Pre-Operative Trial (PGHA vs. PGH) for Resectable Pancreatic Cancer

Inclusion Criteria

* Participants with biopsy-proven adenocarcinoma of the pancreas that is determined to be potentially or borderline resectable by NCCN criteria
* Karnofsky performance status of 70-100%
* No active second malignancy with the exception of basal or squamous cell carcinoma of the skin
* Patient has adequate biological parameters as demonstrated by the following blood counts at screening (obtained ≤14 days prior to randomization)

  * Absolute neutrophil count (ANC) ≥ 1.5 × 109/L,
  * Platelet count ≥100,000/mm3 (100 × 109/L),
  * Hemoglobin (Hgb) ≥9 g/dL. Patient may receive transfusion as needed.
* Patient has the following blood chemistry levels at Baseline (obtained ≤14 days prior to randomization):

  * AST (SGOT), ALT (SGPT) ≤ 2.5 × upper limit of normal range (ULN).
  * Total bilirubin ≤ ULN (Except in patients who have Gilbert's Syndrome or patients with recently placed stents for biliary obstruction when bilirubin should be \< 1.5 X ULN).
  * Serum Creatinine ≤ 1.5mg/dl OR calculated creatinine clearance ≥ 50 for those patients with creatinine greater than 1.5.
  * CPK \< ULN.
  * Patients who have an elevated lipase or amylase and no history of autoimmune pancreatitis, nor physical exam concerning for, or CT correlates of pancreatitis can be enrolled. The elevated levels will serve as the new baseline. Changes above that will be termed toxicities as per CTCAE guidelines with relation to the new baseline.
  * PT WNL+/- 15 % unless on active anticoagulation.
  * PTT WNL+/- 15 % unless on active anticoagulation (suggested to be drawn peripherally to prevent port drawn elevation due to routine heparin flush of ports).
* Age \>18 years
* Patient must be able to swallow enteral medications with no requirement for a feeding tube. Patient's must not have intractable nausea or vomiting which prohibits the patient from oral medications
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

* Subjects deemed surgically unresectable or subjects unwilling to undergo surgical resection
* Prior use of chemotherapy, radiotherapy, and / or investigational agents for pancreatic cancer
* Any evidence of metastasis to distant organs (liver, lung, peritoneum)
* Symptomatic evidence of gastric outlet obstruction
* Inability to adhere to study and/or follow-up procedures
* History of allergic reactions or hypersensitivity to the study drugs (hydroxychloroquine, gemcitabine, nab-Paclitaxel, Avelumab)
* Known or suspected HIV infection
* Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

  * Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
  * Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen are eligible for the study.
* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

  * Rash must cover \< 10% of body surface area.
  * Disease is well controlled at baseline and requires only low-potency topical corticosteroids.
  * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
* History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
* Patient with a history of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis

  \- History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
* Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening

  * Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible for the study.
  * Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
* Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty liver disease, and inherited liver disease
* Active tuberculosis
* Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
* Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 12 months prior to initiation of study treatment, or unstable arrhythmia or unstable angina within 3 months prior to initiation of study treatment
* Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment
* Prior allogeneic stem cell or organ transplantation including corneal transplant
* Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment.

  \- Placement of a stent or central venous access catheter (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted.
* Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications as determined by the investigator
* Pregnant or breastfeeding, or intending to become pregnant during the study
* The effects of HCQ, gemcitabine, nab-Paclitaxel and Avelumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. All females of childbearing potential (please refer to ECOG's definition in section 5.1) must have a blood test or urine study within two weeks prior to randomization to rule out pregnancy. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately. If a man impregnates a woman while participating in this study, he should inform his treating physician immediately as well.
* Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment with Avelumab or within 5 months after the last dose of Avelumab

  \- Attenuated live vaccines include but are not limited to:
* Tuberculosis (BCG)
* Oral polio vaccine
* Measles, Mumps, Rubella, alone or as part of MMR
* Rotavirus
* Yellow Fever
* Typhoid
* Rabies vaccine should be utilized as recommended by an Infectious Disease specialist
* Nasal flu vaccine
* History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies
* Known allergy or hypersensitivity to any of the study drugs or any of their excipients
* Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the study, with the following exceptions:

  * Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.
  * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
  * Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection).
* Patients requiring the use of enzyme-inducing anti-epileptic medication that includes but not limited to: phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine are excluded
* Patients with previously documented macular degeneration or diabetic retinopathy are excluded
* Baseline EKG with QTc \> 470 msec (including subjects on medication). Subjects with ventricular pacemaker for whom QT interval is not measurable will be eligible on a case-by-case basis at MD discretion
* Patients on Coumadin must be willing to switch to an alternative subcutaneous LMWH or oral agent (At PI discretion exceptions can be permitted, as determined on a case by case basis and documented)