Chemo4METPANC Combination Chemokine Inhibitor, Immunotherapy, and Chemotherapy in Pancreatic Adenocarcinoma

Inclusion criteria:

1. Histological or pathological confirmation of metastatic pancreas adenocarcinoma

2. Cytologic or histologic proof of pancreas adenocarcinoma needs to be verifiedby the treating institution pathologist, either from the initial diagnosticbiopsy or from the required pre-treatment biopsy, prior to initiation of anystudy-related therapy.

3. Pathologic confirmation of metastatic (stage IV) disease (unresectable) onresearch pretreatment biopsy is required prior to initiation of therapy.

4. Patients with endocrine or acinar pancreatic carcinoma are not eligible for thestudy.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

6. Age ≥18 years

7. Adequate hematological and end-organ function (test results from within 14 daysprior to initiation of study treatment):

8. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L without granulocytecolony-stimulating factor support

9. White Blood Cell Count (WBC) count ≥ 2.5 x 109 /L (2500/uL)

10. Lymphocyte count ≥ 0.5 x 109/L (500/uL)

11. Platelet count ≥ 100 x 109/L (100,000/uL) without transfusion

12. Hgb ≥ 9.0 g/dL

13. Aspartate aminotransferase (AST), alanine transaminase (ALT), and alkalinephosphatase (ALP) ≤ 2.5X upper limit of normal (ULN), unless elevated secondaryto biliary obstruction from the pancreas mass and amenable to decompressionprior to initiation of therapy

14. Serum total bilirubin ≤ 1.5X ULN, unless in patients with known Gilbert disease (≤ 3X ULN), or unless elevated secondary to biliary obstruction from thepancreas mass and amenable to decompression prior to administration ofinvestigational therapy

15. Albumin ≥ 3.5 g/dL

16. Creatinine within ULN or calculated creatinine clearance (CrCl) >50 mL/minusing the Cockcroft-Gault formula

17. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5X ULN, except for those on stable anticoagulation for at least twoweeks

18. Measurable disease according to Immune Modified (IM)-RECIST and tumor accessible forfresh biopsy

19. Negative pregnancy test: Women of child-bearing potential must have a negative serumpregnancy test at screening and must agree to use an effective form of contraceptionfrom the time of the negative pregnancy test until a minimum of 3 months after thelast dose of study drug. Effective forms of contraception include abstinence,hormonal contraceptive (injectable or implantable) in conjunction with a barriermethod. Women of non-child-bearing potential must have been postmenopausal for ≥ 1year or surgically sterile.

20. Birth control agreement: Fertile men must agree to use an effective method of birthcontrol with female partners of childbearing potential (condoms plus an additionalcontraceptive method such as an injectable or implantable hormonal contraceptive)during the study and for up to 3 months after the last dose of study drug.

21. Informed consent: Participants must be willing and able to provide written informedconsent prior to any study-related procedures and to comply with all studyrequirements.

22. Ability to comply: Participants must be able to comply with the study protocol,according to the investigator's judgement.

23. DVT testing Participants must have undergone lower extremity dopplers to rule outdeep venous thrombosis (DVT) within the screening period, and undergo therapeuticanticoagulation if evidence of DVT is identified.

24. Anticoagulation treatment Subjects who are stable on full-dose anticoagulationmedication for at least 2 weeks are considered eligible. However, subjects who havean increased clot burden on full-dose anticoagulation, such as central pulmonaryembolism, or peripheral pulmonary embolism, and DVT within the extremities will beconsidered eligible only with the approval of the Principal Investigator.

Exclusion criteria:

1. Prior systemic therapy for PDAC: Participants may not have had systemicchemotherapy, investigational therapy, or treatment with T-cell co-stimulating orimmune check point blockade therapies (including anti-CTLA-4, anti PD-1, and antiPD-L1 therapeutic antibodies) prior to initiation of study treatment.

2. Prior radiation therapy for PDAC Participants may not have had radiation therapy towithin two weeks prior to initiation of study treatment. Participants may not havehad previous radiotherapy to the primary pancreas lesion or a metastatic site exceptfor palliation for pain. Participants who receive radiation to 25% or more of thebone marrow will be excluded.

3. Prior surgery for PDAC Participants may not have had surgical resection of PDACprior to initiation of study treatment

4. Patients currently receiving any other investigational agents

5. Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1 orbetter, with the exception of alopecia of any grade and Grade ≤ 2 peripheralneuropathy

6. Concomitant treatment with other anti-neoplastic agents (hormone therapy acceptable)

7. Uncontrolled pleural effusion, pericardial effusion, or ascites. Subjects whorequired drainage within the four weeks prior or require pleural, pericardial, orperitoneal catheters for drainage are ineligible.

8. Uncontrolled tumor-related pain Patients requiring narcotic pain medication must beon a stable regimen for at least two weeks prior to study entry.

9. History of leptomeningeal or brain/ Central Nervous System (CNS) metastases

10. Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, orcorrected serum calcium > upper limit of normal) or symptomatic hypercalcemiarequiring continued use of bisphosphonate therapy.

11. Recent major surgery or significant traumatic injury Participants may not haveundergone major surgery or experienced significant traumatic injury within 14 daysprior to initiating study treatment, or be recovering from procedure related adverseevents of > Grade 1.

12. Active or history of autoimmune disease or immune deficiency Includes, but is notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barrésyndrome, or multiple sclerosis, with the following exceptions:

13. Patients with a history of autoimmune-related hypothyroidism who are on stablethyroid-replacement hormone for the past three months are eligible for thestudy.

14. Patients with controlled Type 1 diabetes mellitus who are on a stable insulinregimen for the past month are eligible for the study.

15. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet:

• Rash must cover <10% of body surface area;
• Disease is well-controlled at baseline and requires only low-potencytopical corticosteroids;
• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oralcorticosteroids within the previous 12 months.

13. History of idiopathic pulmonary fibrosis, interstitial lung disease, organizingpneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathicpneumonitis, or evidence of active pneumonitis on screening chest computedtomography scan (history of radiation pneumonitis or fibrosis in the radiation fieldis permitted).

14. Positive for HIV at screening or any time prior to screening Patients without priorpositive HIV test result will undergo an HIV test at screening, unless not permittedunder local regulations.

15. Hepatitis B virus (HBV) infection (chronic or acute) Defined as having a positivehepatitis B surface antigen (HBsAg) test at screening. Patients with a past orresolved HBV infection, defined as having a negative HBsAg test and a positive totalhepatitis B core antibody test at screening, are eligible for the study.

16. Active hepatitis C virus (HCV) infection: Defined as positive HCV antibody testfollowed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCVantibody test.

17. Known clinically significant liver disease, including alcoholic hepatitis,cirrhosis, fatty liver disease, and inherited liver disease.

18. Active tuberculosis

19. Infection: Patients may not have had a severe infection requiring antibiotictreatment within the two weeks prior to initiation of study treatment. Thisincludes, but is not limited to, hospitalization for complications of infection,bacteremia, or severe pneumonia. However, patients who were admitted for biliarytract infection due to bile duct obstruction at time of diagnosis must have afunctioning biliary stent (as evidenced by declining total bilirubin and ≤ 2X ULN)and resolved infection (defined by normalization of elevated white blood cell count,absence of signs of infection) and completion of an antibiotic course (at least aseven-day course) prior to initiation of therapy. Patients receiving prophylacticantibiotics (e.g., to prevent a urinary tract infection or chronic obstructivepulmonary disease exacerbation) are eligible for the study.

20. Significant cardiovascular disease: Patient may not have significant cardiovasculardisease (such as New York Heart Association Class II or greater cardiac disease,myocardial infarction, or cerebrovascular accident) within 12 months prior toinitiation of study treatment, seizure disorder, uncontrolled hypertension, orunstable arrhythmia or unstable angina within 3 months prior to initiation of studytreatment.

21. Left ventricular ejection fraction below institutional lower limit of normal orbelow 50%, whichever is lower.

22. Baseline QTcF ≥ 450 ms (males) or ≥ 470 ms (females)

23. Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of studytreatment

24. Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation

25. History of other malignancy Patient may not have a history of malignancy other thanPDAC within two years prior to screening, with the exception of those with anegligible risk of metastasis or death (e.g., 5- year overall survival of > 90%),such as adequately treated carcinoma in situ of the cervix, non-melanoma skincarcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterinecancer.

26. Recent vaccination: Patients may not have been treated with a live, attenuatedvaccine within four weeks prior to initiation of study treatment, or anticipate theneed for such a vaccine during treatment with cemiplimab or within five months afterthe last dose of cemiplimab.

27. History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins

28. Known allergy or hypersensitivity to any of the study drug excipients

29. Recent immunosuppressive treatment: Patients may not have been treated with systemicimmunosuppressive medication (including, but not limited to, corticosteroids,cyclophosphamide, azathioprine, methotrexate, thalidomide, calcineurin inhibitors,and anti-tumor necrosis factor alpha agents) within two weeks prior to initiation ofstudy treatment, or anticipate the need for systemic immunosuppressive medicationduring the course of the study, with the following exceptions: a. Patients who received a one-time pulse dose of systemic immunosuppressantmedication are eligible for the study after approval from the PrincipalInvestigator.

30. Pregnancy: Pregnant women are excluded from this study because there is an unknown,but potential risk for adverse events to the fetus. Breastfeeding should bediscontinued prior to start of treatment because there is an unknown, but potentialrisk for adverse events in nursing infants secondary to treatment.

31. Other contraindicated conditions Any other disease, metabolic dysfunction, physicalexamination finding, or clinical laboratory finding that contraindicates the use ofan investigational drug, may affect the interpretation of the results, or may renderthe patient at high risk from treatment complications in the opinion of the treatinginvestigator.

32. Uncontrolled psoriasis, porphyria, proximal myopathy or neuropathy

33. Severe depression Subjects hospitalized for depression within the past two years, orwho have prior suicidal attempts will be excluded.

34. Has received transfusions of blood products (including platelets or red blood cells)within 4 weeks prior to study Day 1.

35. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroidsfor chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids fororthostatic hypotension or adrenal insufficiency are eligible for the study ifreceiving equivalent to ≤ 10 mg of prednisone daily (10mg prednisone is equivalentto either cortisone - 50mg; hydrocortisone - 40mg; triamcinolone - 8mg; prednisolone

• 10mg; methylprednisolone - 8mg; betamethasone - 1.5mg; or dexamethasone - 1.5mg).Patients receiving > 10 mg of prednisone or equivalent per day for greater than fivedays within 28 days of starting study related therapy are not eligible. Steroidsadministered prior to gemcitabine and nab-paclitaxel should be administered as perstandard institutional guidelines.