malignancy. Patients having the following are still eligible:

  1. No active stage 4 cancer
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  3. Adequately treated carcinoma in situ without evidence of disease

• Known low or absent dihydropyrimidine dehydrogenase (DPD) activity

• Use of strong inhibitors or inducers of Cytochrome P450 3A (CYP3A), CYP2C8 and UGT1A1

• History or evidence of clinically significant or uncontrolled cardiovascular, CNS,and/or other systemic disease that in the investigator's opinion would preclude participation in the study or compromise the patient's ability to give informed consent

• History of HIV or active tuberculosis (TB) (PPD response without active TB is allowed)

• Underlying medical conditions that, in the Investigator's opinion, will make the administration of pembrolizumab hazardous (e.g., interstitial lung disease, active infections requiring antibiotics, recent hospitalization with unresolved symptoms)

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

• Any active autoimmune disease or a documented history of autoimmune disease or history of a syndrome that required systemic steroids or immunosuppressive medications, except for vitiligo or resolved childhood asthma/atopy and the following scenarios below:

  1. Participants with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study.
  2. Physiologic doses of corticosteroids (≤10 mg/day of prednisone or its equivalent) or short pulses of corticosteroids (≤3 days) may be permitted.
  3. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  4. Patients having any chronic skin condition that does not require systemic therapy
  5. Patients without active disease in the last 5 years (allowed only after consultation with the study physician)
  6. Patients with celiac disease controlled by diet alone

• Is currently using or previously used immunosuppressive medication within 14 days before the first dose of pembrolizumab. The following medications are exceptions to this criterion:

  1. intranasal, inhaled, topical steroid, or local steroid injections (e.g., intra articular injection)
  2. Systemic corticosteroids at physiologic doses not to exceed 10mg/day of prednisone or its equivalent
  3. steroids as premedication for hypersensitivity reactions (e.g., computer tomography [CT] scan premedication)