Preoperative Extended Chemotherapy vs. Chemotherapy Plus Hypofractionated Radiation Therapy for Borderline Resectable Adenocarcinoma of the Head of the Pancreas
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma, Borderline Resectable Adenocarcinoma of the Head of the Pancrease
Sponsor: Alliance for Clinical Trials in Oncology



Alliance A021501 
3 
Version Date: 10/19/2018 
Update #04 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For study data submission:  
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal: 
 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory tab). 
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 
to receive further instruction 
and support.  
 
Contact the CTSU Regulatory 
Help Desk at
 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_
SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page of the CTSU Member website located at https://www.ctsu.org. Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS.   
 
For clinical questions (i.e. patient eligibility or treatment-related) see Protocol Contacts, Page 2. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line –
. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU website is located at https://www.ctsu.org. 
 
 
 

Alliance A021501 
4 
Version Date: 10/19/2018 
Update #04 
PREOPERATIVE EXTENDED CHEMOTHERAPY VS. CHEMOTHERAPY PLUS 
HYPOFRACTIONATED RADIATION THERAPY FOR BORDERLINE RESECTABLE 
ADENOCARCINOMA OF THE HEAD OF THE PANCREAS 
Pre-Registration Eligibility Criteria (see Section 3.2.1) 
Required Initial Laboratory Values 
Cytologic or histologic proof of adenocarcinoma of the  
Absolute neutrophil 
count (ANC) 
 
≥ 1500/mm3 
pancreatic head or uncinate process.  
TNM Stage: T1-4N0-1orNxM0 
Platelet Count 
≥ 100,000/mm3 
Local radiographic reading consistent with borderline resectable cancer of the pancreatic 
head 
Creatinine 
≤ 1.5 x upper limit 
of normal (ULN) 
Registration Eligibility Criteria (see Section 3.3) 
Calc. Creatinine or 
Clearance (see 
Alliance website) 
> 45 mL/min 
Confirmation of radiographic stage as borderline resectable by central radiographic review 
No prior chemotherapy or radiation for pancreatic cancer and no definitive resection of 
pancreatic cancer 
Total Bilirubin 
≤ 2.0 x mg/dL 
No strong CYP3A4 inhibitors or inducers (See Section 3.3.3) 
No grade ≥ 2 neuropathy 
No known Gilbert’s Syndrome or known homozygosity for UGAT1A1*28 
polymorphism. 
AST / ALT  ≤ 2.5 x ULN 
No uncontrolled gastric ulcer disease (Grade 3 gastric ulcer disease) within 28 days of registration 
Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. 
Age ≥ 18 years 
ECOG Performance Status 0 or 1 
 
Schema 
As of 08/13/2018, patients will no longer be registered/randomized to Arm 2. 
 
 
 
 
 
 
Patient 
with 
BLR 
PDAC 
(Inter-
group 
Definit
ion) 
 
 
 
 
 
 
 
 
 
PRE-REGISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central 
Review 
by 
IROC 
Ohio 
 
 
 
 
 
 
 
 
 
REGISTRATION/RANDOMIZATION 
 
 
 
 

 
 
 
 
Arm 1 
 
 
mFOLF- 
IRINOX 
x 
4 cycles 
RESTAGE 
 
 
mFOLFIRINOX 
x 
4 cycles 
 
RESTAGE 
(Central Review 
by IROC Ohio) 
 
 
 
Surgery 
RESTAGE 
 
 
FOL-
FOX 
x 
4 cycles 
FOLLOW-UP 
 
 
 
 
 
 

 
 
 
 
Arm 2 
(closed 
August 
2018) 
 
 
mFOLF- 
IRINOX 
x 
4 cycles 
RESTAGE 
 
 
mFOLF-
IRINOX 
x 
3 cycles 
* 
 
 
 
RT 
RESTAGE 
(Central Review 
by IROC Ohio) 
 
 
 
Surgery 
RESTAGE 
 
 
FOL-
FOX 
x 
4 cycles 
FOLLOW-UP 
* RT simulation and EUS/fiducial marker placement is performed during cycle 5 or 6 of mFOLFIRINOX 
 
Surgery and imaging must be conducted at the registering institution. Radiation therapy must be performed at a facility participating 
in the IROC monitoring program. Chemotherapy may be given at a non-registering institution. If the NCTN Group credited for 
enrollment is a non-Alliance Group, then other requirements from the credited Group may apply. All protocol conduct must be 
followed and the registering institution is responsible for ensuring all data is reported per protocol. 
 
Treatment is to continue until disease progression or unacceptable adverse event. Patients will be followed for 5 years 
or until death, whichever comes first. 
 
Please refer to the full protocol text for a complete description of the eligibility criteria (Section 3.0) and 
treatment plan (Section 7.0). 
 
All sites must fulfill imaging and radiotherapy credentialing requirements. Refer to Section 15.0 of the protocol 
for full description of requirements. 
 

Alliance A021501 
5 
Version Date: 10/19/2018 
Update #04 
Table of Contents 
1.0 
BACKGROUND .............................................................................................................................. 7 
1.1 
Background and Rationale ............................................................................................................. 7 
1.2 
Rationale for Trial Design .............................................................................................................. 8 
1.3 
Trial Importance ............................................................................................................................. 8 
1.4 
Pertinent Existing Data ................................................................................................................... 9 
1.5 
Impact of the Trial ........................................................................................................................ 13 
2.0 
OBJECTIVES ................................................................................................................................ 14 
2.1 
Primary Objective......................................................................................................................... 14 
2.2 
Secondary Objectives ................................................................................................................... 14 
2.3 
Other Objective ............................................................................................................................ 14 
2.4 
Correlative Science Objectives..................................................................................................... 14 
3.0 
PATIENT SELECTION ............................................................................................................... 14 
3.1 
On-Study Guidelines .................................................................................................................... 14 
3.2 
Pre-Registration Eligibility Criteria ............................................................................................. 15 
3.3 
Eligibility Criteria......................................................................................................................... 16 
4.0 
PATIENT REGISTRATION ....................................................................................................... 18 
4.1 
CTEP Registration Procedures ..................................................................................................... 18 
4.2 
CTSU Registration Procedures .................................................................................................... 19 
4.3 
Patient Pre-Registration Requirements ......................................................................................... 21 
4.4 
Patient Registration/Randomization Requirements ...................................................................... 22 
4.5 
Patient Pre-Registration and Registration/Randomization Procedures ........................................ 22 
4.6 
Registration to Correlative and Companion Studies .................................................................... 23 
4.7 
Stratification Factors and Treatment Assignments ....................................................................... 23 
5.0 
STUDY CALENDAR .................................................................................................................... 24 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................... 26 
6.1 
Data Collection and Submission .................................................................................................. 26 
6.2 
Specimen Collection and Submission .......................................................................................... 26 
6.3 
Submission of Digital Radiation Therapy Data ............................................................................ 30 
6.4 
Imaging Requirements, Credentialing, and Submission Instructions ........................................... 32 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 34 
7.1 
Chemotherapy (Arm 1 and Arm 2) .............................................................................................. 35 
7.2 
Radiotherapy (Arm 2 Only) ......................................................................................................... 36 
7.3 
Surgery (Arm 1 and Arm 2) ......................................................................................................... 44 
7.4 
Imaging ......................................................................................................................................... 49 
8.0 
DOSE AND TREATMENT MODIFICATIONS........................................................................ 51 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care........................................... 51 
8.2 
Dose Modifications ...................................................................................................................... 54 
9.0 
ADVERSE EVENTS ..................................................................................................................... 57 
9.1 
Routine Adverse Event Reporting ................................................................................................ 57 
9.2 
Surgical Adverse Events .............................................................................................................. 58 
9.3 
CTCAE Routine Reporting Requirements ................................................................................... 58 
9.4 
Expedited Adverse Event Reporting (CTEP-AERS) ................................................................... 59 
9.5 
CDUS Reporting .......................................................................................................................... 63 
10.0 
DRUG INFORMATION ............................................................................................................... 63 
10.1 General Considerations ................................................................................................................ 63 

Alliance A021501 
6 
Version Date: 10/19/2018 
Update #04 
10.2 Oxaliplatin (Eloxatin) – NSC #266046 ........................................................................................ 63 
10.3 Irinotecan (Camptosar) – NSC #616348 ...................................................................................... 67 
10.4 Leucovorin Calcium – NSC #3590 .............................................................................................. 70 
10.5 5-Fluorouracil (5-FU) (Efudex, Arucil, Carac, Fluroplex) – NSC #19893 .................................. 71 
11.0 
MEASUREMENT OF EFFECT .................................................................................................. 73 
11.1 Schedule of Evaluations ............................................................................................................... 73 
11.2 Definitions of Measurable and Non-measurable Disease ............................................................. 74 
11.3 Guidelines for Evaluation of Measurable Disease ....................................................................... 74 
11.4 Measurement of Treatment/Intervention Effect ........................................................................... 75 
11.5 Definitions of Analysis Variables ................................................................................................ 78 
11.6 Surgical Pathologic Determination of Treatment Response ......................................................... 78 
11.7 Histopathologic Determination of R-status .................................................................................. 79 
11.8 Treatment Evaluation after Completion of Surgery and Post-operative Chemotherapy .............. 79 
12.0 
END OF TREATMENT/INTERVENTION ............................................................................... 79 
12.1 Duration of Treatment .................................................................................................................. 79 
12.2 Managing Ineligible Patients and Registered Patients Who Never Receive Protocol Intervention .  
 
 ...................................................................................................................................................... 81 
12.3 Extraordinary Medical Circumstances ......................................................................................... 81 
13.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 81 
13.1 Study Endpoints ........................................................................................................................... 82 
13.2 Sample Size .................................................................................................................................. 83 
13.3 Power Justification ....................................................................................................................... 83 
13.4 Statistical Analysis Plan ............................................................................................................... 85 
13.5 Safety Monitoring......................................................................................................................... 86 
13.6 Descriptive Factors ....................................................................................................................... 87 
13.7 Inclusion of Women and Minorities ............................................................................................. 87 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 89 
14.1 Pharmacogenetic Studies in Alliance A021501: A021501-PP1 ................................................... 89 
14.2 Imaging Science Studies in Alliance A021501: Alliance A021501-IM1 .................................... 91 
15.0 
GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING ...................... 95 
15.1 Institutional Credentialing ............................................................................................................ 95 
16.0 
REFERENCES .............................................................................................................................. 97 
APPENDIX I: 
REGISTRATION QOL/MENTAL WELL-BEING/FATIGUE AND PRO-
CTCAE MEASURES ............................................................................................................................. 100 
APPENDIX II: 
DEFINITION OF BORDERLINE RESECTABLE DISEASE TABLE FOR 
SECTION 3.2.1 (ELIGIBILITY) .......................................................................................................... 110 
APPENDIX III: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ........ 111 
APPENDIX IV: STANDARD LYMPHADENECTOMY ILLUSTRATION ................................ 114 
APPENDIX V: 
EXAMPLE FIDUCIAL MARKER ORDERING INFORMATION ................... 115 
 
 
 

Alliance A021501 
7 
Version Date: 10/19/2018 
Update #04 
1.0 
BACKGROUND 
1.1 
Background and Rationale 
Borderline resectable pancreatic ductal adenocarcinoma (PDAC) is an increasingly recognized 
clinical stage of localized PDAC [1]. Although borderline resectable cancers, like locally 
advanced pancreatic cancers (LAPC), infiltrate to involve adjacent vital structures, the extent to 
which they do so is relatively minimal so surgical resection represents a technical option. 
However, the extent to which borderline resectable cancers infiltrate into the local anatomy is 
greater than that of potentially resectable cancers so the potential for incomplete (R1 or R2) 
operations is significant when surgery is used as primary therapy [2, 3]. Given that complete 
microscopic (R0) resection represents a requisite component of curative therapy for patients 
with PDAC, neoadjuvant regimens designed to both select patients for surgery and optimize 
surgical outcomes are increasingly being administered to patients with borderline resectable 
cancers in an attempt to maximize the likelihood for long-term survival.  
The therapeutic strategy utilized most frequently for borderline resectable PDAC in the United 
States is currently based entirely upon consensus [4, 5]. Typically, patients first receive a 
predefined period of systemic chemotherapy (2 to 4 months) followed by a conventional 5-6 
week course of gemcitabine or 5-FU-based chemoradiation. Patients who complete this 
multimodality regimen without evidence of disease progression undergo pancreatectomy with 
curative intent; those who progress prior to the intended operation are treated with additional 
non-operative therapies with palliative intent. This approach leverages theoretical benefits 
associated with systemic chemotherapy (e.g., systemic antitumor activity upon micrometastatic 
disease known to exist in almost all patients), chemoradiation (e.g., “sterilization” of surgical 
margins) and time (e.g., patient selection) in an attempt to maximize systemic control, local 
control, and ultimately, overall survival. 
Three important considerations are noteworthy in this regard. First, the sequential administration 
of chemotherapy and chemoradiation was proposed at a time when gemcitabine—a systemic 
agent with a response rate against PDAC less than 10%—was standard. In the “gemcitabine 
era”, the rationale for following systemic chemotherapy with chemoradiation was the latter’s 
direct cytotoxic effect on the primary tumor, possibly leading to an improvement in local control 
or even a reduction in the size or anatomic extent (“downstaging”) of the cancer to an extent 
that might facilitate an R0 resection. However, the added benefit of conventional 
chemoradiation remains unclear in this setting, as it is unclear in other stages of localized PDAC 
[6-9]. Indeed, the sequential administration of gemcitabine-based chemotherapy and 
chemoradiation led to a radiographic response in only 12% of borderline resectable primary 
tumors evaluated, and downstaged only 0.8% to technically resectable in one large, albeit 
retrospective analysis of this approach [10].  
Second, chemoradiation as routinely administered to patients with localized PDAC and as 
advocated in the consensus guidelines is dosed over a duration of 5-6 weeks prior to a 6 week 
break before surgery. Because chemoradiation acts only upon the primary tumor and regional 
lymph nodes, the systemic micrometastatic disease that may exist in all patients with localized 
PDAC is suboptimally untreated for as many as 3-4 months prior to resection.  
The third consideration is that the daily radiotherapy treatments used in conventional 
chemoradiation regimens are associated with significant direct and opportunity costs as patients 
must spend time away from work or even family, and they may be associated with moderate 
toxicity. And, to the extent that clinical trials of novel treatment strategies may be conducted at 
high volume centers located at a distance from patients’ homes, the length of time associated 
with conventional chemoradiation represents a critical barrier both to enthusiastic enrollment to 
such trials and to progression in the field. 

Alliance A021501 
8 
Version Date: 10/19/2018 
Update #04 
The consensus treatment algorithm of systemic chemotherapy and conventional chemoradiation 
that is routinely used for patients with borderline resectable PDAC must be rigorously evaluated 
in the context of significant advances in both chemotherapy and radiation that have occurred 
within the past 5 years.  The systemic regimens now in routine use for patients with metastatic 
pancreatic cancer—FOLFIRINOX and gemcitabine plus nab-paclitaxel—are associated with 
objective response rates of 32% and 23%, respectively, in the setting of metastatic disease [11, 
12]. Given the high response rates associated with FOLFIRINOX and gemcitabine plus nab-
paclitaxel, it is conceivable that continuous dosing of chemotherapy alone may allow better 
treatment of the systemic disease that more commonly represents the source of morbidity and 
mortality among patients with PDAC without forgoing any theoretical effect on the primary 
tumor previously associated with chemoradiation. Furthermore, to the extent that radiation 
therapy may have a role in “sterilizing” the surgical margins of patients with borderline 
resectable disease, thereby enhancing rates of R0 resection and local control, attractive 
alternatives to conventional chemoradiation now exist that appear to yield rates of local control 
and acute and late toxicity rates equivalent to those associated with conventional chemoradiation 
using dosing schedules as short as 5 days [13, 14]. 
In this trial, we seek to identify one treatment program that meet clinically-relevant benchmarks 
for activity, and which can provide the foundation for future randomized comparison trials in a 
space where there are currently limited high-level data to guide treatment choices. 
1.2 
Rationale for Trial Design 
Herein we propose to evaluate the efficacy of two rational neoadjuvant treatment backbones in 
a randomized study. The study builds upon our previous work as requested by CTEP and will 
define standard preoperative treatment regimens to which future novel regimens can and will be 
compared in subsequent randomized trials.  
We have proposed a randomized frequentist design using exact binomial distribution for this 
study. This design focuses on evaluating whether clinical meaningful improvement of survival 
rate can be achieved by the tested regimens comparing to historical data. The evaluation of each 
treatment arm will be conducted separately, based on a practical assessment of whether the arm 
is “clinically relevant” alone, as well as the outcome comparisons between two treatments if 
both arms are deemed promising at the end of the trial.  This study uses a critically important 
interim endpoint (R0 resection rate) that is different from the final endpoint (18 month OS rate) 
and an interim analysis which allows elimination of any futile arm after only 30 patients enrolled 
to that arm. If both arms are deemed promising at the end of the trial, a pick-a-winner strategy 
will be employed to choose one arm as the “winner”.  Using a fast maturing end point, R0 
resection rate, for interim analysis prevent the possibility of halting the trial at interim analysis 
while the whole study still powered to detect clinical meaningful improvement in OS rate.  
1.3 
Trial Importance  
A trial to define a standard preoperative treatment backbone for borderline resectable PDAC is 
critically necessary to provide a regimen for current use and a fundamental therapeutic backbone 
to which future novel regimens can be compared in subsequent studies.  
The concept and design of this trial has evolved within the Pancreatic Cancer Task Force over 
the past two years and has been vetted with multiple votes and polls of its members. The trial 
also represents a natural next step in an investigational program that has proceeded with the 
advice, investment, and involvement of CTEP. Indeed, at the request of CTEP, we performed 
an initial pilot study designed to rapidly assess the feasibility of a multi-institutional study of 
borderline resectable PDAC and to develop a standardized clinical and research infrastructure 
(e.g., rapid review of imaging, pathologic assessments, quality control of radiation protocols) 
specific to this disease stage that is necessary to study it [15, 16]. That trial represented one of 

Alliance A021501 
9 
Version Date: 10/19/2018 
Update #04 
the most collaborative studies that has ever been conducted in the pancreas cancer space: it met 
its accrual endpoint early and within a year due to the enthusiasm of centers from the Alliance, 
ECOG, SWOG and RTOG. Alliance Trial A021101—the results of which were recently 
presented as an oral presentation at the 2015 annual meeting of ASCO and published on the 
JAMA surgery website [17]—demonstrated that rapid, real-time central review of imaging is 
feasible, established other infrastructural elements viewed as critical to the conduct of 
multimodality treatment trials for pancreatic cancer, and set the stage for the subsequent 
randomized phase II study that CTEP agreed would represent the natural next step in this line 
of investigation. 
This successor trial has the support of all major clinical trials groups as well as the Pancreatic 
Cancer Task Force. Furthermore, the Task Force has declared the search for a treatment 
paradigm for patients with this stage of disease as a strategic priority. 
If both arms of this trial are found to be able to provide clinically meaningful improvement of 
OS rate, “pick-a-winner” approach will be conducted and one regimen will be recommend as 
the rational backbone for future regimens and studies. If only one arm is “clinically relevant”, 
then that arm will serve as the control arm for future randomized trials. If no arm is “clinically 
relevant” then the rationale for an alternative approach should be investigated. 
1.4 
Pertinent Existing Data 
Existing data are primarily from small, single-center, and often retrospective studies exploring 
novel treatment strategies for borderline resectable PDAC. The results of these studies are 
therefore difficult to compare because of heterogeneity in trial design, variability in enrolled 
populations, and absence of quality control. However, the following observations are useful: 
1.4.1 
Neoadjuvant Chemotherapy Alone for Resectable PDAC 
Neoadjuvant chemotherapy alone does not preclude R0 resection of 
radiographically resectable PDAC, and it is associated with reasonable rates of OS. 
In a small European study of 28 patients with resectable pancreatic cancer, an R0 
resection was accomplished in 80% of patients who received gemcitabine and 
cisplatin prior to intended resection [18]. In a more recent single-center study, 27 
(71%) of 38 resectable patients who received preoperative gemcitabine and 
oxaliplatin underwent surgical resection, and 26 of these received postoperative 
gemcitabine. The median OS for all 38 patients was 27.2 months [19].  
1.4.2 
Neoadjuvant Chemotherapy Alone for Borderline Resectable PDAC 
Neoadjuvant chemotherapy is well tolerated and selects patients with borderline 
resectable PDAC for surgical resection. In a retrospective evaluation of 64 patients 
treated with neoadjuvant gemcitabine/docetaxel and a variety of second line 
agents, 31 (48%) were resected; 87% had an R0 resection and 10% (N=3) had a 
complete pathologic response. Median OS of all 64 patients was 23.6 months; that 
of unresected patients was 15.4 months [20]. 
1.4.3 
Neoadjuvant 
Gemcitabine-based 
Chemotherapy 
with 
Conventional 
Chemoradiation for Borderline Resectable PDAC 
Neoadjuvant gemcitabine-based chemotherapy with standard chemoradiation is 
associated with favorable outcomes and high R0 resection rates in patients with 
borderline resectable PDAC but is not associated with a high radiographic response 
based on RECIST or “downstaging” of the pancreas tumor. In a retrospective 
evaluation of 129 patients with borderline resectable PDAC, only 12% had a 
RECIST response to neoadjuvant therapy that consisted of gemcitabine-based 

Alliance A021501 
10 
Version Date: 10/19/2018 
Update #04 
systemic therapy followed by conventional chemoradiation with concurrent 
gemcitabine or capecitabine. Only 1 patient (0.8%) had their disease downstaged 
to resectable status following receipt of chemoradiation. Nonetheless, 66% of all 
patients underwent pancreatectomy and their median OS was 22 months (95% CI: 
14-30 months) [10]. 
1.4.4 
Neoadjuvant 
Therapy 
with 
FOLFIRINOX 
and 
Conventional 
Chemoradiation for Borderline Resectable PDAC 
In our initial pilot study we showed that FOLFIRINOX-based multimodality 
therapy for borderline resectable PDAC is well tolerated and study of this approach 
is feasible in the cooperative group setting [16]. 22 of 23 enrolled patients started 
therapy (median age 64 years, 64% ECOG PS 0). All patients completed 
mFOLFIRINOX and 21 (95%) completed CRT. Fourteen (64% [95% confidence 
interval (CI), 41-83%]) patients had grade ≥3 adverse events during preoperative 
therapy. The best RECIST radiographic responses during preoperative treatment 
were 2 CR, 4 PR, 14 SD and 2 PD. 7 patients did not undergo planned resection 
due either to progression (6) or refusal (1). 15 (68% [95% CI, 49–88%]) patients 
underwent pancreatectomy. Fourteen (93%) operations had microscopically 
negative margins, 5 (33%) operative specimens had <5% residual viable tumor 
cells, and 2 (13%) specimens had pathologic complete responses. Overall survival 
of all patients at 18 months was 50%. 
1.4.5 
Standard Chemoradiation for Locally Advanced PDAC 
The role of CRT in patients with locally advanced disease is unclear. The 
Gastrointestinal Tumor Study Group 9283 [GISTG 1998] and Eastern Cooperative 
Oncology Group 4201 [21] studies reported improved OS with chemoradiation. 
However, the chemoradiation arms were associated with substantial grade 3-4 
toxicity. In a retrospective review of two prospective studies, the Groupe 
Coopérateur Multidisciplinaire en Oncologie (GERCOR) reported a superior OS 
in patients receiving chemotherapy and CRT versus those receiving chemotherapy 
alone [22]. The Fédération Francophone de Cancérologie Digestive and Société 
Francophone de Radiothérapie Oncologique (FFCD-SFRO) study reported 
inferior OS and worse toxicity with the addition of chemoradiation to 
chemotherapy [23]. Recently, preliminary results of the phase III GERCOR LAP 
07 study demonstrated no OS benefit with the addition of chemoradiation [9]. 
1.4.6 
Hypofractionated Radiation Therapy: Modern Techniques 
Hypofractionated radiation therapy may be delivered using two similar techniques 
over an abbreviated 5 day schedule. Both short-course hypofractionated image 
guided radiation therapy (HIGRT, 5 Gy x 5) and stereotactic body radiation 
therapy (SBRT, 6.6 Gy x 5) are delivered over 5 consecutive days (see figures 
below for comparison). HIGRT delivers a homogeneous dose of radiation therapy 
to the tumor plus a 0.5-1 cm expansion to account for microscopic extension and 
set-up error as well as breathing motion.  This means that the treated volume 
(tumor plus margin) receives a homogeneous dose of 5 Gy per day—a dose limited 
to minimize the risk of long-term bowel or stomach toxicity in the event the patient 
is not able to undergo subsequent surgery. SBRT also delivers RT over 5 days but 
a heterogeneous dose is delivered and the volume includes only the tumor plus 2-
3 mm.  Using this technique a higher daily dose of RT is given (6.6 Gy). However 
since the dose is heterogeneous, some areas of the target will receive up to 8 Gy 

Alliance A021501 
12 
Version Date: 10/19/2018 
Update #04 
60/83.3), but without concurrent chemotherapy and treating a smaller tumor 
margin (0.3 cm vs. ~2 cm). Furthermore, the proposed 6.6 Gy x 5 fractionation 
schedule has a much lower late BED (105.6 vs. 146.7) with a similar early BED 
(54.8 vs. 70) as the previous 40 Gy x 5 regimen. In this study, we will refine our 
current understanding of radiation tolerance of the pancreas and adjacent organs. 
Table 1. Estimated biological equivalent dose (BED) of Fractionation Schedules 
Dose / fractions 
Nodes Tx 
Chemo 
BED 
early 
BED 
late 
 
 
α/β=10 
α/β=-3 
50 Gy/25 
Yes 
Yes 
60 
83.3 
30 Gy/10 
Yes 
Yes 
39 
60 
25 Gy/5 
Yes 
No 
37.5 
66.7 
33 Gy/5 
No 
No 
54.8 
105.6 
40 Gy/5 
No 
No 
70 
146.7 
1.4.8 
Neoadjuvant Hypofractionated Radiation Therapy for Resectable PDAC 
Hypofractionated radiation therapy, either alone or preceded by systemic therapy, 
does not preclude R0 resection of radiographically resectable PDAC, and it is 
associated with reasonable rates of local control and OS. Two consecutive single-
arm trials performed at MD Anderson evaluated gemcitabine-based CRT (30 Gy 
in 10 treatments) with and without induction gemcitabine and cisplatin [29].  In 
these two trials, the most common reason patients failed to undergo resection 
following chemoradiation was metastatic disease; only 1 out of 176 patients had 
isolated local progression that precluded surgery. The overall median survival 
durations of the no induction versus induction chemotherapy arms were 22.7 
months and 17.4 months, respectively, and the median survival durations of the 
resected patients was 34 and 31 months. These results were encouraging and better 
than historical controls of patients with resectable cancers who received an initial 
operation.  
In a study of preoperative proton-based radiation (5 Gy x 5) with capecitabine, 
followed by surgery and adjuvant gemcitabine, toxicity was low (4.1% grade 3 and 
no grade 4/5). 37/48 patients underwent surgery and progression-free survival of 
all 48 patients was 10 months and median overall survival was 10 months. Distant 
recurrence was the primary mode of failure (72.9%), highlighting the need for 
more aggressive systemic therapy in this population [30]. 
1.4.9 
Neoadjuvant Hypofractionated Radiation Therapy for Borderline Resectable 
PDAC 
Hypofractionated radiation therapy may be effective in the neoadjuvant setting for 
patients with borderline resectable disease. A retrospective study including 73 
PDAC patients (57 borderline resectable, 16 locally advanced) who received 
induction chemotherapy followed by 5-fraction SBRT at Moffitt Cancer Center 
was published in 2013 [31].  Most borderline resectable patients received induction 
GTX (67%); only 5% received induction FOLFIRINOX. Among the borderline 
resectable patients, 56% underwent surgery with 97% achieving negative margins.  
Median OS in the patients who underwent margin-negative resection was 
significantly higher than in unresected patients (19.3 vs. 12.3 months; P=.03).  
Furthermore this approach was well tolerated with no acute grade 3+ toxicity 
reported and only 5.3% late grade 3+ toxicity.  This single institution series was 

Alliance A021501 
13 
Version Date: 10/19/2018 
Update #04 
recently updated to include a total of 159 patients (110 borderline resectable, 49 
locally advanced) [14]. Among the borderline resectable patients, 51% underwent 
surgery with 97% achieving negative margins. Median OS in the resected 
borderline resectable patients was 34 months. Acute grade 3+ toxicity was 2% and 
late grade 3+ toxicity was 5%. 
Single-institution data from Johns Hopkins reported patients who received 25-33 
Gy SBRT in 5 fractions followed by surgical resection.  Median OS from date of 
diagnosis was 18.4 months. Of the 19 patients (21.6%) who underwent surgery 
following SBRT, 11% had borderline resectable cancers, and 84% had margin-
negative resections [27]. 
1.4.10 Hypofractionated Radiation Therapy for Locally Advanced PDAC 
Results of SBRT in patients with locally advanced PDAC are encouraging. Early 
phase I/II studies using single-fraction SBRT (25 Gy in 1 fraction) demonstrated 
excellent freedom from local progression (FFLP) at 1 year (>90%) and minimal 
acute toxicity in patients with locally advanced disease, but resulted in high late 
grade 2-4 gastrointestinal (GI) toxicity [24, 32-35]. A single-arm phase II multi-
institutional study to determine whether gemcitabine with fractionated SBRT (in 5 
fractions of 6.6 Gy, total 33.0 Gy) would achieve reduced late grade 2-4 GI toxicity 
compared with a historical cohort of patients treated with gemcitabine and a single 
25 Gy-fraction of SBRT was subsequently conducted [Herman 2014]. Forty-nine 
LAPC patients received up to 3 doses of GEM (1,000 mg/m2) followed by a one-
week break and SBRT (33.0 Gy in 5 fractions). Following SBRT, patients 
continued GEM until progression or toxicity. Rates of acute and late (primary 
endpoint) grade ≥2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, 
respectively. QLQ-C30 global quality of life scores remained stable from baseline 
to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for 
both). Patients reported a significant improvement in pancreatic pain (P<.001) 4 
weeks after SBRT on the QLQ-PAN26 questionnaire. Median plasma CA19-9 was 
reduced following SBRT (median time post-SBRT 4.2 weeks, 220 vs. 62 U/mL, 
p<0.001). Median overall survival was 13.9 months (95% CI, 10.2-16.7). FFLP at 
1 year was 78%. Four patients with LAPC at diagnosis (8%) underwent margin- 
and node-negative resections. 
1.5 
Impact of the Trial 
A trial to help understand the respective roles of preoperative systemic and local therapies for 
patients with borderline resectable PDAC is critically necessary. This study will establish a 
treatment strategy to which future novel regimens can be compared in future trials. The study 
will compare the efficacy of two commonly employed preoperative regimens, one of which only 
utilizes systemic therapy and one that also uses a novel local treatment modality. The trial will 
provide the only multi-center, quality-controlled data for this stage of disease. 
 
 

Alliance A021501 
14 
Version Date: 10/19/2018 
Update #04 
2.0 
OBJECTIVES  
2.1 
Primary Objective 
To evaluate and estimate 18 months overall survival (OS) rate of patients with borderline 
resectable PDAC receiving  neoadjuvant therapy consisting of one of the following regimens 
prior to intended surgical resection and adjuvant therapy with 4 cycles of FOLFOX:  
1) Arm 1: 8 cycles of systemic FOLFIRINOX, or 
2) Arm 2: 7 cycles of systemic FOLFIRINOX followed by hypofractionated radiation therapy 
2.2 
Secondary Objectives 
2.2.1 
To evaluate and estimate the R0 resection rates in patients receiving each of the 
two multimodality treatment regimens. 
2.2.2 
To evaluate and estimate the event-free survival in patients receiving each of the 
two multimodality treatment regimens. 
2.2.3 
To evaluate and estimate the pathologic compete response (pCR) rates in patients 
receiving each of the two multimodality treatment regimens 
2.2.4 
To assess the adverse events (AE) profile and safety of each treatment arm, using 
the CTCAE and PRO-CTCAE. 
2.3 
Other Objective 
Results of the primary analysis will be examined for consistency, while taking into account the 
stratification factors and/or covariates of baseline overall QOL, mental well-being, physical 
well-being, and fatigue. 
2.4 
Correlative Science Objectives 
2.4.1 
Pharmacogenetic Studies in Alliance A021501: A021501-PP1 
To test the effect of the rs2853564 VDR variant on OS rate and discover novel 
candidate genes associated with OS and severe toxicity of chemotherapy by using 
genome-wide genotyping approaches. 
2.4.2 
Imaging Science Studies in Alliance A021501: A021501-IM1 
• 
To evaluate risk classification previously developed by Koay et al [36] 
using NAUC. 
• 
To access prognostic value of NAUC ratio defined as post-neoadjuvant 
NAUC divided by pre-neoadjuvant therapy NAUC. 
• 
To evaluate risk classification previously developed by Koay et al using 
delta measure. 
 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 

Alliance A021501 
15 
Version Date: 10/19/2018 
Update #04 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed 
consent. 
• 
Medical condition such as uncontrolled infection (including HIV), 
uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the 
treating physician, would make this protocol unreasonably hazardous for the 
patient. 
• 
“Currently active” second malignancy other than non-melanoma skin cancers 
or cervical carcinoma in situ. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and are free of disease for 
≥ 3 years. 
• 
Patients who are unable to lie flat on their back on a hard surface with their 
arms up for at least 20 minutes. 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate 
method of birth control throughout their participation in this study due to the 
teratogenic potential of the therapy utilized in this trial. Appropriate methods 
of birth control include abstinence, oral contraceptives, implantable hormonal 
contraceptives or double barrier method (diaphragm plus condom). 
3.2 
Pre-Registration Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive 
months). 
3.2.1 
Documentation of Disease 
___ 
Pathology: Cytologic or histologic proof of adenocarcinoma of the pancreatic 
head or uncinate process. Diagnosis should be verified by local pathologist. 
___ 
TNM Stage: Tx-4, N0-1, M0* 
*M1 disease includes spread to distant lymph nodes, organs, and ascites 
___ 
Criteria for borderline resectable disease: Local radiographic reading must be 
consistent with borderline resectable cancer of the pancreatic head as defined by 
intergroup radiographic criteria and must meet any one or more of the following 
on CT/MRI: 
• 
An interface is present between the primary tumor and the superior 
mesenteric vein or portal vein and measures ≥ 180° of the 
circumference of the vessel wall 

Alliance A021501 
16 
Version Date: 10/19/2018 
Update #04 
• 
Short-segment occlusion of the SMV-PV is present with normal vein 
above and below the level of obstruction that is amenable to resection 
and venous reconstruction 
• 
Short segment interface (of any degree) is present between tumor and 
hepatic artery with normal artery proximal and distal to the interface 
that is amenable to resection and reconstruction 
• 
An interface is present between the tumor and superior mesenteric 
artery or celiac axis measuring < 180° of the circumference of the 
vessel wall 
Patients with less extensive disease than the above four (4) criteria are considered 
potentially resectable and are NOT eligible 
Patients with more extensive disease than the above 4 criteria are considered 
locally advanced and are NOT eligible.  
In addition patients with the following are considered locally advanced and are 
NOT eligible: 
• 
Any interface between the tumor and the aorta. 
See Appendix II for additional clarification and definitions of less and more 
extensive disease. 
3.3 
Eligibility Criteria 
3.3.1 
Disease Status 
___ 
Confirmation of radiographic stage as borderline resectable disease by real-time 
Alliance central radiographic review 
3.3.2 
Prior Treatment 
___ 
No prior chemotherapy or radiation for pancreatic cancer 
___ 
No definitive resection of pancreatic cancer 
3.3.3 
Concomitant Medications 
___ 
Chronic concomitant treatment with strong CYP3A4 inhibitors is not allowed on 
this study. Patients must discontinue the drug(s) 14 days prior to registration. See 
Section 8.1.10 for more information. 
___ 
Chronic concomitant treatment with strong CYP3A4 inducers is not allowed on 
this study. Patients must discontinue the drug(s) 14 days prior to registration. See 
Section 8.1.11 for more information. 
3.3.4 
Medical History 
___ 
No grade ≥ 2 neuropathy 
___ 
No known Gilbert’s Syndrome or known homozygosity for UGAT1A1*28 
polymorphism. 
___ 
No uncontrolled gastric ulcer disease (Grade 3 gastric ulcer disease) within 28 
days of registration 

Alliance A021501 
17 
Version Date: 10/19/2018 
Update #04 
3.3.5 
Pregnancy and Nursing Status 
___ 
Not pregnant and not nursing, because this study involves an agent that has 
known genotoxic, mutagenic and teratogenic effects. 
Therefore, for women of childbearing potential only, a negative pregnancy test 
done ≤ 7 days prior to registration is required. 
3.3.6 
Age ≥ 18 years  
3.3.7 
ECOG Performance Status: 0 or 1 
3.3.8 
Required Initial Laboratory Values: 
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Platelet Count 
≥ 100,000/mm3 
Creatinine 
≤ 1.5 x upper limit of normal (ULN) 
or 
 
Calc. Creatinine Clearance 
> 45 mL/min 
Total Bilirubin 
≤ 2.0 mg/dL 
AST / ALT  
≤ 2.5 x upper limit of normal (ULN) 
 
 

Alliance A021501 
19 
Version Date: 10/19/2018 
Update #04 
Radiology’s (ACR) image exchange application. TRIAD provides sites 
participating in clinical trials a secure method to transmit DICOM, DICOM RT 
and other digital files. TRIAD anonymizes and validates the images as they are 
transferred. 
Use of TRIAD for submission of imaging and RT data on this trial is optional, but 
preferred. TRIAD must be installed locally for this purpose.  See Section 6.3 for 
information on the use of TRIAD for submission of digital RT data and Section 
6.4 for information on the use of TRIAD for submission of imaging data. 
TRIAD Access Requirements: 
• 
Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have 
a valid and active CTEP Identity and Access Management (IAM) account, 
and be registered as an AP, NPIVR or IVR.  Please refer to the CTEP 
Registration Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in RCR. 
• 
To submit images, the site physics user must be on the site’s affiliated 
rosters and be assigned the 'TRIAD site user' role on the CTSU roster. 
Users should contact the site’s CTSU Administrator or Data Administrator 
to request assignment of the TRIAD site user role. RAs are able to submit 
standard of care imaging through the same method. 
TRIAD Installations: 
• 
When a user applies for a CTEP-IAM account with the proper user role, 
he/she will need to have the TRIAD application installed on his/her 
workstation to be able to submit images. TRIAD installation 
documentation 
can 
be 
found 
by 
following 
this 
link 
 
• 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password and RCR registration. 
• 
If you have any questions regarding this information, please send an e-
mail to the TRIAD Support mailbox at TRIAD-Support@acr.org. 
4.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
IRB Approval:   
Please note: This study is not reviewed by the NCI Central Institutional Review Board (CIRB).  
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients. Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 

Alliance A021501 
20 
Version Date: 10/19/2018 
Update #04 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office. In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
4.2.1 
Downloading Site Registration Documents  
Site registration forms may be downloaded from the A021501 protocol page 
located on the CTSU members’ website. Permission to view and download this 
protocol and its supporting documents is restricted and is based on person and site 
roster assignment housed in the CTSU RSS. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, 
or 
• 
Clink on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol #A021501 
• 
Click on LPO Documents, select the Site Registration Documents link, 
and download and complete the forms provided. 
4.2.2 
Requirements for A021501 Site Registration  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of 
Human Subjects Assurance Identification/IRB Certification/Declaration 
of Exemption Form, or combination is accepted ) 
• 
Alliance Imaging Core Lab at IROC Ohio Credentialing (See Section 
15.1.1) 
• 
Radiation Therapy Site Credentialing required prior to the delivery of 
radiation therapy on any protocol patient (See Section 15.1.2) 
o Note: Arm 2 closed to new patient enrollment on 08/13/2018. As 
of Update #04, RT Credentialing is no longer required. 
• 
For applicable NCTN studies with a radiation and/or imaging (RTI) 
component, the enrolling site must be aligned to a RTI provider. To 
manage provider associations access the Provider Association tab on the 
CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to 
add or remove associated providers. Sites must be linked to at least one 
IROC credentialed provider to participate on trials with an RT component. 

Alliance A021501 
21 
Version Date: 10/19/2018 
Update #04 
Enrolling sites are responsible for ensuring that the appropriate 
agreements are in place with their RTI provider, and that appropriate IRB 
approvals are in place.   
• 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to 
IROC to begin the modality credentialing process.  
4.2.3 
Checking Your Site’s Registration Status  
You can verify your site registration status on the member’s section of the CTSU 
website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the Lead 
Network. It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or 
their affiliated networks. 
4.2.4 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal, where they will be entered and tracked in the CTSU 
RSS. 
Regulatory Submission Portal: www.ctsu.org (members’ area)  Regulatory Tab 
 Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. 
4.2.5 
Credentialing 
• 
Alliance Imaging Core Lab at IROC Ohio Credentialing 
• 
Radiation Therapy Site Credentialing 
o Note: Arm 2 closed to new patient enrollment on 08/13/2018. As 
of Update #04, RT Credentialing is no longer required. 
See Section 15.0 for credentialing requirements.   
4.3 
Patient Pre-Registration Requirements 
Informed Consent: the patient (or guardian, where institutional policy and IRB of record allow) 
must be aware of the neoplastic nature of his/her disease and willingly consent after being 
informed of the procedure to be followed, the experimental nature of the therapy, alternatives, 

Alliance A021501 
22 
Version Date: 10/19/2018 
Update #04 
potential benefits, side-effects, risks, and discomforts. Current human protection committee 
approval of this protocol and a consent form is required prior to patient consent and registration. 
Eligibility of patients as outlined in Section 3.2 of the protocol should be confirmed prior to pre-
registration. 
After the patient has been pre-registered the staging scans should be sent to the IROC Ohio 
Alliance Imaging Core Lab (ICL), per Section 6.4. Registration must occur within 21 days of 
image submission. 
4.4 
Patient Registration/Randomization Requirements 
Local Review of Case: Patient case must be evaluated by a medical oncologist, surgeon and 
radiation therapist prior to registration. 
Central Review Confirmation: The Alliance Imaging Core Lab at IROC Ohio will notify the 
pre-registering site, within 5 business days of receipt, whether or not the patient is eligible based 
on the central imaging review. IROC Ohio will send an email confirmation to the pre-registering 
site whether the patient is eligible, and will also carbon copy the Alliance Registration office. 
The Registration office will open the gate for the patient registration to proceed. The radiology 
reviewer will enter the central review results into Rave. 
Patient Completed Booklets: Patient questionnaire booklets are to be ordered prior to the 
registration of any patients. Patient questionnaire booklets can be ordered by downloading and 
completing the CTSU supply request form (located under the site registration documents section 
of the A021501 CTSU site) and faxing the form to the CTSU data operations center at 1-888-
691-8039. Samples of the booklets are found starting on the second page of Appendix I which 
are to be used for reference and IRB submission only. They are not to be used for patient 
completion. There is no booklet for the Registration QOL/Mental Well-being/Physical Well-
being/Fatigue assessment (first page of Appendix I). If needed, the first page of Appendix I can 
be adapted to use as a source document. 
Protected Health Information: Blood/tissue collected for this study will be sent directly to the 
Alliance Biorepository at Washington University (WUSTL). These samples will be labeled with 
patient initials, study ID, and collection date/time. 
4.5 
Patient Pre-Registration and Registration/Randomization Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user must have an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam) and a 
'Registrar' role on either the LPO or participating organization roster. Registrars must hold a 
minimum of an AP registration type.   
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in 
the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the 
CTSU members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the 
treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in 
OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on 
the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 

Alliance A021501 
23 
Version Date: 10/19/2018 
Update #04 
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional 
questions contact the CTSU Help Desk at 
 
4.6 
Registration to Correlative and Companion Studies 
4.6.1 
Registration to Substudies Described in Section 14.0  
There are 2 substudies within Alliance A021501. These correlative science studies 
must be offered to all patients enrolled on Alliance A021501 (although patients 
may opt to not participate). These substudies do not require separate IRB approval. 
These substudies included within Alliance A021501 are: 
• 
Alliance A021501-PP1, Pharmacogenetic studies in Alliance A021501 
(Section 14.1) 
• 
Alliance A021501-IM1, Imaging science studies in Alliance A021501 
(Section 14.2) 
If a patient answers “yes” to “I agree to have my specimen collected and I agree 
that my specimen sample(s) and related information may be used for the laboratory 
study(ies) described above,” they have consented to participate in the substudies 
described in Section 14.1. The patient should be registered to Alliance A021501-
PP1 at the same time they are registered to the treatment trial (A021501). Samples 
should be submitted per Section 6.2. 
If a patient answers “yes” to “I agree have my scan images be collected and 
submitted for the research stated above,” they have consented to participate in the 
substudy described in Section 14.2. The patient should be registered to Alliance 
A021501-IM1 at the same time they are registered to the treatment trial (A021501). 
Images should be submitted per Section 6.4. 
4.7 
Stratification Factors and Treatment Assignments 
Note: Arm 2 closed to new patient enrollment on 08/13/2018.  
ECOG PS: 0 vs. 1 
 
 

Alliance A021501 
24 
Version Date: 10/19/2018 
Update #04 
 5.0 STUDY CALENDAR 
Note: Arm 2 closed to new patient enrollment on 08/13/2018.  
The pre-study intervals are guidelines only. Laboratory and clinical parameters during treatment 
are to be followed using individual institutional guidelines and the best clinical judgment of the 
responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
Pre-study Testing Intervals  
• To be completed ≤ 28 DAYS before pre-registration: CT/MRI scans used for staging 
• To be completed ≤ 21 DAYS before registration: All laboratory studies, history and physical 
 
 
 
 
Prior to 
Pre-
Reg 
 
Prior to 
Reg* 
 
Day 1 of 
each cycle 
of 
mFOLFIR-
INOX* 
 
RT (day 1 
to day 5) 
(Arm 2 
only)** 
 
 
Surgery 
 
Day 1 of 
each cycle of 
FOLFOX * 
 
Post Tx 
Follow- 
up*** 
Tests & Observations 
 
 
 
 
 
 
 
History and Physical, Weight, PS 
**** 
 
X (1) 
X (1) 
X (1) 
 
X (1) 
X (1) 
Pulse, BP 
 
X (1) 
X (1) 
X (1) 
 
X (1) 
X (1) 
Height 
 
X (1) 
 
 
 
 
 
Adverse Event Assessment 
(CTCAE) † 
 
X (1) 
X (1) 
X (1) 
D (1) 
X (1) 
 
Adverse Event Assessment (PRO-
CTCAE) †† 
 
X (2) 
X 
X 
D 
X 
 
Registration QOL/Mental Well-
being/Physical Well-being/Fatigue 
 
X (2) 
 
 
 
 
 
Laboratory Studies 
 
 
 
 
 
 
 
CBC, Differential, Platelets 
 
X 
X 
X 
X 
X 
X (3) 
Chemistry (Serum Creatinine, 
Electrolytes, AST, ALT, Alk. 
Phos., Albumin, Total Bilirubin) 
 
X 
X 
X 
X 
X 
X (3) 
Pregnancy Test # 
 
X 
 
 
 
 
 
CA 19-9 
 
A 
A 
A 
A 
A 
X 
RT Planning 
 
 
 
 
 
 
 
EUS with Fiducial Placement for 
RT 
 
 
 
B 
 
 
 
Staging 
 
 
 
 
 
 
 
Staging CT Scan of Chest or Chest 
X-ray/CT or MRI of Abdomen 
X (4) 
 
C (4) 
C (4) 
C (4) 
C (4) 
X (4) 
Central Radiographic Review 
 
C 
 
 
C 
 
 
Central Pathology Review 
 
 
 
 
X (5) 
 
 
Optional Correlative Studies: For patients who consent to participate 
Blood Specimen Sample 
(A021501-PP1) 
Between registration and C1D1. See Section 6.2. 
Imaging (A021501-IM1) 
See Section 6.4.2 for CT images submission time points and requirements. 
* 
Labs completed prior to registration may be used for day 1 of cycle 1 if obtained ≤ 7 days prior to 
treatment (except pregnancy test and CA 19-9, as detailed below). For subsequent cycles, labs, tests 
and observations may be obtained +/- 3 days from scheduled day of assessment. Radiographic 
windows are +/- 7 days from scheduled day of assessment.   
** 
To be completed once at any point during Day 1 – Day 5 of RT for Arm 2 patients (except for PRO-
CTCAE; see footnote ††). RT should begin ≥ 5 days after the last dose of chemotherapy. 
 
 

Alliance A021501 
25 
Version Date: 10/19/2018 
Update #04 
*** After off-treatment (evaluation of the last treatment cycle), patients will have physical examinations, 
labs, and staging scans every 16 weeks (+/- 28 days) until they have reached 24 months post-
registration or until documented progression, whichever occurs first. Thereafter, survival information 
is required every 6 months for 5 years post-registration. For patients who discontinue treatment for 
progressive disease or are removed from protocol treatment, survival information is required every 6 
months for 5 years post-registration. See Section 12.0 for removal of patients from protocol therapy. 
**** Drug dosages need not be changed unless the calculated dose changes by ≥ 10%. 
1 
May be performed by physician, NP, or PA responsible for oncologic care of the patient.  
2 
To be completed after pre-registration but ≤ 21 days prior to treatment. See Appendix I. 
3 
CBC, Differential, Platelets, and Chemistry during the post-treatment follow-up period should be 
performed if clinically indicated. Examples of clinical indications would be fatigue, nausea, etc. 
4 
Chest scans must be CT or chest X-ray. Abdominal baseline and restaging scans can include either a 
CT or MRI, although CT is preferred. Contrast should be used unless there is a medical 
contraindication. The same method of scanning used at baseline must be used for all subsequent 
evaluations. The CT must be acquired with 3 mm or less slice thickness. See Section 7.4.1 for further 
details. Supporting documentation is to be submitted, per Section 6.1.1. The baseline scan and 
restaging scan after completion of preoperative therapy/prior to surgery are to be centrally reviewed 
by the Alliance ICL at IROC Ohio, per Section 7.4.2. 
5 
Central pathology review is retrospective. Sites must submit slides within 60 days of surgery of 
patient. See Section 6.2. 
† 
Solicited AEs are to be collected starting at baseline. Routine AEs are to be collected starting after 
registration. See Section 9.1 for the list of solicited AEs. See Section 9.4 for expedited reporting of 
SAEs. See Section 9.2 for reporting of surgical AEs, to be completed within 90 days after surgery.  
†† 
Patients complete PRO-CTCAE by paper booklet ordered through the CTSU website. See Section 
9.1 for administration instructions. See Appendix I for PRO-CTCAE assessments for IRB submission 
and review only. See Section 4.4 for ordering instructions. PRO-CTCAE booklets should be 
administered at the following time points: ≤ 21 days prior to treatment; day 1 of each cycle of 
mFOLFIRINOX (+/- 3 days); RT days 1-5 (Arm 2 only); prior to surgery (+/- 7 days); and day 1 of 
each cycle of FOLFOX (+/- 3 days). 
# 
For women of childbearing potential (see Section 3.3.6). Must be done ≤ 7 days prior to registration. 
A 
CA19-9 may be performed < 28 days prior to registration. Subsequently, CA19-9 may be performed 
+/- 14 days from the scheduled date. During treatment, CA19-9 should be performed every 28 days. 
For patients who have normal CA19-9 levels at baseline, continued testing of CA19-9 is not required. 
B 
EUS/fiducial marker placement must be attempted for patients in the RT arm. Immediately following 
review of first restaging studies, planning for EUS/fiducial placement and RT simulation should be 
scheduled to be performed during either cycle 5 or 6 of mFOLFIRINOX.  
C 
Restaging scans should be performed for both Arm 1 and Arm 2 at the following time points: 1) after 
the first 4 cycles of mFOLFIRINOX; 2) prior to surgery; 3) post-surgery but prior to first cycle of 
FOLFOX; 4) after 4 cycles while on FOLFOX. The baseline and restaging scan after completion of 
preoperative therapy and prior to surgery are to be centrally reviewed by the Alliance ICL at IROC 
Ohio per Section 7.4.2. After protocol treatment, scans should be performed per the schedule 
indicated by footnote “***”. 
D 
Surgery-related AEs should be assessed and captured within 90 days of surgery. 
 
 

Alliance A021501 
26 
Version Date: 10/19/2018 
Update #04 
6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data Collection and Submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA 
Lab Admin, SLA, or Site Investigator) on either the LPO or participating organization roster at 
the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type. To hold the Rave Site Investigator role, the individual must 
be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed. Trainings will be 
in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in 
the upper right pane of the iMedidata screen. 
Users who have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 
    
A Schedule of Forms is available on the Alliance study webpage, within the Case Report Forms 
section. The Schedule of Forms is also available on the CTSU site within the study-specific 
Education and Promotion folder, and is named Time & Events. 
6.1.1 
Supporting Documentation 
This study requires supporting documentation for diagnosis, response, and 
progression. Supporting documentation will include radiology, pathology, and 
surgical operation reports; these must be submitted at the following time points: 
• 
Baseline: Imaging report, pathology/cytology report, clinic note 
• 
Completion of preoperative therapy: Imaging report 
• 
Resection: Operative report, pathology report 
• 
Response: Imaging report  
• 
Progression/relapse/recurrence: Imaging report, and pathology report if 
applicable  
6.2 
Specimen Collection and Submission  
For all patients registered to Alliance A021501: Retrospective histopathology review will be 
conducted using a representative paraffin embedded block of pancreatic tumor from the surgical 
resection specimens. If the surgical resection specimen does not show residual cancer, the 
specimen from the diagnostic biopsy or a representative FNA cytologic slide should be 
submitted in addition to the surgical specimen. The submission of tumor (or diagnostic 
pathology specimen for patients that have a pCR at surgery) for histopathology review is 

Alliance A021501 
27 
Version Date: 10/19/2018 
Update #04 
required for all patients registered to this study, including those who are found to be 
ineligible and those who do not receive protocol therapy. 
For patients registered to substudy A021501-PP1: All participating institutions must ask patients 
for their consent to participate in the correlative substudies planned for Alliance A021501-PP1, 
although patient participation is optional. Biomarker and pharmacogenetic studies will be 
performed. Rationale and methods for the scientific components of this study is described in 
Section 14.1.  
For patients who consent to participate, specimens will be collected at the time points listed in 
the table below: 
 
 
Prior to 
Initiation of 
Treatment 
At surgery 
Storage/ 
Shipping  
Submit to: 
Mandatory for all patients on A021501: 
Paraffin block AND one 
stained H&E slide 
A 
X 
Ambient temp/ 
ship overnight 
WUSTL 
To be submitted ONLY for patients that consent to A021501-PP1*: 
Whole blood1 
(EDTA/lavender top) 
1 x 10 mL 
 
Cool pack/ship 
overnight 
WUSTL 
To be submitted ONLY for patients that consent to biobanking for future research**: 
Paraffin block 
A 
 
Ambient temp/ 
ship overnight 
WUSTL 
 
* 
Patients who consent to A021501-PP1 are those who answer “Yes” to the model consent 
question, “I agree to have my blood specimen collected and I agree that my specimen 
samples and related information may be used for the laboratory studies described above.” 
** Patients who consent to biobanking for future research are those who answer “Yes” to the 
model consent question, “My samples and related information may be kept in a Biobank 
for use in future health research.” 
A 
To be collected any time prior to the initiation of treatment. For patients who have a pCR 
at time of surgery, if possible, please submit at least one H&E slide from pretreatment FNA 
or core biopsy. If possible, please also submit a paraffin-embedded tissue block or block-
alternative (as many unstained slides as possible, up to 10) from the pretreatment FNA or 
core biopsy. For patients who consent to biobanking for future research and who do not 
have a pCR at time of surgery, if possible, please also submit a paraffin-embedded tissue 
block or block-alternative (as many unstained slides as possible, up to 10) from 
pretreatment FNA or core biopsy. For patients who consent to biobanking for future 
research and who do have a pCR at time of surgery, no additional submissions are required 
if a pretreatment specimen was already submitted for mandatory histopathology review. 
See Section 6.2.2 for details. 
1 
For patients who consent to correlative study A021501-PP1, whole blood is to be used for 
pharmacogenomic analyses described in Section 14.1. This tube of blood is preferred to be 
collected prior to the initiation of treatment but can be collected at any time while a 
consented patient is on study. 
6.2.1 
Specimen Submission Using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM 
(BioMS) IS MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND 
SHIPPED VIA THIS SYSTEM.  

Alliance A021501 
29 
Version Date: 10/19/2018 
Update #04 
Following protocol surgery, in the event that the surgical pathology report of the 
resected tumor demonstrates no pathologic evidence of malignancy (i.e. pathologic 
complete response; pCR) or an unexpected histology other than adenocarcinoma, 
the pretreatment diagnostic cytology/pathology specimens and representative 
slides of the resected post-treatment specimen will be requested and reviewed at 
The Ohio State University by the Pathology Co-Chair. 
For all patients who undergo surgery, the following specimens are required to 
be submitted within 60 days of surgical resection: 
• 
One stained H&E slide from the surgical resection specimen 
• 
A paraffin-embedded block or block-alternative (as many unstained slides 
as possible, up to 10) from the surgical resection specimen 
For patients whose resection specimen shows pCR or an unexpected histology 
other than adenocarcinoma, the following specimens are required (if possible) 
to be submitted within 60 days (in addition to the surgical resection specimen): 
• 
One stained H&E slide from the pretreatment FNA/core biopsy tissue 
• 
A paraffin-embedded block or block alternative (as many unstained slides 
as possible, up to 10) from the pretreatment FNA/core biopsy tissue 
For patients who consent to biobanking for future research and whose 
resection specimen does not show pCR or an unexpected histology other than 
adenocarcinoma, if possible, please submit the following within 60 days of 
surgical resection: 
• 
A paraffin-embedded block or block alternative (as many unstained slides 
as possible, up to 10) from the pretreatment FNA/core biopsy tissue 
The de-identified surgical pathology report, coded with the Alliance patient ID 
number, must accompany all tissue specimen submissions. Usually, this is 
generated by obscuring all PHI (names and dates) with white-out or a black magic 
marker, labeling each page of the report with the Alliance patient ID, and 
photocopying the report. 
For patients who consent to future unspecified research (model consent question, 
“My samples and related information may be kept in a Biobank for use in future 
health research”) any unused tumor tissues from histology review will be stored at 
the Alliance Biorepository for later use. 
Block Alternatives: The Alliance has instituted special considerations for the 
small percentage of hospitals whose policy prohibits long-term storage of blocks, 
and the smaller percentage of hospitals whose policies prohibit release of any 
block. If, due to institutional policy, a block cannot be sent, one stained and 10 
unstained slides (or as many as possible) (thickness of 4-5 micron) will be sent to 
the Alliance Biorepository (WUSTL). However, blocks are strongly preferred 
over slides. 
All unstained slides should be labeled with thickness (e.g. 5 micron), the specimen 
surgical pathology number, and block number either via your institution’s standard 
method for labeling clinical slides or using a permanent marker. Labeling with 
sticky labels is not acceptable. 
The goal of the Alliance Biorepository is to provide investigators with quality 
histology sections for their research while maintaining the integrity of the tissue. 
For these reasons it is preferred that the Alliance Biorepository bank the block until 

Alliance A021501 
30 
Version Date: 10/19/2018 
Update #04 
the study investigator requests thin sections. Please contact the Alliance 
Biorepository if additional assurances with your hospital pathology department are 
required. 
6.2.3 
Blood Specimen Submission for A021501-PP1 
For patients who consent to participate, whole blood specimen will be used for the 
pharmacogenomic studies described in Section 14.1. This specimen should be 
collected prior to the initiation of protocol treatment. 
Collect 10 mL of peripheral venous blood in an EDTA (lavender) tube. The tubes 
should be inverted several times to mix the EDTA and refrigerated until shipped 
on cool pack by overnight mail to the Alliance Biorepository at Washington 
University (WUSTL). The specimens should be shipped the same day that the 
blood is drawn in ambient temperature per Section 6.2.1.  
Label specimens with the following identification information: 
1. Procurement Date and Time 
2. Patient Initials 
3. Alliance Patient ID Number 
4. Alliance Study Number (i.e. A021501-PP1) 
5.  Sample Type (i.e. Whole Blood) 
Ship blood per instructions in Section 6.2.1. 
6.3 
Submission of Digital Radiation Therapy Data 
Note: Arm 2 closed to new patient enrollment on 08/13/2018. 
6.3.1 
Digital RT Data Submission Requirements 
Submission of treatment plans in digital format as DICOM RT is required. Digital 
data must include CT scans, structures, plan, and dose files. This study uses TRIAD 
for RT data submission. Use of TRIAD requires several preliminary steps. See 
Section 
4.1.1 
for 
details. 
Additional 
information 
is 
available 
at: 
http://triadhelp.acr.org/ClinicalTrials/NCISponsoredTrials.aspx 
In the event that a site has not completed all steps required for TRIAD data submission 
in time to meet the timeline for pre-treatment review, data submitted via SFTP will 
also be accepted.  See the instructions for submission of data via SFTP on the IROC 
Rhode Island website under Digital Data. 
Any items on the list below that are not part of the digital submission may be included 
with the transmission of the digital RT data. 
One week prior to the start of radiotherapy, the following data shall be submitted 
for pre-treatment review: 
6.3.1.1 Treatment Planning System Output 
RT treatment plans including CT, structures, dose and plan files. These 
items are included in the digital plan. 
Dose volume histograms (DVH) for the composite treatment plan for all 
target volumes and required organs at risk. For all RT plans, a DVH shall 
be submitted for a category of tissue called “unspecified tissue.” This is 
defined as tissue contained within the skin, but which is not otherwise 

Alliance A021501 
33 
Version Date: 10/19/2018 
Update #04 
the entire study should be saved until the scan is accepted by the Imaging 
Core Laboratory. The Imaging Core Lab will notify site and Alliance 
A021501 imaging committee within 2 business days of the data receipt 
as well as within 3 business days of the quality check report upon data 
receipt.  
Sites need to de-identify the patient data using institutional procedures to 
remove patient name and medical record number while preserving the 
Alliance patient ID number (e.g. 112136) and protocol number (e.g. 
A021501), respectively.  
For baseline staging and pre-surgical restaging CT/MR scans, imaging 
data must be submitted to the Imaging Core Lab electronically via 
TRIAD, Web-based data transfer, or FTP data transfer approaches for 
real-time central review purposes. For patients that consent to A021501-
IM1, CT/MRI images will be collected digitally for the research 
described in Section 14.2. 
TRIAD data transfer: see Section 4.1.1 for details. Additional information 
is 
available 
at 
http://triadhelp.acr.org/ClinicalTrials/NCISponsoredTrials.aspx 
6.4.2.2 Web-based Data Transfer 
Any PCs with Internet access can be used to upload images to the Imaging 
Core Lab via this approach. The standard Web access information will be 
provided 
separately 
through 
the 
specific 
trial 
e-mail 
 per the request by participating sites 
before their first data submission. 
6.4.2.3 FTP Transfer 
Any FTP software can be used to upload images to the secure FTP Server 
of the Imaging Core Laboratory. The standard FTP access information 
will be provided separately through the specific trial e-mail 
 per the request by participating sites 
before their first data submission. 
De-identified local scan interpretation reports must be sent along with all 
image submissions. These de-identified reports can be sent to the ICL at 
IROC Ohio via 
 
Send an e-mail notification to inform the Imaging Core Lab at 
 of the imaging data submission once the 
data transfer is complete. Any questions or problems about the data 
transfer to the Imaging Core Lab, call the Core Lab IT group at 
 for help. 
Please note, institutions located in states with dosimetry reporting 
requirements specified by state law must include dosimetry data in the 
final imaging report. 
 
 

Alliance A021501 
34 
Version Date: 10/19/2018 
Update #04 
7.0 
TREATMENT PLAN/INTERVENTION 
NOTE: Arm 2 closed to new patient enrollment on 08/13/2018, and further Arm 2 treatment 
for enrolled patients ceased as of 08/13/2018. 
Protocol treatment is to begin ≤ 14 days of registration. 
For questions regarding treatment, please see the study contacts page.  
It is acceptable for individual chemotherapy doses to be delivered ≤ a 24-hour (business day) 
window before and after the protocol-defined date for Day 1 of a new cycle. For example, if the 
treatment due date is a Friday, the window for treatment includes the preceding Thursday through 
the following Monday. In addition, patients are permitted to have a new cycle of chemotherapy 
delayed up to 7 days for major life events (e.g., serious illness in a family member, major holiday, 
vacation that cannot be rescheduled) without this being considered a protocol violation. 
Documentation to justify this delay should be provided. 
Surgery and imaging will be conducted at the registering institution. Radiation therapy must be 
performed at a radiation therapy facility participating in the IROC monitoring program. 
Chemotherapy may be given at a non-registering institution. All protocol conduct must be followed 
and the registering institution is responsible for ensuring all data is reported per protocol. Please 
refer to the Alliance policy and procedures document posted on the Alliance website for the policy 
on engagement in research by non-registering institutions. If the NCTN Group credited for 
enrollment is a non-Alliance Group, then other requirements from the credited Group may apply. 
Patients will be randomized to either Arm 1 or Arm 2 (closed to new patient enrollment on 
08/13/2018) of the study. Patients will progress through treatment in the absence of any criteria 
described in Section 12.1.3. 
Patients on both Arm 1 and Arm 2 will receive 4 cycles of mFOLFIRINOX and then undergo 
restaging imaging studies, as per Section 7.4.1. These scans are NOT centrally reviewed. 
After the first set of restaging scans, patients who do not show progression on the local read per 
Section 12.1.3 will be treated as follows: patients on Arm 1 will receive 4 additional cycles of 
mFOLFIRINOX, and patients on Arm 2 will receive 3 additional cycles of mFOLFIRINOX and 
then hypofractionated radiotherapy per Section 7.2. These additional cycles of mFOLFIRINOX for 
both Arm 1 and Arm 2 should start within 14 days after cycle 4 day 1 unless dose modifications 
indicate delay. 
After preoperative therapy is completed, patients will be restaged, and, if still considered a surgical 
candidate for resection per the criteria of Section 3.2.1 after central review, will proceed to surgery 
per Section 7.3. Surgery must occur 4 to 8 weeks after last dose chemotherapy (Arm 1) or of 
radiation (Arm 2). 
Patients considered inappropriate for surgery will go off of study treatment, and are to be followed 
per the follow-up schedule provided in the study calendar (Section 5.0). 
Following surgery, patients will receive post-operative chemotherapy with 4 cycles of FOLFOX 
starting 4 to 12 weeks from date of surgery. 
Treatment will continue until disease progression or unacceptable adverse event or inability to 
tolerate treatment even with all allowed dose reductions, or completion of the full treatment 
program and entrance onto clinical follow-up. Also, see Sections 12.1.3 and 12.3 for additional 
information regarding discontinuation of treatment. 
See Section 8.1 for ancillary/concomitant therapy guidelines. 

Alliance A021501 
35 
Version Date: 10/19/2018 
Update #04 
7.1 
Chemotherapy (Arm 1 and Arm 2) 
7.1.1 
Neoadjuvant mFOLFIRINOX 
Arm 1: 8 Cycles of mFOLFIRINOX 
Arm 2: 7 Cycles of mFOLFIRINOX 
1 cycle = 14 days 
A cycle of mFOLFIRINOX is delivered as follows*: 
• 
Oxaliplatin: 85 mg/m2 IV over 2 hours on day 1, followed by, 
• 
Irinotecan: 180 mg/m2 IV over 90 minutes on day 1, followed by, 
• 
Leucovorin**: 400 mg/m2 IV over 2 hours on day 1, followed by, 
• 
5-FU***: 2400 mg/m2 IV over 46-48 hours. 
* 
Minor variations in the timing of mFOLFIRINOX delivery due to 
local institutional policy are allowed so long as dose and dose 
modifications do not vary. 
** Alternatively, leucovorin may be administered concurrently with the 
last 30 min of oxaliplatin, and the entire 90 minutes of irinotecan. 
*** 5-FU is administered via IV infusion only; there is no bolus injection 
of 5-FU. White blood cell growth factor is required after completion 
of 5-FU, administered according to institutional procedures. See 
Section 8.1.9 for further details. 
Table 2. Neoadjuvant mFOLFIRINOX Dosing 
Agent 
Dose 
Route 
Day 
ReRx 
Oxaliplatin 
85 mg/m2 
IV 
Day 1 
every 2 weeks 
Irinotecan 
180 mg/m2 
IV 
Day 1 
every 2 weeks 
Leucovorin 
400 mg/m2 
IV 
Day 1 
every 2 weeks 
Fluorouracil 
2,400 mg/m2 
IV 
Days 1-2 
every 2 weeks 
See Section 7.4 for restaging scan imaging requirements and Section 7.3 for details 
on surgery. 
7.1.2 
Adjuvant FOLFOX 
Arm 1 or Arm 2: 4 Cycles of FOLFOX 
1 cycle = 14 days 
FOLFOX is to be initiated 4 to 12 weeks from date of surgery. 
A cycle of FOLFOX is delivered as follows: 
• 
Oxaliplatin: 85 mg/m2 IV over 2 hours on day 1, followed by, 
• 
Leucovorin: 400 mg/m2 IV over 2 hours (Alternatively, leucovorin may 
be administered (via separate infusion containers) concurrently with 
oxaliplatin), on day 1, followed by, 
• 
5-FU: 400mg/m2 IV bolus, then 2400 mg/m2 continuous IV over 46-48 
hours. 

Alliance A021501 
36 
Version Date: 10/19/2018 
Update #04 
Table 3. Adjuvant FOLFOX Dosing 
Agent 
Dose 
Route 
Day 
ReRx 
Oxaliplatin 
85 mg/m2 
IV 
Day 1 
every 2 weeks 
Leucovorin 
400 mg/m2 
IV 
Day 1 
every 2 weeks 
Fluorouracil 
400 mg/m2 bolus 
then 
2,400 mg/m2 
IV 
Days 1-2 
every 2 weeks 
7.2 
Radiotherapy (Arm 2 Only) 
NOTE: Arm 2 closed to new patient enrollment on 08/13/2018, and further Arm 2 treatment for 
enrolled patients ceased as of 08/13/2018. 
An optional, yet recommended, short online tutorial for radiation planning and treatment is 
available for review. 
• 
Go to the EduCase website – http://www.educase.com 
• 
Register on educase.com by clicking the “Login” tab, “Don’t have an account?” link, 
and complete the required registration information. 
• 
Once logged in, navigate to EduCase > Case Listing. In the right-hand menu, navigate 
to: EduCase > Events > Alliance 
• 
The password is “borderline” 
• 
On the Alliance Case Listing page will be all of the links to optional video tutorials for 
physicians (treatment planning), dosimetry, physics, and therapists. 
• 
There is also a practice case to review contouring of anatomy.  
Patients will receive either: 
• 
Stereotactic body radiation therapy (SBRT)  
or 
• 
Hypofractionated image guided radiation therapy (HIGRT).   
SBRT should be used for all patients (if appropriate) as it is strongly preferred. The 
following are required for patients to be eligible for SBRT: 
• 
Centers delivering SBRT must be credentialed for SBRT (Section 15.1.2). 
• 
Patients with active duodenal or gastric ulcers are not acceptable for SBRT. Patients 
with previous ulcers that have resolved (no active bleeding or symptoms) are acceptable 
for SBRT. 
• 
Patients with direct tumor invasion of the bowel or stomach based on endoscopy are 
not acceptable for SBRT, but may be considered for HIGRT. 
• 
Patients should not be treated with SBRT if SBRT-specific organ at risk (OAR) 
constraints cannot be met; these patients should be considered for HIGRT. 
• 
Patients should have 4D CT simulation to assess tumor motion with respiration 
• 
Patients should be treated with SBRT only if tumor motion can be minimized using 
motion management techniques, when applicable. 
• 
SBRT requires the ability to perform daily image guidance. 
HIGRT should only be considered in the following situations: 
1. Centers that are not credentialed for SBRT may treat with HIGRT if appropriately 
credentialed (Section 15.1.2). 
2. Direct tumor invasion of the bowel or stomach on endoscopy is acceptable for HIGRT.   

Alliance A021501 
37 
Version Date: 10/19/2018 
Update #04 
3. Active duodenal or gastric ulcers are not acceptable for HIGRT. Patients with previous 
ulcers that have resolved are acceptable. This must be confirmed at the time of fiducial 
placement.  
Regardless whether SBRT or HIGRT is used, this protocol requires pre-treatment 
review of the contours and plan PRIOR TO DELIVERY of radiation treatment for all 
patients. See Section 6.3 for pre-treatment review requirements. See Section 15.1.2 for 
the credentialing requirements for this study. 
7.2.1 
Radiotherapy Technical Factors and Treatment Planning  
• 
Only ≥ 6 MV photons are permitted for HIGRT and SBRT. 
• 
Particle therapy is not permitted. 
Fiducial marker placement must be attempted for all patients receiving 
HIGRT and SBRT as described below: 
• 
1-5 (preferably ≥ 3) fiducial markers should be placed for targeting 
purposes. Examples of markers include Civco, Visicoil, and Gold anchor 
(see Appendix V for ordering information on these marker examples). 
• 
The fiducial markers will be placed in or directly at the tumor periphery 
and/or within 1 cm of the tumor (normal pancreas) under endoscopic 
ultrasound (preferred) or CT guidance. 
• 
Fiducials may be implanted prior to enrollment or during a planned 
research biopsy as this is an acceptable standard of care procedure for any 
patient receiving RT for localized pancreatic or periampullary cancer. If 
fiducials are not placed prior to enrollment, it is recommended that they 
be placed during either the 5th or 6th cycle of FOLFIRINOX. 
• 
The fiducial markers will be used as surrogates for targeting the daily 
tumor position during treatment.  
• 
In the rare event when fiducials cannot be placed, the patient can receive 
HIGRT alone per local PI discretion.  
CT simulation is done in the supine position with a customized immobilization 
device. 
• 
Simulation should not be done on the same day as fiducial marker 
placement.  An interval of at least 12 hours is required between fiducial 
marker placement and simulation.  
• 
Patients will be positioned supine, arms above the head, in an Alpha 
Cradle and wing board or equivalent immobilization device that will be 
custom-made for each patient. 
• 
Patients should be NPO 3 hours prior to CT simulation and treatment.  
• 
Administration of IV and oral contrast or water during simulation is highly 
recommended for target and normal tissue delineation unless patient has a 
contrast allergy refractory to premedication. If IV contrast is not available 
during simulation, a recent IV contrast CT scan or MRI should be fused 
with the non-contrast simulation scan. A pretreatment renal scan to assess 
kidney differential will be performed prior to initiation of treatment as 
clinically appropriate. 
• 
A 4D CT scan (when available) will be performed to assess respiratory 
motion. If 4D CT scan is not available then fluoroscopy on the treatment 
machine or simulator can be used to determine maximal motion based on 

Alliance A021501 
38 
Version Date: 10/19/2018 
Update #04 
the fiducial marker.  If > 5 mm of tumor motion in any direction is noted, 
then the use of respiratory motion management (i.e. breath-holding 
technique, respiratory tracking, abdominal compression or gating) is 
recommended. If ≤ 5 mm of tumor motion, respiratory motion 
management is still recommended, but not required. 
• 
MRI or PET simulation may be performed in the treatment position and 
later fused to the CT simulation scan to assist in target volume delineation, 
but this is not required. 
7.2.1.1 HIGRT/SBRT Treatment Planning  
See the tutorial for examples of contouring the tumor, vessels, and organs 
at risk (OARS). 
Organs at Risk (OARs):  Follow the upper abdominal contouring atlas 
located:https://www.rtog.org/CoreLab/ContouringAtlases/UpperAbdom
inalNormalOrganContouringConsensusGuidelines.aspx 
o The diagnostic CT, respiratory-correlated 4D-CT scan, pancreas 
protocol CT, MRI, and/or FDG-PET/CT scan (when available) 
should be reviewed to facilitate accurate delineation of the gross 
tumor volume (GTV) and the tumor vessel interface (TVI). See 
below for definition. 
o Review of these contours in the axial, coronal, and sagittal view 
with a radiologist who has expertise in pancreatic cancer is 
encouraged. 
o The spinal cord, bilateral kidneys, liver, stomach, duodenum, and 
other small bowel should be contoured carefully. Spleen should 
also be contoured and added as an OAR, although no formal dose 
constraint will be used for spleen. 
o Radiation dose to OARs must be minimized. 
Target Volumes Definitions for HIGRT and SBRT: 
o GTV = gross tumor on free breathing scan 
o iGTV = GTV, accounting for motion. Contoured and/or expanded 
on all phases of the breathing scan or breath-hold scan(s). 
o TVI = tumor vessel interface contoured for each vessel separately 
at level of tumor 
 
The TVI will include the segment of portal vein (PV), 
superior mesenteric vein (SMV), superior mesenteric 
artery (SMA), common hepatic artery (CHA), and/or 
celiac artery that is in direct contact with tumor.  
 
TVI structures will be contoured to include the entire 
radial extent of any vessel that contacts the tumor. For 
example, the SMA TVI will include the entire 360⁰ extent 
of SMA at that level even if there is only 90⁰ involvement 
of the SMA by tumor. This radial contour should extend 
superiorly and inferiorly on each axial slice where there 
is GTV contoured (see tutorial for full explanation).  

Alliance A021501 
39 
Version Date: 10/19/2018 
Update #04 
 
Contour the TVI on the “primary” scan (usually the 
contrast enhanced scan), and then expand the iTVI as 
necessary based on the breathing phases of the 4D-CT 
(which are pulled in as secondary scans) or on the breath 
hold scan(s).  
o iTVI = TVI, accounting for motion. Contoured and/or expanded 
on all phases of the breathing scan or breath-hold scan(s). 
o PRVGi = planning risk volume = (duodenum + small bowel + 
stomach) + 3 mm 
 
For PRVGi, contour small bowel, duodenum, and stomach 
on the free breathing scan or breath-hold scan if used for 
planning 
Dose Prescription and Constraints:  
o SBRT: A simultaneous integrated boost will be used to treat 
PTV1, PTV2, and PTV3. 
 
PTV1= (iGTV + iTVI) + 3 mm = 25 Gy in 5 fractions 
 
PTV2= PTV1 – PRVGi = 33 Gy in 5 fractions 
 
PTV3= (iTVI + 3 mm) –PRVGi = 36 Gy in 5 fractions  
 
For PTV1 Dmin > 22.5 Gy, for PTV2 Dmin > 29.7 Gy, 
and for PTV3 Dmin > 32.4 with a maximum of 40 Gy 
 
Note: If the goals above for SBRT cannot be met within 
the Variation Acceptable range (see Section 7.2.2.1), the 
patient should be treated with HIGRT. 
o HIGRT: 
 
PTV1= (iGTV + iTVI) + 3 mm = 25 Gy in 5 fractions 
 
≥ 95% PTV1 should be covered by ≥ 95% Rx dose, 110% 
max (Rx dose is 5 Gy x 5). 
o The following dose constraints must be met for the stomach, 
duodenum, and other small bowel: V20 < 20cc. V20 is defined as 
the absolute volume receiving less than 20 Gy. No more than 1cc 
of the duodenum, other small bowel, or stomach may exceed 35 
Gy. The remainder of the constraints are outlined in the tables 
below: 
SBRT Required OARs and Dose Constraints: 
Description 
Planning System Name 
Constraints 
(iGTV + iTVI) + 3 mm 
PTV1 
PTV1: 25 Gy, Dmin > 22.5 Gy 
PTV1-PRVGi 
PTV2 
PTV2: 33 Gy, Dmin > 29.7 Gy 
(iTVI + 3 mm) – PRVGi 
PTV3 
PTV3: 36 Gy, Dmin > 32.4 (maximum 
of 40 Gy) 
OAR 
 
Constraints 
Duodenum 
Duodenum 
V20 < 20cc 
 
 
V35 < 1cc 
Small Bowel (other) 
Bowel 
V20 < 20cc 

Alliance A021501 
40 
Version Date: 10/19/2018 
Update #04 
 
 
V35 < 1cc 
Stomach 
Stomach 
V20 < 20cc 
 
 
V35 < 1cc 
Liver 
Liver 
V12 < 50% 
Combined Kidneys 
Kidneys 
V12 < 25% 
Spinal Cord 
Spinal_Cord 
V20 < 1cc 
Spleen 
Spleen 
No constraint 
 
HIGRT Required OARs and Dose Constraints: 
Description 
Planning System Name 
Constraints 
(iGTV + iTVI) + 3 mm 
PTV1 
≥ 95% PTV1 should be covered by     
≥ 95% Rx dose, 110% maximum 
(Rx dose is 5 Gy x 5) 
Right Kidney 
Kidney_R 
70% one kidney less than 15 Gy 
Left Kidney 
Kidney_L 
70% one kidney less than 15 Gy 
Liver 
Liver 
Mean < 15 Gy 
Spinal Cord 
Spinal_Cord 
V20 < 1cc 
Small Bowel (other) 
Bowel 
V27.5 < 1cc 
 
 
V20 < 30cc 
Duodenum 
Duodenum 
V27.5 < 1cc 
 
 
V20 < 30cc 
Stomach 
Stomach 
V27.5 < 1cc 
 
 
V20 < 30cc 
Spleen 
Spleen 
No constraint 
Fiducials/Clips: 
o Fiducials and/or clips should be contoured separately starting 
superiorly and moving inferiorly in numeric order. It is often 
easier to delineate them in the bone window. The stent can also 
be contoured for reference, but the fiducials should be the 
primary surrogate for tumor motion and localization. 
o If treating free-breathing, the fiducials should be contoured at the 
two extreme phases of the breathing cycle on 4D CT to outline 
the range of motion during breathing. 
o The fiducial volumes should be expanded 3 mm to create “fiducial 
exp.” 
o Note: If insurance does not cover fiducial placement, HIGRT only 
will be allowed. 
Clinical Target Volume (CTV):  
o Because elective nodal irradiation will NOT be performed for 
either SBRT or HIGRT, a CTV will NOT be defined. 
Treatment Technique: 
o HIGRT: 3D conformal radiation therapy (3DCRT), static IMRT, 
or volumetric arc therapy (VMAT) are all permissible techniques 
for HIGRT. Flattening Filter Free (FFF) treatment is allowed. 

Alliance A021501 
41 
Version Date: 10/19/2018 
Update #04 
o SBRT: Due to the close proximity of OARs (especially GI 
luminal structures) to the PTV and TVI, static IMRT or VMAT 
must be used; 3DCRT is not permissible. It is recommended that 
6-12 co-planar static IMRT fields or 1-3 arc fields 
(VMAT/Rapid-Arc) be used in the radiation treatment plan. 
Flattening Filter Free (FFF) treatment is allowed. CyberKnife is a 
permissible technique for treatment delivery but must be 
credentialed individually. See Section 15.1.2 for credentialing 
instructions 
o HIGRT and SBRT:  HIGRT and SBRT treatment plans will be 
developed using commercially available systems based on 
tumor geometry and location. Institutional standards for radiation 
quality assurance and radiation delivery will be utilized (see 
Section 
6.3 
for 
protocol-specific 
Quality 
Assurance 
Documentation). 
Motion Management: 
o Motion management using respiratory gating or breath-hold 
(active breathing control), (Varian, Elekta, Novalis), respiratory 
tracking (CyberKnife), or abdominal compression can reduce 
cranial-caudal fiducial marker motion from typically 11-22 mm 
peak to ≤ 5 mm.   
o Use of respiratory gating, ABC, or respiratory tracking 
requires real time cone beam CT, fluoroscopy, or KV imaging to 
confirm fiducial location during treatment.   
o If tumor/fiducial marker motion is > 5 mm despite the use of 
abdominal compression and/or other motion management 
techniques listed above are not available, then patients should 
receive HIGRT instead of SBRT (see Section 7.2.1). 
o The selection of which radiotherapy treatment machine to use is 
left to each investigator. As long as the specified dosimetric 
parameters for SBRT are reached, patients may be treated on any 
IGRT-enabled machine. 
o HIGRT: Motion management described above should be used 
when possible for HIGRT, but is not required. At a minimum daily 
port films aligned to spine should be performed. 
o SBRT: Cranial-caudal tumor motion must be limited to ≤ 5 mm 
in all directions and motion management techniques should be 
used to achieve this when applicable. 
7.2.1.2 HIGRT/SBRT Treatment Schedule 
All patients must start HIGRT or SBRT within 6 weeks of the simulation 
scan. RT should begin ≥ 5 days after the last dose of chemotherapy. 
7.2.1.3 HIGRT/SBRT Treatment Delivery 
Patients will receive 5 once daily fractions of HIGRT or SBRT given over 
1-2 weeks.  It is preferred that all 5 fractions be delivered in consecutive 
daily fashion, starting on a Monday and ending on a Friday. It is 

Alliance A021501 
42 
Version Date: 10/19/2018 
Update #04 
acceptable for fractions to be delivered every other day, such that at least 
2 or 3 fractions per week are delivered. 
Patients may be treated on any image-guided (IGRT)-enabled machine. 
Synchrony respiratory tracking will be required for all patients treated 
with CyberKnife. 
For SBRT and HIGRT, patients should be instructed to be NPO at least 
3 hours prior to each fraction. 
For SBRT and HIGRT, initial patient positioning will be based on 
volumetric kV or cone-beam CT imaging with shifts to bony anatomy at 
the level of the tumor as appropriate. 
Orthogonal kV/MV, kV/kV projection, or CBCT imaging will be used to 
verify the location of the fiducials prior to delivery of the first treatment 
beam. A secondary shift based on the location of fiducials should be 
utilized, as indicated by the position of the fiducials.  For free-breathing 
treatments, kV fluoroscopic images should be obtained to confirm the 
anticipated position of the fiducials (fiducial ITV) during the entire 
respiratory cycle. 
For SBRT and HIGRT, active monitoring of treatment delivery accuracy 
will be accomplished using kV and/or MV projection imaging, either 
immediately before or during all (or a subset of) treatment fields. 
For SBRT and HIGRT, patient-specific dosimetric quality assurance 
(QA) will be performed as per standard practice. 
7.2.2 
Compliance Criteria 
7.2.2.1 Prescription Dose 
Variation Acceptable (SBRT): 
o PTV1  
 
Between 85-95% of PTV1 is covered by ≥ 95% of the Rx 
dose (Rx dose is 5 Gy x 5) 
 
Maximum is 110% of the Rx dose 
 
Dmin between 20 and 22.5 Gy 
o PTV2  
 
Between 90-95% of PTV2 is covered by ≥ 95% of the Rx 
dose (Rx dose is 6.6 Gy x 5) 
 
Maximum is 110% of the Rx dose  
 
Dmin between 27 and 29.7 Gy 
o PTV3  
 
Between 90-95% of PTV3 is covered by ≥ 95% of the Rx 
dose (Rx dose is 7.2 Gy x 5) 
 
Maximum is 110% of the Rx dose 
 
Dmin between 30 and 32.4 Gy 
o Small bowel, duodenum, or stomach  
 
V20 between 20-40cc  
Deviation Unacceptable (SBRT):  
o PTV1  

Alliance A021501 
43 
Version Date: 10/19/2018 
Update #04 
 
< 85% of PTV1 is covered by ≥ 95% of the Rx dose (Rx 
dose is 5 Gy x 5) 
 
Dmin < 20 Gy 
o PTV2  
 
< 90% of PTV2 is covered by ≥ 95% of the Rx dose (Rx 
dose is 6.6 Gy x 5) 
 
Dmin < 27 Gy 
o PTV3  
 
< 90% of PTV3 is covered by ≥ 95% of the Rx dose (Rx 
dose is 7.2 Gy x 5) 
 
Dmin < 30 Gy 
o Small bowel, duodenum, or stomach  
 
V20 > 40cc 
Note: If there is any unacceptable deviation, then the patient should 
receive HIGRT. 
Variation Acceptable (HIGRT): 
o PTV1 
 
Between 90-95% of PTV1 is covered by ≥ 95% of the Rx 
dose (Rx dose is 5 Gy x 5) 
 
Maximum is 110% of the Rx dose 
o Small bowel, duodenum, or stomach 
 
V20 > 50cc 
Deviation Unacceptable (HIGRT): 
o < 90% of  PTV1 is covered by ≥ 95% of the Rx dose (Rx dose is 
5 Gy x 5) 
7.2.2.2 Volume 
Deviation Unacceptable:  
1. Incomplete contouring of the entire GTV or PTVs;  
2. Use of different margins than specified for the PTV;  
3. Over-contouring of the GTV by > 30cc (15cc if it results in 
inclusion of extra duodenum, small intestine, or stomach);  
4. Incorrect contouring of the duodenum, stomach, or small intestine 
that results in > 15cc overlap of the PTV with the OAR. 
7.2.2.3 Treatment Interruptions 
Per Protocol: All treatments occur within 15 calendar days. 
Variation Acceptable: All treatments occur within 16 to 21 calendar days. 
Deviation Unacceptable: All treatments take 22 or more calendar days to 
complete. 

Alliance A021501 
45 
Version Date: 10/19/2018 
Update #04 
chemotherapy and/or radiation. It is presumed that multidisciplinary teams enrolling patients on 
this study will have surgeons with significant experience in the management of these tumors. At 
a minimum, surgeons operating in the context of this study should be skilled and credentialed at 
their institution to perform vascular resection in addition to performing pancreatic surgery, 
and/or should team with a transplant or vascular surgery colleague who themselves are skilled 
and credentialed to perform vascular portions of the operations. 
7.3.1 
Surgical Quality Assurance  
7.3.1.1 General Considerations 
Pancreaticoduodenectomy should occur within 4-8 weeks after the last 
dose of chemotherapy (Arm 1) or preoperative radiation (Arm 2). Staging 
laparoscopy may be performed at the time of planned laparotomy but is 
not 
required. 
Either 
standard 
or 
pylorus-preserving 
pancreaticoduodenectomy may be performed. Surgical drains and enteral 
tubes (e.g. gastrostomy and/or jejunostomy tubes) may be placed at the 
discretion of the operating surgeon. 
The operation should be performed in accordance with techniques 
espoused in the first edition of Operative Standards for Cancer Surgery, 
published by the American College of Surgeons and the Alliance for 
Clinical Trials in Oncology [37]. 
7.3.1.2 Specific Considerations 
Exploration of the peritoneal cavity should include evaluation for 
radiographically occult macroscopic peritoneal or hepatic metastases. 
Lymph node sampling or frozen section lymph node biopsy is not 
required or recommended as part of the intraoperative assessment for 
extra-pancreatic disease, and is at the discretion of the surgeon. 
A standard lymphadenectomy should be performed routinely, to include 
lymph node stations 8a, 12a2, 12p2, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, 
17b, as depicted in Appendix IV. Other lymph node stations dissected 
should be detailed if performed in the operative report. 
The retroperitoneal dissection along the medial edge of the uncinate 
process and the right lateral border of the superior mesenteric artery 
(SMA) is believed to be an important oncologic part of the operation. All 
soft tissue to the right of the SMA should be removed. This requires 
exposure and dissection along the right lateral border of the SMA. 
Vascular resection and/or reconstruction of the superior mesenteric vein, 
portal vein, SMA/portal vein confluence, or hepatic artery will be 
performed at the discretion of the operating surgeon. In general, vascular 
resection should be performed when necessary to achieve an R0 
resection. The operating surgeon or a vascular/transplant surgeon consult 
can perform this reconstruction. The technical details of the operation 
should be delineated in the operative report. 
7.3.1.3 Intraoperative Frozen Section Assessment of Surgical Margins   
Frozen section evaluation of the pancreatic parenchymal and hepatic (or 
bile) duct margins should be performed. In the event of a positive frozen 
section margin at either of these loci, further resection in an effort to 

Alliance A021501 
46 
Version Date: 10/19/2018 
Update #04 
achieve microscopically negative margins should be performed if 
possible. However, the extent of additional parenchymal resection should 
be left to the discretion of the operating surgeon. 
The superior mesenteric arterial (SMA) margin should be evaluated on 
permanent section only. 
7.3.1.4 Specimen Orientation for Surgical Pathology 
The surgeon should ensure that the specimen is oriented for the surgical 
pathologist. Any segment of resected vascular structure (e.g. superior 
mesenteric or portal vein) should be identified and marked. Relevant 
margins evaluated by intraoperative frozen section (i.e. the hepatic (bile) 
duct, and pancreatic parenchymal) should be identified. The SMA margin 
(the soft tissue immediately adjacent to the SMA) should be separately 
inked using the principles outlined in the 8th edition AJCC staging system 
for exocrine pancreatic cancer. Note: The SMA margin cannot be 
identified accurately after the specimen has been fixed in formalin or after 
the specimen has been dissected for histopathologic analysis.   
7.3.1.5 Aborting Surgery 
The planned resection should be aborted if the operating surgeon 
identifies: 
1. Metastatic disease in distant organs (e.g. liver). Presumed disease 
should be biopsied and confirmed as metastatic cancer on frozen 
section. 
2. Localized cancer that is nonetheless, in the opinion of the 
operating surgeon, unsafe to resect. In such cases, the specific 
reasons for aborting the operation should be enumerated in the 
operative report. 
7.3.1.6 Operative Note Dictation and Editing: Resection Classification 
The attending surgeon should dictate the operative note. The operative 
report should contain:  
• 
A section detailing the operative findings with respect to the 
extent of disease and the primary tumor anatomy.   
• 
A statement as to whether or not the surgeon believes there is 
residual macroscopic tumor following completion of the 
resection.  
The surgeon should integrate the operative findings with the microscopic 
surgical margins reported on the final pathology report in order to assign 
a resection classification prefix of R0, R1, or R2 (defined below). 
Whenever possible, this prefix should be added to the final operative note 
before finalizing the document. An example of the final procedure 
description for a patient who underwent macroscopically complete tumor 
removal with a positive SMA margin on permanent section final 
pathology is: “R1 pylorus-preserving pancreaticoduodenectomy.” The 
definitions for the resection classification that should be utilized in 
operative notes include:  

Alliance A021501 
47 
Version Date: 10/19/2018 
Update #04 
• 
R0 – macroscopically complete tumor removal with negative 
microscopic surgical margins (bile duct, pancreatic parenchyma, 
and SMA margins)   
• 
R1 – macroscopically complete tumor removal with any positive 
microscopic surgical margin (bile duct, pancreatic parenchyma, or 
SMA margins)   
• 
R2 – macroscopically incomplete tumor removal with known or 
suspected residual gross disease  
7.3.1.7 Surgical Pathology 
A local pathologist experienced in the diagnosis of pancreatic 
adenocarcinoma should carry out pathological examination of the 
resected pancreatic tumor specimen. Following local review, a tissue 
block will be sent for central re-review. See Section 6.2.2. 
Three primary margins (bile duct, pancreatic neck, and SMA) should be 
identified and inked by the surgeon and/or pathologist. Any segment of 
resected vascular structure (e.g. superior mesenteric or portal vein) 
should be identified and marked. The SMA margin (that tissue 
immediately adjacent to the SMA) should be separately inked according 
to the procedures and recommendations of the American Joint 
Commission on Cancer 8th edition staging system and the College of 
American Pathologists guidelines for reporting of resected exocrine 
pancreatic cancer (2012). The tumor should be thoroughly sampled (at 
least one section per 1 mm of greatest tumor dimension, taken 
perpendicular to the inked SMA margin). The distance between the 
closest tumor cell and the inked SMA margin (the “SMA margin 
distance”) should be reported.  
7.3.1.8 Frozen Section Assessment of Margins  
Section assessment of bile duct and pancreatic neck margins should be 
performed by the local pathologist in all cases as requested by the 
surgeon. 
7.3.1.9 Permanent Section Assessments and Final Pathology Report 
The pathology report should contain all of the elements outlined in the 
College of American Pathologists guidelines for reporting of resected 
exocrine pancreatic cancer (2012). In particular, there should be specific 
comment on:  
• 
Histologic diagnosis with comment on the cell of origin 
(pancreatic vs. bile duct vs. ampulla)   
• 
Degree of differentiation (well, moderate, poor)   
• 
Total number of lymph nodes examined   
• 
Number of positive nodes   
• 
Final margins status for the bile duct, pancreatic parenchymal, and 
SMA margin   
• 
Distance (in mm) from the tumor to the inked SMA margin   

Alliance A021501 
48 
Version Date: 10/19/2018 
Update #04 
• 
Extent of tumor infiltration (if present) of the blood vessel wall 
for any resected major blood vessels including the maximum 
histologic depth of invasion (e.g. adventitia, media).   
7.3.1.10 Central Re-review of Resected Tumor Specimen 
Representative slides should be sent for central re-review to standardize 
determination of both treatment effect score and tumor grade. 
Treatment effect score will be determined using the following system:  
• 
Treatment Effect Score I - 0% residual tumor cells in the specimen 
(pCR) 
• 
Treatment Effect Score II - 1 to < 5% residual tumor cells in the 
specimen   
• 
Treatment Effect Score III - ≥ 5% residual tumor cells in the 
specimen  
7.3.2 
Definitions of Variations in Surgical Performance  
Minor Variations 
The following will be considered minor surgical variations:  
• 
Failure to perform a frozen section of bile duct or pancreatic neck margins 
at the time of surgery.   
• 
Documentation of an incomplete dissection of uncinate off of SMA. 
• 
Documentation of a lymphadenectomy less extensive than that described 
above. 
7.3.3 
Surgical Quality Control 
Sites scheduling patients for surgery should notify the study chair of their intent to 
operate at the time the operation is scheduled. This notification should consist of 
an email to the study chair with the Alliance patient ID number and date of surgery, 
along with contact information of the site treating surgeon and credited study PI 
on the OPEN form. 
For all patients who undergo surgery during protocol treatment (including 
resection or not), the Study Chair and Surgical Co-chair will review the 
preoperative CT scan, the operative note, the surgical pathology report, and the 
adverse events associated with surgery (30 days postoperative) within 60 days of 
surgery. This requires that sites upload the required source documentation in a 
timely manner (see Section 6.1.1), and complete the AE CRF without delinquency. 
Specific attention will be paid to deviations as listed above, as well as adverse 
events that occur in association with surgery. Operative reports and outcomes 
which, in the opinion of the Study Chair and Surgical Co-chair, raise potential 
patient safety concerns will be discussed and reviewed with the credited study PI 
immediately. Two operations which lead to such a discussion may lead to the site 
being restricted from enrolling future patients. 
 
 

Alliance A021501 
49 
Version Date: 10/19/2018 
Update #04 
7.4 
Imaging 
7.4.1 
Imaging Guidelines 
CT scans are the preferred imaging modality, and the images should be collected 
both with and without contrast, if possible. MRI scans are allowed, and they can 
be used if, for example, the patient is allergic to contrast or has renal insufficiency 
or other medical contraindication to contrast. This study requires a baseline 
calculated creatinine clearance of at least 45 mL/min for eligibility. Caution should 
be exercised with iodine-based contrast and gadolinium contrast for patients with 
limited renal function. Investigators should follow standard safety guidelines and 
local institutional policies and discuss with the Study Chair when there is concern 
about the use of imaging contrast agents. Chest scans must be CT or chest X-ray. 
Abdominal baseline and restaging scans can include either a CT or MRI. The same 
method of scanning used at baseline must be used for all subsequent evaluations. 
Sites are to use their optimal preoperative image acquisition protocol to optimize 
their ability to interpret the scans. 
7.4.1.1 CT Scan 
Dual phase imaging 
• 
Slice thickness: No thicker than 3mm images (however, a set of 
axial images 2-3 mm for review of each phase is needed). Thinner 
images, if obtained, should also be submitted (in case 
reconstructions are needed).  
• 
Injection rate: Faster is preferable, but whatever the injection rate, 
the duration of the injection should be at least 30 seconds (in order 
to image during the pancreatic parenchymal phase, and given an 
average cardiac circulation time of 13-16 seconds). Injection rates 
should be 3-5cc/second (unless poor IV access requires slower 
injection times).  
• 
Pancreatic parenchymal phase: Imaging of the abdomen (whether 
the entire abdomen, or just of the pancreas) should finish 
approximately 45-50 seconds after contrast injection terminating 
below the level of the horizontal course of the duodenum.  
• 
Portal venous phase: Imaging of the entire abdomen, to begin 55-
70 seconds after the start of contrast injection, to cover the liver, 
and pancreas to the level of the iliac crest.  
• 
For both phases, coronal and sagittal reconstructions (2-3 mm 
thick, every 2-3 mm) are encouraged, but optional. 
NOTE: Separate/dedicated CTs of chest/upper abdomen must be 
obtained at all required time points. 
7.4.1.2 Chest Scans 
• 
Lung lesions should be excluded with CT of the chest or chest X-
ray. 

Alliance A021501 
50 
Version Date: 10/19/2018 
Update #04 
7.4.1.3 Pre-contrast Imaging  
1. SSFSE/ HASTE T2 coronal scouts 5-8 mm thickness (with or 
without breath-hold, per institutional standards).  
2. In-Out phase T1 breath-hold T1 GRE (4-6 mm thickness) to cover 
liver and pancreas.  
3. Out- phase T1 GRE with or without fat sat (4-5 mm thickness) for 
pancreas only.  
4. Respiratory Triggered FSE T2 weighted images (4-6 mm 
thickness for liver and pancreas).  
5. 2D or 3D MRCP sequence for the pancreas as performed in your 
institution.  
7.4.1.4 Contrast Scanning  
• 
Sequence- 3D or 2D VIBE or SPGR/ LAVA T1 GRE (2-6 mm 
thickness, not > 7 mm for 2D sequence) acquired preferably in the 
coronal or axial plane. First acquire a non-contrast sequence for 
confirming the coverage and quality.  
• 
Inject Gd-chelate MR contrast volume with weight-based dosing 
according to the product label @ 2cc/sec.  
• 
Dynamic scanning using a 3D or 2D VIBE or SPGR/ LAVA T1 
GRE (2-6 mm thickness) is then performed in the same plane as 
the pre-contrast scanning at 20/70/180 seconds delay after contrast 
medium injection.  
• 
Axial and coronal T1 out-phase T1FS GRE/VIBE through the 
liver and pancreas (same thickness as dynamic above). If needed 
use two sequences to cover the anatomy. 
7.4.2 
Central Review of Scans 
Scans should be submitted to the ICL as outlined in Section 6.4. There are 2 real-
time scans that are reviewed by a central radiologist, which will be the reading 
utilized to make decisions on the protocol. If there are any uncertainties or the 
participating site disagrees with the first central review result, a second review by 
either another central reviewer or an adjudicator will be performed. This process 
may take additional 24-48 hours turnaround time, and such review result will be 
used as the final decision for the outcome determinations. 
The 1st real-time review is a determination of whether the patient has borderline 
resectable pancreatic cancer. If the review determines the patient is eligible, then 
registration procedures are followed per Section 4.4. 
The 2nd real-time review takes place after preoperative therapy completion, and is 
a determination of whether the tumor is potentially resectable.  
If the patient does NOT have borderline pancreatic cancer by central review, then 
they are not eligible for the study and are deemed a screen failure. The expected 
rate of screen failures is provided in Section 13.2. If they are designated by the 
central reviewer to have borderline pancreatic cancer, then they meet eligibility 
criteria as per Section 3.2.1.  

Alliance A021501 
51 
Version Date: 10/19/2018 
Update #04 
The 2nd real-time review takes place after preoperative therapy completion, and is 
a determination of whether the tumor is potentially resectable.  If the 2nd central 
review determines that the tumor meets criteria for resection, the IROC Ohio 
notifies the site via email, and the reviewer enters the data into Rave. The patient 
should then proceed to surgery as per Section 7.3. 
If the review determines the patient is NOT potentially resectable, then the patient 
should be removed from protocol therapy, and followed as per Section 5.0, post-
treatment follow-up. Protocol treatment will be discontinued and further treatment 
is at the discretion of the treating physician. See Section 12.0 for further details.  
8.0 
DOSE AND TREATMENT MODIFICATIONS 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other agent which would be considered treatment 
for the primary neoplasm or impact the primary endpoint. 
8.1.2 
Patients should receive full supportive care while on this study. 
This includes blood product support, antibiotic treatment, and treatment of other 
newly diagnosed or concurrent medical conditions. All blood products and 
concomitant medications such as antidiarrheals, analgesics, and/or antiemetics 
received from the first day of study treatment administration until 30 days after the 
final dose will be recorded in the medical records. 
8.1.3 
Treatment with hormones or other chemotherapeutic agents may NOT be 
administered except for steroids given for adrenal failure; hormones administered 
for non-disease-related conditions (e.g. insulin for diabetes); and intermittent use 
of dexamethasone as an antiemetic in solid tumor protocols. 
8.1.4 
Antiemetics may be used at the discretion of the attending physician, with the 
exception of steroids above. 
As this regimen has high emetogenic potential, it is suggested that all subjects on 
study should receive an aggressive prophylactic antiemetic regimen, consisting of 
a 5HT-3 antagonist, steroid, and NK1 antagonist.  
8.1.5 
Diarrhea management is per the discretion of the treating physician. 
This regimen has a high incidence of severe diarrhea. For symptoms of diarrhea 
(and/or abdominal cramping) that occur at any time during a treatment cycle, it is 
suggested that patients should be instructed to take an anti-diarrheal, such as 
loperamide. It is recommended that the anti-diarrheal should be started at the 
earliest sign of: (1) a poorly formed or loose stool; (2) an increase in bowel 
movements by 1 to 2 episodes per day compared to baseline, or (3) an increase in 
stool volume or liquidity. Additional anti-diarrheal measures may be implemented 
at the discretion of the treating physician. Patients should also be instructed to 
increase fluid intake to help maintain fluid and electrolyte balance during episodes 
of diarrhea, and IV fluids should be considered for severe diarrhea, at the discretion 
of the treating physician. 
8.1.6 
Antibiotics 
Prophylactic oral antibiotic therapy is not recommended to be given at the start of 
study treatment. However, antibiotics should be considered for patients who have: 

Alliance A021501 
52 
Version Date: 10/19/2018 
Update #04 
(a) endobiliary stent(s) with an ANC that falls below 500 mm3 or have fever; (b) 
diarrhea persisting for more than 48 hours despite treatment or fever with diarrhea. 
8.1.7 
Anticoagulants 
Due to drug interactions, treatment dose warfarin for goal INR > 1.5 is not 
recommended. Other anticoagulants are recommended to be used for prophylaxis 
and treatment. 
8.1.8 
Palliative radiation therapy may not be administered while a subject is on the 
study. 
8.1.9 
Alliance Policy Concerning the Use of Growth Factors 
Please note that during pre-surgical FOLFIRINOX treatment, WBC growth factors 
are required (see Section 7.1.1). During post-surgical FOLFOX, WBC growth 
factors are NOT required and may be used at the discretion of the physician. 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors 
should follow published guidelines of the American Society of Clinical Oncology 
Recommendations for the Use of WBC Growth Factors Update.  Journal of 
Clinical Oncology 33(28): 3199-3212, 2015. 
The use of erythropoiesis–stimulating agents (ESAs) is allowed at the discretion 
of the treating investigator. If an ESA is used, it should be within the context of 
the most current guidelines. 
The use of prophylactic white blood cell growth factor support is required for all 
study subjects, beginning with the first treatment cycle and administered as per 
established institutional guidelines. The use of biosimilar WBC growth factor 
products is acceptable.  
Filgrastim (G-CSF) tbo-filgrastim, and sargramostim (GM-CSF) 
1. Filgrastim (G-CSF)/pegfilgrastim, tbo-filgrastim and sargramostim 
(GM-CSF) treatment for patients on protocols that do not specify 
their use is discouraged. 
2. Filgrastim/pegfilgrastim, tbo-filgrastim and sargramostim may not 
be used: 
a) To avoid dose reductions, delays or to allow for dose escalations 
specified in the protocol. 
b) For the treatment of febrile neutropenia the use of CSFs should 
not be routinely instituted as an adjunct to appropriate antibiotic 
therapy. However, the use of CSFs may be indicated in patients 
who have prognostic factors that are predictive of clinical 
deterioration such as pneumonia, hypotension, multi-organ 
dysfunction (sepsis syndrome) or fungal infection, as per the 
ASCO guidelines.  Investigators should therefore use their own 
discretion in using the CSFs in this setting.  The use of CSF 
(filgrastim/pegfilgrastim or sargramostim) must be documented 
and reported. (e.g. on CRFs per protocol requirements) 
c) If filgrastim/pegfilgrastim, tbo-filgrastim or sargramostim are 
used, they must be obtained from commercial sources. 

Alliance A021501 
53 
Version Date: 10/19/2018 
Update #04 
8.1.10 CYP3A4 Inhibitors 
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed 
on this trial. The following drugs are EXAMPLES of strong inhibitors of CYP3A4 
and are not allowed during treatment with irinotecan. 
• 
Indinavir 
• 
Clarithromycin 
• 
Ketoconazole 
Because lists of these agents are constantly changing, please consult and review 
any drugs for their potential to inhibit CYP3A4. Examples of resources that may 
be utilized include the product information for the individual concomitant drug in 
question, medical reference texts such as the FDA website, or your local 
institution’s pharmacist. 
An information handout and wallet-size card providing information for patients 
and their caregivers regarding potential drug interactions have been made available 
in Appendix III. 
8.1.11 CYP3A4 Inducers 
Chronic concomitant treatment with strong inducers of CYP3A4 is not allowed on 
this trial. The following drugs are EXAMPLES of strong inducers of CYP3A4 and 
are not allowed during treatment with irinotecan. 
• 
Rifampin 
• 
Carbamazepine 
Because lists of these agents are constantly changing, please consult and review 
any drugs for their potential to induce CYP3A4. Examples of resources that may 
be utilized include the product information for the individual concomitant drug in 
question, medical reference texts such as the FDA website, or your local 
institution’s pharmacist. 
An information handout and wallet-size card providing information for patients 
and their caregivers regarding potential drug interactions have been made available 
in Appendix III. 
8.1.12 Biliary Obstruction  
Biliary decompression should be performed if clinically warranted. Biliary 
decompression should ideally be performed during the pre-registration phase and 
should be accomplished endoscopically, preferably with a short metallic stent. 
8.1.13 Hypersensitivity/Infusion Reactions 
Treat hypersensitivity and infusion reactions as per institutional standards. 
8.1.14 Cholinergic Reaction  
Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal 
cramping, diarrhea, or other symptoms of early cholinergic syndrome may occur 
during or shortly after receiving irinotecan. Atropine, 0.25-1 mg IV or SC may be 
used to treat these symptoms. In patients with troublesome or recurrent symptoms, 
prophylactic administration of atropine shortly before irinotecan therapy may be 
considered. Additional antidiarrheal measures may be used at the discretion of the 
treating 
physician. 
Combination 
anticholinergic 
medications 
containing 

Alliance A021501 
54 
Version Date: 10/19/2018 
Update #04 
barbiturates or other agents (e.g. DonnatalR) should not be used because these may 
affect irinotecan metabolism. Anticholinergics should be used with caution in 
patients with potential contraindications (e.g. obstructive uropathy, glaucoma, 
tachycardia, etc.).  
8.1.15 Neurologic Toxicity 
Supportive care is allowed at the discretion of the treating physician. For pharyngo-
laryngeal dysesthesia, it is recommended to increase the duration of oxaliplatin 
infusion to 6 hours for subsequent cycles. 
8.1.16 Extravasation 
Extravasation of oxaliplatin has been associated with necrosis. Extravasation 
should be treated according to institutional guidelines. 
8.2 
Dose Modifications 
CTEP-AERS reporting may be required for some adverse events (See Section 9.4). 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting serious adverse events.  
8.2.1 
Dose Levels for Neoadjuvant mFOLFIRINOX and Adjuvant FOLFOX 
General Guidelines for mFOLFIRINOX and FOLFOX: 
If multiple adverse events are seen, administer dose based on greatest reduction 
required for any single adverse event observed.  Reductions or holds for new cycles 
of treatment are based on treatment given in the preceding cycle and adverse events 
observed since the prior dose. 
Dose modifications of 5FU, irinotecan, and oxaliplatin may occur independently 
of each other, based on the pattern of toxicity. Patients unable to tolerate one or 
more drugs due to toxicity will remain on treatment with the other drugs.  
During FOLFOX, follow the same instructions for modifications, excluding 
instructions for irinotecan. 
If 5-FU is omitted, leucovorin should also be omitted.  
Once the dose of any drug has been reduced, the dose cannot be re-escalated.  
If any drug is held for > 4 weeks, then that drug should be permanently 
discontinued.  
There are no further dose reductions beyond those listed in the tables below for 
each drug. If further dose reduction is required, that drug should be discontinued. 
 
mFOLFIRINOX Dose Levels: 
Dose 
Level 
5-FU infusion 
(mg/m2) 
Leucovorin 
(mg/m2) 
Irinotecan 
(mg/m2) 
Oxaliplatin 
(mg/m2) 
0* 
2400 
400 
180 
85 
-1 
1920 
400 
150 
65 
-2 
1600 
400 
120 
50 
-3 
1360 
400 
100 
40 
*Dose level 0 refers to the starting dose. 

Alliance A021501 
55 
Version Date: 10/19/2018 
Update #04 
 
FOLFOX Dose Levels: 
Dose 
Level 
5-FU bolus 
(mg/m2) 
5-FU infusion 
(mg/m2) 
Leucovorin 
(mg/m2) 
Oxaliplatin 
(mg/m2) 
0* 
400 
2400 
400 
85 
-1 
320 
1920 
400 
65 
-2 
250 
1600 
400 
50 
-3 
200 
1360 
400 
40 
*Dose level 0 refers to the starting dose. 
8.2.2 
Dose Modifications for mFOLFIRINOX and FOLFOX 
8.2.2.1 Hematologic Toxicity 
For grade 2 neutrophil count decreased on day 1, delay 5FU, 
oxaliplatin, and irinotecan until grade ≤ 1, then resume oxaliplatin, 
irinotecan, and 5FU at same dose  
For grade 3 neutrophil count decreased on day 1, delay 5FU, 
oxaliplatin, and irinotecan until grade ≤ 1, then resume oxaliplatin and 
irinotecan at 1 dose level decreased, and 5FU at same dose  
For grade 4 neutrophil count decreased or febrile neutropenia, delay 
5FU, oxaliplatin, and irinotecan until grade ≤ 1, then resume 5FU, 
oxaliplatin, and irinotecan with one dose level decreased  
For grade 2 platelet count decreased, delay 5FU, oxaliplatin, and 
irinotecan until grade ≤ 1, then resume oxaliplatin and irinotecan at one 
dose level decreased, and 5FU at same dose  
For grade 3 or 4 platelet count decreased, delay 5FU, oxaliplatin, and 
irinotecan until grade ≤ 1, then resume 5FU, oxaliplatin, and irinotecan 
with one dose level decreased 
8.2.2.2 Gastrointestinal Toxicity with Optimal Medical Management 
For grade 2 diarrhea, delay 5FU, oxaliplatin, and irinotecan until 
recovery to grade ≤ 1 or baseline, then resume 5FU, oxaliplatin, and 
irinotecan  at the same dose level.  
For grade 3 diarrhea, delay 5FU, oxaliplatin, and irinotecan until 
recovery to grade ≤ 1 or baseline, then resume 5FU, and oxaliplatin at the 
same dose level and irinotecan at the next lower dose level.  
For grade 4 diarrhea, delay 5FU, oxaliplatin, and irinotecan until 
recovery to grade ≤ 1 or baseline then resume 5FU, oxaliplatin, and 
irinotecan at the next lower dose level. 
For grade 3 or 4 nausea/vomiting, delay 5FU, oxaliplatin, and 
irinotecan until recovery to grade ≤ 1, then resume 5FU, oxaliplatin, and 
irinotecan at the next lower dose level. 

Alliance A021501 
56 
Version Date: 10/19/2018 
Update #04 
8.2.2.3 Mucositis 
For grade 3 mucositis, delay 5FU, oxaliplatin, and irinotecan  until 
recovery to grade ≤ 1, then resume irinotecan and oxaliplatin at the same 
dose level and 5FU at the next lower dose level.  
For grade 4 mucositis, delay 5FU, oxaliplatin, and irinotecan until 
recovery to grade ≤ 1, then resume 5FU, oxaliplatin, and irinotecan at the 
next lower dose level. 
8.2.2.4 Neuropathy (Sensory or Motor) 
For grade 2 neurotoxicity, decrease oxaliplatin by one dose level.  
For grade 3 or 4 neurotoxicity, discontinue oxaliplatin. 
8.2.2.5 Hepatobiliary Toxicity 
For grade 2 bilirubin increased, omit irinotecan until grade ≤ 1, then 
resume at same dose. 
For grade 3 or 4 bilirubin increased, delay 5FU, oxaliplatin, and 
irinotecan until recovery to grade ≤ 1, then resume 5FU, oxaliplatin, and 
irinotecan at the next lower dose level. 
For grade 3 ALT/AST increased, delay 5FU, oxaliplatin, and irinotecan 
until recovery to grade ≤ 1, then resume 5FU, oxaliplatin, and irinotecan 
at the next lower dose level. 
For grade 4 ALT/AST increased, discontinue 5FU, oxaliplatin, and 
irinotecan. 
8.2.2.6 Renal Insufficiency 
For grade 3 or 4 creatinine increased and NOT attributed to study 
treatment, delay 5FU, oxaliplatin, and irinotecan until grade ≤ 1, then 
restart 5FU, oxaliplatin, and irinotecan at the same doses. 
8.2.2.7 Other Non-hematologic Toxicities 
For all other grade 3 non-hematologic toxicities considered at least 
possibly related to treatment, omit the responsible drug(s) until toxicity 
improves to ≤ grade 1, then resume the responsible drug(s) at the next 
lower dose level.  
For grade 4 non-hematologic toxicities considered at least possibly 
related to treatment, discontinue the responsible drug(s). 
8.2.3 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when 
dosing is performed according to actual body weight. Therefore, all dosing is to be 
determined solely by actual weight without any modification unless explicitly 
described in the protocol. This will eliminate the risk of calculation error and the 
possible introduction of variability in dose administration. Failure to use actual 
body weight in the calculation of drug dosages will be considered a major protocol 
deviation. Physicians who are uncomfortable with calculating doses based on 
actual body weight should recognize that doing otherwise would be a protocol 
violation. Physicians may consult the published guidelines of the American 

Alliance A021501 
57 
Version Date: 10/19/2018 
Update #04 
Society of Clinical Oncology Appropriate Chemotherapy Dosing for Obese Adult 
Patients with Cancer: American Society of Clinical Oncology Clinical Practice 
Guideline.  J Clin Oncol 30(13): 1553-1561, 2012. 
8.2.4 
Dose Modifications for HIGRT and SBRT 
Note: Arm 2 closed to new patient enrollment on 08/13/2018. 
Radiation treatment should be delayed one day if patients are unable to tolerate 
radiation treatment because of nausea, vomiting, or other illness. Also, if stomach 
or bowel gas/filling makes treatment set-up unreliable, treatment should be 
delayed. Every effort should be made to provide supportive management (nausea 
medications) in order to complete radiation treatment within the two week time 
frame. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in 
clinical research, as required by Federal Regulations. Adverse events must be described and 
graded using the terminology and grading categories defined in the NCI’s Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0. However, CTCAE Version 
5.0 must be used for serious AE reporting through CTEP-AERS as of April 1, 2018. The CTCAE 
is 
available 
at 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Attribution to protocol treatment for each adverse event must be determined by the investigator 
and reported on the required forms. Please refer the NCI Guidelines: Adverse Event Reporting 
Requirements for further details on AE reporting procedures. To complement CTCAE reporting, 
patients will self-report their side effects using the PRO-CTCAE. The specific PRO-CTCAE 
items for this protocol can be found in Appendix I. They can also be found at: 
 
 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting of serious adverse events. 
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the form, “Adverse Events: 
Solicited,” is used for routine AE reporting in Rave. 
PRO-CTCAE paper booklets ordered from the CTSU website are to be administered by a 
nurse/CRA and completed by the patient at scheduled times according to the study calendar in 
Section 5.0, and then entered into Rave.  
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment by CTCAE, PRO-CTCAE, or both. 

Alliance A021501 
58 
Version Date: 10/19/2018 
Update #04 
CTCAE v4.0 Term 
PRO-CTCAE v1.0 Term 
CTCAE v4.0 System Organ 
Class (SOC) 
Blood bilirubin increased 
 
Investigations 
Hypoalbuminemia 
 
Investigations 
Wound infection 
 
Infections and infestations 
Bile duct stenosis 
 
Hepatobiliary disorders 
Diarrhea 
Loose or watery stools (diarrhea) 
Gastrointestinal disorders 
Nausea 
Nausea 
Gastrointestinal disorders 
Fatigue 
Fatigue, tiredness, or lack of energy 
General disorders 
Weight loss 
 
Investigations 
Peripheral sensory neuropathy 
Numbness or tingling in your hands 
or feet 
Nervous system disorders 
 
Dry mouth 
Gastrointestinal disorders 
 
Problems with tasting food or drink 
Nervous system disorder 
 
Decreased appetite 
Metabolism and nutrition 
disorders 
 
Vomiting 
Gastrointestinal disorders 
 
Heartburn 
Gastrointestinal disorders 
 
Bloating of the abdomen (belly) 
Gastrointestinal disorders 
 
Pain in the abdomen (belly area) 
Gastrointestinal disorders 
 
Itchy skin 
Skin and subcutaneous tissue 
disorders 
 
Pain 
General disorders 
 
Anxiety 
Psychiatric disorders 
 
Sad or unhappy feelings 
Psychiatric disorders 
9.2 
Surgical Adverse Events 
Specific toxicities related to pancreatic cancer surgery must be evaluated to best determine the 
adverse events of the protocol. The following events are collected at a single time point, which 
is 90 days after surgery: 
 
Event 
Data to be entered 
Pancreatic fistula requiring drainage within 90 
days of surgery 
Yes/No 
Abdominal abscess requiring drainage within 90 
days of surgery 
Yes/No 
Patients with a hospitalization within 90 days of 
surgery: Length of hospital stay 
Number of days 
Reoperation for any reason within 90 days of 
surgery 
Yes/No 
9.3 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
 
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting serious adverse events.  

Alliance A021501 
59 
Version Date: 10/19/2018 
Update #04 
*Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and 
within 30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up 
Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.4 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Investigational Drug Branch 
(IDB), the Alliance Central Protocol Operations Program, the Study Chair, and their 
Institutional Review Board if a patient has a reportable serious adverse event. The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. All reactions determined to be “reportable” in 
an expedited manner must be reported using the Cancer Therapy Evaluation Program Adverse 
Event Reporting System (CTEP-AERS). A copy of the CTCAE version 5.0 can be downloaded 
from 
the 
CTEP 
website 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
NOTE: PRO-CTCAE data should not be used for determining attribution, dose modifications, 
or reporting serious adverse events.  
Note: All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
9.4.1 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND/IDE trial ≤ 30 Days of the Last Day of Treatment1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 

Alliance A021501 
60 
Version Date: 10/19/2018 
Update #04 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially 
report the AE via CTEP-AERS ≤ 24 hours of learning of the event 
followed by a complete CTEP-AERS report ≤ 5 calendar days of 
the initial 24-hour report. 
 “10 calendar days” – A complete CTEP-AERS report on the AE 
must be submitted ≤ 10 calendar days of the investigator learning 
of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be 
reported regardless of attribution and designation as expected or 
unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions (see below). 

Alliance A021501 
61 
Version Date: 10/19/2018 
Update #04 
• 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS 
if the event occurs following treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting 
Requirements  
• 
All adverse events reported via CTEP-AERS (i.e. serious adverse events) 
should also be forwarded to your local IRB. 
• 
Grade 1-3 nausea or vomiting and hospitalization resulting from such do 
not require AERS reporting, but should be reported via routine AE 
reporting.  
• 
Grade 3 or 4 nausea or vomiting does not require AERS reporting, but 
should be reported via routine AE reporting 
• 
Grade 1-3 diarrhea and hospitalization resulting from such does not 
require AERS reporting, but should be reported via routine AE reporting 
• 
Grade 3 or 4 diarrhea does not require AERS reporting, but should be 
reported via routine AE reporting 
• 
Grade 1-3 mucositis and hospitalization resulting from such does not 
require AERS reporting, but should be reported via routine AE reporting 
• 
Grade 3 or 4 mucositis does not require AERS reporting, but should be 
reported via routine AE reporting 
• 
Grade 1-3 neuropathy and hospitalization resulting from such does not 
require AERS reporting, but should be reported via routine AE reporting.  
• 
Grade 3 neuropathy does not require AERS reporting, but should be 
reported via routine AE reporting 
• 
Grade 1-3 hand foot syndrome and hospitalization resulting from such 
does not require AERS reporting, but should be reported via routine AE 
reporting 
• 
Grade 3 hand foot syndrome does not require AERS reporting, but should 
be reported via routine AE reporting 
• 
Grade 1-4 hypersensitivity reaction and hospitalization resulting from 
such does not require AERS reporting, but should be reported via routine 
AE reporting 
• 
Grade 3 or 4 hypersensitivity reaction does not require AERS reporting, 
but should be reported via routine AE reporting 
• 
Grade 1-3 dehydration and hospitalization resulting from such does not 
require AERS reporting, but should be reported via routine AE reporting 
• 
Grade 3 dehydration does not require AERS reporting, but should be 
reported via routine AE reporting 
• 
Grade 1-3 fatigue and hospitalization resulting from such does not require 
AERS reporting, but should be reported via routine AE reporting.  
• 
Grade 3 or 4 fatigue does not require AERS reporting, but should be 
reported via routine AE reporting 
• 
Grade 1-4 hematosuppression (leukopenia, neutropenia, lymphopenia, 
anemia, and thrombocytopenia) with hospitalization resulting from such 

Alliance A021501 
62 
Version Date: 10/19/2018 
Update #04 
do not require AERs reporting, but should be reported via routine AE 
reporting 
• 
Grade 3 or 4 hematosuppression (leukopenia, neutropenia, lymphopenia, 
anemia, and thrombocytopenia) does not require AERs reporting, but 
should be reported via routine AE reporting 
• 
Deaths that occur within 90 days of surgery required CTEP-AERS 
reporting regardless of attribution, including in the case of progressive 
disease. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a 
manifestation of underlying disease (e.g. radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with disease 
process) should be submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to the investigational agent/intervention requires expedited 
reporting within 24 hours. 
• 
Any death occurring greater than 30 days after the last dose of the 
investigational agent/intervention requires expedited reporting within 24 
hours only if it is possibly, probably, or definitely related to the 
investigational agent/intervention. 
• 
Pregnancy loss 
 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
 
Any Pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
 
A Pregnancy loss should not be reported as a Grade 5 event under 
the Pregnancy, puerperium and perinatal conditions SOC, as 
currently CTEP-AERS recognizes this event as a patient death. 
• 
A neonatal death should be reported expeditiously as Grade 4, “Death 
neonatal” under the General disorders and administration SOC. 
• 
All new malignancies must be reported via CTEP-AERS whether or not 
they are thought to be related to either previous or current treatment. All 
new malignancies should be reported, i.e. solid tumors (including non-
melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ 
tumors. In CTCAE version 5.0, the new malignancies (both second and 
secondary) may be reported as one of the following: (1) Leukemia 
secondary to oncology chemotherapy, (2) Myelodysplastic syndrome, (3) 
Treatment-related secondary malignancy, or (4) Neoplasms benign, 
malignant and unspecified-other. Whenever possible, the CTEP-AERS 
reports for new malignancies should include tumor pathology, history or 
prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new 
malignancy may have been present, when and how the new malignancy 
was detected, molecular characterization or cytogenetics of the original 
tumor (if available) and of any new tumor, and new malignancy treatment 
and outcome, if available. 
CTEP-AERS reports should be submitted electronically. 

Alliance A021501 
63 
Version Date: 10/19/2018 
Update #04 
9.5 
CDUS Reporting 
The following is for Alliance Statistician and Data Center use only: 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, July 31, and 
October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web 
site (http://ctep.cancer.gov/reporting/cdus.html). 
This study has been assigned CDUS-Abbreviated reporting. 
Note: If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above. If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS, but expedited adverse events are still required to be submitted 
via CTEP-AERS. 
10.0 DRUG INFORMATION 
10.1 
General Considerations 
It is not necessary to change the doses of chemotherapy drugs due to changes in weight unless 
the calculated dose changes by ≥ 10%. 
Study agents may be administered at a non-registering institution. If the NCTN Group credited 
for enrollment is a non-Alliance Group, then other requirements from the credited Group may 
apply. 
10.2 
Oxaliplatin (Eloxatin) – NSC #266046 
For more information, please refer to the drug package insert. 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available as: 
Solution for Injection: 50 mg/10 mL (10 mL); 100 mg/20 mL (20 mL); 200 mg/40 mL (40 mL) 
Lyophilized Powder for Injection: 50 mg and 100 mg 
Preparation, Storage, and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store intact vials 
in original outer carton at room temperature and; do not freeze. According to the manufacturer, 
solutions diluted for infusion are stable up to 6 hours at room temperature or up to 24 hours 
under refrigeration. Oxaliplatin solution diluted with D5W to a final concentration of 0.7 mg/mL 
(polyolefin container) has been shown to retain >90% of its original concentration for up to 30 
days when stored at room temperature or refrigerated; artificial light did not affect the 
concentration (Andre, 2007). As this study did not examine sterility, refrigeration would be 
preferred to limit microbial growth. Do not prepare using a chloride-containing solution (e.g., 
NaCl). Dilution with D5W (250 or 500 mL) is required prior to administration. Infusion 
solutions do not require protection from light. 

Alliance A021501 
64 
Version Date: 10/19/2018 
Update #04 
Administration 
Refer to the treatment section for specific administration instructions. Administer as IV infusion 
over 2-6 hours. Flush infusion line with D5W prior to administration of any concomitant 
medication. Patients should receive an antiemetic premedication regimen. Cold temperature 
may exacerbate acute neuropathy. Avoid mucositis prophylaxis with ice chips during oxaliplatin 
infusion. 
Drug Interactions 
Increased Effect/Toxicity: Nephrotoxic agents may increase oxaliplatin toxicity.  
When administered as sequential infusions, observational studies indicate a potential for 
increased toxicity when platinum derivatives (carboplatin, cisplatin, oxaliplatin) are 
administered before taxane derivatives (docetaxel, paclitaxel). 
Decreased Effect: Oxaliplatin may decrease plasma levels of digoxin 
Pharmacokinetics 
Distribution: Vd: 440 L 
Protein binding: >90% primarily albumin and gamma globulin (irreversible binding to platinum) 
Metabolism: Nonenzymatic (rapid and extensive), forms active and inactive derivatives 
Phase: 16.8 hours 
Excretion: Primarily urine (~54%); feces (~2%) 
Adverse Events 
Consult the package insert for the most current and complete information. Percentages reported 
with monotherapy. 
Common known potential toxicities, > 10%:   
Central nervous system: Fatigue, fever, pain, headache, insomnia 
Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, constipation, anorexia, stomatitis  
Hematologic: Anemia, thrombocytopenia, leukopenia 
Hepatic: Liver enzymes increased 
Neuromuscular & skeletal: Back pain, peripheral neuropathy (may be dose limiting). The most 
commonly observed oxaliplatin toxicity is acute and cumulative neurotoxicity, observed in 
patients treated at doses above 100 mg/m2/cycle.  This neurotoxicity has included paresthesias 
and dysesthesias of the hands, feet, and perioral region as well as unusual laryngopharyngeal 
dysesthesias characterized by a loss of sensation of breathing without any objective evidence of 
respiratory distress (hypoxia, laryngospasm, or bronchospasm).  OXAL neurotoxicity appears 
to be exacerbated by exposure to cold.  Patients on this study will be counseled to avoid cold 
drinks and exposure to cold water or air.  Should a patient develop laryngopharyngeal 
dysesthesia, their oxygen saturation should be evaluated via a pulse oximeter; if normal, an 
anxiolytic agent should be given and the patient observed in the clinic until the episode has 
resolved.  Because this syndrome may be associated with the rapidity of OXAL infusion, 
subsequent doses of OXAL should be administered as a 6-hour infusion (instead of the normal 
2-hour infusion). 
Acute and cumulative neurotoxicities are dose limiting for OXAL.  The acute neurotoxicity is 
characterized by paresthesias and dysesthesias that may be triggered or exacerbated by exposure 
to cold.  These symptoms occur within hours of exposure and are usually reversible over the 
following hours or days.  Cumulative doses of OXAL above 680 mg/m2 may produce functional 

Alliance A021501 
65 
Version Date: 10/19/2018 
Update #04 
impairment characterized by difficulty performing activities requiring fine sensory-motor 
coordination; impairment is caused by sensory rather than motor changes.  
The likelihood of experiencing neurotoxicity is directly related to the total cumulative dose of 
OXAL administered.  The relative risk of developing neurotoxicity was 10%, 50%, and 75% in 
patients who received total cumulative OXAL doses of 780 mg/m2, 1,170 mg/m2, and 1,560 
mg/m2, respectively.  Both acute and cumulative neurotoxicities due to OXAL have lessened in 
82% of patients within 4 to 6 months, and have completely disappeared by 6 to 8 months in 41% 
of patients.  In addition, the likelihood that neurologic symptoms will regress has been shown 
to correlate inversely with cumulative dose.  
Respiratory: Dyspnea, cough 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Edema, chest pain, peripheral edema, flushing, thromboembolism 
Central nervous system: Dizziness 
Dermatologic: Rash, alopecia, hand-foot syndrome 
Endocrine & metabolic: Dehydration, hypokalemia 
Gastrointestinal: Dyspepsia, taste perversion, flatulence, mucositis, gastroesophageal reflux, 
dysphagia 
Genitourinary: Dysuria 
Hematologic: Neutropenia 
Local: Injection site reaction 
Neuromuscular & skeletal: Rigors, arthralgia 
Ocular: Abnormal lacrimation 
Renal: Serum creatinine increased 
Respiratory: URI, rhinitis, epistaxis, pharyngitis, pharyngolaryngeal dysesthesia 
Miscellaneous: Allergic reactions, hypersensitivity (includes urticaria, pruritus, facial flushing, 
shortness of breath, bronchospasm, diaphoresis, hypotension, syncope, hiccup 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
Gastrointestinal: Life threatening enteric sepsis secondary to neutropenia and diarrhea. 
Hepatic: Veno-occlusive disease of the liver is a rare serious adverse event that has occurred in 
association with administration of oxaliplatin and fluorouracil.  
Otic: Clinical ototoxicity occurs in less than 1% of patients following oxaliplatin administration, 
and sever ototoxicity has not been reported 
Nursing Guidelines 
GI toxicity similar to cisplatin occurs with doses above 30 mg/m2.  It can be almost constant and 
frequently severe, but not always dose-limiting. Monitor for nausea and vomiting and treat 
accordingly. 
Dose-limiting side effect can be paresthesias of hands, fingers, toes, pharynx, and occasionally 
cramps which develops with a dose-related frequency (> 90 mg/m2).  Duration of symptoms 
tend to be brief (less than a week) with the first course, but longer with subsequent courses.  
Phase I patients have reported exacerbation of paresthesias by touching cold surfaces or 
exposure to cold. Advise patient of these possibilities and instruct patient to report these 
symptoms to the health care team. Also advise patient to refrain from operating dangerous 
machinery that requires fine sensory-motor coordination, if symptoms appear. 

Alliance A021501 
66 
Version Date: 10/19/2018 
Update #04 
These sensory neuropathies developed after subsequent courses with increasing intensity (Grade 
3 toxicity after the fourth course) and with increasing duration. In 63% of the patients tested in 
phase I at high doses (135-200 mg/m2), neuropathies became long-term with slow reversal over 
several months. Disabling walking and handwriting difficulties, as well as mouth and throat 
dysesthesias and laryngospasms were seen.  Instruct patient to report any swallowing difficulties 
or gait changes. 
OXAL is incompatible with NS.  Flush lines with D5W prior to and following OXAL infusion. 
Low back pain is a common side effect, perhaps a form of hypersensitivity reaction. Instruct 
patient in good body mechanics, advise light massage, heat, etc. 
Laryngopharyngeal dysesthesia (LPD) occurs in about 15% of patients and is acute, sporadic, 
and self-limited. It usually occurs within hours of infusion, is induced or exacerbated by 
exposure to cold, and presents with dyspnea and dysphagia. The incidence and severity appear 
to be reduced by prolonging infusion time. Instruct patient to avoid ice and cold drinks the day 
of infusion. If ≥ Grade 2 laryngopharyngeal dysesthesia occurs during the administration of 
OXAL, do the following: 
• 
Stop OXAL infusion 
• 
Administer benzodiazepine and give patient reassurance 
• 
Test oxygen saturation via a pulse oximeter 
• 
At the discretion of the investigator, the infusion can be restarted at 1/3 the original rate 
of infusion. 
• 
Rapid resolution is typical within minutes to a few hours. Can recur with retreatment. 
Comparison of the Symptoms and Treatment of Laryngopharyngeal Dysesthesias and 
Platinum Hypersensitivity Reactions 
Clinical Symptoms 
Laryngopharyngeal 
Dysesthesias 
Platinum 
Hypersensitivity 
Dyspnea 
present 
present 
Bronchospasm 
absent 
present 
Laryngospasm 
absent 
present 
Anxiety 
present 
present 
O2 saturation 
normal 
decreased 
difficulty swallowing 
present 
(loss of sensation) 
absent 
Pruritus 
absent 
present 
urticaria/rash 
absent 
present 
cold-induced 
symptoms 
yes 
no 
BP 
normal or increased 
normal or decreased 
Treatment 
anxiolytics, observation 
in a controlled clinical 
setting until symptoms 
abate or at the 
physicians’ discretion 
oxygen, steroids, 
epinephrine, 
bronchodilators; fluids and 
vasopressors, if appropriate 
Alopecia is rare with OXAL alone, but is seen with 5-FU-OXAL combination. Advise patient. 
Mild-moderate diarrhea has been seen - usually of short duration. Treat accordingly. See Section 
8.0 for ancillary treatment. 

Alliance A021501 
67 
Version Date: 10/19/2018 
Update #04 
Respiratory problems (i.e. pulmonary fibrosis, cough, dyspnea, rales, pulmonary infiltrates, 
hypoxia, air hunger and tachypnea) have been observed in patients administered OXAL. In rare 
cases, death has occurred due to pulmonary fibrosis. Please monitor and instruct the patient to 
report any respiratory difficulties and hold OXAL until interstitial lung disease is ruled out for 
cases of Grade ≥ 3. If patient is experiencing shortness of breath, a chest x-ray and assessment 
of oxygenation via either finger oximetry or arterial blood gas evaluation are required to confirm 
the absence or presence of pulmonary infiltrates and/or hypoxia (treat accordingly: no 
intervention, steroids, diuretics, oxygen, or assisted ventilation). 
Veno-occlusive disease (VOD) is a rare but serious complication that has been reported in 
patients receiving oxaliplatin in combination with 5-FU. This condition can lead to 
hepatomegaly, splenomegaly, portal hypertension and/or esophageal varices. Instruct patients 
to report any jaundice, ascites, or hematemesis to the MD immediately as these could be a sign 
of VOD or other serious condition. 
Acute vein irritation can occur with infusion. Apply heat to arm of infusion if you are using a 
peripheral line. However, extravasation of drug can cause severe pain, redness, soreness, and 
exfoliation of the skin in the affected area with loss of affected vein for a long period. If a patient 
has a problem with pain or sclerosis when chemotherapy is given by a peripheral line, then 
placement of a central line should be considered. 
Hemolytic Uremic Syndrome (HUS) may result in kidney damage. Oxaliplatin is to be 
discontinued in cases where hematocrit is <25%, thrombocytopenia <100,000, and creatinine 
≥1.6 mg/dL. 
Patients may experience sleep disturbances, specifically insomnia. Encourage good sleep 
hygiene, and instruct patient to report any problems with sleep to the MD, to assess for the 
potential use of sleeping aids. 
Cold-induced transient visual abnormalities can be experienced by patients while receiving 
OXAL, although the relationship to OXAL has not been completely determined.  Instruct patient 
to report any problems with vision to the MD. 
Extrapyramidal side effects and/or involuntary limb movement has been seen with OXAL 
administration.  Patients may also experience restlessness.  Instruct patient to report any of these 
side effects to the MD. 
10.3 
Irinotecan (Camptosar) – NSC #616348 
For more information, please refer to the drug package insert. 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection 20 mg/mL (2 mL, 5 mL) [contains sorbitol 45 mg/mL; do 
not use in patients with hereditary fructose intolerance]. 
Preparation, Storage, and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store intact vials 
at room temperature and protect from light. Doses should be diluted in 250-500 mL D5W or 
0.9% NaCl to a final concentration of 0.12-2.8 mg/mL. Due to the relatively acidic pH, 
Irinotecan appears to be more stable in D5W than 0.9% NaCl. Solutions diluted in D5W are 
stable for 24 hours at room temperature or 48 hours under refrigeration at 2ºC to 8ºC. Solutions 
diluted in 0.9% NaCl may precipitate if refrigerated. Do not freeze. 

Alliance A021501 
68 
Version Date: 10/19/2018 
Update #04 
Administration 
Administer by I.V. infusion, usually over 90 minutes. 
Drug Interactions 
Cytochrome P450 Effect: Substrate (major) of CYP2B6, 3A4 
Increased Effect/Toxicity: CYP2B6 and CYP3A4 inhibitors may increase the levels/effects of 
irinotecan. Bevacizumab may increase the adverse effects of irinotecan (e.g. diarrhea, 
neutropenia). Ketoconazole increases the levels/effects of irinotecan and active metabolite; 
discontinue ketoconazole 1 week prior to irinotecan therapy; concurrent use is contraindicated. 
Decreased Effect: CYP2B6 and CYP3A4 inducers may decrease the levels/effects of irinotecan.  
Ethanol/Nutrition/Herb Interactions Herb/Nutraceutical: St. John’s Wort decreases therapeutic 
effect of irinotecan; discontinue ≥ weeks prior to irinotecan therapy; concurrent use is 
contraindicated. 
Pharmacokinetics 
Distribution: Vd: 33-150 L/m2 
Protein binding, plasma: Predominantly albumin; Parent drug: 30% to 68%, SN-38 (active 
metabolite): ~95% 
Metabolism: Primarily hepatic to SN-38 (active metabolite) by carboxylesterase enzymes; SN-
38 undergoes conjugation by UDP- glucuronosyl transferase 1A1 (UGT1A1) to form a 
glucuronide metabolite. Conversion of irinotecan to SN-38 is decreased and glucuronidation of 
SN-38 is increased in patients who smoke cigarettes, resulting in lower levels of the metabolite 
and overall decreased systemic exposure. SN-38 is increased by UGT1A1*28 polymorphism 
(10% of North Americans are homozygous for UGT1A1*28 allele). Patients homozygous for 
the UGT1A1*28 allele are at increased risk of neutropenia; initial one-level dose reduction 
should be considered for both single-agent and combination regimens. The lactones of both 
Irinotecan and SN-38 undergo hydrolysis to inactive hydroxyl acid forms. 
Half-life elimination: SN-38: Mean terminal: 10-20 hours 
Time to peak: SN-38: Following 90-minute infusion: ~1 hour 
Excretion: Within 24 hours: urine: Irinotecan (11% to 20%), metabolites (SN-38 < 1%, SN-38 
glucuronide, 3%) 
Adverse Events 
Consult the package insert for the most current and complete information including U.S. Boxed 
Warnings pertaining to severe diarrhea and severe myelosuppression. 
Common known potential toxicities, > 10%:   
Cardiovascular: Vasodilation 
Central nervous system: Cholinergic toxicity (includes rhinitis, increased salivation, miosis, 
lacrimation, diaphoresis, flushing and intestinal hyperperistalsis); fever, pain, dizziness, 
insomnia, headache, chills 
Dermatologic: Alopecia, rash 
Endocrine & metabolic: Dehydration 
Gastrointestinal: Late onset diarrhea, early onset diarrhea, nausea, abdominal pain, vomiting, 
cramps, anorexia, constipation, mucositis, weight loss, flatulence, stomatitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, neutropenia 

Alliance A021501 
69 
Version Date: 10/19/2018 
Update #04 
Hepatic: Bilirubin increased, alkaline phosphatase increased  
Neuromuscular & skeletal: Weakness, back pain 
Respiratory: Dyspnea, cough, rhinitis 
Miscellaneous: Diaphoresis, infection 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Edema, hypotension, thromboembolic events 
Central nervous system: Somnolence, confusion 
Gastrointestinal: Abdominal fullness, dyspepsia 
Hematologic: Neutropenic fever, hemorrhage, neutropenic infection 
Hepatic: AST increased, ascites and/or jaundice 
Respiratory: Pneumonia 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
ALT increased, amylase increased, anaphylactoid reaction, anaphylaxis, angina, arterial 
thrombosis, bleeding, Bradycardia, cardiac arrest, cerebral infarct, cerebrovascular accident, 
circulatory failure, colitis, deep thrombophlebitis, dysrhythmia, embolus, gastrointestinal 
bleeding, gastrointestinal obstruction, hepatomegaly, hiccups, hyperglycemia, hypersensitivity, 
hyponatremia, ileus, interstitial lung disease, intestinal perforation, ischemic colitis, lipase 
increased, lymphocytopenia, megacolon, MI, muscle cramps, myocardial ischemia, pancreatitis, 
paresthesia, peripheral vascular disorder, pulmonary embolus, pulmonary toxicity (dyspnea, 
fever, reticulnodular infiltrates on chest x-ray), renal failure (acute), renal impairment, syncope, 
thrombophlebitis, thrombosis, typhlitis, ulceration, ulcerative colitis, vertigo 
Nursing Guidelines 
If possible, check for any history of hypersensitivity reaction to any previous drug formulated 
with polysorbate 80. 
Cholinergic symptoms of lacrimation, nasal congestion, diaphoresis, flushing, ABD cramping, 
and diarrhea can occur at the beginning, during, or immediately after the CPT-11 infusion. It is 
suggested that the patient remain in the treatment area for a minimum of one hour following the 
completion of the very first CPT-11 infusion. If diarrhea occurs within one hour of infusion, 
refer to Section 8.1.5 for management. 
Patient education is extremely important. Impress on the patient the importance of compliance 
with treatment of diarrhea management. Stress the need for prompt recognition and early 
intervention. Motivate the patient to report any complications immediately. The cholera-like 
syndrome can be unresponsive to conventional antidiarrheals and can result in severe 
dehydration. 
Ondansetron 
and 
diphenhydramine 
should 
provide 
good 
relief 
from 
the 
nausea/vomiting/cramping. Avoid prochlorperazine on the day of treatment due to its 
association with akathisia (motor restlessness). Prochlorperazine may be taken between 
treatments. 
Advise avoidance of excess caffeine, a GI stimulant.  Avoid magnesium-based antacids such as 
Mylanta, Maalox, Rolaids, MOM, Mag-Ox 400, and Tylenol with antacid. 
The pulmonary toxicity seen is usually manifested by dyspnea beginning 42-175 days after 
treatment and occurs at a cumulative dose ranging from 400-1000 mg/m2 (median 750). Instruct 
patient to report any cough or SOB. 
Patients are at risk for developing eosinophilia and will improve on steroid therapy. 

Alliance A021501 
70 
Version Date: 10/19/2018 
Update #04 
Hepatic enzyme elevations have been transient and did not require intervention. 
Monitor CBC closely. Leukopenia occurs primarily as neutropenia but can be severe and dose 
limiting. The simultaneous occurrence of grade 4 diarrhea and grade 4 neutropenia is rare but 
may render the patient more susceptible to polymicrobial sepsis and potentially death. 
Advise patients of probable hair loss. 
10.4 
Leucovorin Calcium – NSC #3590 
For more information, please refer to the drug package insert. 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available: 
Solution for Injection 100 mg/10mL (10mL, 30 mL) 
Lyophilized Powder for Injection 50 mg, 100 mg, 200 mg, 350 mg, 500 mg 
Preparation, Storage and Stability 
Powder for injection: Store at room temperature of 25°C (77°F). Protect from light. Solutions 
reconstituted with bacteriostatic water for injection U.S.P., must be used within 7 days. 
Solutions reconstituted with SWFI must be used immediately. Parenteral admixture is stable for 
24 hours stored at room temperature (25°C) and for 4 days when stored under refrigeration 
(4°C). Powder for injection: Reconstitute with SWFI or BWFI; dilute with D5W or NS for 
infusion. When doses > 10 mg/m2 are required, reconstitute using sterile water for injection, not 
a solution containing benzyl alcohol.   
Solution for injection: Prior to dilution, store vials under refrigeration at 2°C to 8°C (36°F to 
46°F). Protect from light. Dilute in D5W or NS for infusion.  
Administration 
Combination therapy with fluorouracil: Fluorouracil is usually given after, or at the midpoint, 
of the leucovorin infusion. Leucovorin is usually administered by IV bolus injection or short 
(10-120 minutes) IV infusion. Other administration schedules have been used; refer to 
individual protocols. 
Drug Interactions 
Capecitabine: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of 
Capecitabine. Risk C: Monitor therapy 
Fluorouracil (Systemic): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic 
effect of Fluorouracil (Systemic). This effect is associated with the ability of leucovorin or 
levoleucovorin to enhance the anticancer effects of fluorouracil. Risk C: Monitor therapy 
Fluorouracil (Topical): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic 
effect of Fluorouracil (Topical). Risk C: Monitor therapy 
Fosphenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Fosphenytoin. Risk C: Monitor therapy 
PHENobarbital: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
PHENobarbital. Risk C: Monitor therapy 

Alliance A021501 
71 
Version Date: 10/19/2018 
Update #04 
Phenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Phenytoin. Risk C: Monitor therapy 
Primidone: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Primidone. Additionally, leucovorin/levoleucovorin may decrease concentrations of active 
metabolites of primidone (e.g., phenobarbital). Risk C: Monitor therapy 
Raltitrexed: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of 
Raltitrexed. Risk X: Avoid combination 
Tegafur: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Tegafur. 
This effect is associated with the ability of leucovorin or levoleucovorin to enhance the 
anticancer effects of fluorouracil. Risk C: Monitor therapy 
Trimethoprim: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of 
Trimethoprim. Management: Avoid concurrent use of leucovorin or levoleucovorin with 
trimethoprim (plus sulfamethoxazole) for Pneumocystis jiroveci pneumonia. If trimethoprim is 
used for another indication, monitor closely for reduced efficacy. Risk X: Avoid combination 
Pharmacokinetics 
Absorption: Oral, IM: Well absorbed 
Metabolism: Intestinal mucosa and hepatically to 5-methyl-tetrahydrofolate (5MTHF; active) 
Bioavailability: Saturable at oral doses > 25 mg; 25 mg (97%), 50 mg (75%), 100 mg (37%) 
Half-life elimination: ~ 4-8 hours 
Time to peak: Oral: ~ 2 hours; IV: Total folates: 10 minutes; 5MTHF: ~ 1 hour 
Excretion: Urine (primarily); feces 
Adverse Events 
Consult the package insert for the most current and complete information. 
Dermatologic: Rash, pruritus, erythema, urticaria 
Hematologic: Thrombocytosis 
Respiratory: Wheezing 
Miscellaneous: Allergic reactions, anaphylactoid reactions 
Nursing Guidelines 
Headache may occur.  Advise patient that analgesics such as Tylenol may help.  Instruct patient 
to report any headache that is unrelieved. 
Observe for sensitization reaction (rash, hives, pruritus, facial flushing, and wheezing).  
May potentiate the toxic effects of fluoropyrimidine (5-FU) therapy, resulting in increased 
hematologic and gastrointestinal (diarrhea, stomatitis) adverse effects. Monitor closely. 
May cause mild nausea or upset stomach. Administer antiemetics if necessary and evaluate for 
their effectiveness. 
10.5 
5-Fluorouracil (5-FU) (Efudex, Arucil, Carac, Fluroplex) – NSC #19893 
For more information, please refer to the drug package insert. 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 

Alliance A021501 
72 
Version Date: 10/19/2018 
Update #04 
Formulation 
Commercially available as Intravenous Solution: 500 mg/10 mL (10 mL); 1 g/20 mL (20 mL); 
2.5 g/50 mL (50 mL); 5 g/100 mL (100 mL) 
Preparation, Storage, and Stability 
Store intact vials at room temperature and protect from light. A slight discoloration may occur 
with storage but usually does not denote decomposition. Dilute in 50 – 1000 mL of 0.9% NaCl 
or D5W. If exposed to cold, a precipitate may form; gentle heating to 60ºC will dissolve the 
precipitate without impairing the potency. Solutions in 50 – 1000 mL 0.9% NaCl or D5W or 
undiluted solutions in syringes are stable for 72 hours at room temperature. Fluorouracil should 
not be coadministered with either diazepam, doxorubicin, daunorubicin, idarubicin, cisplatin, or 
cytarabine. However, fluorouracil and leucovorin are compatible for 14 days at room 
temperature. Fluorouracil is compatible with vincristine, methotrexate, and cyclophosphamide. 
Administration 
Fluorouracil may be given IV push, IV infusion. Refer to the treatment section for specific 
administration instructions.  Avoid extravasation, may be an irritant. 
Drug Interactions 
Fluorouracil may increase effects of warfarin. Avoid ethanol (due to GI irritation). Avoid black 
cohosh. 
Pharmacokinetics 
Distribution: Vd ~ 22% of total body water; penetrates extracellular fluid, CSF, and third space 
fluids (e.g., pleural effusions and ascitic fluid) 
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; Fluorouracil must be metabolized to 
be active. 
Half-life elimination: Biphasic: Initial: 6-20 minutes; two metabolites, FdUMP and FUTP, have 
prolonged half-lives depending on the type of tissue. 
Excretion: Lung (large amounts as CO2); urine (5% as unchanged drug) in 6 hours. 
Adverse Events 
Consult the package insert for the most current and complete information. 
Common known potential toxicities, > 10%:   
Dermatologic: Dermatitis, pruritic maculopapular rash, alopecia. 
Gastrointestinal (route and schedule dependent): Heartburn, nausea, vomiting, anorexia, 
stomatitis, esophagitis, anorexia, diarrhea. GI toxicity (anorexia, nausea, and vomiting) is 
generally more severe with continuous-infusion schedules. 
Emetic potential: <1000 mg: Moderately low (10% to 30%) ≥ 1000 mg: Moderate (30% to 60%) 
Hematologic: Leukopenia; Myelosuppressive (tends to be more pronounced in patients 
receiving bolus dosing of FU). Decreased white blood cell count with increased risk of infection; 
decreased platelet count with increased risk of bleeding. 
Local: Irritant chemotherapy.  
Less common known potential toxicities, 1% - 10%:  
Dermatologic: Dry skin 
Gastrointestinal: GI ulceration 

Alliance A021501 
73 
Version Date: 10/19/2018 
Update #04 
Rare known potential toxicities, <1% (Limited to important or life-threatening):  
Cardiac enzyme abnormalities, chest pain, coagulopathy, dyspnea, ECG changes similar to 
ischemic changes, hepatotoxicity; hyperpigmentation of nail beds, face, hands, and veins used 
in infusion; hypotension, palmar-plantar syndrome (hand-foot syndrome), photosensitization. 
Cerebellar ataxia, headache, somnolence, ataxia are seen primarily in intracarotid arterial 
infusions for head and neck tumors. 
Nursing Guidelines 
Monitor complete blood count and platelet count. Instruct patient to report signs and symptoms 
of infection, unusual bruising or bleeding to the physician. 
Administer antiemetics as indicated. 
Diarrhea may be dose–limiting; encourage fluids and treat symptomatically. 
Assess for stomatitis; oral care measures as indicated. May try vitamin E oil dabbed on sore, six 
times daily.  Cryotherapy recommended with IV push administration. 
Monitor for neurologic symptoms (headache, ataxia). 
Inform patient of potential alopecia. 
Those patients on continuous infusion may need instruction regarding central intravenous 
catheters and portable intravenous or IA infusion devices. 
5FU–induced conjunctivitis is a common problem. Advise patient to report any eye soreness or 
redness to the healthcare team. 
Photosensitivity may occur. Instruct patients to wear sun block when outdoors. 
11.0 MEASUREMENT OF 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) guidelines 
(version 1.1) [38].  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the short axis measurements in the case of lymph nodes are used in the RECIST 
guideline. 
11.1 
Schedule of Evaluations 
Restaging cross sectional imaging studies are performed as scheduled throughout the study 
timeline:  
• 
Prior to treatment (includes real-time central review),  
• 
Following 4 cycles of neoadjuvant chemotherapy,  
• 
Following either 4 cycles of neoadjuvant chemotherapy but before surgery (Arm 
1) or following 3 cycles of neoadjuvant chemotherapy and radiation but before 
surgery (Arm 2) (Note: Arm 2 closed to new patient enrollment on 08/13/2018) 
• 
Following surgery but prior to postoperative chemotherapy 
• 
Following 4 cycles of adjuvant chemotherapy 
Surveillance is per the schedule outlined in the Study Calendar in Section 5.0. 
Supporting documentation of surgical and pathologic response and progression should be 
submitted per Section 6.1.1. 

Alliance A021501 
74 
Version Date: 10/19/2018 
Update #04 
11.2 
Definitions of Measurable and Non-measurable Disease 
11.2.1 Measurable Disease 
A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥ 2.0 cm with chest X-ray, or as ≥ 1.0 cm with CT scan or 
MRI.  
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in 
diameter as assessed using calipers (e.g. skin nodules) or imaging.  In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
A malignant lymph node is considered measurable if its short axis is > 1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm).   
11.2.2 Non-measurable Disease 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥ 1.0 to < 1.5 cm).  Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable as well. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.  In addition, lymph nodes that have a short axis < 
1.0 cm are considered non-pathological (i.e. normal) and should not be recorded 
or followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods:   
• 
All measurements should be recorded in metric notation (i.e. decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to less 
than 2 cm must use CT imaging for both pre- and post-treatment tumor 
assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used at the same evaluation to 
assess the antitumor effect of a treatment.  
11.3.2 Acceptable Modalities for Measurable Disease: 
• 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 3 
mm or less. 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease.  The lesions should be measured on the same pulse 
sequence.  Ideally, the same type of scanner should be used and the image 

Alliance A021501 
75 
Version Date: 10/19/2018 
Update #04 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
• 
Chest X-ray:  Lesions on chest X-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, 
CT scans are preferable. 
11.3.3 Measurement at Follow-up Evaluation:   
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the 
treatment) and progressive disease. 
• 
Cytologic and histologic techniques can be used to differentiate between 
PR and CR in rare cases (e.g. residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain.) 
11.4 
Measurement of Treatment/Intervention Effect 
11.4.1 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as 
“Target Lesions” and recorded and measured at baseline. These lesions 
can be non-nodal or nodal (as defined in Section 11.2.1), where no more 
than 2 lesions are from the same organ and no more than 2 malignant nodal 
lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified 
(as there often will be), there is no reason to perform additional studies 
beyond those specified in the protocol to discover new lesions.   
• 
Target lesions and target lymph nodes should be selected on the basis of 
their size, be representative of all involved sites of disease, but in addition 
should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion (or 
malignant lymph node) does not lend itself to reproducible measurements 
in which circumstance the next largest lesion (or malignant lymph node) 
which can be measured reproducibly should be selected.   
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target lymph nodes 
will be calculated and reported as the baseline sum of dimensions (BSD).  
The BSD will be used as reference to further characterize any objective 
tumor response in the measurable dimension of the disease.   
• 
Post-baseline Sum of the Dimensions (PBSD): A sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target 
lymph nodes will be calculated and reported as the post-baseline sum of 
dimensions (PBSD). If the radiologist is able to provide an actual measure 
for the target lesion (or target lymph node), that should be recorded, even 
if it is below 0.5 cm. If the target lesion (or target lymph node) is believed 
to be present and is faintly seen but too small to measure, a default value 
of 0.5 cm should be assigned. If it is the opinion of the radiologist that the 

Alliance A021501 
76 
Version Date: 10/19/2018 
Update #04 
target lesion or target lymph node has likely disappeared, the measurement 
should be recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the 
BSD and the PBSD. 
11.4.2 Non-target Lesions & Non-target Lymph Nodes 
Non-measurable sites of disease (Section 11.2.2) are classified as non-target 
lesions or non-target lymph nodes and should also be recorded at baseline. These 
lesions and lymph nodes should be evaluated in accordance with Section 11.4.3. 
11.4.3 Response Criteria 
All target lesions and target lymph nodes followed by CT/MRI/Chest X-
ray/physical examination must be measured on re-evaluation at the evaluation time 
points specified in Section 11.1. Specifically, a change in objective status to either 
a PR or CR cannot be done without re-measuring target lesions and target lymph 
nodes.  
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. In 
selected circumstances, certain non-target organs may be evaluated less frequently.  
For example, bone scans may need to be repeated only when complete response is 
identified in target disease or when progression in bone is suspected. 
Evaluation of Target Lesions 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to < 1.0 cm. 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference the BSD (see Section 11.4.1). 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes at current 
evaluation) taking as reference the MSD (Section 11.4.1).  In addition, the 
PBSD must also demonstrate an absolute increase of at least 0.5 cm from 
the MSD.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking as reference the MSD. 
Evaluation of Non-target Lesions & Non-target Lymph Nodes 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all non-target lesions.  
b. Each non-target lymph node must have a reduction in short axis to <1.0 cm. 

Alliance A021501 
79 
Version Date: 10/19/2018 
Update #04 
Histopathologic response to preoperative therapy will be determined by analysis of the resected 
surgical specimen by the pathologist (see Section 7.3). The following grades will be used to 
semi-quantitatively characterize treatment response:  
I - 0% residual tumor cells in the specimen (pCR) 
II - 1 to < 5% residual tumor cells in the specimen   
III - ≥ 5% residual tumor cells in the specimen 
11.7 
Histopathologic Determination of R-status  
11.7.1 “Macroscopic disease” is assessed by surgeon and “microscopic disease” is 
assessed by the histopathologist.  
11.7.2 Margins to be assessed in this trial include: 1) common bile duct, 2) SMA 
margin, 3) pancreatic neck as described in pathology section:  
R0- Macroscopically complete tumor removal with negative microscopic 
surgical margins.  
R1- Macroscopically complete tumor removal with positive microscopic 
margins (any or all).  
R2- Macroscopically incomplete tumor removal with known or suspected 
residual gross disease. 
11.8 
Treatment Evaluation after Completion of Surgery and Post-operative Chemotherapy  
11.8.1 The term “recurrence” is used if cancer returns either in the locoregional area 
of the primary tumor or at distant sites following R0 or R1 resection.  
11.8.2 Recurrence is determined radiographically and biopsy need not be performed 
except as detailed below or when CT findings are equivocal in the 
determination of the enrolling physician.  
Locoregional Recurrence: identified by a new soft-tissue mass around the 
mesenteric vasculature or regional lymph nodes. Note that soft-tissue in this 
location on early postoperative scans may be benign and due to postoperative 
changes. Such findings may be difficult to distinguish from early tumor 
progression. In cases in which the diagnosis is ambiguous, discussion with the PI 
should occur. Performance of tissue biopsy should be considered prior to assigning 
a diagnosis of locoregional recurrent disease. 
Distant Recurrence: identified by a new hypodensity in the liver or nodule(s) in 
the lungs or peritoneum. Other sites of presumptive distant recurrence (adrenal, 
brain) should require prompt biopsy confirmation. New ascites should be 
interrogated with aspiration and cytology if it is an isolated finding and should not 
necessarily be taken to indicate carcinomatosis, particularly following the 
performance of resection and reconstruction of the mesenteric vein(s).  
12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment 
12.1.1 CR, PR, or SD: Patients who are in CR, PR or SD will continue on therapy until 
disease progression (see Section 12.1.3), excess toxicity or patient withdrawal.  

Alliance A021501 
80 
Version Date: 10/19/2018 
Update #04 
After treatment is discontinued, patients will be followed per the Study Calendar 
in Section 5.0. 
12.1.2 Disease Progression 
Remove from protocol therapy any patient with disease progression as per Section 
12.1.3 or recurrence after surgery (either Arm 1 or Arm 2 patients). Document 
details, including tumor measurements, on data forms. 
After disease progression, patients should be followed for survival per the study 
calendar (Section 5.0). 
Note: Biochemical progression (B-PROG) without the demonstration of objective 
progression (PD) of target or non-target lesion will not be sufficient indication to 
remove the patient from the study (see Section 11.4.3). 
12.1.3 Removal of Patients from Protocol Therapy:  
In the absence of treatment delays due to adverse events, treatment will be 
completed unless the patient experiences any one of the following scenarios. The 
specific indication should be described as: 
• 
Metastatic disease identified on imaging studies 
• 
For patients with RECIST PD with local progression only, the treating 
investigator should decide whether continuing protocol treatment is in the 
best interest of the patient 
• 
The presence of locally advanced disease on pre-surgical restaging 
imaging studies (see Appendix II for definition of locally advanced 
pancreatic cancer) 
• 
Decline in PS in the absence of radiographic evidence for disease 
progression if PS cannot be recovered (symptomatic deterioration) 
• 
Metastatic disease identified intraoperatively and biopsy-proven 
• 
Unresectable disease identified intraoperatively (e.g., locally infiltrative 
disease without metastases for which the surgeon does not feel resection 
is safe) 
• 
R2 surgical resection 
• 
Nontherapeutic (aborted) operation for any other reason  
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient’s condition that render the 
patient unacceptable for further treatment in the judgment of the 
investigator 
Patient should be removed from protocol therapy, and followed as per Section 5.0, 
post-treatment follow-up. Protocol treatment will be discontinued and further 
treatment is at the discretion of the treating physician. 

Alliance A021501 
81 
Version Date: 10/19/2018 
Update #04 
12.1.4 Follow-up for Patients Removed from Protocol Therapy:  
For patients who are removed from protocol therapy in any instance listed in 
Section 12.1.3, follow patients per the schedule found in Section 5.0 of the protocol 
for clinical and survival status. 
12.2 
Managing Ineligible Patients and Registered Patients Who Never Receive Protocol 
Intervention  
12.2.1 Definition of Ineligible Patient 
A study participant who is registered to the trial but does not meet all of the 
eligibility criteria is deemed to be ineligible.  
12.2.2 Follow-up for Ineligible Patients Who Continue with Protocol Treatment 
Patients who are deemed ineligible after registering may continue protocol 
treatment, provided the treating physician, study chair, and executive officer agree 
there are no safety concerns if the patient continues protocol treatment. All scans, 
tests, and data submission are to continue as if the patient were eligible. 
Notification of the local IRB may be necessary per local IRB policies. 
12.2.3 Follow-up for Ineligible Patients Who Discontinue Protocol Treatment 
For patients who are deemed ineligible after registering to the trial, who start 
treatment, but then discontinue study treatment, the same data submission 
requirements are to be followed as for those patients who are eligible and who 
discontinue study treatment. 
12.2.4 Follow-up for Patients Who Are Registered, but Who Never Start Protocol 
Treatment 
For all study participants who are registered to the trial but who never receive study 
intervention (regardless of eligibility), the follow-up requirements are specified 
below.  
Baseline, off treatment, and post-treatment follow up (i.e. relapse, progression, and 
survival) data submission is required. See the Data Submission Schedule 
accompanying the All Forms Packet. 
12.3 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
 
13.0 STATISTICAL CONSIDERATIONS 
Note: Arm 2 closed to new patient enrollment on 08/13/2018. 

Alliance A021501 
82 
Version Date: 10/19/2018 
Update #04 
13.1 
Study Endpoints 
13.1.1 Primary Endpoint 
The primary endpoint of this study is the 18-month OS rate, defined as the number 
of patients who are alive at 18 months after randomization divided by the total 
number of evaluable patients in each arm. An evaluable patient is defined as any 
patient who signed informed consent, deemed eligible by central review and 
received any protocol-defined treatment.  
13.1.2 Secondary Endpoints 
13.1.2.1 R0 Resection Rate 
R0 resection rate is defined as the proportion of patients in whom an 
achieved R0 resection was achieved during surgery (see Section 11.7.2). 
The R0 resection rate will be estimated in two cohorts, 1) patients who 
signed the consent form, deemed eligible by central review, and received 
any protocol defined treatment in each arm and 2) patients who signed 
the consent form, deemed eligible by central review, and underwent 
surgery in each arm.  The R0 resection rate will be estimated by the 
number of patients in whom R0 resection was performed divided by total 
number of patients in cohort 1) and cohort 2) in each arm.  
13.1.2.2 Event-free Survival 
Event-free survival is defined as time from randomization to the first 
documentation of event where events considered are 1) disease 
progression, per RECIST, prior to surgery, 2) surgery with R2 resection, 
3) recurrent disease following surgery, or 4) death due to any cause. 
13.1.2.3 Pathologic Complete Response (pCR) Rate 
Pathologic complete response (pCR) rate is defined as the proportion of 
patients in whom a pCR was confirmed by histopathologic review of the 
surgical specimen (see Section 11.6) The pCR rate will be estimated in 
two cohorts, 1) patients who signed the consent form, deemed eligible by 
central review, and received any protocol-defined treatment in each arm 
and 2) patients who signed the consent form, deemed eligible by central 
review, and underwent surgery. The pCR rate will be estimated by the 
number of patients in whom a pCR was confirmed divided by total 
number of patients in cohort 1) and cohort 2) in each arm.   
13.1.2.4 Adverse Events (AE) 
AEs and the maximum grade for each type of adverse events will be 
recorded for each patient separately for the following 3 periods: 
1. During neoadjuvant chemotherapy and chemoradiation therapy 
2. Surgical complications during surgery and post-op period for 90 
days or prior to adjuvant therapy 
3. During adjuvant therapy. See Section 9.1. 
Similarly, scores (0-4) and maximum score for each PRO-CTCAE item 
will be recorded for each patient separately for the 3 periods. 

Alliance A021501 
83 
Version Date: 10/19/2018 
Update #04 
13.2 
Sample Size 
We anticipate enrolling a maximum of 124 evaluable patients (62 per arm) per statistical design.  
Additional 10 (5 per arm) patients will be accrued to account for cancelations, ineligibilities, 
major violations, and lost-to-follow up, etc. Thus the total targeted accrual will be 134 patients.  
We anticipate to pre-register 5 patients per month. Since we estimate 80% of patients who are 
pre-registered for central review will be randomized to therapy, the actual accrual will be 4 
patients per month. Thus, we expect to pre-register 168 patients to reach the targeted accrual of 
134 patients.  The accrual period of this study is estimated to be 34 months. 
We also expect that 40% of patients randomized to therapy will be off protocol treatment prior 
to surgery (i.e. will not undergo surgery). Therefore we expect that of the 134 patients, 80 will 
proceed to surgery. The primary endpoint, overall survival at 18 month post randomization, is 
well-defined even among patients who do not receive surgery.  Therefore, the percentages of 
patients who do not undergo surgery do not affect the trial design.   
13.3 
Power Justification 
The primary aim of this randomized phase II study is to evaluate 18-month OS rate in  patients 
with borderline resectable cancer of the head of the pancreas treated neoadjuvantly using one of 
the following regimens: 1) Arm 1: 8 cycles of systemic FOLFIRINOX or 2) Arm 2: 7 cycles - 
of systemic FOLFIRINOX followed by short-course hypofractionated radiation therapy. All 
patients who are able to undergo subsequent surgery will also receive 4 cycles of postoperative 
FOLFOX. Eligible patients will be randomized and stratified by ECOG performance score onto 
two arms. Within each arm, single-arm sequential design with one interim analysis for futility 
will be implemented. The final efficacy analysis and interim analysis will be based on 18-month 
OS rate and R0 resection rate, respectively, and evaluated in each arm separately. The 
comparison of OS between arms will be carried out only if both arms are deemed promising at 
the end of the trial. “Pick-a-winner” strategy will be implemented to choose one treatment 
strategy for recommendation.  
An extensive literature review was conducted to evaluate median OS and R0 resection rate in 
patients purported to have “borderline resectable” tumors who received chemo, chemoRT, etc. 
were conducted. Twenty-six studies published between 2004 and 2015 are identified with 
number of borderline resectable patients range from 8 to 129. All but three of these studies are 
retrospective studies.  
The following table summarizes the historical data of median OS and R0 resection rate among 
all patients started treatment, including both patients with and without surgery. 

Alliance A021501 
84 
Version Date: 10/19/2018 
Update #04 
 
Among Studies with N > 20 
Among Studies with N > 50 
Time 
era 
N of 
studies 
Weighted 
Median 
Range (IQR) 
N of 
studies 
Weighted 
Median 
Range 
(IQR) 
Median OS in months 
Prior 
to 2012 6 
21.3 
21.5 
14.2 – 25 
(18.0 – 22.8) 
3 
22.0 
22.0 
14.2 – 25 
(21.5 – 
22.5) 
2012 
and 
later 
9 
21.2 
19.9 
17.2 – 28 
(18.0 – 23.6) 
6 
21.2 
21.0 
17.2 – 28 
(17.9 – 
23.2) 
All 
studies 
15 
21.2 
21.0 
14.2 – 28 
(17.6 – 23.3) 
9 
21.5 
22.0 
15 – 28 
(19.0 – 
23.0) 
R0 Resection Rate Among All Patients Started Neoadjuvant Treatment 
Prior 
to 2012 6 
41.4% 
36.9% 
30 – 59% 
3 
43.0% 
38.8% 
30 – 59% 
2012 
and 
later 
9 
61.2% 
54.4% 
42 – 92% 
6 
60.0% 
54.2% 
42 – 92% 
All 
studies 
15 
53.0% 
53.4% 
30 – 92% 
9 
52.8% 
53.9% 
37 – 92% 
We consider studies with reasonable number of borderline resectable patients (e.g. N > 20, 
and/or N > 50) to estimate the historical estimates of the median OS and R0 resection rate for 
sample size and power determinations. There is substantial variability in the literature reported 
median OS across studies. The median OS reported in these studies varies from 14 to 28 months, 
with a median of 21 to 22 months and an interquartile range of about 18 to 23 months. Most of 
the previous studies are retrospective single-institution studies subject to patient selection bias, 
which likely to skew the reported OS higher. Thus, we consider the median OS of at most 18 
months (equivalent to 18m OS rate of 0.50, assuming exponential survival function) which is 
the lower bound of the IQR of literature reported data as the null hypothesis. To demonstrate 
clinical meaningful improvement in OS, we target an alternative hypothesis of median OS of at 
least 27 months (equivalent to 18m OS rate of 0.63; a 50% increase in median OS time). 
The summary data in the table shows clear increase trend of R0 resection rate over time. For 
interim analysis based on R0 resection rate, if R0 resection rate is at least 60% (null hypothesis) 
based on weighted R0 resection rate from historical data, the arm warrants continuing to full 
accrual for OS final analysis. If the observed R0 resection rate is significantly less than 60%, 
we consider early futility of the arm and stop accrual of patients onto that arm. Therefore, the 
interim analysis based on R0 resection rate will be testing alternative hypothesis of R0 resection 
rate ≤ 40% against the null hypothesis of R0 resection rate ≥ 60%. 
The study operating characteristics were assessed by simulation studies based on the estimation 
procedures and decision rules specified for final and interim analysis described in Section 
13.4.1. A maximum of 62 evaluable patients in each arm will provide 82% power to detect an 
improvement of 13% in 18 months OS rate, i.e., testing alternative hypothesis that the 18 months 
OS rate is at least 63% against the null hypothesis that the 18 months OS rate is at most 50%, at 
a one-sided significance level of 0.07. The probability of stopping accrual at interim is 43% and 
0.8% if the true R0 resection rate is 40% and 60%, respectively.  

Alliance A021501 
85 
Version Date: 10/19/2018 
Update #04 
13.4 
Statistical Analysis Plan 
13.4.1 Primary Endpoint 
Treatment Efficacy Decision Rules: 
13.4.1.1 Interim Analysis 
One interim analysis will be performed to assess treatment futility for 
each arm separately. For each given treatment arm, the R0 resection rate 
will be evaluated when surgical data become available for first 30 
evaluable patients, approximately 8 months after trial activation. If at 
most 11 patients (i.e. ≤ 11 patients) among 30 evaluable patients 
underwent R0 resection, then the given treatment arm will be deemed not 
promising and the accrual to this treatment arm will be terminated. An 
evaluable patient is defined as any patient who signed informed consent, 
deemed eligible by central review and received any protocol-defined 
treatment. 
13.4.1.2 Final Analysis 
The primary efficacy analysis will be performed on 18-month OS rate for 
the two treatment arms, separately, based on all evaluable patients, For 
each given treatment arm, if full accrual is reached and at least 36 patients 
(i.e. ≥ 36 patients) out of 62 evaluable patients are alive up to 18 months 
after randomization, the regimen of the evaluated arm will be considered 
worthy of further testing in this disease population. Otherwise, the 
regimen will be deemed inefficacious. The final analysis will be carried 
out approximately 18 months after the last patient, in each arm, is 
enrolled. This will occur approximately 52 months after trial activation. 
13.4.1.3 Analysis Plan 
The treatment arm specific 18 month OS rate and 95% confidence 
interval will be estimated based on standard method  [39]. Chi-squared 
test (or Fisher’s exact test if the data in contingency table is sparse) will 
be used to compare 18 month OS rates among treatment arms. Overall 
survival within each arm will be summarized by Kaplan-Meier method. 
Median, 1-year and 2-year rates will be estimated based on Kaplan-Meier 
curves. 
If both arms are deemed worthy of further testing in this disease 
population, a log-rank test will be used to compare the median OS 
between the two arms. A “pick-the-winner” approach will be utilized, 
meaning that the nominally better arm (the arm with higher 18-month OS 
rate, by any amount) will be prioritized for future study.    
13.4.2 Secondary Endpoints 
13.4.2.1 Event-free Survival 
The distribution of event-free survival will be estimated using the method 
of Kaplan-Meier in each arm. Event-free survival will be compared 
between treatment groups using the log-rank test. The correlation 
between pCR status and event-free survival time will be assessed by Cox 
model with landmark approach. 

Alliance A021501 
86 
Version Date: 10/19/2018 
Update #04 
13.4.2.2 R0 Resection Rate 
R0 resection rate and confidence intervals for the R0 resection rate will 
be calculated according to the approach of Duffy and Santner. Chi-square 
test (or Fisher’s exact test if the data in contingency table is sparse) will 
be used to compare R0 resection rate between treatment arms. Sensitivity 
analysis will be conducted among patients in cohort 1) and cohort 2). The 
association between R0 resection rate and OS/PFS will be assessed by 
log-rank test and Cox model. 
13.4.2.3 Pathologic Complete Response (pCR) Rate 
pCR rate and confidence intervals for the pCR rate will be calculated 
according to the approach of Duffy and Santner. Chi-square test (or 
Fisher’s exact test if the data in contingency table is sparse) will be used 
to compare pCR resection rate between two treatment arms. Sensitivity 
analysis will be conducted among patients in cohort 1) and cohort 2). The 
association between pCR rate and OS/PFS will be assessed by log-rank 
test and Cox model. 
13.4.2.4 Adverse Events (AE) 
For CTCAE data, the frequency tables will be reviewed to determine the 
patterns.  The overall adverse event rates will be compared between 
treatment groups using Chi-square test (or Fisher’s exact test if the data 
in contingency table is sparse). 
PRO-CTCAE data will, at minimum, be analyzed similarly to CTCAE 
data.  Reasons for missed PRO-CTCAE assessments will be collected and 
we will describe the extent of missing data as well as its patterns and 
causes.  The initial analysis of each PRO-CTCAE item will use all 
available scores in an analysis which mirrors the approach used for the 
CTCAE data.  Supplemental analysis will use model-based multiple 
imputation incorporating baseline patient characteristics and physician-
rated performance status (which is collected at each cycle).  CTCAE data 
may be incorporated as axillary data into multiple imputation models for 
AEs which are captured by both PRO-CTCAE and CTCAE. Results from 
supplemental analysis will be descriptively compared to the results of the 
initial analysis to assess the robustness of results to missing data.  Since 
a preferred or optimal statistical methodology for PRO-CTCAE data is 
yet to be determined, additional analyses of PRO-CTCAE data beyond 
those specified above may be undertaken based on the current state of the 
science at time of data maturity for this study. 
13.4.3 Subgroup Analysis 
Subgroup analysis will be performed by radiation type (HIGRT vs. SBRT) to 
examine potential differential effect on overall survival (OS). 
13.5 
Safety Monitoring 
The stopping rule specified below is based on the knowledge available at study development. 
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the 
study re-opening to accrual or (2) at any time during the conduct of the trial and in consideration 
of newly acquired information regarding the adverse event profile of the treatment(s) under 

Alliance A021501 
87 
Version Date: 10/19/2018 
Update #04 
investigation. The study team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time in either arm we observe the 
following:  
• 
The rate of on-study deaths during treatment, or within the first 90 days following off-
protocol treatment, exceeds 2 or more in the first 10 patients or, after 10 patients enrolled, 
20% or more of all treated patients. The rate will be assess for each arm separately. 
Accrual will also be temporarily suspended to this study if prior to surgery we observe events 
considered at least possibly related to study treatment (i.e. an adverse event with attribute 
specified as “possible”, “probable”, or “definite”) in each treatment arm, separately, that satisfy 
the following:  
• 
If 4 or more patients in the first 20 treated patients (or 20% of all patients after 20 are 
accrued) experience a grade 4 or higher non-hematologic adverse event. 
The principal investigator and the study statistician will review the study at least twice a year to 
identify accrual, adverse event/safety, and any endpoint problems that might be developing. The 
Alliance Data Safety Monitoring Board (DSMB) is responsible for reviewing accrual and safety 
data for this trial at least twice a year, based on reports provided by the study statisticians. 
13.6 
Descriptive Factors  
• 
Age: < 55yo versus > 55yo 
• 
Gender 
• 
Albumin < LLN: yes/no 
13.7 
Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. 
There is no information currently available regarding differential effects of this regimen in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences 
to exist. Therefore, although the planned analysis will, as always, look for differences in 
treatment effect based on racial and gender groupings, the sample size is not increased in order 
to provide additional power for subset analyses. 
Accrual Targets 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
2 
2 
0 
0 
4 
Asian 
3 
7 
0 
0 
10 
Native Hawaiian or Other 
Pacific Islander 
2 
10 
0 
0 
12 
Black or African American 
6 
1 
0 
1 
8 
White 
41 
53 
3 
3 
100 
More Than One Race 
0 
0 
0 
0 
0 
Total 
54 
73 
3 
4 
134 
 

Alliance A021501 
88 
Version Date: 10/19/2018 
Update #04 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
 

Alliance A021501 
89 
Version Date: 10/19/2018 
Update #04 
14.0 CORRELATIVE AND COMPANION STUDIES  
There will be two substudies and all patients are encouraged to participate.  
14.1 
Pharmacogenetic Studies in Alliance A021501: A021501-PP1 
14.1.1 Background 
Pharmacogenetics examines inter-individual genetic variability that influences the 
course of drug action so that medication regimens may be optimized to maximize 
response, while minimizing drug-induced toxicity.  The ability to predict prognosis 
and efficacy, as well as mitigate adverse drug reactions in oncology is of 
paramount importance because a majority of chemotherapeutic agents are dosed 
to their maximally tolerated dose, and possess a narrow therapeutic index between 
efficacy and toxicity. There is currently a dearth of clinically relevant prognostic 
and predictive pharmacogenetic markers derived from germline variants that have 
been translated for incorporation into clinical practice. There is an opportunity to 
better understand the relationship between germline variants, efficacy, prognosis, 
and toxicity so that more of these pharmacogenetic markers may be utilized 
clinically to individualize therapies for cancer patients [40]. 
This could be particularly helpful in the setting of pancreatic cancer, for example, 
a disease that is rarely curable at the time of diagnosis and that is almost always 
associated with survival of little more than a year. 
Currently, no biomarkers are available to predict response in patients with this 
disease, and several targeted therapies have failed to confer a survival advantage. 
Multidisciplinary efforts have focused on improving tools for early diagnosis and 
cataloguing the architecture of somatic mutations. In conjunction with these 
efforts, the interrogation of the germline genome of patients aims at characterizing 
the constitutive basis of biological systems of fundamental importance for tumor 
biology, like angiogenesis, inflammation, immunity, and others.  
A previous genome-wide association study (GWAS) in 294 pancreatic cancer 
patients treated with gemcitabine in CALGB 80303 identified several new 
candidate genes for overall survival (OS) [41, 42]. To discover and validate novel 
genes and pathways of importance in the biology of pancreatic cancer and the 
pharmacology of its treatment, we set out to use an external cohort of pancreatic 
cancer patients from the Mayo Clinic where GWAS information for OS had 
already been obtained [43]. 
In the Mayo Clinic patients, three SNPs located in genes (VDR, CMYA5, CAMK4) 
had an effect on OS concordant with that observed in the CALGB 80303 patients 
(p < 0.05). Consistent with a link between the vitamin D receptor gene (VDR) and 
pancreatic cancer, a common SNP in VDR (rs2853564, A>G) was associated with 
OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70-0.94, p = 0.0059) 
and CALGB 80303 (0.74, 0.63-0.87, p = 0.0002). Presence of high pre-treatment 
levels of endogenous vitamin D interacted with rs2853564 to confer improved OS 
(p < 0.01). rs2853564 increased transcriptional activity in luciferase assays and 
altered binding of the IRF4 transcription factor to VDR. Functional genetic 
variation in VDR affects the survival of pancreatic cancer patients. This effect is 
potentiated by an interaction with vitamin D levels. 
The prognostic value of the rs2853564 VDR variant has never been tested in the 
setting of borderline resectable disease. In addition, a comprehensive survey of the 
germline DNA variation of patients might inform the discovery of novel candidate 

Alliance A021501 
90 
Version Date: 10/19/2018 
Update #04 
genes and pathways that relate to the pharmacology of treatments and the biology 
of disease. 
14.1.2 Objectives 
Primary Objective 
To test the effect of the rs2853564 VDR variant on the 18 months OS rate using 
both arms combined. We hypothesize that patients with the GG genotype have 
worse survival than patients with either the AA or AG genotype. 
Secondary Objectives 
1. To test an interaction between the rs2853564 VDR variant and treatment 
arm on the 18 months OS rate. We hypothesize that the effect of the 
rs2853564 VDR variant on survival might differ between the two arms.  
Statistical Methods: Logistic regression will be used to test this 
interaction. The response variable will be an indicator for survival at 18 
months. The predictor variables will include clinical variables, an 
indicator for rs2853564 VDR variant [GG vs. (AA or AG)] and an 
indicator for treatment arm, and the interaction between variant and 
treatment arm. 
2. To discover novel candidate genes associated with the 18 months OS rate 
and severe toxicity of chemotherapy.  We hypothesize that the genotyping 
a large series of common germline variants through a genome wide 
approach will allow the identification of novel gene markers of survival 
and severe toxicity. 
3. To run association analyses with the many molecular markers identified 
in the correlative science section of this protocol. We hypothesize that the 
information on the germline variation of patients will associate with 
molecular markers that relate to constitutional systems like inflammation, 
immunity, angiogenesis, stromal functions, and others. 
Statistical Methods: Penalized regression methods such as LASSO or 
elastic net will be utilized to determine combinations of genes that may 
predict the outcomes. Clinical covariates will be forced into the models. 
Cross validation will be used in the model building to reduce over-fitting. 
The logistic framework will be used for dichotomous variables, and a 
Gaussian or time-to-event framework for continuous or survival 
outcomes, respectively. We will stay abreast of the literature for modeling 
strategies that are appropriate for such modeling. 
14.1.3 Methods 
The germline DNA of patients who have consented to these analyses will be 
collected from peripheral blood as described in Section 6.2. 
Genotyping of the rs2853564 VDR variant will be conducted by TaqMan assay 
(Applied Biosystems, Foster City, CA) per the manufacturer’s instructions using a 
CFX384 Real-Time System (Bio-Rad, Hercules, CA) and performed in the 
laboratory of Dr. Innocenti at the University of North Carolina at Chapel Hill. 
Sanger-based DNA sequencing (Mammalian Genotyping Core at the University 
of North Carolina at Chapel Hill) will be used to validate representative samples 
and determine thresholds for allelic discrimination. The allele frequency will be 
compared with those previously reported from the HapMap and 1,000 Genomes 

Alliance A021501 
91 
Version Date: 10/19/2018 
Update #04 
projects. Deviation from Hardy-Weinberg equilibrium (p<0.01 for significance) 
will be tested to evaluate genotyping accuracy.  
Genome-wide genotyping will be performed by the OmniExpress Exome chip, 
which enables whole-genome genotyping of over 700,000 single nucleotide 
polymorphism (SNP) loci. This platform gives an outstanding breadth of coverage 
over the genome for the planned association studies. It will be performed at the 
Mammalian Genotyping Core at the University of North Carolina at Chapel Hill. 
Exome and whole sequencing could be also performed from germline and somatic 
DNA to detect associations between outcome and rare variants. 
Logistic regression will be used to access the relationship between rs2853564 VDR 
variant and 18 month OS rate.  The treatment assignment and the interaction term 
between rs2853564 VDR variant and treatment  assignment  will entered the model 
in order to examine whether the effect of the rs2853564 VDR variant differ 
between 2 arms. 
Fisher’s Exact test will be used to assess the association of the GG genotype with 
worse 18 month OS. With a total sample size of N=125 in both arms, and 85% 
expected rate of consent to this study, we expect a sample size of 106 for this aim. 
We assume 63% 18 month OS rate (the alternative hypothesis in the primary aim 
of this trial) and 16% prevalence of the GG variant. We expect n=17 GG variant 
patients. Under these assumptions, a Fisher’s Exact test has 82% power to detect a 
difference of 44% versus 82% (i.e. a delta of 38%) 18 month OS rates between the 
groups defined by the GG variant. Nonparametric methods such as recursive 
partitioning for classification, regression and survival trees (RPART) will be used 
to explore a possible predictive value of the GG genotype (secondary objective 1), 
and prognostic value of common variants (secondary objective 2) [44]. In 
secondary objective 4, generalized linear model methods and penalized regression 
together with cross validation will be used to evaluate the association between 
germline variation and molecular markers of inflammation, immunity, 
angiogenesis, and stromal functions in an exploratory fashion. 
Similar approaches to Quality Control and Normalization of Expression Data, 
Differential expression, Model Building, and Internal Model Validation will be 
employed. We will stay abreast of the literature for methods that are appropriate 
for data analysis. A detailed analysis plan will be formulated prior to actual data 
analysis. 
14.2 
Imaging Science Studies in Alliance A021501: Alliance A021501-IM1 
We propose three imaging correlates for this study. The primary objective of these correlative 
studies is to prospectively validate prognostic biomarkers derived from imaging. We have 
reviewed how previous clinical trials in this disease could have benefited from stratification and 
proper selection [45] [46]. By validating the imaging-based biomarkers in this trial, we can 
develop a better understanding of the results of this trial and design the next generation of trials 
with these biomarkers in mind. We have previously shown that standard imaging can correlate 
with drug delivery in PDAC [36]. Our group has pilot data to suggest that two imaging-based 
properties independently predict overall survival (OS) outcomes of patients. These 
measurements are the degree of enhancement in the tumor relative to the normal pancreas (called 
normalized area under the enhancement curve, NAUC) and a measurement of the morphology 
of the tumor (called the delta measurement). Our pilot data also indicate that changes in NAUC 
associate with local control of the tumor, and we hypothesize this observation is due to the 

Alliance A021501 
92 
Version Date: 10/19/2018 
Update #04 
pathological response in the tumor after neoadjuvant therapy. With a planned accrual of 134 
patients in this Alliance trial, we will be well powered to prospectively validate our pilot data. 
14.2.1 Primary Objectives 
To evaluate risk classification previously developed by Koay et al. [36] using 
NAUC. 
To access prognostic value of NAUC ration defined as post-neoadjuvant NAUC 
divided by pre-neoadjuvant therapy NAUC. 
To evaluate risk classification previously developed by Koay et al. using delta 
measure. 
14.2.2 NAUC and OS 
In a pilot study of 110 patients who underwent neoadjuvant gemcitabine-based 
chemoradiation for resectable pancreatic cancer, NAUC from pre-therapy CT 
scans associated with OS as a survival variable. Exploratory analysis (Koay et al, 
JCI 2014) identified a cutoff of 0.6 for NAUC, differentiating patients into two 
prognostic groups: high NAUC (20% of patients) and low NAUC (80% of 
patients) [36]. The hazard ratio for this cutoff was 0.46 [0.24, 0.79], favoring 
patients with a higher NAUC.  
To validate the cutoff, NAUC will be calculated for each evaluable patient based 
on pre-therapy CT scans. Patients will then be categorized into two groups based 
on NAUC value (> 0.6 versus ≤ 0.6). Proportional hazard model will be used to 
examine the associate between NAUC grouping (high versus low) and overall 
survival adjusting for treatment arm to assess the prognostic value of NAUC.  
Assuming 20% of patients will have NAUC > 0.6, we will have 80% power to 
detect a difference in overall survival at a one-sided 5% significance level with a 
hazard ratio of 0.47. The power curve for different percentages of patients who 
have NACU > 0.6 is shown in Figure 4 below. This power analysis assumes an 
accrual period of 31 months, a minimum follow up of 20 months, an accrual rate 
of 4 patients per month, and median survival in the worst group of 18 months. 
 
Figure 4. Power curve for different percentages of patients who have NAUC > 0.6. 

Alliance A021501 
93 
Version Date: 10/19/2018 
Update #04 
 
NAUC will be calculated for each evaluable patient based on pre-therapy CT 
scans.  Patients then will be categorized into 2 groups based on NAUC value (> 
0.6 vs. ≤ 0.6).  Proportional hazard model will be used to examine the association 
between NAUC grouping and overall survival  
If NAUC > 0.6 cutoff is not validated, we will explore an additional cut-point to 
better differentiate patients to two risk groups. The methods used for exploratory 
analysis including, but not limited to, 1) graphical approaches based on Martingale 
Residual plot [47], 2) Mazumdar and Classman cut-off identification strategy [48] 
(minimum p-value and maximum HR approach), and 3) Contal and O’Quidley 
method (changepoint method) [49]. A detailed analysis plan will be formulated 
prior to actual data analysis.  
14.2.3 Changes in NAUC and Pathological Response. 
As a second correlate for the mass transport properties, the change in NAUC 
during therapy may also provide important information. As an exploratory 
exercise, NAUC will be calculated for each evaluable patient based on pre-therapy 
and pre-surgery CT scans.  A NAUC ratio of pre-surgery to pre-therapy NAUC 
will then be calculated for each patient.  Proportional hazard model will be used to 
examine the association between NAUC ratio grouping, progression free survival 
and overall survival 
Additionally, we propose analyzing changes in the NAUC (comparing post-
neoadjuvant therapy and pre-neoadjuvant therapy) as a prognostic biomarker of 
the pathological response to neoadjuvant therapy. Our pilot data indicate that 
patients who have a decrease in NAUC after neoadjuvant therapy (NAUC ratio of 
post- to pre- NAUC less than 1) have significantly better local control than those 
who have a NAUC ratio above 1, with a hazard ratio of 3.01 [1.45, 6.25]). We 
hypothesize this difference in the groups is based on response at the pathological 
level. As an exploratory study, we will score the pathological response in patients 
who undergo resection on this Alliance trial and measure NAUC on post- and pre-
therapy CT scans, similar to our previously published methods.[36] This estimate 
was based on a conservative estimate of the hazard ratio from our pilot study (2.2) 
and the same assumptions as (A). The model will include a treatment arm indicator. 
In addition, the predictive value will be assessed by testing the interaction between 
NAUC and treatment arm. 
If our preliminary data reflect the differences that we can expect, then we estimate 
we will need a minimum of 62 patients to detect a difference in the NAUC ratio 
between those who have an excellent response to therapy from all others. This 
estimate was based on a conservative estimate of the hazard ratio from our pilot 
study (2.2) and the same assumptions as (A).  
NAUC ratio of pre-surgery to pre-therapy NAUC will be calculated for each 
patient.  Proportional hazard model will be used to examine the association 
between NAUC ratio (as a continuous variable) and overall survival adjusting for 
treatment arm to assess the prognostic value of NAUC ratio. Optimal cut point of 
NAUC ratio will be explored to dichotomize patients into two risk groups. 
Assuming 60% of evaluable patients (N=74) undergo resection, there will be are 
41 events.  The power curve is a function of hazard ratio and the variance of the 
NAUC ratio (Figure 5). 

Alliance A021501 
94 
Version Date: 10/19/2018 
Update #04 
Figure 5. Power curve as a function of hazard ratio and the variance of the NAUC 
ratio.  
We will have 80% power to detect a difference in overall survival at a two-sided 
5% significance level with a hazard ratio of 1.55 if the variance of NAUC ratio is 
one.  Similarly, we can detect a difference of 1.32 and 2.4 if the variance of NAUC 
ratio is 1.5 and 0.5, respectively.  This power analysis assumes a minimal follow-
up of 20 months and accrual rate of 4 patients per month. A detailed analysis plan 
will be formulated prior to actual data analysis. 
14.2.4 Tumor Morphological Measurements and OS 
The final imaging correlate that we will perform will also involve analysis of the 
pre-therapy CT images. We will obtain a measurement of the tumor-pancreas 
interface (the delta measurement). In our pilot study, we identified a cutoff for this 
delta measurement from the CT scans by quantifying the amount of stroma in 
treatment naïve specimens of 12 patients who underwent upfront resection. 
Patients with a delta measure ≥ 40 Hounsfield Units (HU) had significantly less 
stroma than patients with a delta measure < 40 HU. This cutoff was validated in a 
separate cohort of 33 patients who underwent upfront resection.  This defined high 
and low delta classes. 
We have found this delta classification to differentiate 156 patients who received 
neoadjuvant therapy into two distinct prognostic groups, where patients with a low 
delta tumor have significantly better prognosis than those with a high delta tumor 
(difference in OS, HR 0.58 [0.40, 0.81]), due to differences in the tumor biology 
between tumors that have a high delta (> 40 ounce/unit) compared to those with a 
low delta (≤ 40 ounce/unit), as defined by our quantitative image analysis.  
We will validate the delta classification as a prognostic biomarker to OS. The delta 
classification will be calculated for each evaluable patient based on pre-therapy 
CT scans. Proportional hazard models will be used to examine the association 
between delta classification (high or low) and overall survival adjusting for 
treatment arm. 
Assuming 40% of evaluable patients will have high delta, we will have 80% power 
to detect a difference in OS at a two sided 5% significance level with a hazard ratio 
of 0.51. We will analyze this imaging marker independent of randomization on the 
study. This power analysis assumes an accrual period of 31 months, a minimum 

Alliance A021501 
95 
Version Date: 10/19/2018 
Update #04 
follow-up of 20 months, an accrual rate of 4 patients per month, and a median 
survival in the worst group of 18 months. 
If delta measure > 40 HU is not validated, we will explore an additional cut-point 
to better differentiate patients into two risk groups. The methods used for 
exploratory analysis include, but are not limited to, the following: 1) graphical 
approaches based on Martingale Residual plot [47] 2) Mazumdar and Classman 
cut-off identification strategy [48] (minimum p-value and maximum HR 
approach), and 3) Contal and O’Quidley method (changepoint method) [49]. A 
detailed analysis plan will be formulated prior to actual data analysis. 
The delta measurement will be calculated for each evaluable patients based on pre-
therapy CT scans. We will examine measurement and search for a cut-point which 
will separate patients into two distinct prognostic groups.  Proportional hazard 
model will be used to examine the association between delta measurement 
grouping and overall survival. 
The delta measurement will be calculated for each evaluable patient based on pre-
therapy CT scans. Proportional hazard models will be used to examine the 
association between delta measurement grouping and overall survival adjusting for 
treatment arm. In addition, the predictive value will be assessed by testing the 
interaction between the delta variable and treatment arm. We will examine the 
delta measurement and outcome, and evaluate the possibility of search for a cut-
point which may separate patients into two distinct prognostic groups.  
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
15.1 
Institutional Credentialing 
15.1.1 IROC Ohio Institutional Requirements 
Prior to the enrollment of patients, institutions that have not previously been 
credentialed for any other Alliance trials must be credentialed to participate in the 
trial by the Imaging Core Laboratory at IROC Ohio. For institutions that have 
previously been credentialed by the Imaging Core Laboratory at IROC Ohio to 
participate in imaging studies, the ICL will provide a brief A021501 protocol 
refresher prior to patient enrollments. Institutions  should  contact  the  Alliance  
ICL  directly  to  complete  credentialing  or  a refresher for A021501. 
Contact information for IROC Ohio can be found under protocol contacts near the 
title page. 
15.1.2 Radiation Therapy Requirements 
Note: Arm 2 closed to new patient enrollment on 08/13/2018. As of Update #04, 
RT Credentialing is no longer required. 
Institutions that have been previously credentialed for participation in RTOG 1112 
need only update their Facility Questionnaire as indicated in the table below. All 
other institutions must be credentialed for the modality they plan to use prior to 
delivery of radiation therapy on any protocol patient.  Credentialing requirements 
are listed in the table below. Use of IMRT is required for those treating with SBRT.  
Use of proton therapy is not allowed. 
Web 
Link 
for 
Credentialing 
Procedures 
and 
Instructions: 
http://irochouston.mdanderson.org 
 

Alliance A021501 
97 
Version Date: 10/19/2018 
Update #04 
16.0 REFERENCES 
1. 
Katz, M.H., et al., Borderline resectable pancreatic cancer: the importance of this emerging 
stage of disease. J Am Coll Surg, 2008. 206(5): p. 833-46; discussion 846-8. 
2. 
Ishikawa, O., et al., Preoperative indications for extended pancreatectomy for locally advanced 
pancreas cancer involving the portal vein. Ann Surg, 1992. 215(3): p. 231-6. 
3. 
Nakao, A., et al., Correlation between radiographic classification and pathological grade of 
portal vein wall invasion in pancreatic head cancer. Ann Surg, 2012. 255(1): p. 103-8. 
4. 
Abrams, R.A., et al., Combined modality treatment of resectable and borderline resectable 
pancreas cancer: expert consensus statement. Ann Surg Oncol, 2009. 16(7): p. 1751-6. 
5. 
Callery, M.P., et al., Pretreatment assessment of resectable and borderline resectable pancreatic 
cancer: expert consensus statement. Ann Surg Oncol, 2009. 16(7): p. 1727-33. 
6. 
Oettle, H., et al., Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing 
curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA, 2007. 
297(3): p. 267-77. 
7. 
Neoptolemos, J.P., et al., A randomized trial of chemoradiotherapy and chemotherapy after 
resection of pancreatic cancer. N Engl J Med, 2004. 350(12): p. 1200-10. 
8. 
Abrams, R.A. RTOG 0848: A Phase IIR and A Phase III Trial Evaluating Both Erlotinib (Ph IIR) 
And Chemoradiation (Ph III) As Adjuvant Treatment For Patients With Resected Head Of 
Pancreas Adenocarcinoma. 2014  [cited 2015; Available from: 
https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0848. 
9. 
Hammel, P., et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients 
with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with 
or without erlotinib: Final results of the international phase III LAP 07 study. in ASCO Annual 
Meeting Proceedings. 2013. 
10. 
Katz, M.H., et al., Response of borderline resectable pancreatic cancer to neoadjuvant therapy is 
not reflected by radiographic indicators. Cancer, 2012. 118(23): p. 5749-56. 
11. 
Conroy, T., et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J 
Med, 2011. 364(19): p. 1817-25. 
12. 
Von Hoff, D.D., et al., Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. N Engl J Med, 2013. 369(18): p. 1691-703. 
13. 
Herman, J.M., et al., Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic 
body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. 
Cancer, 2015. 121(7): p. 1128-37. 
14. 
Mellon, E.A., et al., Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic 
body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma. 
Acta Oncologica, 2015(0): p. 1-7. 
15. 
Katz, M.H., et al., Borderline resectable pancreatic cancer: need for standardization and 
methods for optimal clinical trial design. Ann Surg Oncol, 2013. 20(8): p. 2787-95. 
16. 
Katz, M.H., et al. Preoperative modified FOLFIRINOX (mFOLFIRINOX) followed by 
chemoradiation (CRT) for borderline resectable (BLR) pancreatic cancer (PDAC): Initial results 
from Alliance Trial A021101. in ASCO Annual Meeting Proceedings. 2015. 
17. 
Katz, M.G., et al., Preoperative modified folfirinox treatment followed by capecitabine-based 
chemoradiation for borderline resectable pancreatic cancer: Alliance for clinical trials in 
oncology trial a021101. JAMA Surgery, 2016. 151(8): p. e161137. 
18. 
Heinrich, S., et al., Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and 
cisplatin for resectable adenocarcinoma of the pancreatic head. J Clin Oncol, 2008. 26(15): p. 
2526-31. 
19. 
O'Reilly, E.M., et al., A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine 
and oxaliplatin in patients with resectable pancreas adenocarcinoma. Ann Surg, 2014. 260(1): p. 
142-8. 

Alliance A021501 
98 
Version Date: 10/19/2018 
Update #04 
20. 
Rose, J.B., et al., Extended neoadjuvant chemotherapy for borderline resectable pancreatic 
cancer demonstrates promising postoperative outcomes and survival. Ann Surg Oncol, 2014. 
21(5): p. 1530-7. 
21. 
Loehrer, P.J., Sr., et al., Gemcitabine alone versus gemcitabine plus radiotherapy in patients with 
locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol, 
2011. 29(31): p. 4105-12. 
22. 
Huguet, F., et al., Impact of chemoradiotherapy after disease control with chemotherapy in 
locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol, 
2007. 25(3): p. 326-31. 
23. 
Chauffert, B., et al., Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, 
infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with 
gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 
2000-01 FFCD/SFRO study. Ann Oncol, 2008. 19(9): p. 1592-9. 
24. 
Chang, D.T., et al., Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. 
Cancer, 2009. 115(3): p. 665-72. 
25. 
Chang, B.K. and R.D. Timmerman, Stereotactic body radiation therapy: a comprehensive review. 
Am J Clin Oncol, 2007. 30(6): p. 637-44. 
26. 
Timmerman, R., et al., Optimizing dose and fractionation for stereotactic body radiation therapy. 
Normal tissue and tumor control effects with large dose per fraction. Front Radiat Ther Oncol, 
2007. 40: p. 352-65. 
27. 
Moningi, S., et al., The Role of Stereotactic Body Radiation Therapy for Pancreatic Cancer: A 
Single-Institution Experience. Ann Surg Oncol, 2015. 22(7): p. 2352-8. 
28. 
Pollom, E.L., et al., Single-versus multifraction stereotactic body radiation therapy for pancreatic 
adenocarcinoma: outcomes and toxicity. International Journal of Radiation Oncology* Biology* 
Physics, 2014. 90(4): p. 918-925. 
29. 
Varadhachary, G.R., et al., Preoperative gemcitabine and cisplatin followed by gemcitabine-
based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol, 2008. 
26(21): p. 3487-95. 
30. 
Hong, T.S., et al., A phase 1/2 and biomarker study of preoperative short course chemoradiation 
with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic 
ductal adenocarcinoma. International Journal of Radiation Oncology* Biology* Physics, 2014. 
89(4): p. 830-838. 
31. 
Chuong, M.D., et al., Stereotactic body radiation therapy for locally advanced and borderline 
resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys, 2013. 
86(3): p. 516-22. 
32. 
Koong, A.C., et al., Phase I study of stereotactic radiosurgery in patients with locally advanced 
pancreatic cancer. Int J Radiat Oncol Biol Phys, 2004. 58(4): p. 1017-21. 
33. 
Koong, A.C., et al., Phase II study to assess the efficacy of conventionally fractionated 
radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced 
pancreatic cancer. Int J Radiat Oncol Biol Phys, 2005. 63(2): p. 320-3. 
34. 
Schellenberg, D., et al., Gemcitabine chemotherapy and single-fraction stereotactic body 
radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys, 2008. 72(3): 
p. 678-86. 
35. 
Schellenberg, D., et al., Single-fraction stereotactic body radiation therapy and sequential 
gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol 
Phys, 2011. 81(1): p. 181-8. 
36. 
Koay, E.J., et al, Transport properties of pancreatic cancer describe gemcitabine delivery and 
response. Journal of Clinical Investigations, 2014. 124(4): p. 1525-36. 
37. 
Nelson, H., American College of Surgeons, and Alliance for Clinical Trials in Oncology, 
Operative standards for cancer surgery. xxxiii, 332 pages. 
38. 
Eisenhauer, E., et al., New response evaluation criteria in solid tumours: revised RECIST 

Alliance A021501 
99 
Version Date: 10/19/2018 
Update #04 
guideline (version 1.1). European journal of cancer, 2009. 45(2): p. 228-247. 
39. 
Duffy, D.E. and T.J. Santner, Confidence Intervals for a Binomial Parameter Based on 
Multistage Tests. Biometrics, 1987. 43(1): p. 81-93. 
40. 
Crona, D. and F. Innocenti, Can knowledge of germline markers of toxicity optimize dosing and 
efficacy of cancer therapy? Biomarkers in medicine, 2012. 6(3): p. 349-362. 
41. 
Innocenti, F., et al., A genome-wide association study of overall survival in pancreatic cancer 
patients treated with gemcitabine in CALGB 80303. Clinical Cancer Research, 2012. 18(2): p. 
577-584. 
42. 
Kindler, H.L., et al., Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in 
patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B 
(CALGB 80303). Journal of Clinical Oncology, 2010. 28(22): p. 3617-3622. 
43. 
Petersen, G.M., et al., A genome-wide association study identifies pancreatic cancer susceptibility 
loci on chromosomes 13q22. 1, 1q32. 1 and 5p15. 33. Nature genetics, 2010. 42(3): p. 224-228. 
44. 
Therneau, T., and Atkinson, EJ, An introduction to recursive partitioning using the RPART 
routines. Section of Biostatistics, Mayo Clinic, Technical Report Series, 1997. 61. 
45. 
Koay, E.J., et al, Toward stratification of patients with pancreatic cancer: past lessons from 
traditional approaches and future applications with physical biomarkers. Cancer Letters, 2016. 
46. 
Crane, C.H. and C.A. Iacobuzio-Donahue, Keys to Personalized Care in Pancreatic Oncology. 
Journal of Clinical Oncology, 2012. 30(33): p. 4049-4950. 
47. 
Mandrekar, J., et al, Cutpoint determination methods in survival analysis using SAS. . 
Proceedings of the 28th SAS Users Group International Conference (SUGI) 2003, 2003: p. 261–
28. 
48. 
Mazumdar, M. and J.R. Glassman, Categorizing a prognostic variable: review of methods, code 
for easy implementation and applications to decision-making about cancer treatments. Stat Med, 
2000. 19(1): p. 113-32. 
49. 
Contal, C., O'Quigley, J., An application of changepoint methods in studying the effect of age on 
survival in breast cancer. Computational Statistics and Data Analysis,, 1999. 30: p. 253-70. 
 
 
 

Alliance A021501 
100 
Version Date: 10/19/2018 
Update #04 
APPENDIX I: 
REGISTRATION QOL/MENTAL WELL-BEING/FATIGUE AND PRO-CTCAE MEASURES 
 
 
Registration QOL/Mental Well-being/Physical Well-being/Fatigue 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
How would you describe: 
 
1. your overall qualify of life in the past week including today? 
0 
 1 
 2  
3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
As bad as  
 
 
 
 
 
 
 
 
As good as 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
2. your overall mental (intellectual) well being in the past week including today? 
0 
 1 
 2  
3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
As bad as  
 
 
 
 
 
 
 
 
As good as 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
3. your overall physical well being in the past week including today? 
0 
 1 
 2  
3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
As bad as  
 
 
 
 
 
 
 
 
As good as 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
4. your level of fatigue, on average in the past week including today? 
0 
 1 
 2  
3 
 4 
 5 
 6 
 7 
 8 
 9 
 10 
No 
 
 
 
 
 
 
 
 
 
Fatigue  
fatigue  
 
 
 
 
 
 
 
 
as bad as it can be 
 
 

Alliance A021501 
101 
Version Date: 10/19/2018 
Update #04 
 
 
Registration QOL/Mental Well-being/Physical Well-being/Fatigue - Spanish 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
Como usted describe: 
 
1. su calidad de vida durante la pasada semana, incluyendo el dia de hoy? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
Tan 
mala 
como es 
posible 
 
 
 
 
 
 
 
 
Tan buena 
como es 
posible 
 
2. su salud mental (intelectual) durante la pasada semana, incluyendo el dia de hoy? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
Tan 
mala 
como es 
posible 
 
 
 
 
 
 
 
 
Tan buena 
como es 
posible 
 
3. su salud fisica durante la pasada semana, incluyendo el dia de hoy? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
Tan 
mala 
como es 
posible 
 
 
 
 
 
 
 
 
Tan buena 
como es 
posible 
 
4. el nivel de fatiga, en promedio durante la pasada semana, incluyendo el dia de hoy? 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
Ninguna 
fatiga 
 
 
 
 
 
 
 
 
Cansancio 
constante  
 
 
 
 
 
 

Alliance A021501 
102 
Version Date: 10/19/2018 
Update #04 
NCI PRO-CTCAETM Items - English 
Item Library Version 1.0 
 
As individuals go through treatment for their cancer they sometimes experience different symptoms and 
side effects. For each question, please check or mark an in the one box that best describes your 
experiences over the past 7 days… 
 
1. 
In the last 7 days, what was the SEVERITY of your DRY MOUTH at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
2. 
In the last 7 days, what was the SEVERITY of your PROBLEMS WITH TASTING 
FOOD OR DRINK at their WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
3. 
In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did DECREASED APPETITE INTERFERE with your 
usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
4. 
In the last 7 days, how OFTEN did you have NAUSEA? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
5. 
In the last 7 days, how OFTEN did you have VOMITING? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
6. 
In the last 7 days, how OFTEN did you have HEARTBURN? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your HEARTBURN at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 
 
 
 

Alliance A021501 
103 
Version Date: 10/19/2018 
Update #04 
NCI PRO-CTCAETM Items - English 
Item Library Version 1.0 
 
7. 
In the last 7 days, how OFTEN did you have BLOATING OF THE ABDOMEN 
(BELLY)? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your BLOATING OF THE 
ABDOMEN (BELLY) at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
8. 
In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS 
(DIARRHEA)? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
 
9. 
In the last 7 days, how OFTEN did you have PAIN IN THE ABDOMEN (BELLY 
AREA)? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your PAIN IN THE ABDOMEN 
(BELLY AREA) at its WORST? 
○ Never 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did PAIN IN THE ABDOMEN (BELLY AREA) 
INTERFERE with your usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
10. In the last 7 days, what was the SEVERITY of your ITCHY SKIN at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
11. In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING IN 
YOUR HANDS OR FEET at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS 
OR FEET INTERFERE with your usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
12. In the last 7 days, how OFTEN did you have PAIN? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your PAIN at its WORST? 
○ Never 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did PAIN INTERFERE with your usual or daily 
activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 

Alliance A021501 
104 
Version Date: 10/19/2018 
Update #04 
NCI PRO-CTCAETM Items - English 
Item Library Version 1.0 
 
13. In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR 
LACK OF ENERGY at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY 
INTERFERE with your usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
14. In the last 7 days, how OFTEN did you feel ANXIETY? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your ANXIETY at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did ANXIETY INTERFERE with your usual or daily 
activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
15. In the last 7 days, how OFTEN did you have SAD OR UNHAPPY FEELINGS? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your SAD OR UNHAPPY FEELINGS 
at their WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did SAD OR UNHAPPY FEELINGS INTEFERE with 
your usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 
 

Alliance A021501 
105 
Version Date: 10/19/2018 
Update #04 
 
NCI PRO-CTCAETM Items - English 
Item Library Version 1.0 
 
Do you have any other symptoms that you wish to report? 
○ Yes 
○ No 
 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very 
severe 
 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 
 
 
 
 

Alliance A021501 
106 
Version Date: 10/19/2018 
Update #04 
NCI PRO-CTCAETM Items - Spanish 
Item Library Version 1.0 
 
Los pacientes que reciben tratamiento para el cáncer a menudo presentan ciertos síntomas y efectos 
secundarios. Para cada pregunta, haga una marca o escriba una en la casilla que mejor describe sus 
experiencias en los últimos siete días… 
 
1. 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de la SEQUEDAD EN LA BOCA 
en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
 
2. 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de los PROBLEMAS PARA 
NOTAR EL SABOR DE LAS COMIDAS O LAS BEBIDAS en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
 
3. 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de la DISMINUCIÓN DEL 
APETITO en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
En los últimos 7 días, ¿cuánto INTERFIRIÓ la DISMINUCIÓN DEL APETITO en 
sus actividades habituales o diarias? 
○ Nada 
○ Un poco 
○ Algo 
○ Muco 
○ Muchísimo 
 
4. 
En los últimos 7 días, ¿con qué FRECUENCIA tuvo NÁUSEAS? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de las NÁUSEAS en su PEOR 
momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
 
5. 
En los últimos 7 días, ¿con qué FRECUENCIA tuvo VÓMITOS? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de los VÓMITOS en su PEOR 
momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
 
6. 
En los últimos 7 días, ¿con qué FRECUENCIA tuvo ACIDEZ ESTOMACAL? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de la ACIDEZ ESTOMACAL en su 
PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 
 
 

Alliance A021501 
107 
Version Date: 10/19/2018 
Update #04 
NCI PRO-CTCAETM Items - Spanish 
Item Library Version 1.0 
 
7. 
En los últimos 7 días, ¿con qué FRECUENCIA tuvo HINCHAZÓN DEL ABDOMEN 
(EN EL VIENTRE)? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de la HINCHAZÓN DEL 
ABDOMEN (EN EL VIENTRE) en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
 
8. 
En los últimos 7 días, ¿con qué FRECUENCIA tuvo HECES O EXCREMENTOS 
SUELTOS O LÍQUIDOS (DIARREA)? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
 
9. 
En los últimos 7 días, ¿con qué FRECUENCIA tuvo DOLOR EN EL ABDOMEN (EL 
VIENTRE)? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
En los últimos 7 días, ¿cuál fue la INTENSIDAD del DOLOR EN EL ABDOMEN 
(EL VIENTRE) en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
En los últimos 7 días, ¿cuánto INTERFIRIÓ el DOLOR EN EL ABDOMEN (EL 
VIENTRE) en sus actividades habituales o diarias? 
○ Nada 
○ Un poco 
○ Algo 
○ Muco 
○ Muchísimo 
 
10. En los últimos 7 días, ¿cuál fue la INTENSIDAD de la PICAZÓN (COMEZÓN) EN 
LA PIEL en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
 
11. En los últimos 7 días, ¿cuál fue la INTENSIDAD del ADORMECIMIENTO O DEL 
HORMIGUEO EN LAS MANOS O EN LOS PIES en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
En los últimos 7 días, ¿cuánto INTERFIRIERON el ADORMECIMIENTO O EL 
HORMIGUEO EN LAS MANOS O EN LOS PIES en sus actividades habituales o 
diarias? 
○ Nada 
○ Un poco 
○ Algo 
○ Muco 
○ Muchísimo 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 
 
 

Alliance A021501 
108 
Version Date: 10/19/2018 
Update #04 
NCI PRO-CTCAETM Items - Spanish 
Item Library Version 1.0 
 
12. En los últimos 7 días, ¿con qué FRECUENCIA tuvo DOLOR? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
En los últimos 7 días, ¿cuál fue la INTENSIDAD del DOLOR en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
En los últimos 7 días, ¿cuánto INTERFIRIÓ el DOLOR en sus actividades habituales 
o diarias? 
○ Nada 
○ Un poco 
○ Algo 
○ Muco 
○ Muchísimo 
 
13. En los últimos 7 días, ¿cuál fue la INTENSIDAD del AGOTAMIENTO, EL 
CANSANCIO O LA FALTA DE ENERGÍA en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
En los últimos 7 días, ¿cuánto INTERFIRIERON EL AGOTAMIENTO, EL 
CANSANCIO O LA FALTA DE ENERGÍA en sus actividades habituales o diarias? 
○ Nada 
○ Un poco 
○ Algo 
○ Muco 
○ Muchísimo 
 
14. En los últimos 7 días, ¿con qué FRECUENCIA SINTIÓ ANSIEDAD? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de la ANSIEDAD en su PEOR 
momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
En los últimos 7 días, ¿cuánto INTERFIRIÓ la ANSIEDAD en sus actividades 
habituales o diarias? 
○ Nada 
○ Un poco 
○ Algo 
○ Muco 
○ Muchísimo 
 
15. En los últimos 7 días, ¿con qué FRECUENCIA tuvo SENTIMIENTOS DE 
TRISTEZA O DE NO ESTAR FELIZ? 
○ Nunca 
○ Rara vez 
○ A veces 
○ A menudo 
○ Casi siempre 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de los SENTIMIENTOS DE 
TRISTEZA O DE NO ESTAR FELIZ en su PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy intensa 
En los últimos 7 días, ¿cuánto INTERFIRIERON los SENTIMIENTOS DE 
TRISTEZA O DE NO ESTAR FELIZ en sus actividades habituales o diarias? 
○ Nada 
○ Un poco 
○ Algo 
○ Muco 
○ Muchísimo 
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 
 
 

Alliance A021501 
109 
Version Date: 10/19/2018 
Update #04 
NCI PRO-CTCAETM Items - Spanish 
Item Library Version 1.0 
 
¿Presenta otros síntomas de los que desea informar? 
○ Sí 
○ No 
 
Haga una lista de cualquier otro síntoma: 
1. 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de este síntoma en su 
PEOR momento? 
○ Ninguna 
○ Leve 
○ Moderada 
○ Intensa 
○ Muy 
intensa 
2. 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de este síntoma en su 
PEOR momento? 
○ Ninguna 
○ Leve  
○ Moderada  
○ Intensa  
○ Muy 
intensa  
3. 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de este síntoma en su 
PEOR momento? 
○ Ninguna 
○ Leve  
○ Moderada  
○ Intensa  
○ Muy 
intensa  
4. 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de este síntoma en su 
PEOR momento? 
○ Ninguna 
○ Leve  
○ Moderada  
○ Intensa  
○ Muy 
intensa  
5. 
En los últimos 7 días, ¿cuál fue la INTENSIDAD de este síntoma en su 
PEOR momento? 
○ Ninguna 
○ Leve  
○ Moderada  
○ Intensa  
○ Muy 
intensa  
 
The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the 
NATIONAL INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE™ is subject to 
NCI's Terms of Use. 
 
 

Alliance A021501 
Version Date 10/19/2018 
Update #04 
110 
APPENDIX II: DEFINITION OF BORDERLINE RESECTABLE DISEASE TABLE FOR SECTION 3.2.1 
(ELIGIBILITY) 
 
Patient must have 1 or more of the characteristics in the Column II to be eligible. If the patient has all 
characteristics in the Column I (Less Extensive Disease) or any characteristics in the Column III (More 
Extensive Disease), they are NOT eligible. 
 
VESSEL 
Column I: 
POTENTIALLY 
RESECTABLE (NOT 
ELIGIBLE) 
Column II: 
BORDERLINE 
RESECTABLE 
(ELIGIBLE) 
Column III: 
UNRESECTABLE 
(NOT ELIGIBLE) 
 
 
 
 
SMV, PV 
Interface < 180° and no 
occlusion 
Interface ≥ 180° OR 
Short segment 
occlusion amenable to 
reconstruction 
 
Occlusion not amenable 
to reconstruction 
SMA, CA 
No interface 
Interface < 180° 
 
Interface ≥ 180° 
HA 
No interface 
Interface of any degree 
amenable to 
reconstruction 
 
Interface not amenable 
to reconstruction 
AORTA 
Must have no 
involvement 
Must have no 
involvement 
 
Involvement 
 
 
 

Alliance A021501 
111 
Version Date: 10/19/2018 
Update #04 
APPENDIX III: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug, irinotecan. This clinical trial is sponsored by the National Cancer Institute. This form 
is addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
 
Irinotecan interacts with a certain specific enzyme in the liver: 
 
• The enzyme in question is CYP3A4. Irinotecan is broken down by this enzyme. The dose 
of irinotecan which the patient is taking assumes that these enzymes are working normally. 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Irinotecan may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial. It is also very important to tell your doctors if you stop taking any regular medicines, 
or if you start taking a new medicine while you take part in this study. When you talk about your 
current medications with your doctors, include medicine you buy without a prescription (over-the-
counter remedy), or any herbal supplements such as St. John’s Wort. It is helpful to bring your 
medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions. You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.  
 
These are the things that you and they need to know:  
 
Irinotecan must be used very carefully with other medicines that use the liver enzyme CYP3A4. 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that are considered strong 
inducers/inhibitors of CYP3A4. 
 
• Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctors or pharmacist 
to determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine. 

Alliance A021501 
112 
Version Date: 10/19/2018 
Update #04 
Your study doctor’s name is _____________________________________ and he or she 
can be contacted at _____________________________________. 
 

Alliance A021501 
113 
Version Date: 10/19/2018 
Update #04 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
irinotecan.  This clinical trial is sponsored by the NCI.  Irinotecan 
may interact with drugs that are processed by your liver. Because of 
this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
 
Irinotecan interacts with a specific liver enzyme called CYP3A4 and 
must be used very carefully with other medicines that interact with 
CYP3A4. 
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines  and herbal supplements that are considered strong 
inducers/inhibitors or substrates of CYPA4.  
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

Alliance A021501 
115 
Version Date: 10/19/2018 
Update #04 
APPENDIX V: EXAMPLE FIDUCIAL MARKER ORDERING INFORMATION 
Note: Arm 2 closed to new patient enrollment on 08/13/2018. 
• 
Gold Anchor: USA 
Naslund Medical Inc. 
 
 
 
• 
Visicoil: 
BA Dosimetry 
 
 
 
 
     
 
 
• 
Civco: