17-134: Pre-Operative Trial (PGHA vs. PGH) for Resectable Pancreatic Cancer

• Sponsor: Nathan Bahary, MD (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03344172
• Collaborator: Pfizer (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 32
• Location: 1
• Arms: 2
• Actual Duration (Months): 16.5
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

This is a randomized phase II trial that will examine the ability of Avelumab to improve the clinical activity of a pre-operative regimen of gemcitabine, nab-paclitaxel and hydroxychloroquine in subjects with potentially resectable adenocarcinoma of the pancreas.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer Resectable	Drug: Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab; Drug: Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine	Phase 2

Detailed Description

This is a phase II, non-blinded, adaptively randomized trial. Patients with PDA are evaluated prior to protocol entry by standard of care testing, including EUS, contrast-enhanced helical abdominal CT scan, or MRI. Patients meeting NCCN criteria for potentially resectable (borderline or resectable) tumors will be eligible. Subjects are randomized to receive either 2 cycles of PGH - gemcitabine and nab-paclitaxel (1000 mg/m2 & 125 mg/m2, respectively: days 1, 8, and 15) plus oral HCQ (1200 mg PO daily) - or PGH plus Avelumab (PGHA; days 1 and 15 of each 28-day cycle), by means of response-adaptive randomization based on Grade IIB or greater histologic response.

Surgical exploration and pancreatectomy is performed if technically feasible and all toxicities have resolved. HCQ is taken until the evening before surgery. Avelumab is administered every two weeks until up to one week prior to the date of surgery. The Study Coordinator informs subjects of the date of operation. Following successful surgical removal of tumors, patients are then be free to pursue standard of care adjuvant therapy options, at the discretion of their treating physician.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Pre-Operative Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine With or Without Avelumab (PGHA vs. PGH)
• Actual Study Start Date: Dec 13, 2017
• Actual Primary Completion Date: Apr 30, 2019
• Actual Study Completion Date: Apr 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PGHA Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine and Avelumab	Drug: Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab; Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg); Other Names: PGHA
Experimental: PGH Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine	Drug: Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine; Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery; Other Names: PGH

Outcome Measures

Primary Outcome Measures

1. Proportion of Grade IIb or Higher Histolopathologic Responses [up to 3 years]

   Number of grade IIb+lll+lllm+IV+lVm responses / total number of all grade histolopathologic responses. Histoligic appearance will be assess per the Grading System for Pathological Response: Grade I - Characteristic cytologic changes of malignancy present, but little (< 10%) or no tumor cell destruction is evident; Grade II - Characteristic cytologic changes of malignancy; 10% to 90% of tumor cells are destroyed; Grade IIa - Destruction of 10% to 50% of tumor cells; Grade IIb - Destruction of 51% to 90% of tumor cells; Grade III - Few (< 10%) viable-appearing tumor cells are present; Grade IIIm - Sizable pools of mucin present; Grade IV - No viable tumor cells present; Grade IVm - Acellular pools of mucin present.

Secondary Outcome Measures

1. Change in CA19-9 Levels [Up to 3 years]

   Levels of CA19-9 (tumor marker) in preoperative and postoperative tissues will be determined. Higher levels of CA19-9 are associated with progressive disease.

2. Worst Grade of Adverse Event Experienced At Least Possibly Related to Treatment [Up to 6 months]

   Percentage of participants that experienced an adverse event at least possibly related to study treatment, by Grade. Adverse events were evaluated per per NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

3. Worst Grade of Adverse Event Experienced At Least Probably Related to Treatment [Up to 6 months]

   Percentage of participants that experienced an adverse event at least probably related to study treatment, by Grade. Adverse events were evaluated per per NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

4. Autophagy Biomarker Levels by Histopathological Response [Up to 3 years]

   Autophagy biomarker levels in blood by histopathological response (per the Grading System for Pathological Response)

5. Change in Coagulation Index (CI) [up to 3 years]

   Comparison of the preoperative and postoperative Thromboelastogram (TEG) Coagulation Index (CI) profile. TEG is an overall assessment of coagulability, quantitatively measures the ability of whole blood to form a clot. Cancer patients are at greater risk for thromboembolism compared to the normal population due to tumor burden and systemic therapies.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• Nathan Bahary, MD
• Pfizer
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Nathan Bahary, MD, UPMC Hillman Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 21, 2019

More Information

Publications

None provided.

• Responsible Party: Nathan Bahary, MD, associate professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT03344172
• Other Study ID Numbers: HCC# 17-134; R01CA181450
• First Posted: Nov 17, 2017
• Last Update Posted: May 14, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine; Hydroxychloroquine; Paclitaxel; Albumin-Bound Paclitaxel; Avelumab

Study Results

Participant Flow

Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab	PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg)	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery
Period Title: Overall Study
STARTED	16	16
COMPLETED	15	16
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab	PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine	Total
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery	Total of all reporting groups
Overall Participants	15	16	31
Age (years) [Mean (Standard Deviation) ]
Safety cohort	64.4 (6.5)	69.9 (9.8)	67.0 (8.7)
Efficacy cohort	62.2 (6.4)	65.6 (9.7)	64.1 (8.3)
Sex: Female, Male (Count of Participants)
Female	6 40%	7 43.8%	13 41.9%
Male	9 60%	9 56.3%	18 58.1%
Female	3 20%	5 31.3%	8 25.8%
Male	5 33.3%	5 31.3%	10 32.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	15 100%	16 100%	31 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	8 53.3%	10 62.5%	18 58.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Karnofsky Performance Status - Safety Cohort (Count of Participants)
Safety Cohort - Karnofsky Score of 90	6 40%	3 18.8%	9 29%
Safety Cohort - Karnofsky Score of 100	8 53.3%	13 81.3%	21 67.7%
Karnofsky Performance Status - Efficacy Cohort (Count of Participants)
Efficacy Cohort - Karnofsky Score of 90	4 26.7%	1 6.3%	5 16.1%
Efficacy Cohort - Karnofsky Score of 100	3 20%	9 56.3%	12 38.7%

Outcome Measures

1. Primary Outcome

Title	Proportion of Grade IIb or Higher Histolopathologic Responses
Description	Number of grade IIb+lll+lllm+IV+lVm responses / total number of all grade histolopathologic responses. Histoligic appearance will be assess per the Grading System for Pathological Response: Grade I - Characteristic cytologic changes of malignancy present, but little (< 10%) or no tumor cell destruction is evident; Grade II - Characteristic cytologic changes of malignancy; 10% to 90% of tumor cells are destroyed; Grade IIa - Destruction of 10% to 50% of tumor cells; Grade IIb - Destruction of 51% to 90% of tumor cells; Grade III - Few (< 10%) viable-appearing tumor cells are present; Grade IIIm - Sizable pools of mucin present; Grade IV - No viable tumor cells present; Grade IVm - Acellular pools of mucin present.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Participants that received at least one cycle/dose of study treatment for whom tissue samples were available for histological evaluation using the Grading System for Pathological Response.

Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab	PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg)	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery
Measure Participants	6	8
Number (95% Confidence Interval) [percentage of participants]	33.3 222%	50.0 312.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab, PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.30 to 6.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in CA19-9 Levels
Description	Levels of CA19-9 (tumor marker) in preoperative and postoperative tissues will be determined. Higher levels of CA19-9 are associated with progressive disease.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Participants that received at least one cycle/dose of study treatment for whom tissue samples were available for analysis.

Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab	PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg)	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery
Measure Participants	5	5
Mean (95% Confidence Interval) [units per milliliter (U/mL)]	-0.37	-0.88

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab, PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.63
	Confidence Interval	(2-Sided) 95%; -1.00 to -0.25
	Parameter Dispersion	Type: Standard Deviation; Value: 0.52
	Estimation Comments

3. Secondary Outcome

Title	Worst Grade of Adverse Event Experienced At Least Possibly Related to Treatment
Description	Percentage of participants that experienced an adverse event at least possibly related to study treatment, by Grade. Adverse events were evaluated per per NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

Participants that received at least one cycle/dose of study treatment.

Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab	PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg)	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery
Measure Participants	15	16
Grade 1	6.7 44.7%	6.3 39.4%
Grade 2	40.0 266.7%	18.8 117.5%
Grade 3	40.0 266.7%	62.5 390.6%
Grade 4	6.7 44.7%	0.0 0%
Grade 5	6.7 44.7%	6.3 39.4%
No Adverse Events	0.0 0%	6.3 39.4%

4. Secondary Outcome

Title	Worst Grade of Adverse Event Experienced At Least Probably Related to Treatment
Description	Percentage of participants that experienced an adverse event at least probably related to study treatment, by Grade. Adverse events were evaluated per per NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

Participants that received at least one cycle/dose of study treatment.

Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab	PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg)	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery
Measure Participants	15	16
Grade 1	13.3 88.7%	12.5 78.1%
Grade 2	33.3 222%	18.8 117.5%
Grade 3	33.3 222%	43.3 270.6%
Grade 4	0.0 0%	0.0 0%
Grade 5	0.0 0%	0.0 0%
No Adverse Events	20.0 133.3%	25.0 156.3%

5. Secondary Outcome

Title	Autophagy Biomarker Levels by Histopathological Response
Description	Autophagy biomarker levels in blood by histopathological response (per the Grading System for Pathological Response)
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Collected specimens will not be run/analyzed due to lack of funding.

Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab	PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg)	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery
Measure Participants	0	0

6. Secondary Outcome

Title	Change in Coagulation Index (CI)
Description	Comparison of the preoperative and postoperative Thromboelastogram (TEG) Coagulation Index (CI) profile. TEG is an overall assessment of coagulability, quantitatively measures the ability of whole blood to form a clot. Cancer patients are at greater risk for thromboembolism compared to the normal population due to tumor burden and systemic therapies.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Collected specimens will not be run/analyzed due to lack of funding.

Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab	PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg)	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery
Measure Participants	0	0

Adverse Events

Time Frame	Up to 6 months per participant; 18 months for each cohort
Adverse Event Reporting Description	All adverse events were graded according to the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. Serious Adverse Events included only events of Grade 3 or greater.
Arm/Group Title	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab		PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
Arm/Group Description	Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine and Avelumab Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery		Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m^2) and nab-paclitaxel (125mg/m^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery
All Cause Mortality
	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab		PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		1/16 (6.3%)
Serious Adverse Events
	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab		PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/15 (60%)		12/16 (75%)
Blood and lymphatic system disorders
Anemia	0/15 (0%)	0	1/16 (6.3%)	3
Febrile neutropenia	1/15 (6.7%)	8	0/16 (0%)	0
Leukocytosis	0/15 (0%)	0	1/16 (6.3%)	3
Cardiac disorders
Cardiac arrest	1/15 (6.7%)	4	0/16 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/15 (6.7%)	4	0/16 (0%)	0
Gastrointestinal disorders - Other, specify	1/15 (6.7%)	4	0/16 (0%)	0
Nausea	2/15 (13.3%)	8	0/16 (0%)	0
General disorders
Fatigue	0/15 (0%)	0	1/16 (6.3%)	3
Fever	1/15 (6.7%)	4	0/16 (0%)	0
Infections and infestations
Biliary tract infection	1/15 (6.7%)	4	1/16 (6.3%)	3
Infections and infestations - Other, specify	0/15 (0%)	0	1/16 (6.3%)	3
Salivary gland infection	1/15 (6.7%)	4	0/16 (0%)	0
Injury, poisoning and procedural complications
Fall	0/15 (0%)	0	1/16 (6.3%)	4
Investigations
Alanine aminotransferase increased	1/15 (6.7%)	4	0/16 (0%)	0
Lymphocyte count decreased	2/15 (13.3%)	8	1/16 (6.3%)	3
Neutrophil count decreased	3/15 (20%)	12	4/16 (25%)	18
White blood cell decreased	2/15 (13.3%)	8	1/16 (6.3%)	3
Metabolism and nutrition disorders
Anorexia	1/15 (6.7%)	4	0/16 (0%)	0
Dehydration	1/15 (6.7%)	4	2/16 (12.5%)	7
Hypokalemia	0/15 (0%)	0	1/16 (6.3%)	3
Hyponatremia	1/15 (6.7%)	4	3/16 (18.8%)	9
Hypophosphatemia	0/15 (0%)	0	1/16 (6.3%)	3
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/15 (0%)	0	1/16 (6.3%)	3
Skin and subcutaneous tissue disorders
Rash maculo-papular	2/15 (13.3%)	8	2/16 (12.5%)	6
Skin and subcutaneous tissue disorders - Other, specify	2/15 (13.3%)	8	0/16 (0%)	0
Vascular disorders
Hypertension	0/15 (0%)	0	1/16 (6.3%)	3
Hypotension	1/15 (6.7%)	4	1/16 (6.3%)	3
Thromboembolic event	1/15 (6.7%)	4	0/16 (0%)	0
Other (Not Including Serious) Adverse Events
	PGHA: Gemcitabine, Nab-Paclitaxel, Hydroxychloroquine+Avelumab		PGH: Gemcitabine, Nab-Paclitaxel, and Hydroxychloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/15 (100%)		15/16 (93.8%)
Blood and lymphatic system disorders
Anemia	10/15 (66.7%)	60	11/16 (68.8%)	51
Febrile neutropenia	1/15 (6.7%)	8	0/16 (0%)	0
Leukocytosis	0/15 (0%)	0	1/16 (6.3%)	3
Cardiac disorders
Cardiac arrest	1/15 (6.7%)	4	0/16 (0%)	0
Cardiac disorders - Other, specify	0/15 (0%)	0	1/16 (6.3%)	3
Sinus bradycardia	2/15 (13.3%)	16	0/16 (0%)	0
Endocrine disorders
Endocrine disorders - Other, specify	0/15 (0%)	0	1/16 (6.3%)	3
Eye disorders
Blurred vision	0/15 (0%)	0	1/16 (6.3%)	3
Gastrointestinal disorders
Abdominal pain	1/15 (6.7%)	4	0/16 (0%)	0
Colitis	1/15 (6.7%)	4	0/16 (0%)	0
Constipation	2/15 (13.3%)	8	1/16 (6.3%)	3
Diarrhea	6/15 (40%)	24	4/16 (25%)	12
Gastroesophageal reflux disease	1/15 (6.7%)	4	0/16 (0%)	0
Gastrointestinal disorders - Other, specify	3/15 (20%)	12	0/16 (0%)	0
Mucositis oral	1/15 (6.7%)	4	0/16 (0%)	0
Nausea	9/15 (60%)	40	4/16 (25%)	15
Rectal hemorrhage	0/15 (0%)	0	1/16 (6.3%)	3
Vomiting	5/15 (33.3%)	24	1/16 (6.3%)	6
General disorders
Chills	3/15 (20%)	12	0/16 (0%)	0
Edema limbs	1/15 (6.7%)	4	2/16 (12.5%)	6
Fatigue	5/15 (33.3%)	20	7/16 (43.8%)	30
Fever	7/15 (46.7%)	36	0/16 (0%)	0
Hypothermia	1/15 (6.7%)	4	0/16 (0%)	0
Infusion related reaction	3/15 (20%)	12	0/16 (0%)	0
Pain	2/15 (13.3%)	8	3/16 (18.8%)	9
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	1/15 (6.7%)	4	0/16 (0%)	0
Infections and infestations
Biliary tract infection	1/15 (6.7%)	4	1/16 (6.3%)	3
Infections and infestations - Other, specify	0/15 (0%)	0	1/16 (6.3%)	3
Salivary gland infection	1/15 (6.7%)	4	0/16 (0%)	0
Injury, poisoning and procedural complications
Fall	0/15 (0%)	0	1/16 (6.3%)	4
Investigations
Alanine aminotransferase increased	9/15 (60%)	64	4/16 (25%)	12
Alkaline phosphatase increased	6/15 (40%)	40	3/16 (18.8%)	12
Aspartate aminotransferase increased	10/15 (66.7%)	60	5/16 (31.3%)	15
Blood bilirubin increased	1/15 (6.7%)	4	0/16 (0%)	0
CPK increased	4/15 (26.7%)	20	1/16 (6.3%)	3
Creatinine increased	1/15 (6.7%)	12	1/16 (6.3%)	6
Lipase increased	2/15 (13.3%)	12	4/16 (25%)	12
Lymphocyte count decreased	5/15 (33.3%)	32	2/16 (12.5%)	12
Neutrophil count decreased	9/15 (60%)	64	6/16 (37.5%)	39
Platelet count decreased	8/15 (53.3%)	40	13/16 (81.3%)	57
Serum amylase increased	1/15 (6.7%)	4	0/16 (0%)	0
Weight loss	0/15 (0%)	0	3/16 (18.8%)	9
White blood cell decreased	9/15 (60%)	60	9/16 (56.3%)	48
Metabolism and nutrition disorders
Anorexia	1/15 (6.7%)	4	0/16 (0%)	0
Dehydration	1/15 (6.7%)	4	3/16 (18.8%)	10
Hypercalcemia	1/15 (6.7%)	4	0/16 (0%)	0
Hyperglycemia	1/15 (6.7%)	4	1/16 (6.3%)	3
Hypoalbuminemia	5/15 (33.3%)	40	6/16 (37.5%)	33
Hypocalcemia	1/15 (6.7%)	4	0/16 (0%)	0
Hypokalemia	3/15 (20%)	24	5/16 (31.3%)	21
Hypomagnesemia	3/15 (20%)	20	1/16 (6.3%)	3
Hyponatremia	7/15 (46.7%)	48	8/16 (50%)	42
Hypophosphatemia	1/15 (6.7%)	4	2/16 (12.5%)	9
Musculoskeletal and connective tissue disorders
Arthralgia	1/15 (6.7%)	4	0/16 (0%)	0
Generalized muscle weakness	0/15 (0%)	0	1/16 (6.3%)	3
Nervous system disorders
Dizziness	2/15 (13.3%)	8	0/16 (0%)	0
Dysgeusia	1/15 (6.7%)	4	1/16 (6.3%)	3
Lethargy	1/15 (6.7%)	4	0/16 (0%)	0
Nervous system disorders - Other, specify	0/15 (0%)	0	1/16 (6.3%)	3
Psychiatric disorders
Anxiety	1/15 (6.7%)	8	0/16 (0%)	0
Insomnia	1/15 (6.7%)	4	0/16 (0%)	0
Restlessness	1/15 (6.7%)	4	0/16 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/15 (0%)	0	1/16 (6.3%)	6
Cough	0/15 (0%)	0	1/16 (6.3%)	3
Epistaxis	0/15 (0%)	0	2/16 (12.5%)	6
Nasal congestion	0/15 (0%)	0	1/16 (6.3%)	3
Skin and subcutaneous tissue disorders
Alopecia	0/15 (0%)	0	1/16 (6.3%)	6
Dry skin	0/15 (0%)	0	1/16 (6.3%)	3
Pruritus	1/15 (6.7%)	4	0/16 (0%)	0
Purpura	0/15 (0%)	0	1/16 (6.3%)	3
Rash maculo-papular	5/15 (33.3%)	20	3/16 (18.8%)	12
Skin and subcutaneous tissue disorders - Other, specify	5/15 (33.3%)	36	1/16 (6.3%)	3
Vascular disorders
Hypertension	1/15 (6.7%)	4	2/16 (12.5%)	15
Hypotension	1/15 (6.7%)	12	2/16 (12.5%)	6
Thromboembolic event	1/15 (6.7%)	4	0/16 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.