Endoscopic Ultrasound Radiofrequency Ablation and Immunotherapy Pembrolizumab for Locally Advanced Unresectable and Metastatic Pancreatic Duct Adenocarcinoma

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

• Patients who have undergone prior resection will be excluded unless there is recurrent pancreatic tumor that is amenable to EUS-RFA.
• 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:

• 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).
• 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:

• No active stage 4 cancer
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• 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:

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

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