Clinical trial NCT02427841
Conditions: Pancreatic Adenocarcinoma Resectable Pancreatic Carcinoma
Sponsor: OHSU Knight Cancer Institute
Start date: 2016-01-21; Completion date: 2022-12-12
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well nab-paclitaxel and gemcitabine hydrochloride followed by radiation therapy before surgery work in treating patients with pancreatic cancer that can be removed by surgery. Chemotherapy drugs, such as nab-paclitaxel and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving nab-paclitaxel, gemcitabine hydrochloride, and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the R0 (complete resection) resection rate for subjects with borderline resectable or lymph node positive pancreatic adenocarcinoma treated with a multimodality neoadjuvant therapy of preoperative gemcitabine (gemcitabine hydrochloride) and ABRAXANE (nab-paclitaxel) followed by 5-fluorouracil (fluorouracil) based image-guided intensity-modulated radiation therapy (IG-IMRT) chemoradiotherapy.

SECONDARY OBJECTIVES:

I. To determine 1-year relapse-free survival rate with the investigational protocol.

II. To determine 1-year and 2-year overall survival rates. III. To assess response rate by imaging (Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) and pathologic analysis.

IV. To assess the toxicity and safety according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) criteria.

OUTLINE:

PRE-OPERATIVE (NEOADJUVANT) CHEMOTHERAPY: Patients receive nab-paclitaxel intravenously (IV) over 30 minutes and gemcitabine IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo IG-IMRT 5 days a week for 28 fractions and receive fluorouracil IV continuously on days 1-7 for 6 weeks.

SURGICAL RESECTION: Patients undergo surgery 4-10 weeks after the last dose of chemoradiation.

POST-OPERATIVE (ADUJUVANT) CHEMOTHERAPY: Beginning within 8-12 weeks after surgery, patients receive nab-paclitaxel IV over 30 minutes and gemcitabine IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 4 additional courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 1 year.

Arms: arm 1: PRE-OPERATIVE (NEOADJUVANT) CHEMOTHERAPY: Patients receive nab-paclitaxel IV over 30 minutes and gemcitabine IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo IG-IMRT 5 days a week for 28 fractions and receive fluorouracil IV continuously on days 1-7 for 6 weeks.

SURGICAL RESECTION: Patients undergo surgery 4-10 weeks after the last dose of chemoradiation.

POST-OPERATIVE (ADUJUVANT) CHEMOTHERAPY: Beginning within 8-12 weeks after surgery, patients receive nab-paclitaxel IV over 30 minutes and gemcitabine IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 4 additional courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Fluorouracil intervention 2: Gemcitabine intervention 3: Image Guided Radiation Therapy intervention 4: Intensity-Modulated Radiation Therapy intervention 5: Laboratory Biomarker Analysis intervention 6: Nab-paclitaxel intervention 7: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo IG-IMRT intervention 4: Undergo IG-IMRT intervention 5: Correlative studies intervention 6: Given IV intervention 7: Undergo surgery

Protocol documents:
Prot_SAP_000.pdf: 
Revision: 7/24/2020 (Version 6.0) 
 
1
Cover Letter 
 
TITLE:   Phase 2 Study of Preoperative chemotherapy with ABRAXANE and Gemcitabine followed by 
chemoradiation for Borderline Resectable or Node-positive Pancreatic Cancer 
 
NCT02427841 
 
Date of document: July 24,2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Revision: 7/24/2020 (Version 6.0) 
 
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Oregon Health & Science University 
OHSU Knight Cancer Institute 
IRB Protocol #: 11,256 
Other Protocol #: AX-PANC-PI-0053 
  
TITLE:   Phase 2 Study of Preoperative chemotherapy with ABRAXANE and Gemcitabine followed by 
chemoradiation for Borderline Resectable or Node-positive Pancreatic Cancer 
 
Coordinating Center: 
 
 
 
Oregon Health and Science University 
 
 
 
 
 
 
 
 
 
3303 SW Bond Ave, CH15R 
 
 
 
 
 
 
 
 
 
Portland, OR  97239 
 
Principal Investigator:  
Gina M. Vaccaro, MD 
 
 
 
 
 
 
 
 
 
Oregon Health and Science University 
 
 
 
 
 
 
 
 
 
3303 SW Bond Ave, CH15R 
 
 
 
 
 
 
 
 
 
Portland, OR  97239 
503-260-7593 
vaccarog@ohsu.edu 
 
Co-Investigators: 
 
Eric Anderson, MD, PhD 
 
 
 
 
 
 
 
 
 
Oregon Health and Science University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Charles Lopez, MD, PhD 
 
 
 
 
 
 
 
 
 
Oregon Health and Science University 
 
Statistician: 
 
Yiyi Chen, PhD 
 
 
 
 
 
 
 
 
 
Oregon Health and Science University 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator/ 
 
Anne Fahlman 
Central Contact (optional):  
 
Oregon Health and Science University 
 
 
503-494-8236 
 
Supplied Agent: 
ABRAXANE 
 
IND Exempt 
 
Supplied by Celgene 
 
Original Protocol Date:  
Version 1 September 7, 2014  
Protocol Revision Dates: 
Version 2 January 12, 2015 
 
 
Version 3 April 17, 2015 
 
Version 4 May 20, 2017 
 
Version 5 January 19, 2017 
 
Version 6 July 24, 2020 


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SCHEMA 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1.0 
OBJECTIVES……………………………………………………………………… 5 
1.1  
Primary Objective………………………………………………………….. 5 
1.2 
Secondary Objectives……………………………………………………….5 
2.0 
BACKGROUND…………………………………………………………………... 5 
2.1 
Study Disease………………………………………………………………. 5 
2.2 
Neoadjuvant treatment of localized pancreatic adenocarcinoma…………... 5 
2.3 
Borderline resectable pancreatic cancer……..................…………………... 6 
2.4       Study Agent(s).............…………………………………………………….. 7 
 
2.4.1 Preclinical studies with Abraxane………………………………….. 7 
 
2.4.2 Indications and usage of Abraxane………………………………… 7 
 
2.4.3 Clinical studies with Abraxane in pancreatic cancer………………. 7 
2.5 
Other Agent(s)……………………………………………………………....8 
 
2.5.1 Gemcitabine………………………………………………………... 8 
 
2.5.2 5-Fluorouracil……………………………………………………… 8 
2.6       Study and Dose Rationale.............………………….…………………….... 8 
2.7 
Correlative Studies Background…………………………………………… 8 
3.0 
STUDY POPULATION…………………………………………………………… 9 
3.1 
Inclusion Criteria……………………………………………………………9 
3.2 
Exclusion Criteria………………………………………………………….. 10 
4.0 
REGISTRATION PROCEDURES………………………………………………... 11 
4.1 
Subject Registration………………………………………………………... 11 
5.0 
TREATMENT PLAN ……………………………………………………………... 11 
5.1 
Preoperative chemotherapy………………………………………………… 11 
5.2 
Chemoradiotherapy………………………………………………………… 12 
5.3 
Surgical resection…………………………………………………………. 13 
5.4 
Post-operative (adjuvant) chemotherapy…………………………………... 13 
5.5 
General concomitant medication and supportive care guidelines…………. 13 
5.6 
Duration of treatment………………………………………………………. 13 
5.7 
Duration of follow-up……………………………………………………… 14 
5.8 
Criteria for removal from study……………………………………………. 14 
6.0 
DOSING DELAYS/DOSE MODIFICATIONS…………………………………... 14 
7.0 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS…………… 15 
7.1 
Adverse Events and Potential Risks List(s)………………………………... 15 
7.2 
Adverse Event Characteristics……………………………………………... 15 
7.3 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events……16 
7.4 
Central Reporting of Adverse Events for Multicenter Studies…………….. 16 
7.5 
MedWatch Reporting………………………………………………………. 16 
7.6 
Expedited reporting by investigator to Celgene…………………………….17 
8.0 
PHARMACEUTICAL and/or IMAGING AGENT INFORMATION……………. 17 


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8.1 
Agent Accountability………………………………………………………. 17 
8.2 
Study Agent(s)………………………………………………………………17 
8.3 
Commercial Agent(s)………………………………………………………. 19 
 9.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES…………………… 19 
9.1 
Biomarker Studies…………………………………………………………. 19 
10.0 
STUDY PROCEDURES AND SCHEDULE OF EVENTS………………………. 20 
10.1 
Screening/Baseline Visit…………………………………………………… 20 
10.2 
Study Visits………………………………………………………………… 21 
10.3 
Follow-up…………………………………………………………………... 22 
10.4 
Schedule of Events…………………………………………………………. 23 
11.0 
MEASUREMENT OF EFFECT…………………………………………………... 24 
11.1 
Antitumor Effect…………………………………………………………… 24 
11.2 
Duration of response……………………………………………………….. 27 
11.3 
Relapse-free survival………………………………………………………. 28 
11.4 
Histopathologic determination of resection status…………………………. 28 
12.0 
DATA REPORTING/REGULATORY REQUIREMENTS………………………. 28 
12.1    Data Collection and Storage……………………………………………….. 28 
12.2 
Protocol Review……………………………………………………………. 28 
12.3 
Informed Consent…………………………………………………………...29 
12.4 
Changes to Protocol………………………………………………………... 29 
12.5 
Maintenance of Records…………………………………………………… 29 
12.6 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events…... 29 
12.7 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan………… 29 
12.8 
Inclusion of Women, Minorities and Children…………………………….. 29 
13. 
STATISTICAL CONSIDERATIONS…………………………………………….. 31 
13.1 
Study Design……………………………………………………………….. 31 
13.2 
Primary and Secondary Endpoints…………………………………………. 31 
13.3 
Analysis Populations………………………………………………………. 32 
13.4 
Statistical Analysis Plan…………………………………………………….32 
13.5 
Sample Size and Power…………………………………………………….. 33 
13.6 
Randomization Method…………………………………………………….. 33 
13.7 
Handling of Missing Data………………………………………………….. 33 
 
REFERENCES…………………………………………………………………………….. 34 
APPENDIX A (Performance status criteria)………………………………………………. 36 
APPENDIX B (Abraxane package insert)…………………………………………………. 36 
APPENDIX C (Gemcitabine package insert)……………………………………………… 36 
APPENDIX D (Fluorouracil package insert)……………………………………………… 37 
 
 


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1.0 
OBJECTIVES   
 
1.1  
Primary Objective 
 To determine the R0 resection rate for subjects with borderline resectable or lymph node 
positive pancreatic adenocarcinoma treated with a multimodality neoadjuvant therapy of 
preoperative gemcitabine and ABRAXANE followed by 5-fluorouracil based image-
guided IG-IMRT chemoradiotherapy 
 
1.2 
Secondary Objectives 
 
 
 
 
1.2.1 
To determine 1-year relapse-free survival rate with the investigational protocol 
 
 
 
 
1.2.2 
To determine 1-year and 2-year overall survival rates 
 
 
 
 
1.2.3 
To assess response rate by imaging (RECIST 1.1) and pathologic analysis 
 
 
 
 
1.2.4 
To assess the toxicity and safety according to CTCAE v4.0 criteria 
 
 
 
 
 
 
 
 
 
2.0 
BACKGROUND 
 
2.1 
Study Disease 
Pancreatic adenocarcinoma (PDAC) is the second most common gastrointestinal 
malignancy in the United States, with an estimated 45,220 new cases in 2013 and an 
estimated 38,460 deaths (1). This disease continues to have a poor prognosis with a 
median survival in all cases of only 6 months.  Less than 10% of patients present with 
clearly localized disease which is limited to the primary site, while the remainder are 
divided between locally advanced (27%) and distant metastatic disease (53%) at 
diagnosis (2). The only known curative therapy for PDAC is surgical resection, however 
even those patients who undergo a complete (R0) primary tumor resection have a relapse 
rate approaching 90% and a median survival of less than 2 years, while patients who have 
margin positive (R1) resections have a median survival of ~1 year, similar to locally 
advanced, unresectable tumors.  Long-term follow-up suggests that the 5-year survival 
rate for all cases of pancreatic adenocarcinoma is poor at approximately 6%, and has not 
changed in the last several decades.  An analysis of SEER data between 1991 and 1996 
indicated a 3 year survival rate of 34% for patients who have undergone curative intent 
surgery (3).   Additionally, the most important predictor of survival in this population was 
postoperative adjuvant chemoradiation therapy. As resection is the only potential 
pathway to cure, and there is interest in increasing the percentage of patients who are 
eligible for resection by delivering neoadjuvant therapy. 
 
 
2.2 
Neoadjuvant treatment of localized pancreatic adenocarcinoma 
Pre-operative (neoadjuvant) treatment with chemotherapy and/or radiation therapy for 
patients with localized PDAC presents a number of potential advantages.  These include 
the early treatment of micrometastatic disease, the ability to deliver more intensive 
therapy to more patients, as well as a means to identify patients with occult metastatic 
disease who are spared unnecessary aggressive surgery.  Additionally, as the morbidity of 
surgical resection is high, many patients are not able to receive postoperative adjuvant 
therapy.  Therefore, there is increasing interest in delivering this therapy prior to 
resection.  Several institutions have reported on neoadjuvant chemoradiation using 5-FU 
based chemotherapy (4) or Gemcitabine based (5) regimens.  These studies and others 
have demonstrated that neoadjuvant therapy is feasible, safe and that resection can be 
performed with acceptable morbidity.  However, there is no standard regimen for 
neoadjuvant therapy for pancreatic cancer.  Meta-analyses have been performed to assess 
outcomes of neoadjuvant therapy in resectable pancreatic cancer.  One recently published 
analysis included 14 Phase II clinical trials including 536 patients.  This analysis showed 
that in initially resectable patients rates of resection following neoadjuvant therapy were 


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65.8% compared to 31.6% in the group with initially borderline/unresectable tumors (6).  
Median survival in all resected patients was 22-23 months.  It is not clear from the 
available data if neoadjuvant therapy followed by resection is superior, equal to, or 
inferior to upfront resection followed by adjuvant therapy, as randomized trials have not 
been done to answer this question. National guidelines such as NCCN support the use of 
neoadjuvant therapy in patients where the risk of margin positivity with upfront resection 
is high (7). 
 
 
2.3 
Borderline resectable pancreatic cancer 
Borderline resectable pancreatic cancer is a unique clinical and radiographic presentation 
described as vascular involvement of the primary tumor which would result in an 
unacceptably high rate of non-R0 resection in the absence of vascular reconstruction or 
pre-operative therapy.  Vascular reconstruction is feasible in this clinical setting and 
produces survival outcomes comparable to patients who undergo resection without 
needing vascular reconstruction (8). Seventy-five percent of the patients who underwent 
vascular reconstruction in this report received pre-operative therapy. 
It is widely thought that in the case of borderline resectable PDAC, the potential benefit 
of neoadjuvant therapy is an increased likelihood of margin-negative (R0) resection, 
resulting in a lower rate of local and possibly distant recurrence, and ultimately increased 
survival.  
 
The definition of borderline resectable pancreatic cancer has evolved over the last several 
years.  The original definition was suggested in a report from MD Anderson which 
described acceptable outcomes for these patients treated with neoadjuvant therapy 
followed by surgery with a median survival of 40 months (9).  A consensus conference of 
AHBPA/SSO/SSAT was held in 2008 and the definition of borderline resectable 
pancreas cancer was further refined (10): 
 
Tumor-associated deformity of the SMV (superior mesenteric vein) or PV (portal 
vein) 
 
Abutment of the SMV or PV ≥ 1800 
 
Short-segment occlusion of the SMV or PV amenable to resection and venous 
reconstruction 
 
Short-segment involvement of the hepatic artery or its branches amenable to 
resection and reconstruction 
 
Abutment of the SMA < 1800 
 
There is no consensus on the best neoadjuvant regimen to use in this clinical setting. The 
only multi-institutional trial of neoadjuvant therapy to be performed in this population is 
ECOG 1200 (Eastern Cooperative Group), which closed early due to poor accrual.  
Results of this small, randomized Phase II trial demonstrated a median overall survival of 
26.3 months in resected patients (11).  A recent meta-analysis (including over 4000 
patients) evaluated the outcomes of the available studies of neoadjuvant therapy in 
pancreatic cancer.  Patients with initially resectable tumors demonstrated a resection rate 
of 73% compared to 33% for patients with initially non-resectable 
(borderline/unresectable) tumors.  Median survival for these groups was 23.3 and 20.5, 
respectably (12).  
 
Because of the real and potential advantages of neoadjuvant therapy for PDAC, there is a 
pressing need to identify the most active and beneficial neoadjuvant regimen, especially 
for borderline resectable cases.   
 


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2.4 
Study Agent(s) 
Nab-Paclitaxel (ABRAXANE) is a biologically interactive albumin-bound paclitaxel 
combining a protein with a chemotherapeutic agent in the particle form. This composition 
provides a novel approach of increasing intra-tumoral concentrations of the drug by a 
receptor-mediated transport process allowing transcytosis across the endothelial cell. This 
albumin-specific receptor mediated process involves the binding of albumin to a specific 
receptor (gp60) on the intralumminal endothelial cell membrane, resulting in activation of 
a protein (caveolin-1), which initiates an internalization process in the endothelial cell 
through the formation of caveolae, with transport of the intact albumin-bound 
chemotherapeutic complex via these caveolae to the underlying tumor interstitium (13). 
A protein specifically secreted by the tumor (SPARC) binds albumin, allowing release of 
the hydrophobic drug to the tumor cell membrane (14). ABRAXANE is the first 
biologically interactive nanoparticle product leveraging this gp-60/caveolin-
1/caveolae/SPARC pathway to increase intra-tumoral concentration of the drug and 
reducing toxic effects in normal tissue. 
 
2.4.1 
Preclinical Studies with ABRAXANE  
Preclinical studies comparing ABRAXANE to Taxol® (paclitaxel Cremophor® 
EL solvent-based, BMS) demonstrated lower toxicities, with an MTD 
approximately 50% higher for ABRAXANE compared to Taxol.  At equal doses 
there was less myelosuppression and improved efficacy in a xenograft tumor 
model of human mammary adenocarcinoma.  At equitoxic doses of paclitaxel, 
ABRAXANE treated groups showed more complete regressions, longer time to 
recurrence, longer doubling time, and prolonged survival. At equal dose, tumor 
paclitaxel area under the curve was 33% higher for ABRAXANE versus solvent 
based paclitaxel, indicating more effective intratumoral accumulation of 
ABRAXANE (15).  
 
2.4.2 
Indications and Usage of ABRAXANE  
ABRAXANE is FDA approved for metastatic breast cancer at a recommended 
dosage of 260 mg/m2 intravenously over 30 minutes every 3 weeks.  The 
indication for Non-small cell lung cancer is 100 mg/m2 intravenously over 30 
minutes on Days 1,8, and 15 of each 21-day cycle; carboplatin AUC 6 is given 
intravenously on Day 1 of each 21 day cycle immediately after ABRAXANE 
administration. In 2013, ABRAXANE was FDA approved for metastatic 
adenocarcinoma of the pancreas in combination with gemcitabine (see package 
insert, Appendix B).  
 
2.4.3 
Clinical Studies with ABRAXANE in pancreatic cancer 
Members of the taxane family of microtubule stabilizing compounds (paclitaxel 
and docetaxel) have shown encouraging activity in the first and second-line 
treatment of metastatic pancreatic adenocarcinoma. More recent retrospective 
data have shown that the use of neoadjuvant combination chemotherapy 
including docetaxel improves both resectability and survival in borderline 
resectable PDAC (16).  
 
Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is a novel formulation 
of paclitaxel initially developed to avoid the infusion-related toxicities of 
Cremophor-stabilized paclitaxel. Its activity in pancreatic cancer was first 
suggested when Infante and colleagues (17) identified stromal over-expression of 
SPARC (secreted protein acidic and rich in cysteine) as a poor prognostic factor 
in resectable PDAC. SPARC avidly binds albumin, resulting in accumulation of 


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albumin – and albumin-conjugated drugs – in cells with high SPARC expression. 
SPARC over-expression is associated with increased response to ABRAXANE 
in head and neck and breast tumors.  
 
ABRAXANE has shown encouraging activity as a single-agent, and in 
combination with gemcitabine in Phase I and II clinical trials in the settings of 
first- and second-line metastatic pancreatic adenocarcinoma treatment. A recent 
Phase I/II study of ABRAXANE and gemcitabine in metastatic PDAC showed a 
median overall survival of more than 12 months, a significant improvement over 
currently available therapies (18). To date however, ABRAXANE has not been 
evaluated in the perioperative setting or in combination with radiation therapy. 
 
 
 
 
 
 
 
2.5 
Other Agent(s) 
 
 
 
2.5.1 
Gemcitabine 
 Gemcitabine is a nucleoside metabolic inhibitor approved by the FDA for the treatment 
of pancreatic adenocarcinoma.  It is the standard of care for metastatic or locally 
advanced unresectable disease (19), as well as resected disease as adjuvant therapy (20).  
It is approved as a single agent for the treatment of pancreatic cancer, but has undergone 
extensive study in combination with other antineoplastics.  Two Gemcitabine 
combinations have shown a survival benefit in the advanced disease setting; in 
combination with erlotinib (21), and in combination with ABRAXANE (22).  This phase 
III trial demonstrated a median overall survival advantage from 6.7 to 8.5 months and an 
improvement in response rate from 7 to 23%.  Given the significant activity of 
Gemcitabine/ABRAXANE combination chemotherapy in the advanced setting, this trial 
will evaluate this combination in the borderline resectable patient population. 
 
 
 
 
2.5.2 
5-Fluorouracil  
 Fluorouracil is an antineoplastic antimetabolite that is approved by the FDA for the 
treatment of several malignancies, including pancreatic cancer.  It is commonly combined 
with external beam radiation as a radiation sensitizer for the neoadjuvant treatment of 
pancreatic cancer (11). 
 
 
2.6  
Study and Dose Rationale 
 The combination of ABRAXANE and Gemcitabine has been studied in advanced 
pancreatic cancer.  The Phase III study of ABRAXANE and Gemcitabine compared to 
the reference standard single agent Gemcitabine was reported at ASCO GI in January 
2013.  Van Hoff and colleagues reported an improvement in median overall survival from 
6.7 to 8.5 months and an improvement in response rate from 7 to 23% (22).  Based on 
this data, this regimen is becoming a new reference standard in the advanced disease 
setting. Therefore, given the significant activity of Gemcitabine/ABRAXANE 
combination chemotherapy in the advanced setting, this trial will evaluate this 
combination in the borderline resectable patient population. 
 
 
 
2.7 
Correlative Studies Background 
While significant data exist regarding the molecular effects of chemotherapeutic agents 
on pancreatic cancer cells in vitro and in xenograft experiments, the molecular 
mechanisms of resistance to chemotherapy in experimental PDAC and primary human 
tumors is virtually unknown.  Molecular fingerprints of pathways altered in the 


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development and progression of human PDAC have been identified (23,24), however 
they have not yet been correlated with response to therapy.  An initial study by Von Hoff 
and colleagues showed that SPARC expression in peri-tumoral stroma predicts improved 
survival in patients with metastatic PDAC treated with Abraxane (18). Recent data from 
the pivotal MPACT trial has failed to demonstrate a correlation with SPARC and benefit 
from therapy in metastatic disease (27).  It is still possible that SPARC expression may be 
relevant in localized disease, thus this will still be explored.  Elucidation of molecular 
signatures for response and resistance to therapy in localized disease are clearly still 
needed. These approaches have been described and are used clinically to direct therapy 
and provide prognostic information in other tumor types such as breast (25), but it 
remains investigational in adenocarcinoma of the pancreas. 
 
 
3.0 
STUDY POPULATION 
 
3.1 
Inclusion Criteria 
  
 
3.1.1 
Subjects must have histologically or cytologically confirmed adenocarcinoma 
of the pancreas 
 
 
 
3.1.2 
Tumors must be localized (non-metastatic) and classified as borderline resectable 
according to AHPBA/SSO/SSAT consensus criteria (10) or be clinically node-
positive via CT or endoscopic ultrasound. 
 
 
AHPBA/SSO/SSAT criteria (any one of the following): 
 
Tumor-associated deformity of the SMV (superior mesenteric vein) or 
PV (portal vein) 
 
Abutment of the SMV or PV ≥ 1800 
 
Short-segment occlusion of the SMV or PV amenable to resection and 
venous reconstruction 
 
Short-segment involvement of the hepatic artery or its branches 
amenable to resection and reconstruction 
 
Abutment of the SMA < 1800 
 
 
 
3.1.3 
Subjects must have measurable disease (by RECIST 1.1), defined as at 
least one lesion that can be accurately measured in at least one dimension 
(longest diameter to be recorded for non-nodal lesions and short axis for 
nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm 
with spiral CT scan.  (Section 11.1) 
 
 
3.1.4   No prior therapy for pancreatic cancer, including chemotherapy, radiation 
therapy, definitive surgery or investigational therapy  
 
 
3.1.5 
Age ≥ 18 years.  Both men and women and members of all races and ethnic   
 
 
 
groups will be included.  
 
 
3.1.6 
ECOG performance status ≤ 1 (See Appendix A). 
 
 
3.1.7 
Subjects must have normal organ and marrow function as defined below:  
 
- 
Absolute neutrophil count ≥ 1.5 K/cu mm 
- 
Platelets ≥ 100 K/cu mm 
- 
Hemoglobin ≥ 9.0 g/dL 
- 
Total bilirubin ≤ 1. 5 X ULN  
 


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11 
- 
AST (SGOT) ≤ 5 X institutional upper limit of normal 
- 
Creatinine within normal institutional limits or Creatinine clearance ≥ 60 
mL/min 
 
 
 
3.1.8 
No active prior malignancy within 3 years of registration (with the exception of 
non-melanoma skin cancer, in-situ cancers, or Rai Stage 0 CLL).  If patient is 
disease free from a prior malignancy between 3-5 years, special consideration 
can be requested.  In these cases, if the risk of recurrence at 5 years is less than 
20%, and in the opinion of the investigator the prior malignancy will not affect 
the patient's outcome in light of newly diagnosed pancreatic cancer, the patient 
may be eligible.  This will require PI review and approval on a case by case 
basis, and approval will be documented in the medical record.  All patients who 
have been disease free from a prior malignancy for at least 5 years will be 
eligible. 
 
 
3.1.9 
No baseline peripheral sensory neuropathy ≥ grade 2 
 
 
3.1.10 Women of child-bearing potential and men must be willing to use adequate 
contraception during the entire study and for 8 weeks following completion of all 
chemotherapy on study. This includes hormonal or barrier method, or abstinence.  
 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
 
document. 
 
3.2 
Exclusion Criteria 
 
 
3.2.1 
Subjects with locally advanced, unresectable primary tumors will not be eligible.   
 
 
 
 
This includes any of the following: 
 
Abutment of the SMA ≥ 1800 
 
Occlusion of the SMV or PV with insufficient normal vein above 
and below with which to perform venous reconstruction 
 
Involvement of the hepatic artery with insufficient artery proximal 
and distal to perform reconstruction 
 
 
3.2.2 
Any prior therapy (chemotherapy, radiation or surgery) for pancreatic 
adenocarcinoma other than biliary decompression 
 
 
3.2.3 
Subjects who are receiving any other investigational agents  
 
 
3.2.4 
Subjects with known metastases 
 
 
3.2.5 
History of allergic reactions attributed to compounds of similar chemical or  
 
 
 
 
biologic composition to ABRAXANE or other agents used in the study 
 
 
3.2.6 
Active infection requiring intravenous antibiotics at the time of registration  
 
 
3.2.7 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active  
 
 
 
 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac  
 
 
 
 
arrhythmia, or psychiatric illness/social situations that would limit compliance  
 
 
 
 
with study requirements. 
 
 
3.2.8 
History of interstitial lung disease, idiopathic pulmonary fibrosis, silicosis, 
sarcoidosis or connective tissue disorders (including rheumatoid arthritis and 
systemic lupus erythematosus) 
 
 
3.2.9 
Pregnant or breastfeeding women are excluded from this study due to possible 
harm to the fetus or infant 


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12 
 
 
3.2.10 Subjects known to be HIV-positive, including those on combination antiretroviral 
therapy, are ineligible because of the potential for pharmacokinetic interactions 
with chemotherapy.  In addition, these subjects are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.   
 
 
3.2.11 Subjects with plastic biliary stents will be excluded due to risk of occlusion and 
cholangitis.  Metal biliary stents are allowed and will not be excluded. 
 
4.0 
REGISTRATION PROCEDURES 
 
4.1 
Subject Registration 
 
 
4.1.1. Subjects will be identified for eligibility through oncology or surgical referrals to 
outpatient or inpatient service.  Eligibility criteria will be confirmed by the 
enrolling physician and study staff.  Anatomic eligibility (see 3.1.2) will be 
confirmed by consultation with attending abdominal imaging radiologists at the 
biweekly Pancreatic and Periampullary Oncology Tumor Board.  There will be 
no randomization for this study. 
 
 
 
Registrations from all consented subjects will be entered into the electronic  
 
 
 
 
Clinical Research Information System (eCRIS). 
 
 
4.1.2 
Multicenter Registration  
A determination of study efficacy will be made following stage I of the study.  If 
feasible, additional study sites may be added and the OHSU coordinating center 
study team will manage subject registration.  
Investigators at participating sites will identify eligible subjects and send 
screening materials with source documents that support eligibility to OHSU in 
real time and in accordance with study protocol.  Designated Knight clinical staff 
must review and verify eligibility before the participating site may enroll and 
treat its subject. The OHSU coordinating center team will verify completeness of 
documents, enter registration information into eCRIS, and assign a study 
number/identifier.  The coordinating center will send an email to the participating 
site indicating whether or not the subject is eligible, verify registration, and 
assign a participant number/identifier.    
 
 
 
Registration will include a minimum of the following: 
o A completed Subject Enrollment Form (see 
http://ozone.ohsu.edu/cancer/sharedres/kctoresdocs.cfm     
o A completed Eligibility Checklist signed by the investigator 
o Signed copies of the most recently IRB-approved, informed consent form 
and HIPPA authorization 
 
 
 
For more information, refer to the Knight Cancer Institute Investigator Initiated   
 
 
 
Trials Coordinating Center Operations Manual at: 
 
 
 
 
http://ozone.ohsu.edu/cancer/sharedres/kctoresdocs.cfm 
 
 
 
 
 
 
 
Each site must maintain a screening log of all subjects who are approached to go                
 
 
 
on study, all who sign informed consents, including those who withdraw consent.  
 
 
 
The log must also document an  explanation for exclusion due to screen failure.  
 
 
  
This log will be submitted to the coordinating center on a monthly basis. 
 
  
 
Participating sites are required to retain, in a confidential manner, sufficient  
 
 
 
 
information on each subject so that the subject may be contacted should the need 
 
 
 
arise. 
 


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13 
5.0 
TREATMENT PLAN 
 
 
5.1 
Preoperative Chemotherapy 
Treatment will be administered on an outpatient basis. ABRAXANE and Gemcitabine 
chemotherapy will be given for 2 cycles.  Reported adverse events and potential risks 
associated with ABRAXANE, Gemcitabine and 5-fluorouracil are described in Section 7. 
Appropriate dose modifications are described in Section 6.  No investigational or 
commercial agents or therapies other than those described below may be administered 
with the intent to treat the subject's malignancy. 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
ABRAXANE 
125 mg/m2  
 
IV  given per 
institutional 
standards 
Weekly (Days 
1,8,15) 
4 weeks (28 
days) 
Gemcitabine 
1000 mg/m2 
IV given per 
institutional 
standards  
Weekly (Days 
1,8,15) 
 
 
 
* ABRAXANE is to be infused prior to Gemcitabine 
 
 
 
5.1.1 
Pre-medications for ABRAXANE and Gemcitabine Chemotherapy 
Standard pre-medications for the prophylaxis of nausea and emesis will be given 
per institutional guidelines prior to chemotherapy (including corticosteroids and 
5-HT3 inhibitors).  If no standard institutional guidelines exist at a study site, it is 
recommended to administer dexamethasone 8 mg IV/PO and ondansetron 8 mg 
IV/PO prior to Gemcitabine and ABRAXANE chemotherapy.  No pre-
medications are recommended or required for 5-Fluorouracil. 
 
 
 
5.1.2 
Other supportive care medications 
Due to the risk of infection during chemotherapy, subjects will be prescribed oral 
antibiotics and will be instructed to start taking immediately in the event of a 
fever > 380C (100.40F). Recommendations include ciprofloxacin or 
amoxicillin/clavulanate.   
 
 
5.2 
Chemoradiotherapy 
 
Agent 
Dose 
Route 
Schedule 
5-Fluorouracil 
225 mg/m2/d 
IV continuous infusion 
7 days per week 
during radiation 
Radiotherapy (IG-IMRT) 
50.4 Gy total 
 
Monday-Friday 
for 28 fractions 
Protocol radiation treatment must begin no sooner than 3 weeks from the last dose of 
chemotherapy, and within 6 weeks after completion of the second cycle of Gemcitabine 
and ABRAXANE. 
Radio-sensitizing 5-FU chemotherapy will be administered via central catheter (port or 
PICC) as a continuous IV infusion during the entire course of radiotherapy at a dose of 
225 mg/m2/d 7 days a week. Any dose modifications regarding 5-FU chemotherapy will 


Revision: 7/24/2020 (Version 6.0) 
 
14 
be at the investigators discretion.  
Radiation therapy will be performed using image-guided, intensity-modulated radiation 
therapy (IG-IMRT) techniques at a dose of 50.4 Gy in 28 fractions.  Treatment planning 
simulation must be conducted after performing a restaging pancreatic protocol diagnostic 
CT.  In order to optimize target delineation, the diagnostic images must be fused with the 
planning CT, or intravenous contrast must be used at the time of simulation unless there 
is renal insufficiency or iodine allergy, in which case MRI will be obtained and fused 
with simulation images.  Subjects will be simulated (and treated) supine with arms up.  
Immobilization is required.  A thorax board is recommended.  Planning scan slice 
thickness must be no greater than 3 mm. 
 
 
Target Volumes 
 
 
ICRU-50 and ICRU-62 prescription methods and nomenclature shall be utilized for this study 
 
 
 
 
 
Volume Definitions 
 
The GTV (gross tumor volume) will include the primary tumor and regional adenopathy >10 
mm seen on the pre-chemotherapy protocol CT scan.  There will be no intent to treat nodal 
regions prophylactically. 
 
The CTV (clinical target volume) is defined as the GTV plus a 10 mm expansion for 
microscopic extension in regions at risk.  Uninvolved regional nodes will NOT be included in 
the CTV. 
 
The PTV (planning target volume) is defined as the CTV plus a 20 mm expansion in the 
cranial and caudal directions and a 10 mm expansion in the radial (lateral, anterior and 
posterior and oblique dimensions). 
 
 
Dose Prescription 
 
 
The prescription dose will be 50.4 Gy in 28 fractions (1.8 Gy per day), given 5 days per week. 
 
 
 
 
  
5.3 
Surgical Resection 
The surgical resection will be determined by the treating surgeon in consultation with the 
treating oncologist 
Resectability is defined as no involvement of non-reconstructable vascular structures in 
the absence of metastatic disease. 
Surgical resection, pancreaticoduodenectomy or distal pancreatectomy (based on tumor 
location) should occur within 4-10 weeks after the last dose of preoperative 
chemoradiation. Staging laparoscopy may be performed at the time of the planned 
laparotomy but is not required.  Either standard or pylorus-preserving 
pancreaticoduodenectomy may be performed.   
Exploration of the peritoneal cavity should include evaluation for radiographically occult 
macroscopic peritoneal or hepatic metastases.  Biopsy proof of liver or peritoneal 
metastatic disease (by frozen section analysis) should be considered criteria for 
abandoning planned pancreatic resection. 
Vascular resection and/or reconstruction of the superior mesenteric vein, portal vein, 
SMV/portal vein confluence, or hepatic artery will be done at the discretion of the 
operating surgeon.  In general, vascular resection should be performed when necessary to 
achieve an R0 resection. 
Frozen section evaluation of the pancreatic parenchymal and hepatic (or bile duct) 


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15 
margins should be performed.  In the event of a positive frozen section margin at either of 
these loci, further resection in an effort to achieve microscopically negative margins 
should be performed if possible.  The superior mesenteric arterial (SMA) margin should 
be evaluated on permanent section. 
 
 
5.4 
Post-operative (Adjuvant) Chemotherapy 
Within 8-12 weeks of surgical resection, subjects will undergo adjuvant chemotherapy 
with Gemcitabine and ABRAXANE for 4 additional cycles.  The dosing and schedule 
will be identical to the preoperative chemotherapy described in Sec. 5.1. 
 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
Standard pre-medications for the prophylaxis of nausea and emesis will be given per 
institutional guidelines prior to chemotherapy (including corticosteroids and 5-HT3 
inhibitors), as described in Section 5.1.1. 
 
 
5.6 
Duration of Treatment 
 
 
In the absence of treatment delays due to adverse events, treatment may continue  
 
 
until one of the following criteria applies: 
o Development of metastatic disease progression, 
o Delay in chemotherapy greater than 21 days 
o Greater than 2 dose decreases  
o Intercurrent illness that prevents further administration of treatment, 
o Unacceptable adverse events(s), 
o Subject decides to withdraw from the study, or 
o General or specific changes in the subject's condition which render the subject 
unacceptable for further treatment in the judgment of the investigator. 
o For any reason, at the Investigator’s discretion 
 
5.7 
Duration of Follow-up  
Subjects will be followed for minimum 1 year follow-up after completion of all therapy 
or until  death, whichever occurs first.  Subjects removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 
If a subject withdraws consent for further treatment, the study team will clarify and 
document the subject’s willingness to continue in the follow-up phase of the study. If the 
subject does not consent to the follow-up phase of the study every effort should be made 
to follow them for survival. 
 
5.8 
Criteria for Removal from Study 
 
 
Subjects will be removed from study when any of the criteria listed in Section 5.6  
 
 
applies. The reason for study removal and the date the subject was removed must be  
 
 
documented in the Case Report Form. 
 
6.0 
DOSING DELAYS/DOSE MODIFICATIONS 
Day 1 of each cycle ANC must be ≥ 1500 and Platelets ≥ 100,000 to proceed with chemotherapy.  
Day 1 of each cycle, chemo can be delayed no more than 21 days due to toxicity.  If this occurs 
patient will discontinue study. 
Dose Level 
ABRAXANE (mg/m2) 
Gemcitabine (mg/m2) 


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16 
 
 
Dose modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or 
within a Cycle: 
 
Cycle Day 
ANC (cells/mm3) 
 
Platelet count (cells/mm3) 
ABRAXANE/Gemcitabine 
Day 1 
< 1500 
OR 
< 100,000 
Delay doses until recovery 
Day 8 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 1 dose level 
 
< 500 
OR 
< 50,000 
Withhold doses 
Day 15: If Day 8 doses were reduced or given without modification: 
 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 1 dose level from Day 8 
 
< 500 
OR 
< 50,000 
Withhold doses 
Day 15: If Day 8 doses were withheld: 
 
≥
OR 
≥ 75,000 
Reduce 1 dose level from Day 1 
 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 2 dose levels from Day 1 
 
< 500 
OR 
< 50,000 
Withhold doses 
 
 
Dose Modifications for Non-Hematologic Toxicity: 
 
Toxicity 
ABRAXANE 
Gemcitabine 
Febrile Neutropenia 
(Grade 3 or 4) 
Withhold until fever resolves and ANC ≥ 1500: resume at next lower dose 
level 
Peripheral Neuropathy 
(Grade 3 or 4) 
Withhold until improves to ≤ Grade 1; 
resume at next lower dose level 
No dose reduction 
Cutaneous Toxicity 
(Grade 2 or 3) 
Reduce to next lower dose level; discontinue treatment if toxicity persists 
Gastrointestinal Toxicity 
(Grade 3 mucositis or diarrhea) 
Withhold until improves to ≤ Grade 1; resume at next lower dose level 
 
 
Re-escalation of dosing within a cycle could be performed at the provider’s discretion 
 
7.0 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. All 
hematologic AEs, in addition to clinically significant non-hematologic AEs will be recorded.  
Adverse events will be recorded from the first dose of study drug until 28 days after the last 
chemotherapy dose. Any adverse events that are attributed to the study drug will be followed until 
resolution. The following list of AEs (Section 7.1) and the characteristics of an observed AE 
(Section 7.2) will determine whether the event requires expedited reporting.  
 
7.1 
Adverse Events and Potential Risks List(s)  
ABRAXANE:  See attached package insert (APPENDIX B) for complete details.  The 
most common adverse reactions (>= 20%) in metastatic breast cancer are alopecia, 
neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, AST elevation, 
alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea.  The most 
common adverse reactions (>= 20%) in NSCLCA when used in combination with 
carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, 
nausea, and fatigue. The most common (>= 20%) adverse reactions in adenocarcinoma of 
the pancreas are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral 
Full dose 
125 
1000 
1st dose reduction 
100 
800 
2nd dose reduction 
75 
600 
If additional dose reduction required 
Discontinue 
Discontinue 


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17 
edema, diarrhea, pyrexia, vomiting, decreased appetite, rash and dehydration. 
Gemcitabine: See attached package insert (APPENDIX C) for complete details.  The 
most common adverse reactions for single agent (>= 20%) are nausea/vomiting, anemia, 
hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, 
hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema. 
Fluorouracil:  Adverse reactions include stomatitis, diarrhea, anorexia, nausea/emesis, 
leukopenia, alopecia and dermatitis. (See APPENDIX D) 
 
 
 
7.2 
Adverse Event Characteristics  
 
 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found  
 
 
 
 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version  
 
 
 
 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access  
 
 
 
 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be   
 
 
 
 
downloaded from the CTEP web site  
 
 
 
 
 
 
 
 
 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
 
Expectedness:  Adverse Events can be ‘Unexpected’ or ‘Expected’ (see Section 7.1  
 
 
above for expected AEs) based on available safety data.  
 
Attribution of the AE: 
 
Definite – the AE is clearly related to the study treatment. 
 
Possible – the AE may be related to the study treatment. 
 
Unrelated – the AE is clearly NOT related to the study treatment. 
Determination of the CTCAE grading, AE additions, etc is determined by the clinician 
discretion expertise and the patients specific factors and will be reviewed by the treating 
physician (PI or Sub-I) for clinical significance and recorded per standard protocol 
 
 
7.3 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
Unanticipated Problems (UP) and Adverse Events (AE) will be reported to OHSU IRB 
according to the policies, procedures and guidelines posted on the OHSU IRB web site 
http://www.ohsu.edu/xd/about/services/integrity/policies/policy-
detail.cfm?policyid=265729 
 
Fatal and life-threatening events must be reported to OHSU IRB within 7 calendar days 
 
after the PI learns of the event. If any of these require a change (as determined by the PI 
 
or the IRB) to the protocol or consent form, the PI will make those changes promptly and 
 
submit the revised documents to the OHSU IRB. 
 
All other UP reports will be submitted to OHSU IRB no later than 15 calendar days of 
notification of the event.  If the event requires changes as determined by the PI or the 
IRB) to the protocol or consent form, the PI will make the changes promptly and submit 
the revised documents to the IRB.  UP and AE reports are submitted through OHSU e-
IRB and will be reviewed by OHSU IRB.   
 
A serious adverse event (SAE) is defined as an AE that is fatal, is life-threatening, is 
persistent or significantly disabling or incapacitating, results in inpatient hospitalization 
or prolongation of hospitalization, results in psychological or emotional harm requiring 
treatment, creates a persistent or significant disability, causes a congenital anomaly or 
birth defect, or results in a significant medical incident.  


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18 
 
 
7.4 
Central Reporting of Adverse Events for Multicenter Studies  
The SAE/UP reporting for multicenter investigator initiated clinical trials  will follow the 
guidelines outlined in the OHSU Knight Cancer Institute Multi-Center Investigator 
Initiated Trials Coordinating Center Operations Manual.  
A participating site must report an SAE to the to the institution’s local IRB for action as 
required, as well as to the OHSU coordinating center study team by phone, fax, or email 
within 24 hours of learning of the event.   
The OHSU coordinating center study team will review and submit SAEs to the FDA, 
OHSU IRB, and any other required contacts as required by the Knight Data Safety 
Monitoring Plan. The principal investigator at the Coordinating Center is responsible for 
distributing IND and/or IDE Action Letters or Safety Reports, as applicable, to 
participating institutions for review and submission to their institution’s local IRB. 
 
 
7.5 
MedWatch Reporting  
 
For this investigator-initiated study, the investigator is the study sponsor. The 
investigator/sponsor is required to report adverse experiences to the FDA through the 
MedWatch reporting program, even if the trial involves a commercially available agent. 
Adverse experiences to be reported include any unexpected (not listed in the package 
label), serious adverse experiences with a suspected association to the study drug.  
Adverse events that occur during clinical studies are to be reported to FDA as specified in 
the investigational new drug/biologic regulations using Form FDA 3500, the MedWatch 
Voluntary Reporting form, which is available online at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.p
df.   
Investigators may also complete Form FDA 3500 online at: 
https://www.accessdata.fda.gov/scripts/medwatch/ .  
When the serious adverse event is reported to the FDA, copies of Form FDA 3500 and 
supporting materials will be submitted to the OHSU Knight Cancer Institute and the IRB. 
A copy of Form FDA 3500 and supporting materials will be kept on file in the study 
regulatory binder.  
For sponsor-investigators who hold an IND, Form FDA 3500 will be submitted to the 
IND/IDE associate who will assist the study team in a formal safety report to the FDA. 
 
 
7.6 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours/1 business day.  The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (AX-PANC-
PI-0053) and the institutional protocol number should be included on SAE reports (or on 
the fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the 
SAE report to Celgene should be attached to the SAE and retained with the patient 


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19 
records. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.   
Suite 6000     
Berkeley Heights, NJ  07922        
Fax: 
(908) 673-9115 
E-mail:  drugsafety@celgene.com 
 
 
 
 
 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
 
commercial agents administered in this study can be found in Section 7.1. 
 
8.1 
Agent Accountability 
The Investigator, or a responsible party designated by the Investigator, must maintain  
a careful record of the inventory and disposition of the study agent.  This function will be 
performed by the OHSU research pharmacy.  (See the NCI Investigator’s Handbook for 
Procedures for Drug Accountability and Storage).  
 
 
http://ctep.cancer.gov/investigatorResources/investigators_handbook.htm  
 
8.2 
Study Agent(s)  
Availability:  ABRAXANE will be supplied by Celgene Corporation.  
Product description:  ABRAXANE for Injectable Suspension (also known as ABI-007, 
nab-paclitaxel, paclitaxel protein-bound particles for injectable suspension) is an 
albumin-bound form of paclitaxel with a mean particle size of approximately 130 
nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state.  
Solution preparation: ABRAXANE is supplied as a white to yellow, sterile, lyophilized 
powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to 
intravenous infusion. Each single-use vial contains 100 mg of paclitaxel and 
approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted 
suspension contains 5 mg paclitaxel. ABRAXANE is free of solvents.   The active agent 
in ABRAXANE is paclitaxel. 
Storage requirements:  Store the vials in original cartons at 20º C to 25º C (68º F to 77ºF). 
Retain in the original package to protect from bright light. 
Stability: Unopened vials of ABRAXANE are stable until the date indicated on the 
package when stored between 20ºC to 25ºC (68ºF to 77ºF), in the original package. 
Neither freezing nor refrigeration adversely affects the stability of the product. 
Stability of Reconstituted Suspension in the Vial:  Reconstituted ABRAXANE should be 
used immediately, but may be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for a maximum of 
8 hours if necessary. If not used immediately, each vial of reconstituted suspension 
should be replaced in the original carton to protect it from bright light. Discard any 
unused portion.  
Stability of Reconstituted Suspension in the Infusion Bag:  The suspension for infusion 
prepared as recommended in an infusion bag should be used immediately, but may be 
stored at ambient temperature (approximately 25º C) and lighting conditions for up to 8 


Revision: 7/24/2020 (Version 6.0) 
 
20 
hours.  
Route of administration:  ABRAXANE is injected into a vein [intravenous (I.V.) 
infusion] over 30 minutes.  The use of an in-line liter is not recommended.  
Drug distribution: ABRAXANE® will be distributed by Celgene Corporation.  No 
supplies will be shipped to any site until regulatory approval has been obtained.  
Investigational sites will be supplied with ABRAXANE® upon identification and 
screening of a potential trial subject.  Upon identification of a potential subject, sites 
must fax a completed Drug Request Form to Celgene Corporation.  Allow at least 5 
working days for drug shipment.  There are no shipments on Fridays or holidays.  For re-
supply of drug, please complete and fax the Drug Request Form to Celgene Corporation 
at 908-673-2779. 
 
Drug Return: If the investigational site does not have a policy, procedure or SOP detailing 
the process to follow for study drug destruction, the study drug must then be returned to 
Celgene using the Drug Return Form provided in the package containing the study drug.  
The following information must be recorded on the site’s pharmacy drug accountability 
log: quantity of vials to be returned, expiration date and lot number.  A copy of the Drug 
Return Form and the study drug should be returned to Celgene Clinical Supplies Dept. 
using the mailing address on the packaging slip that came with the original study drug 
order.  A copy of the Drug Return Form should be retained at the clinical site.  In the event 
of study completion or termination, a copy of all pharmacy records (drug dispensing log, 
drug accountability log and any destruction memos) must be mailed to Celgene Medical 
Operations.   
Drug Destruction:  If the investigational site has a policy, procedure or SOP detailing the 
process to follow for study drug destruction, the pharmacist or designee can choose to 
destroy the study drug on site.  The following information must be recorded on the site’s 
pharmacy drug accountability log: quantity of vials destroyed, expiration date and lot 
number.  The pharmacist must document that the study drug was destroyed in accordance 
with their institution’s drug destruction policy or SOP.  A drug destruction memo and the 
site’s drug destruction SOP/policy should be sent to Celgene Medical Operations Dept.  A 
copy of the drug destruction memo should be retained at the clinical site.  In the event of 
study completion or termination, a copy of all pharmacy records (drug dispensing log, drug 
accountability log and any destruction memos) must be mailed to Celgene Medical 
Operations. 
Supplier:  
Celgene Corporation 
86 Morris Avenue 
Summit, NJ  07901 
Industry Contact: 
Martha Kennedy 
Associate Director, Medical Operations 
Celgene Corporation 
400 Connell Drive, 7th Floor 
Connell Corporate Park 
Berkeley Heights, NJ 07922 
Mobile: 973-271-3579 
Fax: 908-673-2779 
Email: Jdoyle@celgene.com  


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21 
 
 
8.3 
Commercial Agent(s)  
8.3.1 
Gemcitabine: 
Product description:  Gemcitabine is commercially available.   Gemcitabine (for 
injection USP) is a white to off-white lyophilized powder available in sterile 
single-use vials containing 200 mg or 1 g gemcitabine. 
Solution preparation: See package insert (Appendix C) 
  
 
 
Route of administration:  Gemcitabine is for intravenous use only. 
  
 
8.3.2 
Fluorouracil 
Product description:  Fluouracil is commercially available.  Fluorouracil injection 
is a sterile, nonpyrogenic injectable solution for intravenous administration.  
Each 10 mL contains 500 mg fluorouracil. 
  
 
 
Solution preparation: See package insert (Appendix D) 
  
 
 
Route of administration:  Fluorouracil is for intravenous use only. 
  
 
 
 
9.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
All biomarker studies described below will be done as ancillary/exploratory studies and will not 
affect any study procedures or subject specific outcomes.  All patients will be offered enrollment 
in the Oregon Pancreas Tumor Registry (IRB #00003609, P.I. Brett Sheppard), which allows for 
the collection of blood and tissue samples that are stored for future research and may include 
genetic research.  Not all subjects will have adequate preoperative tissue available for analysis, 
but all patients that undergo resection will have adequate tissue for analysis.  Only those subjects 
who consent to the Oregon Pancreas Tumor Registry (IRB #00003609) will have these special 
studies performed. 
 
 
9.1 
Biomarker Studies 
Our group, in collaboration with Drs. Joe Gray and Paul Spellman at the OHSU Center 
for Spatial Systems Biomedicine, may subject fresh frozen tumor samples to the 
following based on available tissue obtained through the Oregon Pancreas Tumor 
Registry: 
 
Global gene expression analysis using RNASeq 
 
Copy number/genome instability analysis using whole genome arrays  
 
Methylation/epigenetic modification using MethylSEQ and Illumina methylation 
arrays 
 
Analysis of SPARC expression in pre and post-treatment tumor and stroma 
samples  
 
RNA and protein expression of lysyl oxidase (LOX) that has been found to be 
dramatically upregulated following treatment of aggressive pancreatic cancer 
cell lines with paclitaxel (preliminary data, not shown). 
 
To assess molecular predictors of response and survival (serum CA 19-9 and 
SPARC expression) 
 
 
 
 


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22 
10.0 
STUDY PROCEDURES AND SCHEDULE OF EVENTS 
 
10.1 
Screening/Baseline Visit 
Baseline screening evaluations are to be conducted within 14 days prior to start of 
protocol treatment.  Scans and labs must be done within 21 days prior to the start of 
protocol treatment. Labs collected within 72 hours of C1D1 do not need to be repeated. 
The following will be performed: 
 Informed consent 
 Demographics 
 Medical history, concurrent medications 
 Physical exam including vital signs, height, weight and ECOG performance 
status 
 Laboratory studies: CBC with 3 part differential, CMP (see Sec 10.4 for details) 
 CT chest/abdomen/pelvis with contrast (acceptable scans include CT multiphase 
Pancreas and Pelvis with IV contract and CT Chest with or without contrast) 
 Serum -hCG (for women of childbearing potential only) 
 
 
10.2 
Study Visits (+/- 2 day window) 
 
 
 
 
 
 
 
Cycles 1-2 
 
 
 
 
Day 1 
 
Concurrent medications (including herbal and nutritional supplements) 
 
Physical exam including vital signs, oxygen saturation, weight and ECOG 
performance status 
 
Laboratory studies: CBC with 3 part differential, CMP (see Sec. 10.4 for details), 
CA 19-9 
 
Serum -hCG (for women of childbearing potential only) 
 
Adverse event evaluation 
 
ABRAXANE/Gemcitabine IV chemotherapy 
 
 
 
 
 
Day 8, 15 
 
Laboratory studies: CBC with 3 part differential, CMP 
 
ABRAXANE/Gemcitabine IV chemotherapy 
 
 
 
 
 
Staging 1 
 
CT chest/abdomen/pelvis with contrast (acceptable scans include CT multiphase 
Pancreas and Pelvis with IV contract and CT Chest with or without contrast) 
 
 
 
 
 
CRT (chemoradiotherapy) 
 
 
 
 
Subjects will be seen at least every other week for 6 weeks with the following: 
 
Concurrent medications (including herbal and nutritional supplements) 
 
Physical exam including vital signs, oxygen saturation, weight and ECOG 
performance status 
 
Laboratory studies: CBC with 3 part differential, CMP, CA 19-9 (week 1 only) 


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23 
 
Serum -hCG (for women of childbearing potential, week 1 only) 
 
Adverse event evaluation 
 
IG-IMRT to 50.4 Gy in 28 fractions (5 days per week, Monday-Friday) 
 
Fluorouracil 225 mg/m2 IV continuous infusion (via ambulatory infusion pump 
changed weekly) 
 
 
 
 
 
Staging 2 
 
CT chest/abdomen/pelvis with contrast (acceptable scans include CT multiphase 
Pancreas and Pelvis with IV contract and CT Chest with or without contrast) 
 
CA 19-9 serum level 
 
 
 
 
 
Resection 
Appropriateness for surgical resection will be determined by the treating surgeon in 
consultation with the treating oncologist as standard of care. The procedure described in 
Sec. 5.3 will be followed. 
 
 
 
 
 
Staging 3 
 
CT chest/abdomen/pelvis with contrast (acceptable scans include CT multiphase 
Pancreas and Pelvis with IV contract and CT Chest with or without contrast) 
 
 
 
 
 
Cycles 3-6 
 
 
 
 
Day 1 
 
Concurrent medications (including herbal and nutritional supplements) 
 
Physical exam including vital signs, oxygen saturation, weight and ECOG 
performance status 
 
Laboratory studies: CBC with 3 part differential, CMP, CA 19-9 
 
Serum -hCG (for women of childbearing potential only) 
 
Adverse event evaluation 
 
ABRAXANE/Gemcitabine IV chemotherapy 
 
 
 
 
 
Day 8,15 
 
Laboratory studies: CBC with 3 part differential, CMP 
 
ABRAXANE/Gemcitabine IV chemotherapy 
 
 
 
 
 
 
Follow-up every 12 weeks for minimum of 1 years 
 
Concurrent medications (including herbal and nutritional supplements) 
 
Physical exam including vital signs, oxygen saturation, weight and ECOG 
performance status 
 
Laboratory studies: CBC with 3 part differential, CMP, CA 19-9 
 
Adverse event evaluation 


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24 
 
CT chest/abdomen/pelvis with contrast (acceptable scans include CT multiphase 
Pancreas and Pelvis with IV contract and CT Chest with or without contrast) 
 
 
 
Toxicities and adverse events will be assessed at each visit using the NCI  
 
 
 
Common Toxicity Criteria for Adverse Events 4.0.  
 
 
 
 
 
 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
 
 
 
 


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25 
10.4 
Schedule of Events   
 
 
 
   
 
Pre- 
Study 
  
Cycles 1-2 
 
Staging 
1 
 
CRTc.d 
 
Staging 
2 
 
Resection 
 
Staging 
3 
 
Adjuvant Therapy 
Cycles 3-6 
 
Restaging 
every 12 wks 
 
 
 
Day 1 
 
Day 8 
 
Day 15 
 
 
 
 
 
 
Day 1 
 
Day 8,15 
 
 
Study Agent 
 
 
 
A 
 
A 
 
A 
 
 
 
 
 
 
 
 
 
 
 
A 
 
A 
 
 
 
Other Agent(s) 
 
 
 
B 
 
B 
 
B 
 
 
C,D 
 
 
 
 
 
 
 
B 
 
B 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Physical exam 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Vital signs 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Performance status 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
CBC w/diff, plts 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
Serum chemistrya 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
CA 19-9 
 
 
X 
 
 
 
 
X 
X 
 
 
 
X 
 
 
X 
 
Adverse event evaluation 
 
 
  
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
CT chest/abd/pelvis with contrast 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
β-hCG 
 
Xb 
 
X 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
Xb 
 
 
 
 
A:    ABRAXANE 125 mg/m2 IV 
B:    Gemcitabine 1000 mg/m2 IV 
C:    IG-IMT 50.4 Gy over 28 fractions 
D:    Fluorouracil 225 mg/m2/d continuous IV 
a:    CMP= Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein ,AST, ALT, sodium 
b:    Serum pregnancy test (women of childbearing potential) 
c:    CRT= chemoradiotherapy 
d:   Subjects will be evaluated weekly during CRT 


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26 
11.0 
MEASUREMENT OF EFFECT 
 
  
Although response is not the primary endpoint of this trial, subjects with measurable disease will be 
assessed by standard criteria.  In addition to a baseline CT scan, CT scans will also be obtained at the 
conclusion of neoadjuvant chemotherapy and following neoadjuvant chemoradiotherapy.  Follow-up 
imaging to evaluate for recurrent disease will be performed before adjuvant chemotherapy begins and 
during standard follow-up. 
 
 
11.1 
Antitumor Effect  
 
 
Response and progression will be evaluated in this study using the new international  
 
 
 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST)  
 
 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter  
 
 
  
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case   
 
 
of malignant lymph nodes are used in the RECIST criteria. 
 
 
 
 
11.1.1 Definitions 
Evaluable for toxicity:  All subjects will be evaluable for toxicity from the time of their 
first treatment with neoadjuvant chemotherapy. 
Evaluable for objective response:  Only those subjects who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These subjects will have their 
response classified according to the definitions stated below.  (Note:  Subjects who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
Evaluable Non-Target Disease Response:  Subjects who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease response.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
 
 
 
11.1.2 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal lesions 
and short axis for nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or 
>10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 


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27 
since they are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs but, in addition, should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions:  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 
 
 
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Conventional CT:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness.  
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  This data will 
be collected, but not used for purpose of response evaluation. 
 
 
 
 
 
 
 
 
 
 
 
 


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28 
 
 
 
 
11.1.4 Response Criteria 
 
 
 
 
 
 
11.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference 
the baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference 
the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered 
progressions). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on 
study. 
 
 
 
 
 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis). 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
subject to be considered in complete clinical 
response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
Although a clear progression of non-target lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
principal investigator). 
 
 
 
 
 
 
11.1.4.3 
Evaluation of Best Overall Response 


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29 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The subject's best overall response assessment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Subjects with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
For Subjects with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
 
11.2 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented taking as reference 
for progressive disease the smallest measurements recorded since the treatment started. 
The duration of overall CR is measured from the time measurement criteria are first met 


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30 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
 
11.3 
Relapse-Free Survival 
 
Relapse-free survival, is defined as the duration of time from surgical resection to time of 
progression or death, whichever occurs first. 
 
 
11.4 
 Histopathologic Determination of Resection Status 
 
“Macroscopic disease” will be assessed by the surgeon, and “microscopic disease” will 
be assessed by the pathologist. 
Margins to be assessed by the pathologist are standard, and include: SMA margin, 
common bile duct and pancreatic neck. 
R0- defined as macroscopically complete tumor removal with negative microscopic 
surgical margins 
R1- defined as macroscopically complete tumor removal with positive microscopic 
margins (any margin) 
 
 
R2- defined as incomplete tumor removal with known or suspected residual gross disease 
 
 
 
 
  
 
12.0 
DATA REPORTING/REGULATORY REQUIREMENTS 
 
12.1    Data Collection and Storage 
 
 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
  
Basic accrual tracking information (demographic, consent, visit information) will be 
captured in OHSU’s electronic clinical information research system (eCRIS), hosted on 
OHSU servers and managed by OHSU’s information technology group at their data 
center in downtown Portland, Oregon. Study outcome data will be captured in electronic 
case report forms (eCRFs) in the following electronic data capture (EDC) system. The 
web-based system is password protected and encrypted with role-based security, and 
administered by Knight Clinical Research Quality and Administration (CRQA) 
informatics staff. Study team members will have login credentials and have been trained 
in procedures for entering, accessing and storing data. This will facilitate information 
being stored in a unified format and location. Data from correlative studies will be 
entered by research personnel at OHSU. 
 
  
Additional confidentiality will be preserved by limiting PHI captured in an EDC system to just birth date 
and visit dates.  Data extracts will be stored only on OHSU computers and restricted drives, limited only 
to study investigators and staff with authorization to access the data. Quality assurance will be conducted 
as outlined in the Section 12.7, Quality Assurance And Quality Control.  
 


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31 
                                  
 
 
12.2 
Protocol Review 
 
 
The protocol and informed consent form for this study must be reviewed and  
 
 
 
approved in writing by the OHSU Knight Cancer Institute (CI) Clinical Research  
 
 
Review Committee (CRRC) and the appropriate Institutional Review Board (IRB)  
 
 
 
prior to any subject being consented on this study.   
 
 
12.3 
Informed Consent 
Written informed consent will be obtained from all subjects participating in this trial, as 
stated in the Informed Consent section of the case of Federal Regulations, Title 21, Part 
50.  Documentation of the consent process and a copy of the signed consent shall be 
 
 
 
maintained in the subject’s medical record.  
 
 
12.4 
Changes to Protocol  
 
 
Any modification of this protocol must be documented in the form of a protocol revision   
 
 
or amendment signed by the principal investigator and approved by the CRRC and IRB,   
 
 
before the revision or amendment may be implemented.  The only circumstance in which  
 
 
the amendment may be initiated without regulatory approval is for a change necessary to   
 
 
eliminate an apparent and immediate hazard to the subject.  In that event, the investigator  
 
 
must notify the CRRC and IRB in writing within 10 working days after the  
 
 
 
 
implementation. Investigators holding the IND must notify FDA of substantive changes   
 
 
to the protocol.  All protocol revisions will also be sent to Celgene for review. 
 
 
12.5 
Maintenance of Records 
 
 
If the investigator relocates or for any reason withdraws from the study, the study records 
 
 
must be transferred to an agreed upon designee, such as another institution, another  
 
 
 
investigator, or to OHSU Knight Cancer Institute Clinical Trials Office.  Records must be 
 
 
maintained according to sponsor or FDA requirements.  
 
 
12.6 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section  
 
 
7.0 (Adverse Events: List and Reporting Requirements). 
 
 
12.7 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
 
 
In addition to complete study and pharmacy files, complete records must be maintained  
 
 
on each subject treated on this protocol.  OHSU Knight Cancer Institute, through the  
 
 
auditing function of the Knight Clinical Trials Office, is responsible for ensuring that all  
 
 
member investigators and affiliate investigators conduct clinical research studies in  
 
 
compliance with local IRB standards, FDA regulations and NIH policies and in   
 
 
accordance with the Data and Safety Monitoring Plan policies and procedures  
 
 
 
http://ozone.ohsu.edu/cancer/sharedres/kctoresdocs.cfm  
 
 
 
Locally initiated studies will be audited by OHSU Knight CI Auditor.  Newly approved  
 
 
studies may be audited anytime after enrollment has been initiated.  Each OHSU Knight  
 
 
approved treatment protocol will be audited on an annual basis in accordance with the  


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32 
 
 
Knight Data and Safety Monitoring Plan.   
 
 
 
 
12.8 
Inclusion of Women, Minorities and Children 
 
 
12.8.1 Inclusion of Women and Minorities 
 
 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or  
 
 
ethnic subset. No subject will be excluded from the study on the basis of gender, racial or 
 
 
ethnic origin. Male, female and minority volunteers will be recruited for this study from  
 
 
the general population and approximately 50% men and 50% women will be studied.  
 
 
The projected gender, racial, and ethnic composition of the study will  
 
 
 
 
represent that of the state of Oregon.  
  
 
Table 1: Population Demographics - Oregon (%)              
Source:   U.S. Census Bureau, 2010    *Totals may not equal 100 due to rounding. 
 
 
 
 
 
 
 
Table 2: Projected Accrual for the Present Study  
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 
 
11.7 
Not Hispanic or Latino 
 
 
88.3 
Ethnic Category: Total of all subjects* 
 
 
100* 
Racial Category 
 
American Indian or Alaskan Native 
 
 
1.4 
Asian 
 
 
3.7 
Black or African American 
 
 
1.8 
Native Hawaiian or other Pacific Islander 
 
 
0.3 
White 
 
 
83.6 
More than one race 
 
 
3.8 
Unknown/Other 
 
 
5.3 
Racial Category: Total of all subjects* 
 
 
100* 
TOTALS 
50.4 
49.6 
100* 


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33 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
2-3 
2-3 
0 
5-6 
Not Hispanic or Latino 
20-21 
20-21 
0 
40-41 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all subjects* 
23 
23 
0 
46* 
Racial Category 
 
American Indian or Alaskan Native 
0-1 
0-1 
0 
0-1 
Asian 
0-1 
0-1 
0 
1-2 
Black or African American 
0-1 
0-1 
0 
0-1 
Native Hawaiian or other Pacific Islander 
0-1 
0-1 
0 
0-1 
White 
19-20 
19-20 
0 
38-39 
More than one race 
0-1 
0-1 
0 
1-2 
Unknown 
1-2 
1-2 
0 
2-3 
Racial Category: Total of all subjects* 
22 
22 
0 
44* 
Source:   Adapted from U.S. Census Bureau, 2010    *Totals may not equal 100 due to rounding. 
                  
 
 
12.8.2   Inclusion of Children 
 
 
In accordance with NIH guidelines on the inclusion of children as participants in research 
 
 
involving human subjects, children under the age of 18 years must be included in all human 
 
 
subjects’ research, conducted or supported by the NIH, unless there are clear and compelling 
 
 
reasons not to include them. Therefore, proposals for research involving human subjects  
 
 
must include a description of plans for the inclusion of children. 
This protocol does not include children because the number of children with this type of  
cancer is limited. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
 
 
13.1 
Study Design 
This is a single-arm, non-randomized Phase II trial.  The primary objective is to assess 
the R0 resection rate for the neoadjuvant regimen.  The secondary objectives are to assess 
one-year relapse-free survival, overall survival, response rate by RECIST 1.1, toxicity 
and safety profile (per CTCAE v4.0) and molecular predictors of response and survival.  
The projected sample size is 44 subjects over 24 months, with a minimum follow-up of 1 
year following completion of all therapy. 
 
 
13.2 
Primary and Secondary Endpoints 
 
 
 
 
Primary endpoint:  


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34 
R0 resection rate is defined as macroscopically complete tumor removal with negative 
microscopic surgical margins by pathologic assessment. 
 
Secondary Endpoints: 
Relapse-free survival at one year, is defined as the percentage of subjects who are 
without recurrence or death at one year from surgical resection of the primary tumor.  
Overall survival is defined as the percentage of subjects alive at the one and two year 
time points. 
Response rate by RECIST 1.1 is defined as the number of subjects with complete (CR) or 
partial (PR) disease response as confirmed through tumor imaging with CT.  This will be 
assessed following neoadjuvant chemotherapy (Staging 1) and following neoadjuvant 
chemoradiotherapy (Staging 2). 
Toxicity and safety profile will be clinically assessed and graded at the time points 
described. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.   Attribution of the adverse event to the study will be determined as definite, 
possible or unrelated as described in Sec. 7.2. 
Molecular predictors of response and survival will be exploratory only, as described in 
Sec. 9.0. 
 
 
 
 
13.3 
Analysis Populations 
Intent to treat (ITT) analysis will be used for the primary analysis.  Subjects to be analyzed 
are defined as enrolled subjects who have received at least one administration of study drug 
and have at least one efficacy evaluation. 
Safety analysis set (i.e., those who receive at least one does of the drug or treatment) will 
be used for analysis of toxicity, safety and adverse events.  
Per protocol analysis set (i.e., those who complete the treatment protocol) will be used for 
the secondary analyses to further evaluate the treatment efficacy.  
 
 
 
 
 
13.4 
Statistical Analysis Plan 
13.4.1   Analysis of Primary Endpoint 
The R0 resection rate will be computed with 95% confidence interval. A 2-sided 
binomial test will be used to determine whether the R0 resection rate is significantly 
greater than 0.37 at 10% significance level.   The null hypothesis is p=0.37, and the 
alternative hypothesis is p not equal to 0.37. 
 
13.4.2   Analysis of Secondary Endpoints 
The expected 1-year relapse-free survival rate, and the 1-year and 2-year overall survival 
rates will each be reported with an associated 95% confidence interval. In addition, the 
relapse-free survival function and the overall survival function of will be estimated and 
displayed using a Kaplan Meier curve. The median relapse-free survival and the overall 
survival will also be estimated with an associated 95% confidence interval. 
The expected pathologic response rate will be computed with the associated 95% 
confidence interval using Binomial exact method. Frequency and severity of adverse 
events will be tabulated based on the actual treatment and the number of circles the 


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35 
patient receives. In particular, Grade 3 and 4 toxicity rates will be computed and 
summarized for all patients received at least one dose of the assigned treatment. Logistic 
regression will be conducted to associate the Serum CA 19-9 levels and SPARC 
expression with response, and Cox proportional hazard regression will be used to 
associate the Serum CA 19-9 and SPARC expression with overall survival endpoints. 
SAS 9.4 (SAS Institute Inc., Cary, NC, USA) will be used for statistical analysis.  There 
is no separate statistical analysis plan and table specification documented elsewhere. 
 
 
 
 
13.4.3  Interim Analyses and Stopping Rules 
The Simon’s two-stage minimax design will be used based on the null and alternative 
hypothesis (37% vs. 56%).  For the first-stage, we will enroll 19 subjects, and the trial 
will be stopped if 7 or fewer subjects undergo R0 resection.  If the first-stage is met, we 
will continue to enroll 25 subjects to the second stage. The new treatment will be claimed 
not promising if 21 or fewer subjects undergo R0 resection in all 44 subjects.  A 
determination of study enrollment feasibility will be made at that time, and the study may 
add additional study sites as needed.  
 
 
13.5 
Sample Size and Power 
The R0 resection rate is approximately 37% for standard therapy. We expect the R0 
resection rate for the multimodality therapy is 56%, which, if achieved, is a clinically 
meaningful improvement in treatment effect.  
We expect to enroll 44 evaluable patients to achieve 83% power using a 2-sided binomial 
test at 10% significance level. 
 
 
13.6 
Randomization Method 
 
 
 
This is a single-arm, non-randomized study. 
 
 
13.7 
Handling of Missing Data 
Missing information or results will be evaluated by the study investigators to determine if 
what is available is sufficient to include in the data analysis.  If it is determined that there 
is insufficient data available, the subject will be excluded from the analysis and recorded 
as such.  Missing data will not be imputed. 
  
 
 


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36 
REFERENCES 
 
1. 
Siegel R et al., Cancer Statistics, 2013. CA Cancer J Clin 2013; 63:11-30. 
 
2. 
http://seer.cancer.gov/csr/1975_2010/results_merged/sect_22_pancreas.pdf 
 
3. 
Lim, JE, et al.  Prognostic factors following curative resection for pancreatic adenocarcinoma: a 
population-based, linked database analysis of 396 patients. Ann Surg 2003;237(1):74. 
 
4. 
Hoffman, JP et al.  Phase II trial of preoperative radiation therapy and chemotherapy for patients with 
localized, resectable adenocarcinoma of the pancreas: and Eastern Cooperative Oncology Group Study.  J 
Clin Oncol.  1998;16(1):317. 
 
5.  
Talamonti, MS et al.  A multi-institutional phase II trial of preoperative full-dose gemcitabine and 
concurrent radiation for patients with potentially resectable pancreatic carcinoma.  Ann Surg Oncol. 
2006;13(2):150. 
 
6. 
Assifi, MM. et al.  Neoadjuvant therapy in pancreatic adenocarcinoma: a meta-analysis of Phase II trials.  
Surgery. 2011 Sept;150(3):466-73. 
 
7. 
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38 
APPENDIX A 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
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. 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
APPENDIX B 
Abraxane Package Insert 
 
http://www.abraxane.com/downloads/Abraxane_PrescribingInformation.pdf 
 
 
 
 
APPENDIX C 
Gemcitabine Package Insert 
 
http://pi.lilly.com/us/gemzar.pdf 
 
 
 


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39 
 
APPENDIX D 
Fluorouracil Package Insert 
 
http://www.accessdata.fda.gov/drugsatfda_docs/anda/2000/40333_Fluorouracil_Prntlbl.pdf