Conditions: Pancreatic Cancer Resectable
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: no

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

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

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

Arms:
arm 1: Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine and Avelumab arm 2: Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine

Interventions: intervention 1: Gemcitabine, Nab-Paclitaxel, hydroxychloroquine and Avelumab intervention 2: Gemcitabine, Nab-Paclitaxel, and hydroxychloroquine
Intervention descriptions: intervention 1: Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m\^2) and nab-paclitaxel (125mg/m\^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery Day 1 of Cycle 3: avelumab (10mg/kg) intervention 2: Days 1, 8, 15 of Cycles 1 and 2: gemcitabine (1000mg/m\^2) and nab-paclitaxel (125mg/m\^2) Beginning on Day 8 of Cycle 1: hydroxychloroquine (600mg/BID) daily until day of surgery

Protocol document:
Prot_SAP_000.pdf: 
 
1 
TITLE: Randomized Phase II trial of Pre-Operative Gemcitabine, Nab-Paclitaxel, 
and hydroxychloroquine with or without Avelumab (PGHA vs. PGH)   
 
 
 
INSTITUTION STUDY NUMBER: 
 
HCC 17-134 
 
PRINCIPAL INVESTIGATOR: 
 
Nathan Bahary, MD, PhD 
 
 
 
 
 
 
Associate Professor of Medicine  
 
 
 
 
 
 
UPMC Cancer Pavilion 
 
 
 
 
 
 
5th Floor  
 
 
 
 
 
 
5150 Centre Avenue 
 
 
 
 
 
 
Pittsburgh, PA  15232 
 
COORDINATING CENTER: 
UPMC Hillman Cancer Center  
 
5115 Centre Avenue 
 
 
 
 
 
 
Pittsburgh, PA 15232 
 
PROTOCOL VERSION DATE: 
 
2/21/2019 
 
CLINICALTRIALS.GOV IDENTIFIER: 
NCT03344172 
 
COMMERCIALLY AVAILABLE AGENTS: Plaquenil® (Sanofi Aventis) 
 
 
 
 
 
 
Gemzar® (Lilly) 
  
 
 
 
 
 
Abraxane® (Celgene)  
 
 
 
 
 
 
Avelumab® (Pfizer) 
 
 
 
 


 
2 
TABLE OF CONTENTS 
 
Section             
                                                                                                                       Page 
Research Protocol Abstract  
   
 
 
 
 
 4 
 
1.0 
Background and Significance  
  
 
 
 
 4 
 
2.0 
Objectives and Specific Aims  
 
 
 
 
11 
2.1 
Primary Objective  
 
 
 
 
 
 
11 
2.2 
Secondary Objective   
 
 
 
 
 
11 
 
3.0 
Study Design and Methods  
  
 
 
 
11 
 
4.0 
Human Subjects 
 
   
 
 
 
 
12 
4.1 
Inclusion Criteria  
 
 
 
 
 
  
12 
4.2 
Exclusion Criteria  
 
 
 
 
 
  
13 
 
5.0 
Clinical and Laboratory Evaluations  
 
 
 
16 
5.1  
Screening Evaluations 
 
 
 
 
 
17 
5.2  
Treatment Evaluations 
 
 
 
 
 
18 
5.3 
Prior to Chemotherapy Dosing on Cycle 1 and 2 
 
 
18 
5.4 
Prior to Dosing on Cycle 1 and 2  
 
 
 
 
19 
5.5 
Surgery Evaluation (PGH and PGHA Arms)  
 
 
19 
5.6 
Surgery 
 
 
 
 
 
 
 
19 
5.7 
Four (4) Weeks Post Discharge  
 
 
 
 
20 
5.8 
Follow-Up Period (PGH and PGHA Arms) 
 
 
 
20 
 
 
6.0  
Study Medications and Procedures  
 
 
 
20 
6.1 
Study Drug Management and Administration  
 
 
20 
6.2 
Hydroxychloroquine Administration   
 
 
 
21 
6.3  
Avelumab Administration 
 
 
 
 
 
21 
 
6.4 
Management of Toxicities  
 
 
 
 
 
21 
6.5 
Guidelines for Toxicity Management   
 
 
 
21 
6.6 
Dose Modifications  
 
 
 
 
 
 
23 
6.7 
Concomitant Medications  
 
 
 
 
 
31 
 
7.0 
Subject Discontinuation 
 
 
 
 
 
31 
 
8.0 
Recruitment and Costs 
 
 
 
 
 
32 
8.1 
Recruitment Procedures  
 
 
 
 
 
32 
8.2 
Costs and Payments  
 
 
 
 
 
32 
 
9.0 
Statistical Methods 
 
 
 
 
 
 
32 
9.1 
Method of Randomization  
 
 
 
 
 
32 
9.2 
Monitoring for Futility & Autoimmune Toxicity  
 
 
33 
9.3 
Justification of Design  
 
 
 
 
 
33 
9.4  
Study Timelines and Milestones 
 
 
 
 
34 
9.5 
Data Analysis   
 
 
 
 
 
 
34 
9.5.1  Primary Efficacy Endpoint 
 
 
 
 
 
34 


 
3 
9.5.2  Secondary Efficacy Endpoint  
 
 
 
 
34 
9.5.3  Adverse Events 
 
 
 
 
 
 
35 
9.5.4  Secondary Biomarker Endpoints 
 
 
 
 
35 
 
10.0  Adverse Event Reporting 
 
 
 
 
 
35 
10.1 
Adverse Event Definitions  
 
 
 
 
 
35 
10.2 
Reporting of Suspected Adverse Reactions   
 
 
36 
10.3 
Data Safety Monitoring Plan   
 
 
 
 
38 
 
11.0  Retention of Records  
 
 
 
 
 
39 
 
12.0 
Patient Informed Consent: Risk/Benefit Information  
 
39 
 
References 
 
 
 
 
 
 
 
 
44 
 
Appendix A - Performance Status Criteria 
 
 
 
 
46 
 
Appendix B - CTCAE 4.0 
 
 
 
 
 
 
47 
 
Appendix C - Pathologic Response  
 
 
 
 
48 
 
Appendix D - Dose Modifications for Gemcitabine and/or Nab-paclitaxel 
49 
 
Appendix E - Bio-specimen Research Samples 
 
 
 
53 
 


 
4 
RESEARCH PROTOCOL ABSTRACT 
 
This is a randomized phase II trial that will examine the ability of Avelumab to improve the 
clinical activity of a pre-operative regimen of gemcitabine, nab-paclitaxel and 
hydroxychloroquine in subjects with potentially resectable adenocarcinoma of the pancreas. 
Eligible subjects will receive 2 cycles of gemcitabine and nab-paclitaxel (1000mg/m2 & 
125mg/m2 – days 1, 8, 15) and hydroxychloroquine (1200mg/day) with or without Avelumab 
(days 1 and 15 of each 28-day cycle). Subjects will be allocated by means of a response-
adaptive randomization based on Grade IIB or greater histologic response followed by surgical 
resection.  The 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 levels of autophagy in tumor, liver and peripheral blood.   
 
1.0 
BACKGROUND AND SIGNIFICANCE 
 
Pancreatic cancer is a major unsolved public health problem in the United States, with 
approximately 42,000 new cases in the year 2016, 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 clear 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 25% at 5 years, and the median disease-free survival is 10-13 months.  This uniformly poor 
prognosis even in the earliest stage of disease utilizing our best treatment modalities 
underscores the need for newer approaches to pancreatic cancer treatment.  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 the 
metabolic stress response of autophagy plays a major role in the pathogenesis of this disease.  
[1-10] 
 
We have spent the last several years investigating the clinical feasibility and activity of adding an 
autophagy inhibitor to cytotoxic chemotherapy.  The finding that autophagy is a critical mediator 
of damage-associated molecular patterns (DAMP)-induced tumor cell survival led us to 
investigate this pathway as a therapeutic target. We hypothesized that much of the 
immunopathology in the pancreatic cancer tumor microenvironment (PDA TME) could be 
explained by high levels of autophagy induced by release of DAMPs11.  Chloroquine (CQ) and 
its derivatives, such as hydroxychloroquine (HCQ), are synthetic 4-aminoquinolines that have 
been clinically used for 60 years for malaria prophylaxis, and are central for treating patients with 
rheumatoid arthritis and human immunodeficiency virus (HIV). They are inexpensive, orally 
available drugs with a large therapeutic index.  CQ blocks acidification of the lysosome, thus 
inhibiting the last step in autophagy.  Evidence in mouse models and human cancer cell lines 
suggests that CQ has significant anti-tumor activity by inhibiting autophagy induced by cancer 
therapy12-14.  Yang et al. demonstrated significant responses in a xenograft model to single-
agent CQ.  [13,14] 
 
Based on the above findings, we conducted a Phase I/II trial examining preoperative gemcitabine 
in combination with oral hydroxychloroquine for treatment of high risk PDA (UPCI 09-
122/NCT01128296)15.  Fixed dose-rate gemcitabine (1500 mg/m2) was administered every 2 
weeks for two cycles.  HCQ (200 mg/day-120 0mg/day) was administered 48 hours prior to the 


 
5 
first dose of gemcitabine, and continued for 31 consecutive days until the day of surgery.  Toxicity, 
evaluated based on National Cancer Institute (NCI) criteria, was found to be minimal.  Response 
to treatment was assessed by decrease in CA19-9 levels and PET.  Thirty-five patients were 
enrolled.  There were no dose-limiting toxicities, and no Grade 4/5 events related to treatment.  
Nineteen patients (61%) had a decrease in CA19-9 following treatment.  Twenty-nine patients 
(94%) underwent surgical resection as scheduled with a 77% R0 resection rate.  Median overall 
survival was 34.8 months (95% CI [11.57 months, not reached]).  Clinical outcomes were 
compared to those from the previously established cohort of high-risk patients at our institution, 
which defined eligibility for this trial.  [16].  Demographics and high-risk criteria were not different 
between patients from the prior series and the UPCI 09-122 trial.  The resection rate for patients 
treated with Gemcitabine/hydroxychloroquine (GH) was 94% compared to 52% in the prior series 
(p<0.001), with R0 resection achieved in 77% versus only 34% (p<0.01).  Treatment with GH 
resulted in improved overall median survival compared with the prior cohort (34.8 vs. 12.3 months, 
p=0.03).  
 
Next, we launched an NCI-supported (R01CA181450) randomized phase II trial of neoadjuvant 
gemcitabine/nab-paclitaxel, with (PGH), and without (PG), hydroxychloroquine (UPCI-13-
074/NCT01978184), to better assess the true contribution of autophagy inhibition in the setting of 
a gemcitabine/nab-paclitaxel regimen proven to be more effective than gemcitabine alone in 
metastatic disease in patients with PDA.  We have completed the planned 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 III/IV histologic response, as defined by Evans et al.  [17].  Secondary 
endpoints are response of the tumor marker CA19-9, and the proportion of positive lymph nodes 
in resected specimens.  Analysis of the primary endpoint in subjects enrolled to date, 
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, 
enhancing the response to the PGH combination. 
 
We are in the process of examining the 
resected tissues for evidence of autophagy 
inhibition and apoptosis.  However, a pilot 
correlative study performed on the first 18 
subjects accrued to this trial yielded 
provocative data suggesting that addition of 
the autophagy inhibitor to the chemotherapy led to marked upregulation of PDL-1 expression in 
subjects treated on the HCQ arm (Fig.1C).  Interestingly, most of the PDL-1 expression appeared 
to be in infiltrating myeloid cells rather than in tumor cells.  This finding led us back to the bench 
to examine the potential of adding anti-PDL-1 to the backbone of PGH.  There was strong 
TABLE I: Histopathologic responses of the first 
53 evaluable patients from UPCI-13-074 
 
Evans Grade 
 
Tx 
I 
IIA 
IIB 
III 
Total 
PG 
10 
14 
3 
0 
27 
PGH 
3 
9 
9 
5 
26 
 
ArmA
Resectableor
borderline
resectablePDA
Cycle1
(28days)
Cycle2
(28days)
Gemcitabine(1000mg/m2)
nab-paclitaxel(125mg/m2)
Surgery
Gemcitabine(1000mg/m2)
nab-paclitaxel(125mg/m2)
D1 D8 D15
D70-84
D1 D8 D15
D1 D8 D15
D70-84
D1 D8 D15
ArmB
 
Control
HCQ
PG
PGH
-100
0
100
200
300
ChangeinCA19-9(%)
B 
A 
PG
PGH
PDL1
C 
Hydroxychloroquine
(600mg/BID)
Hydroxychloroquine
(600mg/BID)


 
6 
rationale for this, not just from our own bedside studies, but from two recent reports demonstrating 
that targeted ablation of the stromal activation marker, fibroblast activation protein-α (FAP), or 
inhibition of its expression by blockade of C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif 
signaling increased T cell infiltration, increased PD-1 and PDL-1 expression, and unmasked the 
response to immune checkpoint inhibitors in murine models of PDA18,19.  We hypothesized that 
HCQ might be working in a similar fashion on the stroma, based on animal studies demonstrating 
that HCQ can block autophagy and decrease FAP expression in stroma.  In addition, HCQ has 
also been reported to be a direct antagonist of CXCR4, which could directly inhibit stromal 
activation in the murine studies cited above.  We tested the combination of chemotherapy, 
autophagy inhibition and immune check point blockade (anti-PDL1) in our orthotropic murine 
model of PDA.  We observed that addition of checkpoint pathway blockade yielded statistically 
improved survival in this model (Fig.2A).  We also observed reduced pancreas weight, due to 
reduced tumor burden, and that these tumors had the highest level of CD8+ and CD4+ T cell 
infiltration (Fig.2B).  Thus, it appears that the addition of the autophagy inhibitor HCQ to PG 
behaves similarly to agents that target stroma, and results in accumulation of T cells in the PDA 
TME that can then be targeted with immunotherapy. 
 
FIG.2: Enhanced efficacy against Panc02 with cytotoxic chemotherapy in combination with HCQ 
and anti-PDL1. 
 
LEGEND: Mice were injected with 106 Panc02 orthotopically on day 0.  Gemcitabine (25mg/mL) 
and Taxol (10mg/mL) were injected every 7 days starting on day 15.  Anti-PDL1 (250ug) was 
injected every 3 days starting after first chemo treatment.  (A) Morbidity over time assessed.  (B; 
top left) Pancreas was weighed 21 days post-inoculation.  (B; other panels) Lymphocytes were 
isolated and stained for analysis on post-inoculation day 28.  n=2-3.  [Kaplan Meier (A) and 
Unpaired Student’s t-test (B)].  
 
Rationale for this protocol 
As noted above, our preliminary observations at the bedside and bench provide strong rationale 
for adding immune checkpoint blockade to our backbone of chemotherapy and autophagy 
inhibition (PGH).  
 
Gemcitabine  
Gemcitabine chemotherapy is the standard of care for inoperable pancreatic cancer, although its 
clinical activity is modest.  In the initial phase 2 trial of single-agent gemcitabine, an 11% partial 
response rate was observed (Casper, Green et al. 1994).  A phase 3 randomized study of 
gemcitabine versus 5-flourouracil in 126 patients reported a 5% objective response rate in the 
0
50
100
150
#CD8+(x104)/mg 
UT
Chemo
Chemo+HCQ
Chemo+HCQ+anti-PDL1
*
B 
0.0
0.5
1.0
1.5
Pancreas weight (g)
0
100
200
300
400
#Treg (x104)/mg
*
**
0
50
100
150
#CD4+(x104)/mg 
A 
0
50
100
0
50
100
Days post injection (Panc02)
% Morbidity
UT
Chemo + Iso 
Chemo + anti-PDL1
Chemo + HCQ + Iso
Chemo + HCQ + anti-PDL1
****


 
7 
gemcitabine arm, with a median survival of 5.65 months and a 1-year survival rate of 18% (Burris, 
Moore et al. 1997).  Twenty-four percent of patients in the gemcitabine arm experienced a clinical 
benefit, consisting of improved pain control, performance status, or weight stabilization.  In 1996, 
the US Food and Drug Administration (FDA) approved gemcitabine for the treatment of locally 
advanced and metastatic pancreatic cancer.  
 
Paclitaxel Albumin-bound Particles (Nab-Paclitaxel) 
Nab-paclitaxel is a unique protein formulation of a non-crystalline, amorphous form of paclitaxel 
in an insoluble particle state.  Nab-paclitaxel has been developed to reduce the toxicities 
associated with Taxol (paclitaxel) Injection (in which paclitaxel - from the native crystalline form - 
is formulated with Cremophor EL/ethanol as the solvent) while maintaining or improving its 
chemotherapeutic effect.  Nab-paclitaxel has been approved for commercialization in 38 
countries, including the United States (US), Canada, the EU, Australia, China, India and Korea 
for the treatment of women with metastatic breast cancer.  Nab-paclitaxel alone and in 
combination chemotherapy is being evaluated in several cancers, including metastatic 
melanoma, non-small cell lung cancer, pancreatic cancer, and other solid tumors.  
 
A recent phase 3 clinical trial of nab-paclitaxel in combination with gemcitabine in treatment- naïve 
patients with metastatic pancreatic cancer demonstrated a statistically significant improvement in 
overall survival compared to patients receiving gemcitabine alone [(median of 8.5 vs. 6.7 months) 
(HR 0.72, P=0.000015)].  In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) 
study, nab-paclitaxel plus gemcitabine demonstrated a 59% increase in one-year survival (35% 
vs. 22%, p=0.0002), double the rate of survival at two years (9% vs. 4%, p=0.02), and an 
improvement in 3-year survival (4% vs. 0%) as compared to gemcitabine alone.  Nab-paclitaxel 
plus gemcitabine also demonstrated a statistically significant improvement in key secondary 
endpoints compared to gemcitabine alone, including a 31% reduction in the risk of progression or 
death with a median progression-free survival (PFS) of 5.5 vs. 3.7 months (HR 0.69, P=0.000024) 
and an overall response rate (ORR) of 23% compared to 7% (response rate ratio of 3.19, p=1.1 
x 10-10).  
 
The most common grade ≥ 3 treatment-related adverse events in the study for nab-paclitaxel plus 
gemcitabine vs. gemcitabine alone were neutropenia (38% vs. 27%), fatigue (17% vs. 7%), and 
neuropathy (17% vs. 1%).  In the nab-paclitaxel plus gemcitabine arm, the median time to 
neuropathy improvement was 29 days.  There was no difference in serious life-threatening toxicity 
(4% in each arm).  
 
Avelumab (also referred to as MSB0010718C) 
Avelumab is a fully human IgG1 antibody directed against PD-L1. Avelumab binds PD-L1 and 
blocks the interaction between PD-L1 and its receptors PD-1 and B7-H1.  This removes the 
suppressive effects of PD-L1 on anti-tumor CD8+ T cells, resulting in the restoration of cytotoxic 
T cell response.  
 
The PD-1 receptor is expressed on activated CD4+ and CD8+ T cells.  By interaction with its 
ligands, PD-L1 and PD-L2, PD-1 delivers a series of strong inhibitory signals through its 
cytoplasmic tail to inhibit T cell functions (Chemnitz et al 2004, Keir et al 2008, Riley 2009).  PD-
L1 (also called B7-H1 and CD274) can be detected on resting and activated T cells, B cells, 
macrophages, dendritic cells, and mast cells; PD-L1 expression is greatly up-regulated after 
activation or interferon treatment (Keir et al 2008).  Numerous results from in vitro cellular assays 
have demonstrated that blockade of the PD-1/PD-L1 interaction enhances T cell responses, such 
as increases in proliferation and cytokine production (Bennett et al 2003, Blank et al 2004, Blank 
et al 2006, Brown et al 2003, Dong et al 1999, Freeman et al 2000, Waeckerle- Men et al 2007). 


 
8 
In PD-1–/– mice both T and/or B cells responses are unregulated resulting in an array of 
autoimmune pathologies (Okazaki and Honjo 2006, Okazaki and Honjo 2007).  Breaking 
tolerance through blocking PD-1 interaction with its ligands, and thus PD-1 signaling, can be 
applied to enhance T cell activity towards chronic pathologies such as cancer (Blank et al 2005).  
 
External (Okazaki and Honjo 2007) and internal immunohistochemistry studies have 
demonstrated that PD-L1 is also expressed by a variety of human tumors, both by the tumor cells, 
as well as by the immune cells that are present in the tumor microenvironment.  In contrast to 
very strong expression on syncytiotrophoblasts in the placenta and in cancer cells, low levels of 
PD-L1 expression were detected in some normal tissues including fetal cardiac tissue (Brown et 
al 2003).  High levels of PD-L1 expression have been found to be associated with disease 
progression, increased metastasis, poor response to treatment, and decreased survival in a 
number of human cancers (Okazaki and Honjo 2007).  Importantly anti-PD-L1 blockade has 
demonstrated therapeutic efficacy in a variety of murine tumor models as monotherapy and has 
shown synergistic effect in combination therapy setting (Blank et al 2004, Hirano et al 2005, Iwai 
et al 2002, Iwai et al 2004, Nomi et al 2007, Strome et al 2003, Zhang et al 2009).  
 
The antitumor activity of Avelumab has been investigated in various murine tumor models.  
Inhibition of the PD-1/PD-L1 interaction is proposed to exert a therapeutic effect by restoring anti-
tumor CD8+ T cell responses.  To circumvent the need for a surrogate antibody, the lead 
candidate antibody was specifically selected for cross-reactivity to murine PD-L1, and, as 
consequence all nonclinical studies were conducted in syngeneic murine tumor models in which 
the immune system of the host is fully intact.  It was demonstrated that the inhibition of the PD-
1/PD-L1 interaction restores anti- tumor CD8+ T cell responses, which results in an anti-tumor 
activity.  
 
Avelumab has demonstrated significant clinical activity as a monotherapy and in various 
combination therapy settings.  In general, the anti-tumor immunotherapy via blockade of the PD-
1/PD-L1 axis seems not to be limited to any specific tumor types, but there is recent evidence that 
PD-L1 tumor expression is a prerequisite to achieve an objective response upon blockade of the 
PD-1/PD-L1 axis (Topalian et al 2012b).  The clinical relevance of PD-1/PD-L1 blockade has been 
demonstrated in Phase I trials performed with antibodies targeting either PD-L1 or PD-1 (Topalian 
et al 2012b, Brahmer et al 2012).  More recently, Avelumab has been approved for the treatment 
of both Merkel Cell carcinomas and bladder cancer.  (REF) 
 
Clinical Safety Data Related to Dose  
As of 09 June 2016, 53 subjects in the dose escalation part had received Avelumab (4, 13, 15, 
and 21 subjects had received 1.0, 3.0, 10.0, and 20.0mg/kg of Avelumab, respectively) and 1738 
subjects in the pooled safety dataset part (Study EMR100070-001 and EMR100070- 003 Part A) 
had received 10 mg/kg Avelumab.  
 
In the dose escalation portion of the Phase I study, there was no evidence of differences in the 
safety profile across all administered dose levels from 1 mg/kg to 20 mg/kg.  The MTD was not 
reached.  Ongoing review of the safety data by the Safety Monitoring Committee (SMC) suggests 
an acceptable safety profile of Avelumab administered 10 mg/kg every 2 weeks.  In the pooled 
safety dataset (Study EMR100070-001 in solid tumors and EMR100070-003 in MCC) with a data 
cut-off on 09 June 2016, treatment-related TEAEs were observed in 1164 (67.0%) subjects in the 
pooled safety dataset.  The most frequently observed treatment-related TEAEs (with an incidence 
of ≥5%) of any grade were fatigue (17.7%), infusion related reaction (17.0%), nausea (8.6%), 
diarrhea (7.1%), chills (6.7%), pyrexia (6.1%), decreased appetite (5.2%), and hypothyroidism 
(5.0%).  Grade ≥ 3 treatment-related TEAEs were observed in 177 subjects (10.2%) in the pooled 


 
9 
Safety dataset.  The most frequently reported Grade ≥ 3 treatment-related TEAEs were fatigue, 
lipase increased (17 subjects each; 1.0%), GGT increased, infusion related reaction (10 subjects; 
0.6%), AST increased (8 subjects; 0.5%), pneumonitis (7 subjects; 0.4%), anemia, blood CPK 
increased (6 subjects each; 0.3%), diarrhea, asthenia (5 subjects each; 0.3%), autoimmune 
hepatitis, ALT increased, amylase increased, hyponatraemia, hypophosphataemia (4 subjects 
each; 0.2%).  Infusion-related reactions including drug hypersensitivity reactions and immune-
mediated adverse reactions (immune-related pneumonitis, immune-related colitis, immune-
related hepatitis, immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, new 
onset type I diabetes mellitus), other immune-related AEs (myositis and myocarditis) have been 
identified as important risks of Avelumab.  The safety profile of Avelumab is consistent with 
findings reported for other anti-PD-1 or anti-PD-L1 antibodies.  
 
In summary, available data from the dose escalation part of Study EMR100070-001 showed that 
Avelumab at doses up to 20mg/kg IV every 2 weeks was well tolerated, and data from the pooled 
dataset (Study EMR100070-001 and Study EMR100070-003) confirmed the dose of 10 mg/kg 
intravenously every 2 weeks was considered to have an acceptable safety profile.  
 
Efficacy  
Avelumab 10 mg/kg once every 2 weeks has demonstrated meaningful clinical activity across 
various tumor types and treatment settings.  Regardless of the tumor type, responses with 
Avelumab were observed early during treatment and appear durable in nature, including ongoing 
responses >1 year in several of the cohorts.  Overall, many responders experienced ongoing 
response at the time of database lock.  Based on the above analyses, a dose of 10 mg/kg IV once 
every 2 weeks was considered to have a favorable risk benefit profile. 
 
Human Toxicology 
Merkel cell carcinoma is a rare aggressive skin cancer that has previously portended a poor 
prognosis linked to Merkel cell polyomavirus integration.  In a pivotal phase II trial that led to 
FDA approval of Avelumab for Merkel cell carcinoma, eighty-eight patients with chemotherapy 
refractory Stage IV Merkel cell carcinoma were treated with Avelumab 10mg/kg every two 
weeks.  Patients received a median of seven doses (IQR 3–18) of Avelumab, and the median 
duration of treatment was 17 weeks (IQR 7–37).  The objective RR was 28/88 patients (31%) 
with eight CRs and 20 PR’s.  Five grade 3 treatment-related adverse events occurred in four 
(5%) patients 
 
• 
Lymphopenia in two patients 
• 
Blood creatinine phosphokinase (CPK) increase in one patient 
• 
Aminotransferase increase in one patient 
• 
Blood cholesterol increase in one patient  
• 
There were no treatment-related grade 4 adverse events or treatment-related deaths. 
Serious treatment-related adverse events were reported in six (n=1 each) patients (6%) 
• 
Enterocolitis 
• 
Infusion-related reaction 
• 
Aminotransferases increased 
• 
Chondrocalcinosis  
• 
Synovitis 
• 
Interstitial nephritis (n=1 each) 
• 
Grade 1-2 AE’s: 
▪ 
fatigue (24%) 
▪ 
infusion related reaction (17%) 


 
10 
▪ 
diarrhea (9%) 
▪ 
nausea (9%) 
▪ 
asthenia (8%) 
▪ 
rash (7%) 
▪ 
anorexia (7%) 
▪ 
maculopapular rash (6%) 
• 
Potential immune related treatment-related AE’s: 
▪ 
hypothyroidism (3%) 
▪ 
hyperthyroidism (2%) 
▪ 
pneumonitis (1%) 
▪ 
type 1 diabetes mellitus (1%)  
 
In a separate phase 1a study in previously treated solid tumors (JAVELIN), Avelumab was 
assessed at four doses (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort 
expansions to provide additional safety, pharmacokinetics, and target occupancy data.  Patients 
were assigned sequentially at trial entry according to the 3+3 dose-escalation algorithm and 
depending on the number of dose-limiting toxicities during the first 3-week assessment period 
(the primary endpoint).  
 
In 53 enrolled patients (the safety analysis set), common treatment-related adverse events: 
(occurring in > 10% of patients) included  
• 
fatigue (21 patients [40%]),  
• 
influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]).  
 
Grade 3−4 treatment-related adverse events occurred in nine (17%) of 53 patients: 
• 
autoimmune disorder (n=3) 
• 
increased blood creatine phosphokinase (n=2) 
• 
increased aspartate aminotransferase (n=2) each  
 
Six (11%) of fifty-three patients had a serious treatment-related adverse event:  
• 
autoimmune disorder (two [13%]),  
• 
lower abdominal pain (one [7%]),  
• 
fatigue (one [7%]), and  
• 
influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level,  
 
At the 20mg/kg dose level: 
• 
autoimmune disorder (one [5%]),  
• 
increased amylase (one [5%]) 
• 
myositis (one [5%]), a 
• 
dysphonia (one [5%])  
 
No substantial differences were found in absolute lymphocyte count or multiple immune cell 
subsets, including those expressing PD-L1, after treatment with Avelumab.  Thirty-one (58%) of 
fifty-three patients in the overall safety population died; no deaths were related to treatment on 
study. 
 
Together these studies suggest that Avelumab has an acceptable toxicity profile up to 20 mg/kg 
every 2 weeks, but given various PK parameters, 10 mg/kg has been chosen for this study. 
 


 
11 
2.0 
OBJECTIVES AND SPECIFIC AIMS 
 
2.1  
Primary Objective 
 
To determine if addition of Avelumab to the pre-operative regimen gemcitabine/ nab-
paclitaxel and hydroxychloroquine can improve the rate of grade IIB or higher histologic 
responses.  
 
2.2 
Secondary Objectives 
 
• 
To determine if the addition of Avelumab can improve the CA19-9 response 
to preoperative chemotherapy compared with to the control Gemcitabine/Abraxane 
and hydroxychloroquine  
• 
To determine if the level of autophagy and inflammation in the tumor and blood 
of treated patients is correlated with pathological response, and whether that differs 
between the two experimental arms. 
 
3.0 
STUDY DESIGN AND METHOD 
 
This will be phase II, non-blinded, adaptively randomized multicenter trial of 120 participants that 
will build on the histopathologic responses from the UPCI-13-074 trial (Fig.1A).  Patients with 
PDA will be evaluated prior to protocol entry by standard of care testing, including EUS, contrast-
enhanced helical abdominal CT scan, or MRI.  Patients meeting NCCN criteria for potentially 
resectable (borderline or resectable) tumors will be eligible.  Once they provide consent, subjects 
will be randomized to receive either 2 cycles of PGH ─ gemcitabine and nab-paclitaxel (1000 
mg/m2 & 125 mg/m2, respectively: days 1, 8, and 15) plus oral HCQ (1200 mg PO daily) ─ or PGH 
plus Avelumab (PGHA; days 1 and 15 of each 28-day cycle), by means of response-adaptive 
randomization based on Grade IIB or greater histologic response, as detailed in Section 9.1.  Two-
four weeks after the last dose of chemotherapy subjects will undergo a repeat-staging CT scan.  
 
Surgical exploration and pancreatectomy will be performed if technically feasible and all toxicities 
have resolved.  HCQ will be taken until the evening before surgery.  Avelumab will be 
administered every two weeks until up to one week prior to the date of surgery.  The Study 
Coordinator will inform subjects of the date of operation.  Specimens will be collected under sterile 
conditions.  Tissue specimens will be stored at -80°C, and as paraffin-embedded blocks for future 
correlative studies.  Following successful surgical removal of tumors, patients will then be free to 
pursue standard of care adjuvant therapy options, at the discretion of their treating physician.  


 
12 
 
4.0 
HUMAN SUBJECTS 
 
Subject Selection:  Up 120 participants will be enrolled in this study.  The goal for accrual is 30 
participants evaluable for response in each arm.  A participant is deemed evaluable for response 
if he or she has received at least one full cycle of chemotherapy, 80% of the expected HCQ dose, 
at least 3 doses of Avelumab if the participant is on that arm and undergoes successful surgical 
extirpation of disease.  The racial, gender, and ethnic characteristics of the proposed subject 
population reflect the demographics of the patients 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.  
 
 
4.1 
Inclusion Criteria 
 
• 
Participants with biopsy-proven adenocarcinoma of the pancreas that is determined 
to be potentially or borderline resectable by NCCN criteria 
• 
Karnofsky performance status of 70-100% 
• 
No active second malignancy with the exception of basal or squamous cell 
carcinoma of the skin 
• 
Patient has adequate biological parameters as demonstrated by the following blood 
counts at screening (obtained ≤14 days prior to randomization) 
▪ 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, 
▪ 
Platelet count ≥100,000/mm3 (100 × 109/L),  
▪ 
Hemoglobin (Hgb) ≥9 g/dL.  Patient may receive transfusion as needed. 
• 
Patient has the following blood chemistry levels at Baseline (obtained ≤14 days prior 
to randomization): 
▪ 
AST (SGOT), ALT (SGPT) ≤ 2.5 × upper limit of normal range (ULN). 


 
13 
▪ 
Total bilirubin ≤ ULN (Except in patients who have Gilbert’s Syndrome or 
patients with recently placed stents for biliary obstruction when bilirubin 
should be < 1.5 X ULN). 
▪ 
Serum Creatinine ≤ 1.5mg/dl OR calculated creatinine clearance ≥ 50 for 
those patients with creatinine greater than 1.5. 
▪ 
CPK < ULN. 
▪ 
Patients who have an elevated lipase or amylase and no history of 
autoimmune pancreatitis, nor physical exam concerning for, or CT correlates 
of pancreatitis can be enrolled.  The elevated levels will serve as the new 
baseline.  Changes above that will be termed toxicities as per CTCAE 
guidelines with relation to the new baseline. 
▪ 
PT WNL+/- 15 % unless on active anticoagulation.  
▪ 
PTT WNL+/- 15 % unless on active anticoagulation (suggested to be drawn 
peripherally to prevent port drawn elevation due to routine heparin flush of 
ports). 
• 
Age >18 years  
• 
Patient must be able to swallow enteral medications with no requirement for a 
feeding tube.  Patient’s must not have intractable nausea or vomiting which prohibits 
the patient from oral medications 
• 
Ability to understand and the willingness to sign a written informed consent 
document 
 
4.2 
Exclusion Criteria 
 
 
• 
Subjects deemed surgically unresectable or subjects unwilling to undergo surgical 
resection  
• 
Prior use of chemotherapy, radiotherapy, and / or investigational agents for 
pancreatic cancer 
• 
Any evidence of metastasis to distant organs (liver, lung, peritoneum)  
• 
Symptomatic evidence of gastric outlet obstruction 
• 
Inability to adhere to study and/or follow-up procedures 
• 
History of allergic reactions or hypersensitivity to the study drugs 
(hydroxychloroquine, gemcitabine, nab-Paclitaxel, Avelumab)  
• 
Known or suspected HIV infection 
• 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sj澨gren’s syndrome, Guillain-Barr斴 
syndrome, or multiple sclerosis, with the following exceptions: 
▪ 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
▪ 
Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study. 
• 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) 
are eligible for the study provided all of following conditions are met: 
▪ 
Rash must cover < 10% of body surface area. 
▪ 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 


 
14 
▪ 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months. 
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography scan 
• 
Patient with a history of interstitial lung disease, history of slowly progressive 
dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary 
fibrosis or pulmonary hypersensitivity pneumonitis 
▪ 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a 
positive hepatitis B surface antigen (HBsAg) test at screening 
▪ 
Patients with a past or resolved HBV infection, defined as having a negative 
HBsAg test and a positive total hepatitis B core antibody test at screening, 
are eligible for the study. 
▪ 
Active hepatitis C virus (HCV) infection, defined as having a positive HCV 
antibody test followed by a positive HCV RNA test at screening.  The HCV 
RNA test will be performed only for patients who have a positive HCV 
antibody test. 
• 
Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty 
liver disease, and inherited liver disease 
• 
Active tuberculosis 
• 
Severe infection within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia 
• 
Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
12 months prior to initiation of study treatment, or unstable arrhythmia or unstable 
angina within 3 months prior to initiation of study treatment 
• 
Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of study 
treatment 
• 
Prior allogeneic stem cell or organ transplantation including corneal transplant  
• 
Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of 
study treatment. 
▪ 
Placement of a stent or central venous access catheter (e.g., port or similar) 
is not considered a major surgical procedure and is therefore permitted. 
• 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications as determined by the investigator 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study 
• 
The effects of HCQ, gemcitabine, nab-Paclitaxel and Avelumab on the developing 
human fetus are unknown.  For this reason, women of child-bearing potential and 
men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation. 
All females of childbearing potential (please refer to ECOG’s definition in section 
5.1) must have a blood test or urine study within two weeks prior to randomization 
to rule out pregnancy.  Should a woman become pregnant while participating in this 
study, she should inform her treating physician immediately.  If a man impregnates 


 
15 
a woman while participating in this study, he should inform his treating physician 
immediately as well. 
• 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during treatment with 
Avelumab or within 5 months after the last dose of Avelumab 
▪ 
Attenuated live vaccines include but are not limited to: 
• 
Tuberculosis (BCG) 
• 
Oral polio vaccine 
• 
Measles, Mumps, Rubella, alone or as part of MMR 
• 
Rotavirus 
• 
Yellow Fever 
• 
Typhoid 
• 
Rabies vaccine should be utilized as recommended by an 
Infectious Disease specialist 
• 
Nasal flu vaccine 
• 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
• 
Known hypersensitivity to Chinese hamster ovary cell products or recombinant 
human antibodies 
• 
Known allergy or hypersensitivity to any of the study drugs or any of their excipients 
• 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti−tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study 
treatment, or anticipation of need for systemic immunosuppressive medication 
during the study, with the following exceptions: 
▪ 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study. 
▪ 
Patients who received mineralocorticoids (e.g., fludrocortisone), 
corticosteroids for chronic obstructive pulmonary disease or asthma, or low-
dose corticosteroids for orthostatic hypotension or adrenal insufficiency are 
eligible for the study.  
▪ 
Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-
articular injection). 
• 
Patients requiring the use of enzyme-inducing anti-epileptic medication that includes 
but not limited to: phenytoin, carbamazepine, phenobarbital, primidone or 
oxcarbazepine are excluded     
• 
Patients with previously documented macular degeneration or diabetic retinopathy 
are excluded 
• 
Baseline EKG with QTc > 470 msec (including subjects on medication).  Subjects 
with ventricular pacemaker for whom QT interval is not measurable will be eligible 
on a case-by-case basis at MD discretion 
• 
Patients on Coumadin must be willing to switch to an alternative subcutaneous 
LMWH or oral agent (At PI discretion exceptions can be permitted, as determined 
on a case by case basis and documented) 
 
 


 
16 
5.0  
CLINICAL AND LABORATORY EVALUATIONS  
 
Arm A (PGH) and Arm B (PGHA) 
 
 
Pre-
Study 
≤ 28 
days 
Day  
-2 
C1 
Day  
1 
C1 
Day  
8 
C1 
Day  
15 
C2 
Day  
1 
C2 
Day  
8 
C2 
Day  
15 
C3+ 
Day 
1 
(Arm 
B)* 
Pre-Op 
Evaluation 
(≤ 5 
business 
days prior 
to surgery 
+1 day) 
Evening 
before 
Surgery 
Surgery 
(2-6 
wks 
post-
C2D15) 
4 weeks 
Post-
Hospital 
Discharge 
(± 2 
weeks) 
Follow 
up 
(q 4 
months, 
+ 2 
weeks) 
 
(± 3 Days for each visit) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant meds1 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Adverse Event 
Evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Physical exam 
(includes peripheral 
neuropathy 
assessment) 
X 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Height10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight10 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Performance status 
(Karnofsky70) 
X1 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
CBC w/diff, plts11 
X1 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Comprehensive 
Metabolic Panel1 
X1 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
PT/PTT2 
X1 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Serum CA19-9  
X13 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Lipase 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Magnesium 
X1 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Phosphorous 
X1 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
C-Reactive Protein 
X 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
CPK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
HBV, & HCV serology 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function 
Tests4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Research labs3 
X1 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
B-HCG5 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
EUS9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spectral CT or 
contrast enhanced CT 
Scan of chest, 
abdomen and pelvis 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Gemcitabine (1000 
mg/m2 infusion)  
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Nab-Paclitaxel (125 
mg/m2 infusion) 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Avelumab (10mg/kg)* 
 
 
                       X11,4,* 
 
 
 
Hydroxychloroquine  
(600 mg PO BID) 
 
 
                    X7 
 
 
 
Surgical resection 
and research tissue 
collection 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
Survival/Assessment 
of Progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
X8 
*C3+D1 for Avelumab only 
1. To be completed within 14 days of randomization.  Research labs may be drawn within 14 days of dosing of HCQ 
2. If patient is given an exception by the PI during screening for con med warfarin derivative PT/INR must be checked weekly prior 
to treatments.   


 
17 
3. Due to logistical reasons research blood maybe omitted after approval from the investigator 
4. Thyroid function testing: thyroid-stimulating hormone(TSH), at screening a free triiodothyronine (T3) (or total T3 for sites where 
free T3 is not performed), and free thyroxine (also known as T4) will be performed and then as clinically indicated 
5. Serum pregnancy test for women of child bearing potential as defined by ECOG within 14 days of randomization. 
6. 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. 
7. To be self-administered by subjects: Take three 200mg capsules, AM and PM every day through the evening dose before 
surgery. 
8. 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 (see appendix E for specific tests to be completed). 
9. Endoscopic ultrasound for assessing tumor invasion of vascular structures if CT findings of unresectability are equivocal 
10. BSA calculation (recalculated per the site’s standard of care, or if body weight changes by more than 10%) 
11. Patient may receive a transfusion as needed 
12. HBV serology: HBsAg, hepatitis B surface antibody, and total HBcAb  If a patient has a negative HBsAg test and a positive total 
HBcAb test at screening, an HBV DNA test should be performed at screening.  HCV serology: HCV antibody and (if HCV 
antibody test is positive) HCV RNA If a patient has a positive HCV antibody test at screening, an HCV RNA test  must also be 
performed to determine if the patient has an active HCV infection 
13. CA19-9 must be drawn when bilirubin is within eligibility limits 
14. Avelumab to be given every 2 weeks until 1 week prior to surgery for arm B 
 
NOTE: There is a window of ± 1 week available for rescheduling treatment and/or procedures at the discretion of the treating 
investigator, and as discussed with the Sponsor-Investigator if a course is missed or a subject's treatment and/or testing day(s) need 
to be rescheduled due to the subject’s inability to comply with the study calendar [i.e., hospitalizations, business, vacation plans, 
travel from long distances for study treatment, in advance of the scheduled date to allow ready access to the result(s), reduce 
financial burden on the subject (i.e., non-UPMC insurance coverage) or reduce travel inconvenience, illness, transportation issues, 
holidays, family emergencies, etc.]. 
 
5.1  
Screening Evaluations   
 
The following are the required ≤ 28 days prior to randomization, unless otherwise specified:  
• 
Review of medical history 
• 
Concomitant medications 
• 
Adverse event evaluation 
• 
Physical examination  
• 
Height 
• 
Vital signs 
• 
Weight 
• 
Performance status assessed by the KPS scale (see Appendix A). 
• 
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 
• 
Magnesium and Phosphorous within 14 days prior to randomization 
• 
PT, PTT within 14 days prior to randomization 
• 
Amylase and Lipase 
• 
C-Reactive Protein 
• 
CPK 
• 
Serum CA-19-9 
• 
Thyroid function testing: thyroid-stimulating hormone, free triiodothyronine (T3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (also known as 
T4)   


 
18 
• 
HBV serology: HBsAg, hepatitis B surface antibody, and total HBcAb  If a patient 
has a negative HBsAg test and a positive total HBcAb test at screening, an HBV 
DNA test should be performed at screening   
• 
HCV serology: HCV antibody and (if HCV antibody test is positive) HCV RNA If a 
patient has a positive HCV antibody test at screening, an HCV RNA test  must also 
be performed to determine if the patient has an active HCV infection     
• 
LDH   
• 
Serum Pregnancy test for women of child-bearing potential as defined by ECOG.  
Within 14 days prior to randomization 
▪ 
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, and pelvis.  Patients with a contrast allergy may use 
corticosteroid prophylaxis at baseline 
• 
Endoscopic ultrasound for assessing tumor invasion of vascular structures if CT 
findings of unresectability are equivocal  
• 
Electrocardiogram (EKG)  
• 
Research labs within 14 days of randomization  
 
5.2 
 Treatment Phase Evaluations 
  
Once deemed eligible, patients will be assigned to Gemcitabine, Nab-Paclitaxel, and 
Hydroxychloroquine with or without Avelumab.  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 a 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  
 
 
5.3 
Prior to Chemotherapy Dosing on all cyles (Day 1) (PGH and PGHA Arms) 
 
• 
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  
• 
Serum Chemistry to include: total bilirubin, AST, ALT, alkaline  phosphatase, sodium, 
potassium, bicarbonate, chloride, BUN, Cr, glucose, calcium 
• 
Magnesium and Phosphorous 
• 
Serum CA19-9 


 
19 
• 
TSH (free triiodothyronine T3 OR total T3, and free thyroxine T4 should additionally 
be performed if TSH is abnormal) 
• 
CPK 
• 
Amylase, lipase 
• 
C- Reactive Protein 
• 
CPK 
5.4 
Prior to Dosing on Cycle 1 and 2 (Day 8 and 15) (PGH and PGHA Arms) 
 
• 
KPS performance status  
• 
Concomitant medications evaluation  
• 
Vital signs  
• 
Adverse event evaluation  
• 
CBC, differential, and platelet count  
• 
CMP 
• 
TSH (free triiodothyronine T3 OR total T3,  and free thyroxine T4 should additionally 
be performed if TSH is abnormal) 
• 
Magnesium and Phosphorous 
• 
CPK 
• 
Amylase and Lipase 
5.5 
Surgery Evaluation (PGH and PGHA Arms) 
 
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  
• 
TSH 
• 
CPK 
• 
Amylase, lipase 
• 
C-Reactive protein 
5.6 
Surgery (to occur no sooner than 2 weeks post last dose of chemotherapy and no 
longer than 6 weeks post-chemo) (PGH and PGHA Arms) 
• 
Resection and tissue collection for research 


 
20 
• 
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. 
5.7 
Four (4) Weeks Post Discharge From Hospital Stay (+/- 2 Weeks) (PGH and PGHA 
Arms) 
 
• 
Physical examination  
• 
Weight 
• 
Vital signs 
• 
KPS performance status 
• 
Review of concomitant medications 
• 
CMP 
• 
Magnesium and Phosphorous 
• 
CBC, differential, platelets  
• 
Research labs 
• 
Serum CA19-9 level   
• 
TSH 
• 
CPK 
• 
Amylase, lipase 
• 
C reactive protein 
• 
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 (PGH and PGHA Arms) 
 
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 Drug Management and Administration 
 
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.  
 


 
21 
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 will be a 30-day cycle and Hydroxychloroquine (600mg PO BID) will be started on Day -
2 (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 
1, 8, and 15 of cycle 1.  
 
Cycle 2 will start 30 days after the start of Hydroxychloroquine.  Cycle 2 (day 1) 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 sooner 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 twice daily starting at cycle 1 day -2 and continued 
through the evening dose the day before surgery.  
▪ 
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 
  
6.3         Avelumab Administration 
 
▪ 
Subjects randomized to Arm B (PGHA) will receive Avelumab 10mg/kg, administered 
as an intravenous infusion over 60 minutes, every 2 weeks Cycle 1, 2,on Days 1, 15, 
and every two weeks (C3+) up until one week prior to surgery. 
▪ 
Subjects will be premedicated with an antihistamine and with acetaminophen prior to 
the first 4 infusions of Avelumab.  Premedication should be administered for 
subsequent Avelumab doses based upon clinical judgment and presence/severity of 
prior infusion reactions. 
6.4 
Management of Toxicities 
 
Non-Neutropenic Fever 
▪ 
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), 
consider institution of antibiotics per SOC. 
▪ 
Febrile patients (regardless of neutrophil count) should undergo full diagnostic work-
up, while continuing antibiotics if appropriate. 
  
 
 


 
22 
Febrile Neutropenia 
▪ 
Patients can receive white cell growth factors in addition to antibiotic treatment per 
standard of care of the treating physician.  
▪ 
Upon resolution of grade 3 febrile neutropenia, nab-Paclitaxel and gemcitabine 
treatment can be resumed at the current dose.  
▪ 
Should a second instance of Grade 3 Febrile Neutropenia occur, dosage of nab-
Paclitaxel and gemcitabine will be resumed at the next lower dose upon resolution 
▪ 
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.   
▪ 
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.  6 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 gemcitabine, paclitaxel and Avelumab.  
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.   
▪ 
Prevention, Surveillance and Management of Interstitial Pneumonitis  
▪ 
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.  
▪ 
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. 
▪ 
Infections should be ruled out with routine immunological/ microbiological 
methods. 


 
23 
▪ 
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.  
▪ 
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.  
 
6.5      Guidelines for Toxicity Management  
▪ 
Regardless of the reason for holding study drug treatment, the maximum 
allowable length of treatment interruption is 3 weeks.  
▪ 
Examples for discontinuation of nab-Paclitaxel: Persistent 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 or Avelumab (if applicable) 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 will be followed as described in 
section 11.  
▪ 
For patients who have had dosing delays, all evaluations will be correspondingly 
delayed.  
▪ 
Reasons for dose modifications or delays, the supportive measures taken, and 
the outcome will be documented. 
 
6.6 
Dose Modifications 
 
Refer to Appendix D for dose modification details of chemotherapy. 
▪ 
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.  
▪ 
No dose modification of hydroxychloroquine or Avelumab is allowed.  
 
Dose Modifications of Avelumab 
There will be no dose modifications for Avelumab.  The dose of Avelumab will either be given or 
delayed/discontinued.  Patients may develop study drug-related toxicities that may require 
skipping doses or dose discontinuation.  Some of these adverse events may be consistent with 
potentially drug-related immune-mediated phenomena; termed IRAEs.  Details of how to dose 
study medication in the presence of adverse drug reactions that may or may not be IRAEs are 
addressed below. 
 
 
 


 
24 
Patients will delay or discontinue treatment with Avelumab if they experience at least one 
adverse event, specified below, considered by the investigator to be definitely, probably, or 
possibly related to Avelumab treatment.  The following criteria will be used to determine dosing 
delay, restarting doses, or discontinuing Avelumab. 
 
Treatment Modification for Symptoms of Infusion-Related Reactions  
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease Avelumab infusion rate by 50% and 
monitor closely for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for  
24 h. 
Temporarily discontinue Avelumab infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening. 
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
Stop Avelumab infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately from 
study drug treatment and must not receive any 
further study drug treatment. 
-If Avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it must remain 
decreased for the next scheduled infusion.  If no infusion reaction is observed in the next scheduled infusion, the 
infusion rate may be returned to baseline at the subsequent infusions based on investigator’s medical judgment. 
-If hypersensitivity reaction occurs, the subject must be treated according to the best available medical practice.  
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
 
 
 


 
25 
Table 3.  Management of Immune-mediated Adverse Reactions 
Gastrointestinal irAEs 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue Avelumab therapy 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening 
immediately 
If worsens: 
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 
hours; not interfering with ADL 
Colitis: abdominal pain; blood in 
stool  
 
Withhold Avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume Avelumab therapy 
 
If  persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools per 
day over Baseline; incontinence; IV 
fluids ≥ 24 h; interfering with ADL 
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4: life-threatening, 
perforation 
Withhold Avelumab for 
Grade 3. 
Permanently discontinue 
Avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade ≤ 1, then taper 
over at least 1 month; resume Avelumab 
therapy following steroids taper (for initial 
Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs 
after improvement: 
Add infliximab 5mg/kg (if no 
contraindication).  Note: infliximab should 
not be used in cases of perforation or sepsis.  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface area  
Continue Avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold Avelumab therapy  
Consider skin biopsy  
Consider 0.5-1.0 mg/kg/day prednisone or 
equivalent.  Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and 
resume Avelumab therapy following steroids 
taper. 
If worsens:  
Treat as Grade 3 to 4.  


 
26 
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold Avelumab for 
Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume 
Avelumab therapy following steroids taper 
(for initial Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding 
Avelumab therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold Avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month, and then 
resume Avelumab therapy following steroids 
taper  
If not improving after 2 weeks or worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue 
Avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)  


 
27 
Hepatic irAEs 
Grade of Liver Test Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 3.0 
x ULN and/or Total bilirubin > 
ULN to 1.5 x ULN  
Continue Avelumab therapy 
Continue liver function monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4.  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN  
Withhold Avelumab therapy 
Increase frequency of 
monitoring to every 3 days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume 
Avelumab therapy. 
If elevation persists > 5 to 7 days or worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN  
Permanently discontinue 
Avelumab therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted  
If returns to Grade ≤ 1:  
Taper steroids over at least 1 month  
If does not improve in > 3 to 5 days, worsens 
or rebounds:  
Add mycophenolate mofetil 1 gram (g) twice 
daily  
If no response within an additional 3 to 5 
days, consider other immunosuppressants per 
local guidelines. 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x 
ULN 
Continue Avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x 
ULN 
 
 
 
 
 
Withhold Avelumab therapy 
Increase frequency of monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 month, 
and resume Avelumab therapy 
following steroids taper. 
If worsens:  
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x ULN 
Permanently discontinue Avelumab 
therapy 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 


 
28 
 
 
 
 
 
 
 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive 
of myocarditis.  
Withhold Avelumab therapy. 
Hospitalize. 
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management. 
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis.  
Guideline based supportive treatment as 
per cardiology consult.* 
 
Consider myocardial biopsy if 
recommended per cardiology consult. 
If symptoms improve and 
immune-mediated etiology is ruled 
out, re-start Avelumab therapy. 
 
If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-mediated 
etiology is suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue Avelumab. 
Guideline based supportive treatment as 
appropriate as per cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids 
over at least 1 month. 
 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or e.g. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue Avelumab therapy 
Endocrinology consult if needed 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 


 
29 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold Avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Resume Avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤ 1 (with or without 
hormone replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH): 
• 
Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women)  
• 
Hormone 
replacement/suppressive therapy 
as appropriate  
• 
Perform pituitary MRI and visual 
field examination as indicated 
 
If hypophysitis confirmed: 
• 
Continue Avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
Resume Avelumab once symptoms 
and hormone tests improve to 
Grade ≤ 1 (with or without 
hormone replacement). 
 
In addition, for hypophysitis with 
abnormal MRI, resume Avelumab 
only once shrinkage of the pituitary 
gland on MRI/CT scan is 
documented.  
 
Continue hormone 
replacement/suppression therapy as 
appropriate. 


 
30 
• 
Withhold Avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI.  Consider 
hospitalization.  Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) 
followed by corticosteroids taper 
during at least 1 month. 
• 
Add prophylactic antibiotics for 
opportunistic infections. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE 
Withhold Avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
Avelumab therapy 
If irAE is confirmed, treat as Grade 
2 or 3 irAE. 
Grade 2 irAE or first occurrence 
of Grade 3 irAE 
Withhold Avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent   
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
and resume Avelumab therapy 
following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue Avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month. 
Grade 4  
 
Permanently discontinue Avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult. 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue Avelumab 
therapy 
Specialty consult 
 


 
31 
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB;  CT= computed 
tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; 
irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; 
NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; 
PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal. 
 
 
Prohibited and Restricted Therapies during the Study 
Patients in this study may not use vaccines for the treatment of cancer or prevention of disease 
(including those for common medical conditions) for up to one-month pre and post dosing with 
Avelumab.  Concomitant systemic or local anti-cancer medications or treatments are prohibited 
in this study while receiving Avelumab treatments.  
 
Patients may not use any of the following therapies during the study: 
• 
Any non-study anti-cancer agent (investigational or non-investigational) 
• 
Any other investigational agents 
• 
PD1 or PDL1 antagonists 
• 
Immunosuppressive agents 
• 
Chronic systemic corticosteroids 
• 
Any non-oncology vaccine therapies used for the prevention of infectious diseases 
(for up to 30 days prior to or after any dose of study drug) 
 
6.7  
Concomitant Medications 
 
Pre-medications suggested for this regimen may include Kytril and Emend IV, given as per 
standard of care institutional guidelines 
• 
Concomitant medications should be avoided except for analgesics (only 
acetaminophen or narcotics may be given for pain), chronic treatments for 
concomitant medical conditions, anti-nausea medications, anti-diarrheal, and/ or 
agents required for life threatening medical problems.     
• 
The subject should try to 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:  
 
▪ 
Non-steroidal anti-inflammatory medications (NSAIDs). 
▪ 
Clopidogrel (Plavix). 
▪ 
Aspirin > 325 mg/day. 
▪ 
Drugs with laxative properties should generally be avoided because of the 
potential for the exacerbation of diarrhea associated with treatment.  Subjects 
should be advised to contact their physician to discuss any laxative use.  
▪ 
Steroids (unless documented consultation with PI providing waiver upon case by 
case review). 
 
7.0 
SUBJECT 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.  
• 
Intercurrent illness that prevents further administration of treatment. 


 
32 
• 
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 
RECRUITMENT AND COSTS 
 
8.1 
Recruitment Procedures 
 
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. 
 
8.2 
Costs and Payments 
 
Research Study Costs:  The study drugs Avelumab and 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.  
 
Research Study Payments:  Subjects will not be paid for participating in this study. 
 
 
9.0 
STATISTICAL METHODS 
 
9.1 
Method of Randomization  
 
This trial will use the method of Thall and Wathen [Thall P and Wathen J (2005) Covariate-
adjusted adaptive randomization in a sarcoma trial with multi-stage treatments.  Statistics in 
Medicine 24:  1947-64.]   To adaptively randomize participants to PGH versus PGHA based on 
the probabilities that participants experience histologic response of Evans Grade IIb or better, 
P(πPGHA > πPGH).  Adaptive randomization tends to allocate more patients to the better treatment 
when significant evidence accrues during the trial suggesting that one treatment is indeed 
better.  This design makes the randomized trial more palatable to patients, while retaining the 
advantages of randomization.  In UPCI-13-074, out of the first 26 patients randomized to the 
PGH arm, 14 had a histologic response of Evans Grade IIb or better.  Throughout the trial, a 
beta-binomial model will be used to estimate P(πPGHA > πPGH), where the hyperparameters will 
be αPGH=14, βPGH=12, reflecting the UPCI-13-074 experience, and αPGHA=3, βPGHA=2, 
representing some confidence that the probability of response will be greater in the PGHA arm.  
Initially, 30 participants will be randomized to PGH versus PGHA 1:1 (the "burn-in phase").  
Beginning with the 31st participant, P(πPGHA > πPGH) will be calculated from the accrued data and 
the hyperparameters, and participants will be randomized to PGHA with probability p, where p= 
P(πPGHA > πPGH)c, where c=i/2N for the ith randomized participant.  Accrual will continue until a 
total of 120 (including the "burn-in" participants) participants are accrued, or the trial is 
interrupted for futility (Section 10.2).  


 
33 
 
9.2 
Monitoring for Futility and Autoimmune Toxicity 
 
Monitoring for Futility 
Using the same beta-binomial as for the randomization, if, at any time after the first 30 
response-evaluable participants are treated, P(πPGHA > πPGH) < 0.25, accrual to the trial will be 
paused and the protocol will be reconsidered for futility.  
 
Monitoring for Autoimmune Toxicity  
It is anticipated that the proportion of participants on the PGHA arm experiencing autoimmune 
toxicities will be less than or equal to 0.1, and a probability of such toxicity greater than 0.2 
would be unacceptable.  Using a beta-binomial model for toxicity, as above, with α=1 and β=9, 
the following rule will be used to pause the trial if P(P(autoimmune toxicity) ≥ 0.2) ≥ 0.8: 
 
# Participants on PGHA Arm # Autoimmune Toxicities 
5 
4 
10 
5 
15 
6 
20 
8 
25 
9 
30 
10 
35 
11 
40 
12 
45 
13 
50 
14 
55 
15 
60 
17 
65 
18 
70 
19 
 
9.3       Justification of Design 
  
Monte Carlo simulation was employed to determine the operating characteristics of the design.  
It was assumed that the probability of histologic response in the PGH arm was as in UPCI-13-
074, 14/26=0.53.  The probability of histologic response in the PGHA arm was varied from 0.4 
to 0.8 and the randomization and futility rules were applied as above.  One hundred trials were 
simulated for each value of πPGHA between 0.4 and 0.8 (in 0.02 steps).  The operating 
characteristics are displayed in the figure below as a function of the true value of πPGHA.  It is 
seen that, if πPGHA = πPGH, the expected sample size is 80 (compared to a maximum of 120), but 
if if πPGHA = 0.8, the probability the trial is paused for futility equals 0.22.  The estimates 
probability that πPGHA > πPGH increases linearly with πPGHA. 
 
 
 
 


 
34 
 
9.4      Study Timelines and Milestones 
 
Our previous neoadjuvant study (see background) on which this study is based, accrued 60 
evaluable patients in a similar two arm fashion over a period of 36 months.  We have no 
knowledge of any change in referral or other patterns at this time to suggest that we cannot 
reach a similar study milestone.  Indeed, accrual picked up as the trial progressed and 
continued to accrue into an expansion phase.  We expect to similarly accrue to this study.  
However, if after 1 year we have not accrued 10 patients, we would plan remediation efforts 
amongst ourselves and Pfizer.  
 
9.5      Data Analysis 
 
9.5.1 Primary Efficacy Endpoint 
 
The primary endpoint for this trial will be the Grade IIB or greater histologic response as defined 
in Appendix C.  The beta-binomial model above will be used to estimate 95% credible intervals 
for πPGH, πPGHA, and P(πPGHA > πPGH).  An analysis with uninformative priors will be performed to 
check the sensitivity of the results to prior specification.   A frequentist analysis with 95% exact 
binomial confidence intervals for πPGH and πPGHA will also be performed.  In secondary analyses, 
the relationship of histologic response to demographic and baseline clinical and biomarker 
variables will be explored using logistic regression.  The relationship between response and the 
number of cycles of treatment received will be studies in an exploratory fashion.  The 
assumptions required for the validity of all models will be graphically tested. 
 
9.5.2 Secondary Efficacy Endpoint 
 
95% credible intervals for the log-transformed preoperative and postoperative values of CA19-9 
will be calculated, along with P (μPGHA < μPGH).  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.  As for the primary endpoint, secondary analyses for CA 19-9 will be performed by 
means of analysis of covariance. 
 


 
35 
9.5.3 
Adverse Events 
 
Adverse events will be tabulated by type, grade, relatedness to treatment and study arm, along 
with appropriate 95% exact binomial confidence intervals.  For each participant, the worst grade 
event at least possibly related to treatment will be determined, and this metric will be tabulated 
by arm. 
 
9.5.4 
Secondary Biomarker Endpoints 
 
Change in CA19-9 will be related to treatment by repeated measures ANOVA.  The relationship 
between the change in CA19-9 and final histologic response will be explored by cumulative logit 
models (since clinical response is and ordinal variable).   The relationship between various 
biomarkers measured in tumors (indicators of, for example, autophagy, apoptosis and IL-
6/STAT3 signaling) and treatment will be evaluated using two-sample t-tests or Wilcoxon tests, 
as appropriate.  Mixed effects models will be used if multiple samples (e.g., slides or regions) 
are available per patient.  Changes in markers assessed in blood over time will be analyzed 
using mixed effects models; relationships between continuous markers will be by means of 
ANCOVA 
 
10.0 
ADVERSE EVENT REPORTING 
 
Clinical study subjects will be routinely questioned about adverse events at study visits. 
 
10.1 
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. 
• 
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, 


 
36 
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 aggregate 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 possibility" means there is evidence to suggest 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.   
 
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. 
 
10.2 
Reporting of Suspected Adverse Reactions  
 
Safety will be monitored throughout the study at Pre-Study, Cycle 1, Cycle 2, 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. 
 
Subjects will be monitored for treatment-related toxicity from the time study drug is initiated until 
the first outpatient evaluation after surgery, and throughout follow-up for any grade 4 or 5 event 
felt to be directly related to treatment regimen. 
 


 
37 
In the event of a serious adverse event, the PI and the institutional review board, per 
institutional reporting requirements, will be notified using the CRS Departmental SAE form. 
 
All events meeting the definition of a serious adverse event should be recorded on the CRS 
Departmental SAE Form and submitted to: 
 
1. Nathan Bahary, MD 
Phone: (412) 864-7764 
Email: baharyn@upmc.edu 
2. Clinical Research Coordinator 
3. CRSSafetySubmissions@upmc.edu 
4. Local Institutional Review Board per reporting requirements, as 
completed by CRS Safety  
6.  Contact information for submission of reportable events to Pfizer: 
Fax:  Pfizer U.S. Clinical Trial Department, Fax 1-866-997-8322 or  
E-mail: USA.AEReporting@pfizer.com, specifying: Protocol number, 
subject, site and PI, SAE and onset. 
 
Note: Participating Sites must also submit events meeting reporting 
requirements to the contacts listed above, as well as following their internal 
processes and reporting to their IRB of record according to that IRB’s 
reporting guidelines. 
 
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 Narrative (Section C) on the departmental SAE 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 
departmental form and submitting it as follow-up or creating supplemental summary information 
and submitting it as follow-up with the original departmental SAE form. 
 
Pfizer Reporting Requirements 
The investigator primary responsibilities in the safety reporting are to identify and follow-up on 
Serious Adverse Events (SAEs) experienced by participants in the study and to forward the 
information to the local regulatory authorities and Pfizer, as required by local regulations (for 
regulatory reporting) and IIR agreement (for reporting to Pfizer. 
 
The following reportable events must be submitted to Pfizer within 24 hours (or immediately for 
death or life-threatening events) using the provided Investigator-Initiated Research Serious 
Adverse Event Form (IIR SAE) with the Pfizer Reportable Events Fax Cover Sheet with each 
SAE submission. 


 
38 
 
• 
Serious Adverse Events 
• 
Exposure during Pregnancy or Breastfeeding (even if not associated with an 
adverse event) 
• 
Occupational exposure (even if not associated with an adverse event) 
• 
Potential drug-induced liver injury (Hy’s Law cases):  These events are considered 
important medical events and should be reported as SAE’s 
 
10.3 
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: 
• 
serious adverse events 
• 
subject safety issues 
• 
recruitment issues 
• 
accrual 
• 
protocol deviations 
• 
unanticipated problems 
• 
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 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 will 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.  Minutes from the disease center 
DSMB meetings are provided to those who are unable to attend in person. 
 
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. 
 


 
39 
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.  
 
11.0 
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. 
 
12.0 
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 
 
Likely – more than 25 out of 100 people 
• 
Loss of appetite (anorexia) 
• 
Nausea and vomiting 
• 
Abdominal cramping 
• 
Diarrhea 
• 
Fatigue 
 
Infrequent – between 1 and 10 out of 100 people 
• 
Rash 
• 
Discomfort or pain to the eyes due to light exposure (photophobia) 
• 
Irritability, nervousness or emotional changes 
 
Rare – less than 1 out of 100 people 
• 
Abnormal liver function or liver failure (isolated cases) 
• 
Condition when your body’s bone marrow stops producing enough new blood cells, 
causing fatigue and uncontrolled bleeding (Aplastic anemia) 
• 
Condition when your bone marrow does not make enough neutrophils, a type of white 
blood cell, and leukopenia, a low count of all white blood cells, which increases risk of 
infection (agranulocytosis) 
• 
Lowered platelet count, which makes it more likely to bruise or bleed 
• 
Decreased blood sugar level (hypoglycemia) 
• 
Hemolysis, a breakdown of red blood cells, in patients with glucose-6-phosphate 
deficiency 
• 
Dysfunctional muscle fibers leading to progressive muscle weakness and breakdown of 
muscle tissue (myopathy) 
• 
Bleaching of hair 
• 
Complete or partial loss of hair (alopecia) 
• 
Pigmentation changes 
• 
A rare, serious disorder in which the skin and mucous membranes react severely to a 
medication or infection (Stevens-Johnson syndrome).  It often begins with flu-like 
symptoms, followerd by a painful red or purplish rash that spreads and blisters, 
evenutally causing the top layer of skin to die and shed 


 
40 
• 
A rare form of drug hypersensitivity characterized by the rapid appearance of many 
sterile pustules ofn the skin, accompanied by fever and sometimes lowered blood counts 
(Acute generalized exanthematous pustulosis – AGEP) 
• 
Widespread scaling of the skin, often with itching, skin redness, and hair loss (exfoliative 
dermatitis) 
• 
Partial of complete wasting away of part of the body’s muscle groups (atrophy)  
• 
Inflammation or degeneration of the nerves causing tingling, numbness and burning 
(neuropathy) 
• 
Visual disturbances 
• 
Nightmares, psychosis, headache, dizziness, vertigo, seizure, ataxia and lassitude 
• 
Premature of extra heartbeats which could lead to death (heart arrhythmias) 
 
Gemcitabine 
 
Likely – 25 out of 100 people 
• 
Lack of red blood cells, causing unusual tiredness or weakness (anemia) 
• 
Fever and mild flu-like symptoms 
• 
Blood in urine (hematuria) 
• 
Skin rash, with or without itching 
• 
Bone marrow suppression (low red blood cells, low white blood cells, low concentration 
of neutrophils, low platelet count) 
• 
Abnormal liver function, usually transient 
• 
Constipation, nausea and vomiting, usually mild to moderate 
• 
Pain 
 
Common – 10 to 25 out of 100 people 
• 
Swelling of fingers, feet or lower legs (peripheral edema) 
• 
Cloudy urine (proteinuria) 
• 
Partial or complete loss of hair (alopecia) 
• 
Mouth ulcers (stomatitis) 
• 
Diarrhea 
• 
Bleeding 
• 
Sleepiness 
• 
Itchiness of the skin (pruritis) 
 
Infrequent – 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, especailly 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 
• 
Blood in urine or stools (hemorrhage) 
• 
Pinpoint red spots on skin 
• 
Cardiovascular toxicity, including myocardial infarction (pain in chest, arm or back, 
pressure of squeezing in chest), hypertension (high blood pressure), arrhythmia (fast or 
irregular heartbeat) 
• 
Cerebrovascular accident (sudden or severe headache, slurred speech or inability to 
speak, weakness in arm and/or leg on one side of the body) 
• 
Febrile neutropenia or other infection (fever or chills, cough or hoarseness, lower back or 
side pain, painful or difficult urination) 


 
41 
• 
Abnormal renal function 
• 
A tingling sensation like “pins and needles” (paresthesias) 
 
Rare – 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; pinpoin red spots on skin; swelling face, fingers, feet 
or lower legs; unusual bleeding or bruising; unusual tiredness or weakness; yellow eyes 
or skin) 
• 
Lung toxicity, parenchymal or pneumonitis (coughin; shortness of breath) 
• 
Renal failure requiring dialysis 
• 
Severe infection 
• 
Serious liver toxicity including death 
 
Nab-Paclitaxel 
Common – Greater than 10 out of 100 people 
• 
Low red blood cell count (anemia) 
• 
Decrease in platelet count (thrombocytopenia) 
• 
Infections due to low count of a type of white blood cell (neutropenia) 
• 
Decrease in white blood cell count, which can lead to infection (leukopenia) 
• 
Diarrhea, constipation, abdominal pain 
• 
Nausea, vomiting, mouth and lip soreness or swelling 
• 
Fever, fatigue, weakness, chills 
• 
Swelling or fluid retention (edema) 
• 
Hair loss (alopecia) 
• 
Nail changes such as discoloration or pigmentation 
• 
Generalized rash or itchy rash 
• 
Dehydration 
• 
Decreased appetite 
• 
Decreased liver function 
 
Infrequent – Between 1 and 10 out of 100 people 
• 
Fever with low white blood cell count (febrile neutropenia) 
• 
Visual disturbances, including redness and swelling of the cornea and blurred vision 
• 
Low blood pressure (hypotension) or high blood pressure (hypertension) 
• 
Headache 
• 
Tingling, numbness or burning in the hands and /or feet (neuropathy) 
• 
Shortness of breath (dyspnea) 
• 
Decreased heart rate (bradycardia) 
• 
Infection in the lungs (pneumonia) 
• 
Lower of upper respiratory infection 
 
Rare – less than 1 out of 100 people 
• 
Allergic reactions, such as shortness of breath, flushing, low blood pressure, chest pain 
and irregular heartbeat 
• 
Cardiovascular events such as heart attack, blood clots, stroke or mini-stroke 
• 
Formation of blood clots in small blood vessels around the body that leads to a low 
platelet count (thrombotic thrombocytopenic purpura) 


 
42 
Avelumab  
Common – Greater than 10 out of 100 people 
• 
Tiredness 
• 
Nausea and vomiting 
• 
Diarrhea 
• 
Constipation 
• 
Decreased appetite and weight loss 
• 
Decrease in number of red blood cells (anemia) 
• 
Fever, cough, shortness of breath 
• 
Swelling or retention of fluid in the body (peripheral edema) 
• 
Headache, dizziness 
• 
Muscle or joint pain 
• 
Increased blood pressure (hypertension) 
• 
Itchy skin 
• 
Infection 
• 
Allergic reactions during infusion, including symptoms of chills, shaking, fever, flushing, 
back or belly pain, shortness of breath or wheezing, decrease in blood pressure and 
hives. 
 
In addition, Avelumab can cause side effects from the increased activity of the immune system.  
These side effects listed below may be temporary, long-term, and permanent or result in death. 
Most of these side effects are reversible and will stop once drug is discontinued.  The reactions 
that are more severe require treatment with drugs that decrease the immune system function, 
like corticosteroids.  The immune related side effects have been observed in fewer than 10% of 
patients. 
 
Immune-related side effects observed in 5 to less than 10% of patients: 
• 
Abnormal function of the thyroid gland (low or high function, or inflammation) – 
symptoms may include rapid heartbeat, increased sweating, extreme tiredness, weight 
gain or weight loss, hair loss, changes in mood or behavior such as irritability or 
forgetfulness, feeling cold, constipation, change in voice. 
• 
Inflammation of the skin (rash) – symptoms may include skin rash, itchy skin, skin 
redness, skin blisters or peeling. 
 
Immune-related side effects observed in 1 to less than 5% of patients: 
• 
Inflammation or the large intestine (colitis) – Symptoms may include diarrhea or more 
frequent bowel movements than usual, blood in stools or dark, tarry, sticky stools, 
severe stomach are pain or tenderness. 
• 
Inflammation of the lungs (pneumonitis) – Symptoms may include new or worsening 
cough, shortness of breath, chest pain. 
 
Immune-related side effects observed in less than 1% of patients: 
• 
Inflammation of the liver (hepatitis) – Symptoms may include yellowing of skin or of the 
whites of eyes; severe nausea or vomiting; pain on the right side of stomach area 
(abdomen); drowsiness; dark urine (tea colored); bleeding or bruising more easily than 
normal; feeling less hungry than usual. 
• 
Inflammation of the kidneys (nephritis) – Symptoms may include urinating less than 
usual; blood in urine; swelling in ankles; loss of appetite. 


 
43 
• 
Low function of the adrenal glands (glands on top of the kidneys), which may be due to 
the reduced function of the pituitary gland (a gland in the head): may include very low 
blood pressure; extreme tiredness. 
• 
Increase in blood sugar (diabetes) – Symptoms may include urinating more often than 
usual; feeling more hungry or thirsty than usual, nausea or vomiting, stomach area 
(abdomen) pain. 
• 
Inflammation of the eyes (uveitis) – Symptoms may include changes in eyesight. 
• 
Inflammation of the muscles (myositis) – Symptoms may include severe or persistent 
muscle or joint pain; severe muscle weakness. 
• 
Inflammation of the heart (myocarditis) – Symptoms may include chest pain or tightness; 
tiredness; changes in heartbeat, such as beating fast, or seeming to skip a beat, or 
pounding sensation; swelling of feet and legs; trouble breathing. 
• 
Inflammation of the nerves (Guillain-Barre syndrome) – Symptoms may include "pins 
and needles" sensations in arms and legs; weakness in legs that spreads to the upper 
body and may lead to temporary paralysis. 
 
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.  
 
 


 
44 
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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. 


 
45 
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. 
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. 
 
 
 
 
 


 
46 
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. 


 
47 
APPENDIX B. CTCAE 4.0 
 
National Cancer Institute Common Toxicity Criteria, Version 4 
 
Obtained from https://evs.nci.nih.gov/ftp1/CTCAE/About.html    
 
 
 
 
 


 
48 
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. 
 


 
49 
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 
 
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 D.1.4 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 2 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;).  
 
Key: ANC = Absolute neutrophil count. 
Table 1: 
Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity) 
Gemcitabine and nab-paclitaxel related  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 asymptomatic, will be 
exempt from this requirement.   
 


 
50 
D.1.4 Dose Adjustments for Day 1 and within a Treatment Cycle 
 
Cycle 
Day 
ANC 
(cells/mm
3) 
  
Platelet count 
(cells/mm
3) 
nab-Paclitaxel Dose 
Gemcitabine Dose 
Day 1 
≥ 1500  
AND 
≥ 100,000 
Treat on time at current dose levels 
  
≥ 500 between 
< 1000 
OR 
≥ 75,000 but  
< 100,000 
Consider GCSF support 
 
< 500 
OR 
< 75,000 
Hold until recovery and consider GCSF support 
Day 8 
≥ 1000  
AND 
≥ 75,000  
Treat on time at current dose levels 
  
≥ 500 but 
< 1000 
OR 
≥ 50,000 but  
< 75,000 
Reduce doses 1 dose level 
  
< 500 
OR 
< 50,000 
Withhold doses  
Day 15:    IF Day 8 doses were given without modification:  
Day 
15 
≥ 1000  
AND 
≥ 75,000   
Treat on time at current dose levels 
  
≥ 500 but 
< 1000 
OR 
≥ 50,000 but 
< 75,000 
Reduce doses 1 dose level from Day 8; 
consider following with WBC growth factors for 
support* 
  
< 500 
OR 
< 50,000 
Withhold doses 
Day 15:    IF Day 8 doses were reduced:  
Day 
15 
≥ 1000  
AND 
≥ 75,000  
Treat with same doses as Day 8; consider 
following with WBC growth factors for support*  
  
≥ 500 but 
< 1000 
OR 
≥ 50,000 but 
< 75,000 
Reduce doses 1 dose level from Day 8; 
consider following with WBC growth factors for 
support*  
  
< 500 
OR 
< 50,000 
Withhold doses 
Day 15:    IF Day 8 doses were withheld:  
Day 
15 
≥ 1000  
AND 
≥ 75,000  
Option A: Maintain dose level from Day 1 and 
follow with WBC growth factors for support*  
OR 
Option B:  Reduce doses 1 dose levels from 
Day 1   
  
≥ 500 but 
< 1000 
OR 
≥ 50,000 but 
< 75,000 
Option A: Reduce 1 dose level from Day 1 and 
follow with WBC growth factors for support*  
OR 
Option B:  Reduce doses 2 dose levels from 
Day 1  
  
< 500 
OR 
< 50,000 
Withhold doses 
Abbreviations:  ANC = Absolute neutrophil count; G-CSF = Granulocyte colony stimulating 
factor. 
• 
a G-CSF as per SOC 
• 
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. 
• 
When a dose reduction is required at cycle 1, dose re-escalation at cycle 2 will be 
permitted at the treating MD discretion 
 
 
 
 


 
51 
D.1.5 Dose Modifications for Non-Hematological Toxicity within a Cycle 
Dose modifications may also be made for non-hematological toxicity within a cycle as specified 
in Table 2 
 
Table 2: 
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.1.6 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.1.7 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. 
 
D.1.8 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.1.9 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.1.10 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 X) 
Patients who do not experience resolution of neutropenia within 21 days, despite uninterrupted 
G-CSF treatment, will discontinue study treatment. 
 


 
52 
D.1.11  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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
53 
APPENDIX E: Bio-specimen Research Samples 
 
15mL of Research blood will be collected at various study visits (refer to study calendar in section 
5.0).  
 
The following tests will be performed on tissue samples:  
• 
Cl Casp 3 
• 
Ki-67 
• 
PCNA 
• 
Atg7 
• 
Beclin-1 
• 
LC3B 
• 
p62 
• 
HMGB1 
• 
IL-6 
• 
STAT 3 Ser727 
 
The following tests will be completed on blood samples: 
1. A soluble checkpoint/costimulation panel. 
BTLA; GITR; HVEM; IDO; LAG-3; PD-1; PD-L1; PD-L2; TIM-3; CD28; CD80; CD137; CD27; 
CD152 
 
2. Cytokine/chemokine/growth factors: 65-plex.  Target List 
APRIL; BAFF; BLC; CD30; CD40L; ENA-78; Eotaxin; Eotaxin-2; Eotaxin-3; FGF-2; Fractalkine; 
G-CSF; GM-CSF; Gro a; HGF; IFN-a; IFN-g; IL-10; IL-12p70; IL-13; IL-15; IL-16; IL-17A; IL-18; 
IL-1a; IL-1b; IL-2; IL-20; IL-21; IL-22; IL-23; IL-27; IL-2R; IL-3; IL-31; IL-4; IL-5; IL-6; IL-7; IL-8; IL-
9; IP-10; I-TAC; LIF; MCP-1; MCP-2; MCP-3; M-CSF; MDC; MIF; MIG; MIP1a; MIP-1b; MIP-3a; 
MMP-1; NGF beta; SCF; SDF-1a; TNF b; TNF-a; TNF-R2; TRAIL; TSLP; TWEAK; VEGF-A 
 
This is a preliminary list of tests to be completed on bio-specimen research samples that can 
change as the study progresses and the study teams understanding develops.