Clinical trial NCT01978184
Conditions: Pancreatic Cancer
Keywords: Pancreatic Cancer, resectable adenocarcinoma of the pancreas
Sponsor: Nathan Bahary, MD
Start date: 2013-11-01; Completion date: 2018-02-28
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized phase II trial that will examine the ability of the hydroxychloroquine to improve the clinical activity of a pre-operative regimen of gemcitabine and nab-paclitaxel in subjects with potentially resectable adenocarcinoma of the pancreas. Eligible subjects will receive 2 cycles of gemcitabine and nab-paclitaxel (day 1, 8, 15) with or without hydrocychloroquine followed by surgical resection. Primary endpoint will be histologic response as graded by Evans criteria. Secondary endpoints will be CA19-9 response and PET response. Pre and post treatment tissue biopsies will be obtained to assess for levels of autophagy in tumor, liver and peripheral blood.

Detailed description:

Arms: arm 1: Gemcitabine and Abraxane will be administered on an outpatient basis on Days 3, 10, 17, 31, 38, and 45 as an intravenous infusion. The dose on Day 3 will be 1000 mg/m of gemcitabine followed by a 125 mg/m2 of abraxane and the infusion will take 1 hour. The second dose and infusion time may be decreased. Prior to each gemcitabine infusion, subjects will be pre-medicated with an FDA-approved anti-emetic (anti-nausea medication) in an effort to prevent nausea, at the discretion of the study physician. arm 2: Gemcitabine and Abraxane will be administered on an outpatient basis on Days 3, 10, 17, 31, 38, and 45 as an intravenous infusion. The dose on Day 3 will be 1000 mg/m of gemcitabine followed by a 125 mg/m2 of abraxane and the infusion will take 1 hour. The second dose and infusion time may be decreased. Prior to each gemcitabine infusion, subjects will be pre-medicated with an FDA-approved anti-emetic (anti-nausea medication) in an effort to prevent nausea, at the discretion of the study physician.

Hydroxychloroquine is an oral drug (capsule) that subjects will take once or twice a day at home. The dose of hydroxychlorquien will be 1200mg. This is an experimental drug. Subjects will take their first dose of hydroxychloroquine on Day 1 (48 hours before the first infusion of gemcitabine/abraxane), and will continue to take it every day until the day before surgery.
Interventions: intervention 1: gemcitabine intervention 2: abraxane intervention 3: hydroxychloroquine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
UPCI 13-074 
Protocol Version Date: 03/01/2018 
 
 
 
 
TITLE: Randomized Phase II trial of Pre-Operative Gemcitabine and Nab-Paclitaxel with or with out 
Hydroxychloroquine (UPCI# 13-074) 
 
 PRINCIPAL INVESTIGATOR: 
  
Nathan Bahary, MD  
 
 
Pathology 
Aatur Singhi, MD 
 
 
Statistician 
Daniel P. Normolle, PhD 
University of Pittsburgh Cancer Institute & 
Biostatistics Department, University of Pittsburgh 
Suite 325, Sterling Plaza 
Pittsburgh, PA, 15213 
Tel: (412) 383-1591 
Fax: (412) 383-1535 
 
 
Commercially Avalable Agent(s): Plaquenil® (Sanofi Aventis); Gemzar® (Lilly); Abraxane® (Celgene) 
 
Protocol Version: 03/01/2018 
IND #: exempt 


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Table of Contents 
Section 
Page 
 
Table of Contents ........................................................................................................................................................... 
i 
Research Protocol Abstract ............................................................................................................................................ 
  1 
1.0 
Background and Significance ............................................................................................................................... 
  1 
2.0 
Objectives and Specific Aims .............................................................................................................................. 
3   
2.1 
Primary Objective  ...................................................................................................................................... 
3 
2.2 
Secondary Objective  .................................................................................................................................. 
3 
 
3.0 
Study Design and Methods .................................................................................................................................. 
  3 
4.0 
Human Subjects ................................................................................................................................................... 
  4 
 
41. 
Inclusion Criteria  ....................................................................................................................................... 
4 
 
4.2 
Exclusion Criteria  ...................................................................................................................................... 
4 
5.0 
Clinical and Laboratory Evaluations .................................................................................................................... 
  5 
 
5.1 
Screening Evaluations  ............................................................................................................................... 
5 
 
5.2 
Treatment Phase Evaluations  .................................................................................................................... 
6 
 
5.3 
Prior to Chemotherapy Dosing on Cycle 1 Day 3  ..................................................................................... 
6 
 
5.4 
Prior to Dosing on Cycle 1 Day 10 and 17  ................................................................................................ 
6 
 
5.5 
Prior to Dosing on Cycle 2 Day 1  ............................................................................................................. 
6 
 
5.6 
Prior to Dosing on Cycle 2 Days 8 & 15  ................................................................................................... 
6 
 
5.7 
Surgery Evaluation  .................................................................................................................................... 
7 
 
5.8 
Surgery  ...................................................................................................................................................... 
7 
 
5.9 
Four (4) Weeks Post discharge from hospital stay (+/- 2 Weeks)  ............................................................. 
7 
 
5.10 Follow-up Period  ....................................................................................................................................... 
8 
6.0  Study Medication and Procedures ........................................................................................................................ 
8 
 
6.1 
Study Drug Management and Administration  ........................................................................................... 
8 
 
6.2 
Hydroxychloroquine Administration  ......................................................................................................... 
8 
 
6.3  Management of Toxicities  ......................................................................................................................... 
9 
 
6.4 
Guidelines for Toxicity Management  ........................................................................................................ 
10 
 
6.5 
Dose Modifications  ................................................................................................................................... 
10 
 
6.6 
FDG-PET Imaging  .................................................................................................................................... 
10 
 
6.7 
Concomitant Medications  .......................................................................................................................... 
11 
7.0 
Subject Discontinuation ....................................................................................................................................... 
11 
8.0 
Safety Plan ........................................................................................................................................................... 
11 
 
8.1 
General Plan to Manage Safety  ................................................................................................................. 
11 
 
8.2 
Recruitment Procedures ............................................................................................................................. 
12 
 
8.3 
Costs and Payments  ................................................................................................................................... 
12 
9.0 
Correlative Studies/Secondary Endpoints ............................................................................................................ 
12 
 
9.1 
CA19-9 ....................................................................................................................................................... 
12 
 
9.2 
Basic Science Studies of Autophagy and Apoptosis in the Tumor, Peripheral Blood  .............................. 
13 
 
9.3 
Coagulation Studies  ..................................................................................................................................  
13 
 
9.4 
Future Studies  ............................................................................................................................................ 
13 
10.0 Statistical Methods ............................................................................................................................................... 
13 


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10.1 Justification of Design  ............................................................................................................................... 
13 
 
10.2 Monitoring for Futility  .............................................................................................................................. 
13 
 
10.3 Data Analysis  ............................................................................................................................................ 
13  
11.0  Adverse Event ...................................................................................................................................................... 
14 
 
11.1 Adverse Event Definitions  ........................................................................................................................ 
14 
 
11.2 Reporting of Suspected Adverse Reactions  .............................................................................................. 
15 
 
11.3 Data Safety Monitoring Plan  ..................................................................................................................... 
16 
12.0  Retention of Records ............................................................................................................................................ 
17 
13.0 Patient Informed Consent: Risk/Benefit Information .......................................................................................... 
17 
References ...................................................................................................................................................................... 
20 
Appendix A- KPS Performance Status Scoring ............................................................................................................ 
22 
Appendix B- CTCAE 4.0 .............................................................................................................................................. 
23 
Appendix C-Pathology Response ................................................................................................................................. 
25 
Appendix D- Dose Modifications ................................................................................................................................. 
26 
Appendix E- Study Calendar ........................................................................................................................................ 
32 
 


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RESEARCH PROTOCOL ABSTRACT 
 
This is a randomized phase II trial that will examine the ability of the hydroxychloroquine to improve the clinical activity 
of a pre-operative regimen of gemcitabine and nab-paclitaxel in subjects with potentially resectable adenocarcinoma of 
the pancreas. Eligible subjects will receive 2 cycles of gemcitabine and nab-paclitaxel (1000mg/m2 & 125mg/m2 – day 1, 
8, 15) with or without hydrocychloroquine (1200mg/day) followed by surgical resection.  Primary endpoint will be 
histologic response as graded by Evans criteria.  The Secondary endpoint will be CA19-9 response. Pre and post treatment 
tissue biopsies will be obtained to assess for levels of autophagy in tumor, liver and peripheral blood.  
 
1.0 
BACKGROUND AND SIGNIFICANCE 
 
Adenocarcinoma of the exocrine pancreas (pancreatic ductal adenocarcinoma, PDA) 
Pancreatic cancer is a major unsolved public health problem in the United States, with approximately 42,000 new cases in 
the year 2012, making it the tenth most common malignancy in adult men and ninth in women.  It ranks as the fourth 
leading cause of cancer deaths; accounting 
for 5-6 % of all cancer related deaths in the 
United States, in 2008.   Five-year survival 
is less than 5% for all stages.  Currently, the 
only potentially curative therapy is surgical 
resection. Nonetheless, a vast majority of 
patients who undergo surgical resection 
will derive no therapeutic benefit. Survival 
of patients who undergo surgical resection 
followed by adjuvant radio-chemotherapy 
for localized non-metastatic 
adenocarcinoma of the pancreas is at best 
15% at 5 years, and the median disease free 
survival is 10-13 months.  This uniformly 
poor prognosis even in the earliest stage 
disease with best treatment modalities 
underscores the need for radical rethinking 
of our approach to pancreatic cancer.  There 
is a critical need for identification of novel 
pathways with biological activity to 
improve outcomes in this disease. We have 
accumulated a large body of preclinical and 
clinical data suggesting that ancient 
metabolic stress response of autophagy plays a major role in the pathogenesis of this disease.  In this proposal we will 
directly examine several aspects of this hypothesis in human subjects. (Figure 1.) [1-7] 
 
Inhibition of autophagy with chloroquine enhances apoptosis and response to chemotherapy in animal models. The 
finding that autophagy is critical mediator of DAMP induced tumor cell survival lead us to investigate this pathway as a 
target. Chloroquine (CQ) and its derivatives such as HCQ are synthetic 4-aminoquinolines that have been used for 60 
years in humans for malaria prophylaxis and play a role in the treatment of patients with rheumatoid arthritis, and human 
immunodeficiency virus (HIV). They are inexpensive orally available drugs with a large therapeutic index. Chloroquine 
blocks acidification of the lysosome, thus inhibiting the last step in autophagy. Evidence in mouse models and human 
cancer cell lines suggest CQ may have significant anti-tumor activity by inhibiting autophagy induced by cancer therapy. 
[8-10] Yang et al have demonstrated significant responses in a xenograft model to single agent CQ[8]. Our own findings 
confirm that pharmacologic inhibition of autophagy with chloroquine enhances the effects of gemcitabine in an orthotopic 
transplantable model using two distinct murine pancreatic tumors (manuscript in preparation.) Consistent with our 
previous observations, the enhanced anti-tumor effect associated with autophagy inhibition resulted in substantially more 
apoptosis measured by TUNEL staining in treated tumors when compared with chemotherapy alone. Moreover, our 
Kang et al.  Proc NatlAcad Sci
U S A. 2012 May 
1;109(18):7031-6
Kang et al. Cell Death Differ. 
2010 Apr;17(4):666-76
Tang et al.  Oncogene. 2010 Sep 
23;29(38):5299-310


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preliminary clinical experience with hydroxychloroquine and gemcitabine demonstrates substantial promise.  In this 
submission we will directly examine the ability of the autophagy inhibitor hydroxychloroquine to improve the clinical 
efficacy of chemotherapy in human tumors.  We will correlate levels of autophagy, STAT3/IL-6 signaling and apoptosis 
with histologic response in resected tumor treated with chemotherapy alone or chemotherapy and hydroxychloroquine.  
 
Combination of gemcitabine and the autophagy inhibitor hydroxychloroquine demonstrates promising clinical 
activity in human subjects.  Based on the above findings we launched and have accrued 30/40 subjects to a Phase I/II 
trial examining pre-operative gemcitabine (GC) in combination with oral hydroxychloroquine in the treatment of high-risk 
pancreatic adenocarcinoma.  (UPCI09-122; NCT01128296; http://clinicaltrials.gov/show/NCT01128296). Eligibility was 
limited to only those patients predicted to have limited survival advantage of surgical resection[11]. Fixed dose rate 
gemcitabine (1500mg/m2) was administered every two weeks for two doses. HCQ (200mg/day-1200mg/day) was 
administered 48 hours prior to the first dose of 
gemcitabine and continued for 31 consecutive 
days until day of surgery. Toxicity was 
evaluated based on National Cancer Institute 
criteria. Response to treatment was assessed by 
decrease in CA19-9 levels and PET CT. Two 
weeks after the last dose gemcitabine, patients 
underwent pancreatectomy. Twenty-two 
patients have completed treatment, 17 at the 
maximum dose of HCQ (1200 mg/day). (Table 
1)  There were no dose limiting toxicities.  All 
patients underwent surgical resection with an 
R0 resection rate of 86%.  Of these first 22 
subjects, 100% were able to undergo resection 
with 86% R0 (margin negative) which 
compares very favorably to our previous 
experience with this population of high risk 
subjects at our own institution (53% resection 
and 33% R0, p<0.01) [11]. Next 13 /19 (68%) 
of patients with elevated pretreatment levels had 
a greater than 50% decrease in CA19-9 
following the single cycle of gemcitabine based 
treatment. Moreover 11/22 (50%) had >75% decrease and 4/22 (18%) had >90% reduction in this tumor marker. This type 
of CA19-9 response rates following one cycle of gemcitabine based chemotherapy is much greater than any previous 
reports. [12, 13] These data, when compared to historical controls, suggest significant biologic activity of this regimen and 
support larger clinical trials such as this proposal. 
 
Gemcitabine and albumin bound paclitaxel is more clinically active regimen than gemcitabine alone. Since the 
initiation of our clinical trial of gemcitabine and hydroxychloroquine; new clinical data demonstrates that the combination 
of gemcitabine and nab-paclitaxel bound protein bound particles (Abraxanetm) is more clinically active than gemcitabine 
alone. In response to this information we have also participated in a multi-center feasibility trial of preoperative 
gemcitabine/nab-paclitaxel: PCRT # 10-001 Celgene # ABX267-PA09US  Subjects meeting NCCN criteria for 
potentially-resectable pancreatic cancer received 3 cycles of gemcitabine and nab-paclitaxel (1000mg/m2 & 125mg/m2 – 
day 1, 8, and 15) followed by surgical resection. The primary endpoint was grade III/IV pathological response in > 30% of 
resected tumor specimens. The trial has accrued the anticipated 25 patients (10 Female: 15 Male) at four centers. Of 
fifteen patients that completed all 3 cycles, six required dose reduction. Five patients were unable to complete all 3 cycles 
of therapy due to serious adverse events (Grade 3 or 4 toxicities).  To date, ten patients have undergone surgical resection 
(5- Pancreaticoduodenectomy, 5- Distal Pancreatectomy). All ten achieved negative surgical margins (R0 100%) and 
CA19-9 decrease from baseline (mean 181.7 U/ml ) to end of therapy (mean 44.2 U/ml)  was also noted. There were no 
unexpected postoperative complications. A > 90% tumor necrosis (Grade III/IV) was seen in 3 patients, with 4 Grade 2, 1 
Grade I, and 2 without effect. (Personal communication Ramesh Ramanathan). This trial supports the safety and 


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feasibility of preoperative therapy with gemcitabine and nab-paclitaxel with preliminary evidence of improved 
radiological and pathological response in resected tumor specimens.  
 
1.5  We have completed  accrual to this trial (Fig.1A). Toxicity has been equivalent between the two arms.   The primary 
endpoint for this trial is the rate of grade II/IV histologic response as defined by Evans et al33 Secondary endpoints are 
response of the tumor marker CA19-9 and ratio of positive lymph nodes in resected specimens.  Analysis of this primary 
endpoint in subjects at 95 % accrual analysis demonstrates a significant increase in the number of subjects with increased 
Evans grade histopathologic response with the PGH regimen (Fisher’s exact test p=0.0039) (Table I). The percent change 
in CA19-9 was significantly different between arms (Wilcoxson test p=0.014) (Fig.1B).  Similarly, the number of involved 
lymph nodes is statistically different between the arms. We are in the process of examining the resected tissues for evidence 
of autophagy inhibition and apoptosis.  Given that it appears that the experimental arm has increased response rate we now 
propose to extend accrual to this arm (Gem/Abraxane/hydroxychloroquine) in order to better establish biomarkers of 
response that will assist in design of the future therapeutic trials. 
 
Rationale for dosing in proposed clinical trial. The proposed clinical trial is based on a large body of pre-clinical and 
clinical data (outlined above) that suggest that the combination of autophagy inhibition with effective systemic 
chemotherapy will result in substantial improvement in clinical response in subjects with PDA. Safety and promising 
biologic activity of preoperative gemcitabine/hydroxychloroquine and gemcitabine / nab-paclitaxel has been established 
through our two pilot trials. The combination of these three agents has not been specifically studied in the preoperative 
setting however it is currently being examined in metastatic disease in an ongoing phase 1 dose escalation trial at the 
University of Pennsylvania.  No unexpected synergistic toxicities have been identified at the proposed dosing of this trial 
of 1200mg daily of hydroxychloroquine (personal communication Peter O’dwyer).    
 
2.0 
OBJECTIVES AND SPECIFIC AIMS 
2.1. Primary Objective:  
• 
To determine if inhibition of autophagy can improve the rate of grade III/IV histologic response to pre-
operative gemcitabine/ nab-paclitaxel.  
• 
Histological response validated scoring system by Evans[14]  
o 
Grade I: 1-9% tumor destruction 
o 
Grade II: 10 – 90% 
o 
Grade III: >90% tumor destruction 
o 
Grade IV: Absence of viable tumor cells 
2.2. Secondary Objectives 
• 
To determine if inhibition of autophagy can improve the rate CA19-9 response to pre-operative 
gemcitabine/ nab-paclitaxel. 
• 
To determine if inhibition of autophagy can improve Rate of R0 resection and positive lymph node ratio 
 
3.0 
STUDY DESIGN AND METHOD 
This will be an adaptive phase II, non-blinded, randomized, control trial. Patients with pancreatic ductal 
adenocarcinoma will be staged prior to protocol entry by standard of care testing including contrast-enhanced 
helical chest, abdomen, pelvis CT scan done using a pancreas mass protocol used  to determine resectability and to 
rule out metastatic disease.  If the patient has not already undergone an EUS biopsy for pathology confirmation this 
will be performed in screening.  During the EUS biopsy for pathology confirmation an additional biopsy will be 
taken for research purposes.  The pancreatic tumor biopsy will be processed and billed as standard of care.  The 
biopsy of the liver will be for research purposes only.  If the patient has had an EUS biopsy done with positive 
pathology finding for pancreatic cancer prior to screening, it will not be repeated.  The investigator will request the 
archival sample from this biopsy for research purposes.  Patients meeting NCCN criteria for potentially resectable 
or borderline resectable tumors will be eligible. Subjects will then receive 2 cycles of gemcitabine and nab-
paclitaxel (1000mg/m2 & 125mg/m2 – day 1, 8, and 15) plus or minus hydroxychloroquine 1200mg qd from day 1 
through the evening before surgery. Sixty participants will be randomized to gemcitabine + nab-paclitaxel versus 
gemcitabine + nab-paclitaxel + oral HCQ (1200mg PO daily) by means of response-adaptive randomization [15] 
based on Grade III/IV histologic response, as follows.  The first twenty participants will be randomly assigned in a 


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1:1 ratio.  Each participant’s histologic response will be graded, where a Grade III/IV response will count as a 
positive response for the purpose of randomization.  After the first twenty participants, random assignment to 
treatment will continue, but the probability of assignment to gemcitabine + nab-paclitaxel + HCQ will be 
proportional to P(πC< πX | responses)(n/2N) , where πC and πX are the estimated probabilities of response in the control 
and experimental arms given the current data, n is the number of observed patients and N=60.  If there is strong 
evidence that one treatment is better than the other, this allocation will tend to favor the better arm, but if the 
responses in the arms are similar, the probabilities of allocation will remain close to 1:1.  The operating 
characteristics of this allocation are presented in the statistical methods section of the protocol.  After the last dose 
of gemcitabine and prior to surgery, subjects will undergo repeat CT scan. Surgical exploration and pancreatectomy 
will be performed if technically feasible and all toxicities have resolved.  Pathologic specimens will undergo 
detailed histologic and immunohistochemical evaluations. Tissue specimens will be stored at -80C for future 
correlative studies of autophagy and tumor response to protocol therapy. Six to ten weeks following completion of 
successful surgical removal of their tumor, subjects will be free to pursue standard of care adjuvant therapy options 
at the discretion of their treating physician 
 
 
For this extended phase II we will accrue only to Arm A.  All other study interventions will remain the 
same 
 
4.0 
HUMAN SUBJE CTS 
4.0 
Subject Selection The study is powered to have 30 evaluable subjects in each arm this multiple institution 
study. The goal for subject accrual is 60 evaluable subjects, 30 to each arm of the trial.  Because the 
randomization process is not 1:1 and there is attrition; there may be slightly more than 30 subjects accrued to 
one arm in order to get to the required number of evaluable subjects A subject is deemed evaluable if they have 
received at least one cycle of chemotherapy and at least 80% of the expected HCQ doses and they undergo 
successful surgical extirpation their disease. The racial, gender, and ethnic characteristics of the proposed 
subject population reflect the demographics of Pittsburgh and the surrounding area and/or the subject population 
of the University of Pittsburgh Medical Center. We shall attempt to recruit subjects in proportion to these 
demographics. No exclusion criteria shall be based on race, ethnicity, or gender.  
 
 
For this extended phase II we will accrue only to Arm A.  All other study interventions will remain the 
same 
 
4.1 
Inclusion Criteria  
• 
Subjects with biopsy-proven potentially resectable or borderline adenocarcinoma of the pancreas as 
determined by NCCN criteria 
• 
Karnofsky performance status of 70-100% 
• 
No active second malignancy except for basal 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 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 ≤ 1.5xULN 
• 
Serum Creatinine ≤ 1.5mg/dl OR calculated creatinine clearance ≥ 50 for those patients with 
creatinine greater than 1.5 
• 
PT WNL+/- 15 % 


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• 
PTT WNL+/- 15 % 
• 
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. 
 
4.2 
Exclusion Criteria 
• 
Subjects deemed surgically unresectable or subjects unwilling to undergo surgical resection. 
• 
Subjects who have received chemotherapy within 12 months prior to randomization..   
• 
Prior use of radiotherapy 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).  
• 
The effects of HCQ, gemcitabine, and nab-Paclitaxel 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. 
• 
Because patients with immune deficiency are at increased risk of lethal infections when treated with bone 
marrow-suppressive therapy, known HIV-positive patients are excluded from the study. For patients 
receiving combination anti-retroviral therapy, the potential impact of pharmacokinetic interactions with 
HCQ and gemcitabine is unknown. Appropriate studies may be undertaken in patients with HIV and 
those receiving combination anti-retroviral therapy in the future.  Given the low incidence of HIV 
infection in this population; Screening for HIV status will not be performed 
• 
Due to the risk of disease exacerbation, patients with porphyria are ineligible.  
• 
Patients with psoriasis are ineligible unless the disease is well controlled and they are under the care of a 
specialist who agrees to monitor the patient for exacerbations. 
• 
Patients requiring the use of enzyme-inducing anti-epileptic medication that includes: 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. 
• 
Patient with a history of interstitial lung disease, history of slowly progressive dyspnea, sarcoidosis, 
silicosis, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis 
• 
Patient with known active infection with HIV, Hepatitis B or Hepatitis C 
 
5.0 CLINICAL AND LABORATORY EVALUATIONS (see Study Calendar, Appendix E):   
5.1 
Screening Evaluat ions  
5.1.1 
The following are the required ≤28 days prior to randomization, unless otherwise specified:  
• 
Review of medical history 
• 
Physical examination  
• 
Height 
• 
Vital signs 
• 
Weight 
• 
Performance status assessed by the KPS scale (see Appendix A). 


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• 
Review of concomitant medications with particular attention to enzyme-inducing anti-epileptic 
medication that includes: phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine- 
within 14 days prior to randomization. 
• 
Serum Chemistry to include: total bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, 
bicarbonate, chloride, BUN, Cr, glucose, calcium-within 14 days prior to randomization. 
• 
CBC, differential, platelets within 14 days prior to randomization. 
• 
PT, PTT within 14 days prior to randomization. 
• 
Serum CA-19-9 
• 
Serum Pregnancy test for women of child-bearing potential as defined by ECOG.  Within 14  
days prior to randomization. 
o ECOG defines a female of childbearing potential as any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets 
the following criteria: 
▪ 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
▪ 
Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). 
• 
CT Contrast-enhanced or Spectral CT scan, pancreas mass (protocol helical CT scan) of chest, 
abdomen, liver 
• 
Endoscopic ultrasound for assessing tumor invasion of vascular structures if CT findings of 
unresectability are equivocal.  
o This is standard of care for subjects. Examples of unresectability at the time of study entry 
include: soft tissue involvement of the superior mesenteric artery, celiac artery, 
common/proper hepatic artery, aorta, inferior vena cava, or portomesenteric venous 
occlusion. If the subject has not undergone standard of care EUS prior to study enrollment 
then in addition to biopsy of the tumor (SOC) an additional random biopsy of the liver will be 
performed for assessment of autophagy. 
o If the subject has already undergone EUS prior to study enrollment a second EUS will not be 
performed but the cell blocks from this EUS study will be obtained for research purposes and 
the liver biopsies will be omitted. 
• 
Electrocardiogram (EKG)  
• 
Research labs within 14 days of randomization  
 
5.2 
Treatment Phase Evaluations  
Once deemed eligible, patients will be assigned to either the gemcitabine and Nab-Paclitaxel alone or with 
hydroxychloroquine. Please refer to the study calendar for the schedule of events.  Unless otherwise specified, 
all visits must occur within ± 3 days of the planned visit date. Waivers to accommodate holidays, vacations, 
and other scheduling problems may be granted by the Principal Investigator upon request of the treating 
physician. If the Investigator suspects a drug-related toxicity, an extra, unscheduled visit with additional 
laboratory tests should be performed as clinically needed  
 
Refer to Appendix D for dosing parameters/modifications for Gemcitabine and Nab-Paclitaxel.  No dose 
modifications are allowed for hydroxychloroquine. 
 
5.3 
Prior to Chemotherapy Dosing on Cycle 1 (Arm A: Day 3) 
• 
Physical examination to include evaluation for peripheral neuropathy. 
• 
KPS performance status  
• 
BSA calculation and weight (recalculated per the site’s standard of care, or if body weight changes by 
more than 10%)  
• 
Concomitant medications evaluation  
• 
Vital signs  
• 
Adverse event evaluation  
• 
CBC, differential, and platelet counts  


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• 
Serum Chemistry to include: total bilirubin, AST, ALT, alkaline, phosphatase, sodium, potassium, 
bicarbonate, chloride, BUN, Cr, glucose, calcium 
• 
Serum CA19-9 
 
5.4 
Prior to Dosing on Cycle 1 (Arm A: Day 10 and 17)  
• 
KPS performance status  
• 
Concomitant medications evaluation  
• 
Vital signs  
• 
Adverse event evaluation  
• 
CBC, differential, and platelet count  
• 
CMP 
 
• 
Prior to Dosing on Cycle 2 (Arm A) Physical examination to include evaluation for peripheral 
neuropathy 
• 
KPS performance status  
• 
BSA calculation and weight  
• 
Concomitant medications evaluation  
• 
Vital signs  
• 
Adverse event evaluation  
• 
CBC, differential, and platelet counts  
• 
Comprehensive Metabolic Panel (CMP), Serum CA19-9  
 
5.5 
Prior to Dosing on Cycle 2 (Arm A) 
• 
KPS performance status 
• 
Concomitant medications evaluation  
• 
Vital signs  
• 
Adverse event evaluation  
• 
CBC, differential, and platelet count  
• 
CMP  
 
5.6 
Surgery Evaluation (Arm A) 
Laboratory and clinical evaluations will be performed to assess AEs and patients will be evaluated for 
surgery. The following evaluations will be performed ≤5 business days (+1 day) prior to surgery.  
• 
Physical examination 
• 
KPS performance status  
• 
Vital Signs 
• 
Spectral CT or CT Scan of chest, abdomen and pelvis 
• 
Adverse event evaluation  
• 
Concomitant medications evaluation 
• 
CBC, differential, and platelet counts  
• 
Research labs  
• 
Serum Chemistry to include: total bilirubin, AST, ALT, alkaline  phosphatase, sodium, potassium, 
bicarbonate, chloride, BUN, Cr, glucose, calcium 
• 
Serum CA19-9 level   
• 
PT/PTT  
 
• 
Surgery (to occur no sooner than 2 weeks post last dose of chemotherapy and no longer than 6 weeks 
post-chemo) (Arm A)resection and tissue collection for research 


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• 
If patient underwent liver biopsy in screening, at time of resection an additional random liver biopsy will 
be performed to monitor autophagy.  This will not be done in those patient’s that did not have a 
pretreatment liver biopsy. 
 
5.7 Four (4) Weeks Post Discharge From Hospital Stay (+/- 2 Weeks) (Arm A) 
• 
Physical examination  
• 
Weight 
• 
Vital signs 
• 
KPS performance status. 
• 
Review of concomitant medications 
• 
Clinical chemistry panel 
• 
CBC, differential, platelets  
• 
Research labs 
• 
Serum CA19-9 level   
• 
Adverse events evaluation - The protocol will monitor and record post-operative complications. These 
will be recorded at time of post-operative outpatient visit.  The study is not adequately powered to detect 
significant differences in the treatment regimens.  Therefore no safety or stopping evaluations will be 
made on post-operative adverse events. 
 
5.8 
Follow-Up Period (Arm A) 
Following surgery, subjects will return to standard of care treatment by their treating doctor.  Subjects’ data 
will be collected from their medical records or phone calls every 4 months (+/- 2 weeks) to determine disease 
progression/recurrence and overall survival.  If a subject is available, study labs for research will be collected 
every 4 months (+/- 2 weeks) for the first year.  These are not mandatory collections.  
 
6.0 
STUDY MEDICATIONS AND PROCEDURES 
6.1 
Study D rug Manage ment and  Administra tion 
• 
Gemzar will be prepared and administered per manufactures recommendations. For complete details on 
drug administration, storage, clinical pharmacology, and the human pharmacokinetics of Gemzar please 
see the Package insert.  
• 
Nab-paclitaxel will be prepared and administered per manufactures recommendations. For complete 
details on drug administration, storage, clinical pharmacology, and the human pharmacokinetics nab-
Paclitaxel, please see the Package insert.  
• 
Hydroxychloroquine (Plaquenil® Sanofi Aventis); will be prepared and administered per manufactures 
recommendations. For complete details on drug administration, storage, clinical pharmacology, and the 
human pharmacokinetics of Plaquenil, please see the Package insert. 
 
Cycle 1 wil be a 30 day cycle and Hydroxychloroquine (600mg  PO BID) will be started on Day 1 (48 hours 
prior to the first dose of chemotherapy) and continued through the evening dose before surgery.  Subjects will 
be treated on an outpatient basis with nab-Paclitaxel plus gemcitabine.  Nab-Paclitaxel 125 mg/m2 as a 30-
minute infusion (+/- 10 Minutes) followed by  gemcitabine 1000 mg/m2 as a 30-minute infusion (+/- 10 
Minutes) will be administered on Days 3, 10, and 17 of cycle 1. 
 
Cycle 2 wil start 30 days after the start of Hydroxychloroquine.  Cycle 2 (day 31) will be a 28 day cycle. The 
nab- Paclitaxel and gemcitabine will be given on days 1,8,15 of cycle 2.  Surgery will take place no soner 
than 2 weeks after day 15 of cycle 2. Surgery will not occur until recovery from any clinically significant 
toxicities but no later than 6 weeks post-chemotherapy.  Supportive care and anti-emetics per the treating 
physician discretion of care can be provided.  
 
6.2 
Hydroxychloroquine Administration  
• 
Patients will self-administer HCQ every day starting at cycle 1 day 1 and continued through the evening 
dose the day before surgery.  


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• 
HCQ will be administered in divided doses (BID) of 600mg (3 capsules in AM and 3 capsules in PM). 
Patients should be told to swallow the whole capsule in rapid succession without chewing. 
Hydroxychloroquine will not be held when chemotherapy is held for toxicity unless in the opinion of the 
treating physician it is believed to be contributing to ongoing toxicity 
• 
There will be no dose modifications of hydroxychloroquine 
 
 
 


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6.3 
Management of Toxicities 
• 
Non-Neutropenic Fever: 
o Due to the instances of non-neutropenic sepsis in early trials of this regimen, at the first occurrence of 
fever > 38.5 degrees  Celsius (regardless of neutrophil count), institution of ciprofloxacin (500 mg 
orally 2 times daily) or amoxicillin/ clavulanate (Augmentin, 500 mg orally 2 to 3 times daily, in 
patients with allergy to fluoroquinolones) should be initiated.  
o On their first visit, patients are to be provided with enough supplies of ciprofloxacin (or the 
alternative antibiotic) for use at home, and instructed to initiate its intake at the first recorded 
temperature of >38.5 degrees Celsius (or if they feel they are developing a fever and a thermometer is 
not available). They should also immediately contact their physician for guidance on where to go for 
blood counts to be evaluated for sepsis as soon as possible. Hospitalization or evaluation in the 
emergency room may be required depending on the clinical presentation.  
o Febrile patients (regardless of neutrophil count) should have their chemotherapy treatment 
interrupted. A full sepsis diagnostic work-up should be performed while continuing broad spectrum 
antibiotics.  
o Patients with persisting fever after 3 weeks despite uninterrupted antibiotic treatment will discontinue 
study treatment.  
 
• 
Febrile Neutropenia 
o Patients can receive white cell growth factors in addition to antibiotic treatment per standard of care 
of the treating physician.  
o Upon resolution of febrile neutropenia, nab-Paclitaxel and gemcitabine treatment can be resumed at 
the current dose.  
o Should a second instance of Grade 4 Febrile Neutropenia occur, dosage of nab-Paclitaxel and 
gemcitabine will be resumed at the next lower dose  
o Administration of long-term prophylactic ciprofloxacin (or the alternate antibiotic) to prevent 
recurrences in patients already having experienced a first febrile episode (and managed as above) will 
be at the discretion of the treating physician.   
o Administration of prophylactic antibiotics to otherwise uncomplicated patients with biliary stents will 
be at the discretion of the treating physicians. Biliary stents should be monitored closely to determine 
need for replacement. 
 
• 
Interstitial Pneumonitis  
In a recently completed Phase III trial utilizing the ABI-007 and gemcitabine combination in patients with 
metastatic adenocarcinoma, 10 patients have developed interstitial pneumonitis, 9 in the ABI-007 + 
gemcitabine arm (3.0%) of which 3 were fatal, and 1 in the gemcitabine arm (0.3%). The median time to 
onset of interstitial pneumonitis after initiation of study medication was 86 days (range = 50-166 days). In 
the combination arm, 6 of the 9 patients showed ground glass opacities on CT scans and 4 patients had 
lung metastases. None of the patients had any clear evidence of infection. Six of these 9 patients received 
steroids. The outcome was fatal in 3 patients (all in the combination arm). The remaining 7 cases 
(including the 1 case in the gemcitabine monotherapy arm) resolved. Analysis of these cases for common 
trends revealed history of multiple drug or contrast media allergy (4 out of 9 patients or 44% in the 
combination arm) and a higher patient weight (mean of 81.4 kg), with the caveat of the small overall 
numbers precluding generalizations.  Pulmonary toxicity has been reported for both gemcitabine and 
paclitaxel. Epidemiology reports show that gemcitabine monotherapy is weakly associated with lung 
toxicity. A retrospective review (Meadors, 2006) of pooled clinical trial data of 4,448 patients with mixed 
cancer indications reported an incidence of dyspnea of 0.2% and serious pulmonary  toxicity of 0.06%. 
Paclitaxel monotherapy is weakly associated with lung toxicity (Rowinsky, 1995). Dyspnea with 
bronchospasm has been reported in 0.3 to 0.9%, with 30% of type 1 hypersensitivity reactions. 
Combination chemotherapy of gemcitabine/paclitaxel shows a higher incidence of this complication 
compared to either drug alone.  
 


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• 
Prevention, Surveillance and Management of Interstitial Pneumonitis 
o Before enrollment, evaluate candidate patients for familial, environmental or occupational exposure 
to opportunistic pathogens, and do not enroll those with a history of slowly progressive dyspnea and 
unproductive cough, or of conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, 
pulmonary hypersensitivity pneumonitis or multiple allergies.  
o During study treatment, episodes of transient or repeated dyspnea with unproductive persistent cough 
or fever should be paid attention to. Radiographic evaluation with chest X-rays and CT scans (normal 
or high resolution) may be indicated to look for infiltrates, ground-glass opacities or honeycombing 
patterns. Pulse oximetry and pulmonary function tests can show respiratory and ventilation 
compromise. 
o Infections should be ruled out with routine immunological/ microbiological methods. 
o Transbronchial lung biopsy is not recommended, given its limited value and risk of pneumothorax 
and hemorrhage, and should be reserved for cases with unclear etiology.  
o Study drug administration should be interrupted upon diagnosis of interstitial pneumonitis and 
patients permanently discontinued from further study drug treatment. After ruling out an infectious 
etiology, intravenous high-dose corticosteroid therapy should be instituted without delay, with 
appropriate premedication and secondary pathogen coverage. Patients with an added immunological 
component may also require immune modulation with azathioprine or cyclophosphamide. 
Appropriate ventilation and oxygen support should be used when required.  
 
6.4 
Guidelines for Tox icity Managem ent  
• 
Regar dless of the r eason for hol ding study dru g treatment, the maximum allowable length of 
treatment interrup tion is 3 weeks.  
• 
If toxicity during study is predominantly attributed to nab-Paclitaxel or gemcitabine, and if dose reduction 
is also poorly tolerated, and if it is determined that it is not in the best interest of the patient to continue 
combination therapy then therapy may continue with either drug alone with the approval of the principal 
investigator only. If one drug needs to be held due to specific toxicity, the other drug may be given. 
• 
Examples for discontinuation of nab-Paclitaxel: Persistent grade 2 or Grade 3 neuropathy 
• 
Examples for discontinuation of gemcitabine: Persistent drug related fevers, refractory edema, 
neutropenia or thrombocytopenia  
• 
Missed doses are not to be made up 
• 
In the event of dose or drug modification of gemcitabine and nab-Paclitaxel noted above the 
hydroxychloroquine will not be discontinued. 
• 
Toxicity will be graded according to the NCI Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 4.0. A copy of this document can be found at the following internet site: 
http://ctep.info.nih.gov/reporting/ctc.html.   
• 
Patients experiencing serious adverse events wil be followed as described in section 11.  
• 
For patients who have had dosing delays, all evaluations wil be correspondingly delayed. 
• 
Reasons for dose modifications or delays, the supportive measures taken, and the outcome wil be 
documented in progress notes. 
 
6.5 
Dose Modifications 
Refer to Appendix D for dose modification details. 
o Up to 2 dose level reductions of nab-Paclitaxel and 2 dose level reductions of gemcitabine are permitted. 
Patients should be taken off study if further dose reduction is required  
o No dose modification of hydroxychloroquine is allowed   
 
 
6.6 
Concomitant Medications 
• 
Concomitant medications should be avoided with the exception of analgesics (only acetaminophen or 
narcotics may be given for pain), chronic treatments for concomitant medical conditions, or anti-nausea 
medications and agents required for life threatening medical problems.     


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• 
The subject must refrain from taking the following medications beginning 7 days prior to taking study 
drugs and lasting until after the last study drug is taken and a decision about surgical resection has been 
reached:  
 
o Non-steroidal anti-inflammatory medications (NSAIDs) 
o Clopidogrel (Plavix) 
o Aspirin >325 mg/day 
o If possible, the use of drugs with laxative properties should generally be avoided because of the 
potential for the exacerbation of diarrhea associated with gemcitabine. Subjects should be advised to 
contact their physician to discuss any laxative use.  
 
7.0 
SUBJE CT DISCONTINUATION 
Subjects will be removed from the study for the following reasons: 
• 
Progression of disease (i.e. development of metastasis) during protocol treatment. Subjects who develop 
metastases will be removed from the study and evaluated by an oncologist as part of routine cancer care. 
Depending on the subject’s performance status, the subject may be treated with another chemotherapy regimen 
(such as 5-FU) at the discretion of the treating oncologist. 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Treatment-related toxicities, 
• 
Subject decides to withdraw from the study, or is non-adherent,  
• 
General or specific changes in the subject's condition rendering the subject unacceptable for further treatment in 
the judgment of the investigator. 
 
8.0 
SAFETY PLAN 
8.1 
Gener al Plan to Manage Safety 
• 
Subjects will be monitored for treatment-related toxicity from the time of enrollment until the first 
outpatient evaluation after surgery and ongoing for any grade 4 or 5 event felt to be directly related to 
treatment regimen. 
• 
Safety will be monitored throughout the study at Pre-Study, Cycle 1, Day 1, 3, 10, 1; Cycle 2, Day 1 8 
and 15; Pre-Op Evaluation visit and 4 Weeks Post-Discharge (+/- 2 weeks),  for subjects who have 
received one or more doses of study drugs during trial intervention. Subjects will be reevaluated more 
frequently for clinical indications. 
• 
The initial toxicity assessment is dependent on monitoring for toxicity, the criteria for which are defined 
by the NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0, Appendix B). 
The NCI CTC V 4.0 can be downloaded at http://ctep.info.nih.gov/reporting/ctc.html. Toxicities are 
defined as adverse events that are possibly, probably, or definitely related to treatment. 
• 
The Principal Investigator will continuously monitor study progress for safety. The PI, GI Oncology 
Program Manager, Clinical Research Coordinators and other relevant study personnel will meet on a bi-
weekly basis at the GI Oncology data safety monitoring meetings or as needed to review overall conduct 
and progress of the study. During these meetings, study data from the site, subject safety issues and 
subject recruitment, accrual and retention will be reviewed and discussed. Data records will be reviewed 
periodically and safety reports monitored as they are received. An unusual frequency of treatment-related 
adverse events will be reviewed by the GI Oncology Safety Monitoring Board. 
 
8.2 
Recrui tment Procedu res 
Potential subjects will be identified from the Principal Investigator’s and Co-Investigators’ current clinic 
population, or will be referred to the Principal Investigator by their own physician. They will be approached 
and informed of the study by an individual who is involved in their care. No cold-calling will occur, and no 
advertising will be used. The consent process will be carried out as a joint effort among the subject's 
physician, the study coordinator, and/or co-investigators on the study. Informed consent shall be obtained and 
the certification of informed consent statement signed (at the time of obtaining consent) by the investigator or 
co-investigators, all of whom are physicians. 


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8.3 
Costs and Paym ents. 
• 
Resear ch Study C osts:  The study drug hydroxychloroquine will be provided at no cost to subjects or 
their insurance companies. Gemcitabine and nab-Paclitaxel are a standard of care treatment. As a result, 
subjects and/or their insurance will be billed in the standard fashion. Subjects will be billed in the 
standard fashion for the routine clinical care that they receive, and either the subject or their insurance 
provider will be responsible for this payment.  
 
• 
Resear ch Study Paym ents:  Subjects will not be paid for participating in this study. 
 
9.0 
CORRELATIVE STUDIES/SECONDARY ENDPOI NTS 
 
9.1 
CA19-9: The tumor marker Carbohydrate antigen 19-9 (CA19-9) has well-established prognostic value in 
patients with PDA. Baseline levels of CA19-9 corelate with overall survival in patients with all stages of 
disease regardless of the treatment modality (1-6). For patients resectable PDA baseline CA19-9 is predictive 
of tumor resectability and early metastases, and postoperative CA19-9 is prognostic for overall survival 
(OS)[16, 17]. Moreover, increase in CA19-9 levels closely corelate with time to radiographic progression, 
(10-12). Data that changes in CA 19-9 are a reliable maker of response to treatment are is more controversial.  
A number of reports have suggested that changes in CA19-9 reliably predict clinical response while others 
suggest that only baseline levels are prognostic [13, 18, 19].  
 
9.2 
Basic Science Studies of Autophagy and  Apoptosis in the Tu mor, Peripheral Blood: We will compare 
autophagy, apoptosis and IL-6/STAT3 signaling between tumors treated with chemotherapy alone versus 
tumors treated with chemotherapy plus hydroxychloroquine. We will correlate levels of apoptosis, autophagy 
and IL-6/STAT3 with histologic and biomarker response. We will utilize samples from pre-operative cell 
blocks as well as final resected specimen cell blocks as well as final resected specimens. We will examine the 
liver and peripheral blood for markers of autophagy and DAMPs. Each patient will serve as their own control 
pre and post neoadjuvant chemotherapy, pre- and post-operative. We will correlate changes in systemic 
autophagy/inflammation with metrics of clinical efficacy, levels of autophagy, apoptosis and pSTAT3 in the 
tumor. We will perform this analysis first on the remaining specimens in our ongoing clinical trial of 
Gem/HCQ. These studies will be performed in the DAMP Lab and in collaboration with Liotta lab at George 
Mason University  
 
9.3 
Coagulat ion Studies: Preliminary data from murine modles in our lab (DAMP Lab) suggest that 
hydroxychloroquine can reverse hypercoagulability associated with malignancy, thought inhibition of 
autophagy and decreases neutrophil NETS.  Therefore we wil be assessing TEG coagulation profile on all 
subjects at three time points. 1) pre-treatment 2) post chemotherapy 3) post-operative (4-6 weeks) 
 
9.4 
Future S tudies:  All unused portions of the specimens colected will be stored in the DAMP lab for future 
investigation.  Samples collected for research purposes will be stored indefinitely. The samples may be shared 
with scientific colaborators.  If this occurs the samples will not contain personal identifiers (for example, 
name, social security number) and will include assigned code numbers.  The information linking these code 
numbers to subjects’ identity will be kept on a secure UPMC hard drive.  
 
10.0 STATISTICAL MET HODS 


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14 
10.1 Just ification of Design   
Adaptive randomization alocates more patients to the beter treatment 
as significant evidence that one treatment is indeed better accrues 
during the trial.  This makes the randomized trial more palatable to 
patients while retaining the advantages of randomization.  To 
characterize the operating characteristics of the design, we simulated 
4,000 trials assuming different Grade IV histologic response 
probabilities (between 0.03 and 0.3) in the control arm and odds ratios 
for the experimental versus the control arm (1.2,2,3 and 5).  We 
calculated the proportion of trials in which it was concluded that P(πC 
> πX) < 0.05, which we term the “power” of the design.  It was 
determined that, if nab-Paclitaxel alone is sufficiently effective to 
induce a probability of Grade IV response of at least 0.15, adequate 
statistical power will be available for odds ratios of 3.5 or better.  
Following Figure 9 in (34), we anticipate that the standard deviation of log10(CA19-9) will be approximately 
0.5 in responders, and 0.75 in non-responders.  Based on these values, we expect the width of 95% confidence 
intervals for log10(CA19-9) to be between 0.38 and 1.15 for responders, and 0.40 and 0.52 for non-responders.   
 
10.2 Monitoring for Futility   
P(πC > πX) will be calculated at the enrollment of every patient, beginning with the 21st, using the Beta(4,16) 
and Beta(8,12) priors for πC and π
X, respectively (see 10.3.1).  If at any time P(πC > πX) > 0.80, the trial will 
be halted for futility.   
 
10.3 Data Analysis 
10.3.1 Assessment of Primary Endpoint 
The primary endpoint for this trial will be the Evans Grade histologic response, as defined in 
Appendix D. Evans Grade will be tabulated by treatment, with 94% confidence intervals.  The effect 
of treatment on Evans Grade wil be assessed by a cumulative logit model, an extension of logistic 
regression appropriate for ordinal multinomial endpoints.  A likelihood ratio chi-squared test will 
determine the statistical significance of the effect of treatment on Evans Grade.  In secondary 
analyses, the effect of baseline clinical, demographic and biomarker variables on the relationship 
between treatment and Evans Grade will be explored by adding those variables to the primary 
endpoint model.   
 
10.3.2 Assessment of secondary endp oint 
10.3.2.1 CA19-9 
95% credible intervals for the log-transformed preoperative and postoperative values of 
CA19-9 will be calculated, along with P(μC < μX). The change in CA19-9 will be compared 
between arms using ANCOVA, where postoperative CA19-9 will be the dependent 
variable and preoperative CA19-9 the covariate.  If the interaction term between study arm 
and preoperative CA19-9 is significant, the change in postoperative CA19-9 must be 
interpreted conditioned on the baseline value.  CA19-9 will be treated as a continuous 
variable; cutoffs for response will not be used. 
 
11.0 ADVERSE EVENT 
 
Clinical study subjects will be routinely questioned about adverse events at study visits. 
 
11.1 Adverse Event Definitions  
Adverse event means any untoward medical occurrence associated with the use of the drug in humans, 
whether or not considered drug related. 
 
Adverse reaction means any adverse event caused by a drug. 
0.05
0.10
0.15
0.20
0.25
0.30
0.0
0.2
0.4
0.6
0.8
1.0
P(CR in Control Arm)
Power
OR=1.2
OR = 2
OR = 3
OR = 5


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• 
Serious Adverse Event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Specifically, results in death, is life-threatening, requires 
inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event 
(defined as a medical event(s) that may not be immediately life-threatening or result in death or 
hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed in 
the definition above.)  Any subject death within 30 days of the last dose of study drug, regardless of the 
causality or a secondary malignancy should also be recorded as a serious adverse event. 
 
• 
Life-threatening, suspected adverse reaction.  A suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site principal investigator), its 
occurrence places the patient or research subject at immediate risk of death.  It does not include a 
suspected adverse reaction that had it occurred in a more severe form, might have caused death. 
 
• 
Unexpected, suspected adverse reaction. A suspected adverse reaction is considered “unexpected” if it is 
not listed in the general investigational plan or clinical protocol; or is not listed at the specificity or 
severity that has been previously observed and/or specified.  If an investigator brochure is not required or 
available, suspected adverse reaction is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended.  "Unexpected," as used in this 
definition, also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation.  Any clinically important increase in the rate of a serious suspected adverse reaction over 
that listed in the protocol or investigator brochure can also be considered unexpected.  An agregate 
analysis of specific events observed in a clinical trial (such as known consequences of the underlying 
disease or condition under investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group. 
 
• 
Suspected adverse reaction. Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event (considered “possibly related”). For the purposes of safety reporting, 
"reasonable posibility" means there is evidence to sugest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug. 
 
• 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, regardless 
of study group or suspected causal relationship to the study drug(s) will be recorded in the subjects’ case 
histories.  For all adverse events, sufficient information will be pursued and/or obtained so as to permit 1) 
an adequate determination of the outcome of the event (i.e., whether the event should be classified as a 
serious adverse event) and; 2)  an assessment of the casual relationship between the adverse event and the 
study drug(s).   All toxicities encountered during the study will be evaluated on an ongoing basis 
according to the NCI Common Toxicity Criteria version 4.0.  
 
Adverse events or abnormal test findings felt to be associated with the study drug(s) will be followed until the 
event (or its sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the Principal 
Investigator. 
 
In the event of an adverse event the first concern will be for the safety of the subject.   
 


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Review of safety information. The principal investigator / sponsor must promptly review all information 
relevant to the safety of the drug obtained or otherwise received from foreign or domestic sources, including 
information derived from any clinical or epidemiological investigations, animal or in vitro studies, reports in 
the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory 
authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the 
United States.  The study sponsor must notify all participating investigators of potential serious risks, from 
clinical trials or any other source, as soon as possible. 
 
11.2 Reporting of Suspected Adverse Reactions  
In the event of a serious adverse event, the PI and the institutional review board will be notified using the 
FDA Form 3500 MedWatch report.   
 
All events meeting the definition of a serious adverse event should be recorded on a MedWatch 3500 Form 
(link below) and submitted to: 
(http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/UCM082725.pdf )  
 
1. Nathan Bahary, MD 
a. Phone: (412) 412-864-7764 
b. Email: baharyn@upmc.edu 
 
2. Local Institutional Review Board per institutional reporting requirements 
 
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include as applicable the following information that is available at the time of report within the 
Event Description (section 5) of the MedWatch 3500 form: 
 
• 
CTCAE term(s) and grade(s)  
• 
current status of study drug 
• 
all interventions to address the AE (testing and result, treatment and response) 
• 
hospitalization and/or discharge dates 
• 
event relationship to study drug 
 
Follow-up reports: 
 
Additional information may be added to a previously submitted report by adding to the original 
MedWatch 3500 report and submitting it as follow-up or creating supplemental summary information and 
submitting it as follow-up with the original MedWatch 3500 form. 
 
11.3 Data Safety Monitoring Plan 
• 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, clinical 
research associates, data managers, and clinic staff meet monthly in disease center Data Safety 
Monitoring Boards (DSMB) to review and discuss study data to include, but not limited to, the following: 
o serious adverse events 
o subject safety issues 
o recruitment issues 
o accrual 
o protocol deviations 
o unanticipated problems 
o breaches of confidentiality 
 
• 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria version 4.0. All study treatment associated adverse events that are serious, at 


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17 
least possibly related and unexpected will be reported to the IRB.  Any modifications necessary to ensure 
subject safety and decisions to continue, or close the trial to accrual are also discussed during these 
meetings. If any literature becomes available which changes the risk/benefit ratio or suggests that 
conducting the trial is no longer ethical, the IRB will be notified in the form of an Unanticipated Problem 
submission and the study may be terminated. 
 
• 
All study data reviewed and discussed during these meetings wil be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem submission. 
The summaries of these meetings are forwarded to the UPCI DSMC which also meets monthly following 
a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC progress 
reports, to include a summary of all serious adverse events and modifications, and approval will be submitted 
to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be reviewed 
twice a year rather than monthly. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to suspend accrual or 
further investigate treatment on any trial based on information discussed at these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records.  
 
12.0 RETENTION OF RECORDS 
 
• 
Records pertaining to this study will be kept in accordance with institutional guidelines for a period of at least 
two years after final report. 
 
13.0 PATIENT INFORMED CONSENT: RISK/BENEFIT INFORMATION  
 
• 
As with any medication, there may be risks that are unknown at this time. These risks may be severe or life-
threatening. In addition, the possibility exists that this protocol also may not improve the outcome for patients 
with surgically-treated pancreatic cancer.  
 
Hydroxychloroquine 
Known Potential Toxicities of Hydroxychloroquine: 
• 
Central nervous system: Irritability, nervousness, emotional changes, nightmares, psychosis, headache, 
dizziness, vertigo, seizure, ataxia, lassitude. 
• 
Heart arrhythmias (premature or extra heartbeats) may cause death 
• 
Dermatologic: Bleaching of hair, alopecia, pigmentation changes (skin and mucosal; black-blue color), rash 
(urticarial, morbilliform, lichenoid, maculopapular, purpuric, erythema annulare centrifugum, Stevens-Johnson 
syndrome, acute generalized exanthematous pustulosis, and exfoliative dermatitis).  
• 
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, abdominal cramping.  
• 
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, hemolysis (in patients with 
glucose-6-phosphate deficiency).  
• 
Hepatic: Abnormal liver function/hepatic failure (isolated cases). 
• 
Neuromuscular & skeletal: Myopathy leading to progressive weakness and atrophy of proximal muscle groups 
(may be associated with mild sensory changes, loss of deep tendon reflexes, and abnormal nerve conduction). 
• 
Ocular: Disturbance in accommodation, keratopathy, corneal changes/deposits (visual disturbances, blurred 
vision, photophobia - reversible on discontinuation), macular edema, atrophy, abnormal pigmentation, 


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18 
retinopathy (early changes reversible - may progress despite discontinuation if advanced), optic disc 
pallor/atrophy, attenuation of retinal arterioles, pigmentary retinopathy, scotoma, decreased visual acuity, 
nystagmus. 
 
Generic name:  
Hydroxychloroquine sulfate 
Commercial name:  
Plaquenil  
Chemical name:  
7-Chloro-4-[4-[ethyl-(2-hydroxyethyl)amino]-1-methylbutylamino] quinoline 
 
 
 
Supplied by: Commercially available; Sanofi-Synthelabo 
 
Gemcitabine 
Likely- occurs in more than 25% of people (25 out of  100 people) 
• 
Anemia (unusual tiredness or weakness),  
• 
Fever and mild flu-like symptoms 
• 
Hematuria (blood in urine)  
• 
Skin rash, with or without itching,  
• 
Bone marrow suppression (anemia, neutropenia, leukopenia, and thrombocytopenia) 
• 
Abnormal liver function, usually transient 
• 
Constipation; Nausea and vomiting, usually of mild to moderate severity 
• 
Pain 
 
Common - occurs in 10% to 25% of people (10 to 25 out of 100 people): 
• 
Peripheral edema (swelling of fingers, feet, or lower legs)  
• 
Proteinuria (cloudy urine) 
• 
Alopecia (hair loss), usually minimal 
• 
Mouth ulcers (stomatitis) 
• 
Diarrhea 
• 
Constipation 
• 
Bleeding 
• 
Somnolence 
• 
Cutaneous Pruritis 
 
Infrequent - occurs in 1% to 10% of people (1 to 10 out of 100 people):  
• 
Anaphylactoid reaction (change in facial skin color; skin rash, hives, and/or itching; swelling or puffiness of the 
face, especially the eyelids or area around the eyes) and bronchospasm (shortness of breath, troubled breathing, 
tightness in chest, and/or wheezing) in less than 2% due to an allergic reaction to gemcitabine 
• 
Hemorrhage: blood in urine or stools; pinpoint red spots on skin 
• 
Cardiovascular toxicity (2%), including myocardial infarction (pain in chest, arm, or back; pressure or 
squeezing in chest), hypertension (high blood pressure), arrhythmia (fast or irregular heartbeat), cerebrovascular 
accident (headache, sudden and severe; slurred speech or inability to speak; weakness in arm and/or leg on one 
side of the body, sudden and severe), 
• 
Febrile neutropenia or other infection (fever or chills; cough or hoarseness; lower back or side pain; painful or 
difficult urination) 
• 
Abnormal renal function 
• 
Paresthesias (a tingling sensation like “pins-and-needles”), typically mild 
• 
Somnolence (sleepiness) 
• 
Rare- Occurs in less than 1% (less than 1 out of 100 people):  
• 
Congestive Heart Failure (coughing; noisy, rattling, or troubled breathing; generalized weakness, leg swelling)  
• 
Hemolytic-Uremic Syndrome (black, tarry stools; blood in urine or stools; fever; increased or decreased 
urination; pinpoint red spots on skin; swelling of face, fingers, feet, or lower legs; unusual bleeding or bruising; 
unusual tiredness or weakness; yellow eyes or skin), 
• 
Lung toxicity, parenchymal, or pneumonitis ( coughing; shortness of breath),  
• 
Renal failure requiring dialysis.  
• 
Severe infection 
• 
Serious hepatotoxicity including death 


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19 
• 
Severe paresthesias 
 
Blood Samples:  
• 
Obtaining blood can cause pain, bleeding, bruising or swelling at the site of needle insertion. Fainting 
sometimes occurs and infection rarely occurs. 
 
Breach of Confidentiality:  
• 
Knowledge of the subject’s medical and/or research data could potentially impact future insurability, 
employability, or plans for reproduction; or have a negative impact on family relationships; and/or result in 
shame or embarrassment.  
 
Pregnancy and Fertility:  
• 
The effect of the study drugs on fertility is unknown. It is also unknown what effect these drugs will have on 
pregnancy. The risks involving pregnancy and fertility will be explained to subject during the informed consent 
process and are stated in the consent form. Female subjects of childbearing potential will have a serum 
pregnancy test at screening. This test must be negative in order for the subject to be eligible for study 
participation. In addition, subjects will be instructed that if they choose to be sexually active they must use an 
appropriate method of birth control until at least six months after receiving the last dose of study drug. 
Examples of such methods and the length of time that such methods must be used are provided in the consent 
form. Subjects will also be instructed to immediately inform the principal investigator if they suspect that they 
or their partners are pregnant.  
 
Nab-Paclitaxel 
The most common side effects experienced with nab-Paclitaxel, include  
• 
hair loss,  
• 
infections due to low count of a type of white blood cell (neutropenia),  
• 
numbness,  
• 
tingling, or burning in the hands and/or feet (neuropathy),  
• 
fatigue and weakness,  
• 
low red blood cell count (anemia),  
• 
mouth or lip sores (mucositis),  
• 
joint and muscle pain,  
• 
stomach upset,  
• 
vomiting, and diarrhea,  
• 
decreased heart rate (bradycardia), or  
• 
low blood pressure (hypotension) 
 
 
 
 


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20 
References 
 
1. 
Tang DL, K.R., Zeh HJ, Lotze MT. and  HMGB1 and Cancer. . Biochimica et Biophysica Acta 2010. 
1799 p. 131. 
2. 
Kang, R., et al., The receptor for advanced glycation end products (RAGE) sustains autophagy and 
limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ, 2009. 16: p. 16. 
3. 
Tang, D., et al., Endogenous HMGB1 regulates autophagy. The Journal of Cell Biology. 190(5): p. 881-
892. 
4. 
Kang, R., et al., The receptor for advanced glycation end products (RAGE) sustains autophagy and 
limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ. 17(4): p. 666-676. 
5. 
Kang, R., et al., The Receptor for Advanced Glycation End-products (RAGE) Protects Pancreatic Tumor 
Cells Against Oxidative Injury. Antioxid Redox Signal. 2010: p. 2. 
6. 
Tang, D., et al., HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. 
Oncogene. 29(38): p. 5299-5310. 
7. 
Tang, D., et al., The redox protein HMGB1 regulates cell death and survival in cancer treatment. 
Autophagy. 6(8): p. 8. 
8. 
Yang, S. and A.C. Kimmelman, A critical role for autophagy in pancreatic cancer. Autophagy. 7(8): p. 
912-3. 
9. 
Livesey, K.M., et al., Autophagy inhibition in combination cancer treatment. Curr Opin Investig Drugs, 
2009. 10(12): p. 1269-79. 
10. 
Yang, S., et al., Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25(7): p. 717-29. 
11. 
Bao, P., et al., Validation of a prediction rule to maximize curative (R0) resection of early-stage 
pancreatic adenocarcinoma. HPB, 2009. 11(7): p. 606-611. 
12. 
Hammad, N., et al., CA19-9 as a predictor of tumor response and survival in patients with advanced 
pancreatic cancer treated with gemcitabine based chemotherapy. Asia Pac J Clin Oncol, 1111. 6(2): p. 
98-105. 
13. 
Bauer, T.M., et al., Carbohydrate antigen 19-9 is a prognostic and predictive biomarker in patients with 
advanced pancreatic cancer who receive gemcitabine-containing chemotherapy: A pooled analysis of 6 
prospective trials. Cancer, 1002. 2012(11): p. 27734. 
14. 
Chatterjee, D., et al., Histologic grading of the extent of residual carcinoma following neoadjuvant 
chemoradiation in pancreatic ductal adenocarcinoma: a predictor for patient outcome. Cancer, 1002. 
118(12): p. 3182-90. 
15. 
Thall, P.F. and J.K. Wathen, Practical Bayesian adaptive randomisation in clinical trials. Eur J Cancer, 
2007. 43(5): p. 859-66. 
16. 
Hartwig, W., et al., CA19-9 in Potentially Resectable Pancreatic Cancer: Perspective to Adjust Surgical 
and Perioperative Therapy. Ann Surg Oncol. 2012: p. 18. 
17. 
Humphris, J.L., et al., The prognostic and predictive value of serum CA19.9 in pancreatic cancer. Ann 
Oncol, 1713. 23(7): p. 1713-22. 
18. 
Vainshtein, J.M., et al., Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally 
Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and 
Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study. Int J 
Radiat Oncol Biol Phys, 1016. 3016(12): p. 03817-5. 
19. 
Tsutsumi, K., et al., Monitoring of CA19-9 and SPan-1 can facilitate the earlier confirmation of 
progressing pancreatic cancer during chemotherapy. Pancreatology. 12(5): p. 409-416. 
20. 
Dooms, C., et al., Biological Correlates of the Maximum 18-Fluoro-2-Deoxy-Glucose Uptake on 
Positron Emission Tomography in Non-small Cell Lung Carcinoma after Induction Chemotherapy. J 
Thorac Oncol, 2009. 28: p. 28. 


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21 
21. 
Benz, M.R., et al., FDG-PET/CT imaging predicts histopathologic treatment responses after the initial 
cycle of neoadjuvant chemotherapy in high-grade soft-tissue sarcomas. Clin Cancer Res, 2009. 15(8): p. 
2856-63. 
22. 
Hawkins, D.S., et al., [F-18]-fluorodeoxy-D-glucose-positron emission tomography response is 
associated with outcome for extremity osteosarcoma in children and young adults. Cancer, 2009. 
115(15): p. 3519-25. 
23. 
Capirci, C., et al., The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography 
and computed tomography in the staging and restaging workup of locally advanced rectal cancer, 
treated with preoperative chemoradiation therapy and radical surgery. Int J Radiat Oncol Biol Phys, 
2009. 74(5): p. 1461-9. 
24. 
Schwarz, J.K., et al., The role of 18F-FDG PET in assessing therapy response in cancer of the cervix 
and ovaries. J Nucl Med, 2009. 50 Suppl 1(1): p. 64S-73S. 
25. 
Cerfolio, R.J., et al., Change in maximum standardized uptake value on repeat positron emission 
tomography after chemoradiotherapy in patients with esophageal cancer identifies complete responders. 
J Thorac Cardiovasc Surg, 2009. 137(3): p. 605-9. 
26. 
Kumar, A., et al., The role of 18F-FDG PET/CT in evaluation of early response to neoadjuvant 
chemotherapy in patients with locally advanced breast cancer. Eur Radiol, 2009. 19(6): p. 1347-57. 
27. 
Heinrich, S., et al., Neoadjuvant chemotherapy generates a significant tumor response in resectable 
pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg, 2008. 
248(6): p. 1014-22. 
28. 
Heinrich, S., et al., Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and 
cisplatin for resectable adenocarcinoma of the pancreatic head. J Clin Oncol, 2008. 26(15): p. 2526-31. 
29. 
Pisters, P.W., et al., Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and 
intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol, 1998. 16(12): 
p. 3843-50. 
 
 
 
 


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22 
Appendix A: Performance Status Criteria 
 
 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 


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Appendix B. CTCAE 4.0 
 
National Cancer Institute Common Toxicity Criteria, Version 4 
 
Obtain from http://ctep.info.nih.gov/reporting/ctc.html    
 
 
 
 


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24 
 
 
Appendix C. Pathologic Response 
 
Grading System for Pathological Response (adopted from Evans [29]) 
 
 
Grade 
Histologic Appearance 
I 
Characteristic cytologic changes of malignancy present, but little (< 
10%) or no tumor cell destruction is evident. 
II 
Characteristic cytologic changes of malignancy; 10% to 90% of tumor 
cells are destroyed. 
IIa 
Destruction of 10% to 50% of tumor cells. 
IIb 
Destruction of 51% to 90% of tumor cells. 
III 
Few (< 10%) viable-appearing tumor cells are present. 
IIIm 
Sizable pools of mucin present. 
IV 
No viable tumor cells present. 
IVm 
Acellular pools of mucin present. 
 


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25 
Appendix D: Dose Modifications for Gemcitabine and/or Nab-paclitaxel 
 
D.1.1  
Doses will be reduced for hematologic and other toxicities. Dose adjustments are to be made according to the system 
showing the greatest degree of toxicity.  Toxicities will be graded using the NCI CTCAE Version 4.0. 
 
D.1.2 
Two levels of dose modifications are permitted according to the criteria below. If a toxicity requiring dose 
modification occurs following the second dose reduction of either study drug, further treatment should be 
discontinued. 
 
Dose Modifications 
Dose Levela) 
Nab-paclitaxel Dose (mg/m2)b) 
Gemcitabine (mg/m2)b) 
Study Dose 
125 
1000 
-1 
100 
800 
-2 
75 
600 
 
Error! Reference source not found. 
A maximum of 2 dose level reductions are allowed.   
b) Dose reductions may or may not be concomitant.  Please refer to Table 1 and Table 2 for specific recommendations regarding dose modifications for Day 1 
of each cycle for hematologic and non-hematologic toxicity, respectively.  Please refer to Table 3 and Table 4 for specific recommendations regarding dose 
modifications within a cycle for hematologic and non-hematologic toxicities, respectively. 
 
D.1.3  
Patients experiencing study drug-related toxicities that require a delay in scheduled nab-paclitaxel or gemcitabine 
dosing for 21 days will be discontinued from further treatment in this study (except for peripheral neuropathy;).  
When a dose reduction is required, no dose re-escalation will be permitted for the duration of study treatment (with 
the exception mentioned in  
 
Table 3, namely: on Day 15, re-escalation with granulocyte-colony stimulating factor (G-CSF) support is permitted, 
after a previous dose reduction on Day 8 of the same cycle). 
 
D.1.4 Dose Modifications at Day 1 
In the event dose modifications are required at the beginning of a cycle due to AEs or hematologic toxicities, doses of 
nab-paclitaxel and gemcitabine may be adjusted as detailed in Table 1 and Table 2 as presented below:  
 
 
Table 1: Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) 
Treatment day counts and toxicity 
ANC 
 
Platelets 
Timing 
1.5 x 109/L 
And 
100 x 109/L 
Treat on time 
<1.5 x 109/L 
Or 
<100 x 109/L 
Delay by 1 week intervals until recovery 
Key: ANC = Absolute neutrophil count. 
 


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26 
Table 2: Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity) 
Non Hematologic Toxicity and/or Dose Hold with Previous Cycle 
Toxicity/dose held 
Gemcitabine + nab-paclitaxel dose this cycle 
Grade 0, 1 or 2 toxicity 
Same as Day 1 of previous cycle (except for Grade 2 cutaneous toxicity 
where doses of gemcitabine and nab-paclitaxel should both be reduced to 
next lower dose level; please refer to Section F 1.5) 
Grade 3 toxicitya) 
Decrease gemcitabine and nab-paclitaxel to next lower dose level 
Grade 4 toxicityb) 
Off protocol treatment 
Dose held in 2 previous consecutive 
cycles 
Decrease gemcitabine to next lower dose level and continue throughout the 
rest of treatment 
Key: CTCAE = Common terminology criteria for adverse events.   
a) 
If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced. 
b) 
Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or a symptomatic, will be exempt from this requirement.   
 
D.1.5  Dose Adjustments within a Treatment Cycle 
In the event that patients must have treatment delayed within a treatment cycle due to toxicities, those doses held  
during a cycle will not be made up.   
Dose modifications due to hematologic toxicity (as represented by the blood counts and toxicities, below) within a  
treatment cycle should be adjusted as outlined in  


 
 
27 
 
Table 3: Dose Modifications for Hematologic Toxicity within a Cycle 
Day 8 
Blood Counts 
Day 8 
Nab-paclitaxel 
Day 8 
Gemcitabine 
Day 15 
Blood Counts 
Day 15 
Nab-paclitaxel 
Day 15 
Gemcitabine 
Any Day 
Nab-paclitaxel 
Any Day 
Gemcitabine 
ANC >1000 
and 
Platelets ≥75,000 
100% 
100% 
ANC >1000 and 
Platelets ≥75,000 
100% 
100% 
 
 
ANC 500-1000 or 
Platelets 50,000-
74,999 
Full Dose (treat on 
time)  
+ G-CSFa 
Full Dose (treat on 
time)  
+ G-CSFa 
ANC <500 or 
Platelets <50,000 
Hold + G-CSFa 
Hold + G-CSFa 
ANC 500- 1000 b 
or 
Platelets 50,000-
74,999 
Decrease dose 
by 1 level 
(treat on time) 
Decrease dose 
by 1 level 
(treat on time) 
ANC >1000 and 
Platelets ≥75,000 
Return to Previous 
Dose level (treat on 
time) + G-CSFa 
Return to Previous 
Dose Level (treat on 
time) + G-CSFa 
 
 
ANC 500-1000 or 
Platelets 50,000-
74,999 
Same Dose (as Day 8, 
treat on time) + G-CSFa 
Same Dose (as Day 
8, treat on time) + 
G-CSFa 
ANC <500 or 
Platelets <50,000 
Hold + G-CSFa 
Hold + G-CSFa 
ANC <500a 
or 
Platelets <50,000 
Hold 
Hold 
ANC >1000 and 
Platelets ≥75,000 
Decrease Day 8 dose by 
1 level (treat on time) + 
G-CSFa 
Decrease Day 8 
dose by 1 level (treat 
on time) + G-CSFa 
 
 
 
 
 
ANC 500-1000 or 
Platelets 50,000-
74,999 
Decrease Day 8 dose by 
1 level (treat on time)  
+ G-CSFa 
Decrease Day 8 
dose by 1 level (treat 
on time)  
+ G-CSFa 
 
 
 
 
 
ANC <500 or 
Platelets <50,000 
Hold + G-CSFa 
Hold + G-CSFa 
 
 


 
 
28 
Table 3: Dose Modifications for Hematologic Toxicity within a Cycle 
Day 8 
Blood Counts 
Day 8 
Nab-paclitaxel 
Day 8 
Gemcitabine 
Day 15 
Blood Counts 
Day 15 
Nab-paclitaxel 
Day 15 
Gemcitabine 
Any Day 
Nab-paclitaxel 
Any Day 
Gemcitabine 
Febrile 
Neutropenia 
(Grade 3 or 4)c 
 
 
 
 
 
Hold.  Upon 
resuming 
dosing, decrease 
to next lower 
level and do not 
reescalate 
throughout the 
rest of 
treatment. 
Hold.  Upon 
resuming dosing, 
decrease to next 
lower dose level 
and do not 
reescalate 
throughout the 
rest of treatment. 
Recurrent  
Febrile 
Neutropenia 
(Grade 3 or 4)b 
 
 
 
 
 
Decrease to next 
lower dose level 
and do not 
re-escalate 
throughout the 
rest of treatment. 
Decrease 2 dose 
levels (to 
600 mg/m2) and 
do not re-escalate 
throughout the 
rest of treatment. 
 Abbreviations:  ANC = Absolute neutrophil count; G-CSF = Granulocyte colony stimulating factor. 
• 
G-CSF is optional if descent only affects platelets. 
• 
If patients do not experience resolution of neutropenia within 21 days, despite uninterrupted G-CSF treatment, study treatment will be discontinued. 
• 
Febrile patients (regardless of neutrophil count) should have their chemotherapy treatment interrupted.  A full sepsis diagnostic work-up should be performed while continuing broad spectrum 
antibiotics.  If cultures are positive, the antibiotic may or may not be changed, depending on the sensitivity profile of the isolated organism.  Patients with persisting fever after 3 weeks, despite 
uninterrupted antibiotic treatment, will discontinue study treatment.  Febrile neutropenic patients can also receive G-CSF, in addition to antibiotic treatment, to hasten the resolution of their febrile 
neutropenia (following current institutional guidelines).  In all cases, blood counts must have returned to baseline levels before resuming chemotherapy treatment.


 
 
29 
D.1.6  
Dose modifications may also be made for non-hematological toxicity within a cycle as specified in Table 4 
 
Table 4: 
Dose Modifications for Non-Hematological Toxicity within a Cycle 
CTCAE Grade 
Percent of Day 1  
Nab-paclitaxel + Gemcitabine Dose 
0-2 (and Grade 3 nausea/vomiting and alopecia) 
100%a 
3 (except nausea/vomiting and alopecia) 
Hold either one or both drugs until resolution to ≤Grade 1.  Then 
resume treatment at the next lower dose level. 
4  
Hold 
 
D.1.7 Peripheral Neuropathy   
 
Nab-paclitaxel treatment should be withheld in patients who experience ≥Grade 3 peripheral neuropathy.  
Gemcitabine administration can continue during this period.  Nab-paclitaxel treatment may be resumed at the next 
lower dose level in subsequent cycles after the peripheral neuropathy improves to ≤Grade 1.  Patients experiencing 
peripheral neuropathy that requires a delay in scheduled nab-paclitaxel dosing for ≥21 days will discontinue study 
treatment.  The time to resolution to Grade ≤1 should be the adverse event duration used for adverse event reporting. 
 
D.1.8 Cutaneous Toxicity 
 
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to the next lower dose level for 
both drugs.  If the patient continues to experience these reactions, despite dose reduction, treatment should be 
discontinued.  Patients who develop Grade 4 cutaneous toxicity should have treatment discontinued. 
 
D1.9 Gastrointestinal Toxicity 
 
If Grade 3 mucositis or diarrhea occurs, study drug should be withheld until resolution to ≤ Grade 1, then reinstituted 
at the next lower dose level of both drugs.  Patients who develop Grade 4 mucositis or diarrhea should have treatment 
discontinued. 
 
 
D.1.10 Pulmonary Embolism 
 
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular-weight heparin without 
interruption of therapy.  Moderate to severe pulmonary embolism will require permanent discontinuation of treatment. 
 
D.1.11 Interstitial Pneumonitis 
 
During study participation, patients should be carefully monitored for signs and symptoms of pneumonitis (ie, 
episodes of transient or repeated dyspnea with unproductive persistent cough or fever) and, if observed, immediate 
clinical evaluation and timely institution of appropriate management (emphasizing the need for corticosteroids if an 
infectious process has been ruled out as well as appropriate ventilation and oxygen support when required).  Study 
drug administration should be permanently discontinued upon making a diagnosis of interstitial pneumonitis. 
 
D.1.12 Colony Stimulating Factor Administration 
Colony stimulating factors may be given according to institutional guidelines for the treatment of neutropenic fever or 
infections associated with neutropenia and for the prevention of febrile neutropenia in patients with an ANC <500 
cells/µL (as per Table 3) 


 
 
30 
Patients who do not experience resolution of neutropenia within 21 days, despite uninterrupted G-CSF treatment, will 
discontinue study treatment. 
 
D.1.13 Prophylaxis Against Sepsis 
Due to the incidences of non-neutropenic sepsis, at the first occurrence of fever ≥38.5 °C (regardless of neutrophil 
count), institution of ciprofloxacin (500 mg orally, twice daily)—or amoxicillin/clavulanate (Augmentin®, 500 mg 
orally, 2-3 times daily) in patients with allergy to fluoroquinolones—should be initiated.  On their first visit, patients 
should be provided with enough ciprofloxacin (or the alternative antibiotic) for use at home, and they should be 
instructed to begin taking it when they first record a temperature of ≥38.5 °C (or if they feel they are developing a 
fever and a thermometer is not available).  They should also immediately contact their physician for guidance on 
where to go for blood counts to be evaluated for sepsis as soon as possible.  Hospitalization or evaluation in the 
emergency room may be required depending on the clinical presentation. 
 
D.1.14  Hypersensitivity Reactions 
Hypersensitivity reactions are not expected with either nab-paclitaxel or gemcitabine.  If they do occur, minor 
symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia may require temporary interruption 
of the infusion.  However, severe reactions, such as hypotension requiring treatment, dyspnea requiring 
bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of study drug administration 
and aggressive symptomatic therapy. 
 
Patients who develop a severe hypersensitivity reaction should not be re-challenged.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
31 
Appendix E.  STUDY CALENDAR 
Arm A: Gemcitabine + Nab-Paclitaxel + Hydroxycholoquine 
 
Pre-
Study 
≤ 28 
days 
C1 
Day 
1 
C1 
Day 
3 
C1 
Day 
10 
C1 
Day 
17 
C2 
Day  
1 
C2 
Day 
8 
C2 
Day 
15 
Pre-Op Eval. 
(< 5 business 
days prior to 
surgery +1 
day) 
Evening 
before 
Surgery 
Surgery 
(no sooner 
than 2 wks & 
up to 6 wks  
post- C2D15) 
4 weeks     
Post- 
Hospital 
discharge 
(± 2 
weeks) 
Follow 
Up (q 4 
Mo + 2 
wks) 
(± 3 days for each visit) 
 
 
D1 
D3 
D10 
D17 
D31 
D38 
D45 
 
 
D59 
D87 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Physical exam (includes peripheral 
neuropathy assessment 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Performance status (Karnofsky70) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
CBC w/diff, plts1  
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Comprehensive Metabolic 
Panel 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
PT/PTT2 
X2 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum CA19-9  
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Research labs3 
X2 
 
 
 
 
 
 
 
X 
 
 
X 
X4 
Adverse event evaluation 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
B-HCG5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EUS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Spectral CT or CT Scan of chest, 
abdomen and  liver 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Gemcitabine infusion (1000mg/m2) 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Nab-Paclitaxel (125 mg/m2 
infusion) 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Hydroxychloroquine6  
(600 mg PO BID) 
 
 
X8 
 
 
 
 
Surgical resection and research 
tissue collection 
 
 
 
X7 
 
 
Survial/Assessment of Progression 
 
 
 
 
 
X 
 
 
 
 
 
                                                 
1.To be completed within 14 days of randomization 
2 If patient on warfarin PT/PTT must be checked weekly during treatments. The prothrombin time must be monitored weekly for patients taking warfarin. 
3 To include TEG which must be analyzed on same day as draw. Due to logistical reasons research blood maybe omitted after approval from the investigator. 
4 If a subject is available, study labs for research will be collected every 4 months (+/- 2 weeks) for the first year.  These are not mandatory collections. 
5 Serum pregnancy test for women of child bearing potential as defined by ECOG within 14 days of randomization. 
6 To be self-administered by subjects; Take three 200 mg capsules, AM and PM every day through the evening dose before surgery. 
7 If patient underwent liver biopsy in screening, at time of resection an additional random liver biopsy will be performed to monitor autophagy.  This will not be done in 
those patients that did not have a pretreatment liver biopsy. 


 
 
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