Combined MEK, STAT3 and PD-1 Inhibition in Metastatic Pancreatic Ductal Adenocarcinoma

Inclusion Criteria:

1. Histologically confirmed, metastatic pancreatic adenocarcinoma. Patients withadenosquamous carcinoma and mixed adenocarcinoma/neuroendocrine carcinoma (MANEC) ofthe pancreas are eligible, but pure neuroendocrine neoplasms are excluded.

2. Progression of disease or intolerance to at least one standard line of chemotherapy.

3. Patients who are candidate for an anti-PD-1 antibody due to Microsatelliteinstability -High (MSI-H) or tumor mutational burden (TMB)-high status musthave been treated with this drug before being eligible for this trial.

4. Prior treatment with an anti-PD(L)-1 antibody is allowed unless this therapywas stopped due to an immune-related adverse event.

5. Patients who are candidate for a poly (ADP-ribose) polymerase (PARP) inhibitordue to a germline BRCA1/2 mutation must have been treated with this drug beforebeing eligible for this trial.

6. At least one tumor measurable by CT scan. Measurable disease is defined as at leastone lesion that can be accurately measured in at least one dimension (longestdiameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or >10 mm with spiral CT scan.

7. Adult patients (≥ 18 years of age).

8. Male or non-pregnant and non-lactating female. Men and women with intactreproductive potential must agree to use contraception as outlined in Section 4.9.

9. Adequate biological parameters as demonstrated by the following blood counts atScreening (obtained ≤ 21 days prior to enrollment) and at Baseline-Day 0:

10. Absolute neutrophil count (ANC) ≥ 1.0 × 10^9 cells/L.

11. Platelet count ≥ 100,000 cells/mm3 (100 × 10^9 cells/L).

12. Hemoglobin (Hgb) ≥ 9 g/dL.

13. Adequate blood chemistry levels at Screening (obtained ≤ 21 days prior toenrollment) and at Baseline-Day 0:

14. Aspartate aminotransferase (AST) - serum glutamic-oxaloacetic transaminase (SGOT); alanine transaminase (ALT) - serum glutamic-pyruvic transaminase (SGPT) ≤ 2.5 × upper limit of normal (ULN) range, unless liver metastases are present,then ≤ 5 × ULN is allowed.

15. Total bilirubin ≤ 1.5 × ULN.

16. Estimated creatinine clearance of > 60 mL/min (per Cockcroft-Gault formula).

17. Albumin ≥ 3.0 g/dL.

18. Eastern Cooperative Oncology Group (ECOG) performance status from 0 to ≤ 1 (seeAPPENDIX A: PERFORMANCE STATUS SCALES).

19. At least two weeks since the last anti-cancer therapy (e.g., chemotherapy, radiationtherapy).

20. All toxicities from the last anti-cancer therapy should be resolved to < grade 1.

21. Patient has been informed about the nature of the study, has agreed to participatein the study, and signed the Informed Consent Form (ICF) prior to participation inany study-related activities.

Exclusion Criteria:

1. Patients with pure neuroendocrine neoplasms of the pancreas.

2. Brain metastases.

3. Uncontrolled ascites.

4. Increase of ECOG to > 1 between screening and enrollment.

5. Corrected QT interval (QTcF) > 450 msec.

6. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemictherapy.

7. History of HIV and/or Hepatitis B or C infection.

8. History of active autoimmune disease that, in the opinion of the Investigator, coulddeteriorate upon treatment with an immune checkpoint inhibitor.

9. Concurrent use of systemic corticosteroids equivalent to or greater than prednisone 10 mg/day within two weeks of start of study therapy.

10. Receipt of a live vaccine within 30 days prior to enrollment.

11. Patients who are not up to date on FDA-approved coronavirus disease 2019 (COVID-19)vaccination series will be excluded.

12. Any impairment of gastrointestinal function or gastrointestinal disease that maysignificantly alter the absorption of the study drugs (e.g., ulcerative diseases,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive smallbowel resection).

13. History of interstitial lung disease or pneumonitis.

14. History of liver disease as follows:

15. Cirrhosis

16. Autoimmune hepatitis

17. Portal hypertension

18. Drug-induced liver steatosis

19. Clinically significant, uncontrolled heart disease and/or cardiac repolarizationabnormality, including any of the following:

20. History of myocardial infarction, angina pectoris, symptomatic pericarditis, orcoronary artery bypass graft within six months prior to study entry

21. Documented cardiomyopathy

22. Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gatedacquisition (MUGA) scan or echocardiogram (ECHO)

23. Long QT syndrome or family history of idiopathic sudden death or congenital long QTsyndrome or any of the following risk factors for Torsades de Pointe, includinguncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history ofclinically significant/symptomatic bradycardia.

24. Concomitant medication(s) with a known risk to prolong the QT interval and/or knownto cause Torsades de Pointe that cannot be discontinued or replaced by safealternative medication (e.g., within five half-lives or seven days prior to startingstudy drug).

25. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), completeleft bundle branch block, high-grade arterioventricular block (e.g., bifascicularblock, Mobitz type II, and third-degree atrioventricular block).

26. Treatment refractory hypertension defined as a blood pressure of systolic bloodpressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) > 90 mm Hg thatcannot be controlled by anti-hypertensive therapy.

27. A history or current evidence/risk of retinal vein occlusion (RVO) or central serousretinopathy (CSR) including:

28. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma orocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus,or a history of hyperviscosity or hypercoagulability syndromes); or

29. Visible retinal pathology as assessed by ophthalmic examination that isconsidered a risk factor for RVO or CSR.

30. Currently receiving any of the following substances and cannot be discontinued sevendays prior to Cycle 1 Day 1:

31. Known strong inducers or inhibitors of CYP3A4/5, including grapefruit,grapefruit hybrids, pomelos, star-fruit, and Seville oranges.

32. Substances that have a narrow therapeutic window and are predominantlymetabolized through CYP3A4/5.

33. Herbal preparations/medications and/or dietary supplements.

34. History of allergy or hypersensitivity to any of the study drugs, theirpharmaceutical class, or any of their excipients.

35. Concomitant serious medical or psychiatric illness that, in the opinion of theinvestigator, could compromise the patient's safety or integrity of the study data.

36. Concurrently enrolled in any other interventional clinical protocol orinvestigational trial involving administration of antineoplastic compounds for thetreatment of metastatic pancreatic cancer.

37. Patient is unwilling or unable to comply with study procedures.

38. Patients with impaired decision-making capacity.