Modulation of the Gut Microbiome With Pembrolizumab Following Chemotherapy in Resectable Pancreatic Cancer

Inclusion Criteria:

• Histologically confirmed pancreatic adenocarcinoma. Histologies other thanadenocarcinoma, or any mixed histologies, will NOT be eligible. *Note: histologymust be confirmed prior to study treatment, however, participants may be consentedto study based on imaging results consistent with pancreatic adenocarcinoma and thenundergo diagnostic and research biopsy simultaneously.

• Clinical stage T1-3, N0-2, M0 (per AJCC 8th ed)

• Resectable pancreatic cancer as defined by NCCN Guidelines 2.2021 and based onpancreatic protocol dual-phase CT imaging. Multi-detector computed tomography (MDCT)angiography, performed by acquiring thin, preferably sub-millimeter, axial sectionsusing a dual-phase pancreatic protocol, with images obtained in the pancreatic andportal venous phase of contrast enhancement, is required.

• No arterial tumor contact (celiac axis [CA], superior mesenteric artery [SMA],or common hepatic artery [CHA])

• No tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) or ≤180° contact without vein contour irregularity

• Age > 18 years

• Patients must agree to pre-treatment biopsy(which may have been collected on auniversal consent), on-treatment biopsy, and definitive surgical resection

• ECOG performance status of 0 or 1

• No prior treatment for diagnosis of pancreatic cancer

• Normal organ and marrow function as defined below:

• Absolute neutrophil count (ANC) ≥1500/µL

• Platelets ≥100 000/µL

• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (Criteria must be met withouterythropoietin dependency and without packed red blood cell (pRBC) transfusionwithin last 2 weeks. )

• Creatinine ≤1.5 × ULN OR Measured or calculated creatinine clearance (Creatinine clearance (CrCl) should be calculated per institutional standard.,GFR can also be used in place of creatinine or CrCl) ≥30 mL/min for participantwith creatinine levels >1.5 × institutional ULN; ; GFR=glomerular filtrationrate; ULN=upper limit of normal .

• Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with totalbilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN; ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) =aspartate aminotransferase (serum glutamic oxaloacetic transaminase);

• International normalized ratio (INR) OR prothrombin time (PT) Activated partialthromboplastin time (aPTT) ≤1.5 × ULN unless participant is receivinganticoagulant therapy as long as PT or aPTT is within therapeutic range ofintended use of anticoagulants

Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

• Ability to understand and sign a written informed consent document. Participant musthave willingness and ability to comply with scheduled visits, treatment plans,laboratory tests and other study procedures.

• A female participant is eligible to participate if she is not pregnant , notbreastfeeding, and at least one of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) OR

• A WOCBP who agrees to follow the study contraceptive guidance during thetreatment period and for at least 120 days plus 30 days (a menstruation cycle)after the last dose of study treatment.

• Males who are sexually active with WOCBP must agree to follow study instructions formethod(s) of contraception for the duration of treatment with study treatment(s) andfor a total of 180 days post treatment completion. In addition, male participantsmust be willing to refrain from sperm donation during this time.

Exclusion Criteria:

• Borderline resectable, locally advanced or distant metastatic disease

• Any medical condition which makes definitive surgical resection of the pancreaticcancer contraindicated due to high risk of morbidity/mortality

• Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency) is not considered a formof systemic treatment.

• Medical history and concurrent disease as below:

-Participants with a condition requiring systemic treatment with eithercorticosteroids (> 10 mg

• Interstitial lung disease that is symptomatic or may interfere with the detection ormanagement of suspected treatment-related pulmonary toxicity.

• Uncontrolled or significant cardiovascular disease including, but not limited to,any of the following:

• Evidence of uncontrolled, active infection, requiring parenteral or oralanti-bacterial, anti-viral or anti-fungal therapy ≤ 28 days prior to screeningon study.

• Participants with a condition requiring chronic systemic oral treatment witheither antibiotics or anti-fungals

• Any uncontrolled inflammatory GI disease including Crohn's Disease andulcerative colitis.

• Participants with active, known, or suspected autoimmune disease.

• Has received a live vaccine or live-attenuated vaccine within 30 days prior to thefirst dose of study drug. *Note: for those participants who will be undergoingplanned splenectomy, vaccinations against S. pneumoniae, N. meningitidis, H.influenzae type b and influenza virus may be administered per standard practice.

• Use of probiotics ≤ 28 days prior to screening on study.

• Known human immunodeficiency virus (HIV), known active Hepatitis A, or knownHepatitis B

• History of acute diverticulitis within the last 6 months or current chronic diarrhea

• Expected to require any other form of antineoplastic or surgical therapy while onstudy.

• Pre-existing peripheral neuropathy > Grade 1, as defined by CTCAE v5.0.

• Pregnant or lactating women.

• A WOCBP who has a positive urine pregnancy test within 72 hours or no pregnancy testprior to registration.

• WOCBP who are unwilling or unable to use an acceptable method to minimize the riskof pregnancy for the entire study period and 120 days plus 30 days (a menstruationcycle) after the last dose of study treatment. WOCBP who are continuously notheterosexually active are also exempt from contraceptive requirements, but stillmust undergo pregnancy testing.

• Sexually active fertile men not using effective birth control if their partners areWOCBP.

• History of primary immunodeficiency.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

• History of organ allograft or allogeneic bone marrow transplant.

• Any prior radiation therapy, immunotherapy, or biologic ('targeted') therapy fortreatment of the patient's pancreatic tumor. Biliary stent is allowed.

• Treatment for other invasive carcinomas within the last two years who are at greaterthan 5% risk of recurrence at time of eligibility screening. Carcinoma in-situ andbasal cell carcinoma/ squamous cell carcinoma of the skin are allowed.

• Participation in any investigational drug study within 4 weeks preceding the startof study treatment.

• Major surgery, excluding laparoscopy, within 4 weeks of the start of studytreatment, without complete recovery.

• History of allergy to study treatments or any of its components.