Phase II Study of Erlotinib (TarcevaTM) Combined With Chemoradiation and Adjuvant Chemotherapy in Patients With Resectable Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreatic Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
Version: July 13, 2016 
 
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Title:   
Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation 
and Adjuvant Chemotherapy in Patients with Resectable Pancreatic Cancer 
 
Principal Investigator:  
Amol Narang, MD  
 
                   Weinberg 1440-Oncology 
                             401 North Broadway, 
 
 
Baltimore MD 21231-2410 
 
 
(410) 955 7390 
 
 
Anarang2@jhmi.edu 
 
 
Co-Investigators:                                                          
 
Ross Donehower, MD 
 
Daniel Laheru, MD 
 
 
 
 
 
Deborah Frassica, MD 
 
Barish Edil, MD 
 
 
Michelle Rudek, PharmD/PhD 
Joseph Herman, MD, M.Sc. 
 
 
 
 
   
Richard Schulick, MD 
 
Timothy Pawlik, MD 
                         Christopher Wolfang, MD     
Dung Le, M.D.                 
                         
Mary E. Griffith, RN 
 
Luis Diaz, MD 
 
                         
Michael Choti, MD 
 
Nilofer Azad, MD 
 
 
Barbara Biedrzycki, PhD  
Lei Zheng, MD, PhD 
               
 
Protocol Manager: 
 
 
Helen Kim 
 
 
Hkim91@jhmi.edu 
 
 
Phone: 410-614-3950 
 
 
 
 
 
 
Terrence Caldwell 
 
 
caldwte@jhmi.edu 
 
 
Phone: 443-287-1889 
 
 
 
Research Nurses: 
 
 
Ella-Mae Shupe, R.N. 
 
 
Eburke4@jhmi.edu 
 
 
Phone: 410-502-9243 
 
 
 
Shirl DiPasquale, R.N.  
 
 
Sdipasq1@jhmi.edu 
 
 
Phone: 410-614-3158 
 
 
 
 
 
Kristi Purcell, R.N. 
 
 
Kpurcel2@jhmi.edu 
 
 
Phone: 410-502-9242 
 
Statisticians: 
 
 
Amanda L. Blackford, ScM 
alapide1@jhmi.edu 
Phone: 410.614.0361 
 
 
Sponsor: 
NIH R01 CA104900 
 
 
Genentech 
 
IND: 
 
Exempt 
 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
Version: July 13, 2016 
 
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PROTOCOL SYNOPSIS 
 
Objectives 
 
Primary 
 
 
1. To seek preliminary evidence of antitumor activity (progression free survival) of 
Erlotinib in combination with standard adjuvant chemoradiation and chemotherapy in 
patients with resected adenocarcinoma of the pancreas. 
 
Secondary  
 
1. To characterize the toxicity profile of Erlotinib in combination with adjuvant 
chemoradiation in patients with resected pancreatic cancer. 
 
2. To evaluate the quality of life of patients receiving Erlotinib based chemoradiation 
prior to treatment (after surgery), one month following treatment and every 3-4 
months thereafter for one year. 
 
3. To seek preliminary evidence of antitumor activity (overall survival) of Erlotinib in 
combination with standard adjuvant chemoradiation and chemotherapy in patients 
with resected adenocarcinoma of the pancreas. 
 
 
 
 
 
 
 
 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
Version: July 13, 2016 
 
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Study Schema: Adjuvant Chemoradiation followed by Adjuvant Chemotherapy 
 
 
Chemoradiation:  
• Baseline  EORTC QLQ C-30/ PAN26 QOL 
• Capecitabine 800 mg/m2 PO BID (1600 mg/m2/day total) (5 days 
on/ 2 days off regimen)  AND 
• Erlotinib 100 mg PO QD (1 hour prior to Capecitabine) (both 
given daily without interruption) AND 
• Radiotherapy 50.4 Gy delivered over 28 fractions (Mon-Fri) 
(*Note: we will have the ability to treat to 54.0 Gy over 30 
fractions if a patient presents with close or positive margins after 
resection) 
 
 
 
 
 
 
 
 
Four-Eight weeks of recovery from toxicity.  
 
 
 
 
 
  
 
 
Adjuvant Maintenance Therapy: 
• Gemcitabine  1000 mg/m2 D1,8, and 15 every 28 days x 4 cycles 
• Erlotinib 100 mg PO QD x 4 months 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
Version: July 13, 2016 
 
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Trial design: 
 
This study is a phase II trial of erlotinib in combination with chemoradiation in patients with 
resected stage I/II adenocarcinoma of the pancreas who are candidates for adjuvant 
chemoradiation. Eligible patients will receive adjuvant treatment with erlotinib 100 mg plus 
Capecitabine 800 mg/m2 PO BID (5 days on/ 2 days off regimen) and External Beam Radiation 
Therapy (EBRT) at doses of 50.4 Gy in 28 fractions after pancreatectomy (Dosing for 
capecitabine and erlotnib was amended after considering the toxicity profile of the first 6 
patients).  Approximately 4-8 weeks after the conclusion of chemoradiation, it is recommended 
patients will continue treatment with 4 cycles of gemcitabine 1000 mg/m2 days 1, 8, and 15 
every 28 days plus daily erlotinib 100 mg.  
 
 
Patient population: 
 
• Resected adenocarcinoma of the pancreas and candidate for adjuvant 
chemoradiation.  
• ECOG performance status 0-1. 
• Informed consent and ability to comply with treatment plan. 
• Adequate bone marrow, renal and liver function. 
• No previous radiation therapy to the abdomen 
• No previous chemotherapy for pancreatic cancer 
 
Investigational product, dosage and mode of administration: 
 
Erlotinib 100-mg oral daily dose. 
 
Statistical analysis: 
 
Toxicity will be assessed weekly as mild or severe during chemoradiation using the NCI-
CTCAE Version 3 criteria and will be summarized using descriptive statistics.  
 
Progression free and overall survival for patients treated with erlotinib in combination with 
chemoradiation and chemotherapy will be described using Kaplan-Meier methods. The 
relationships between these effects and time to disease progression will be tested using Cox 
proportional hazards model. Quality of life questionnaires will be scored per the EORTC 
guidelines.  A fixed sample size of 40 patients will be enrolled.  This number includes 6 patients 
from the initial portion of the trial which used the same treatment regimen stated in the above 
design.

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
Version: July 13, 2016 
 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................... 2 
1. 
OBJECTIVES ......................................................................................................................... 7 
2.0  INTRODUCTION: .................................................................................................................. 7 
2.1. 
Background ................................................................................................................. 7 
2.1.1. Pancreatic Cancer.......................................................................................................... 7 
2.1.2.  EGFR as a Target for Anticancer Drug Development. ................................................ 8 
2.1.3.  Erlotinib (Tarceva®) .................................................................................................... 8 
2.1.4.  Targeting the EGFR in Pancreatic Cancer ................................................................... 8 
2.1.5.  Rationale for adjuvant chemoradiation in pancreatic cancer. ...................................... 9 
2.1.6.  Rationale for Capecitabine (XelodaTM) in patients with pancreatic cancer. ................ 9 
2.1.7.  Rationale for adding Erlotinib to Capecitabine and radiation therapy ...................... 10 
3.0  ELIGIBILITY CRITERIA..................................................................................................... 11 
3.1.  Inclusion criteria ........................................................................................................... 11 
3.2.  Exclusion criteria .......................................................................................................... 11 
4.0.  TREATMENT ...................................................................................................................... 12 
4.1.  Overview ....................................................................................................................... 12 
4.2.  Treatment Products Description ................................................................................... 14 
4.2.1.  Erlotinib ..................................................................................................................... 14 
4.2.1.1.  Treatment schedule of Erlotinib.............................................................................. 14 
4.2.1.2.  Duration of Erlotinib ............................................................................................... 14 
4.2.1.3.  Expected Toxicities with Erlotinib...……………………………………………...15 
4.2.1.4  Dose modification and management of erlotinib toxicity........................................ 15 
4.2.2.  Capecitabine ............................................................................................................... 17 
4.2.2.1.  Expected Toxicities with Capecitabine……………………………………………18 
4.2.3.   Gemcitabine………………………………………………………………………...19 
4.2.3.1.  Gemcitabine Treatment Schedule…………………………………………………19 
4.2.3.2.  Expected Toxicities with Gemcitabine……………………………………………20 
4.2.4  Radiotherapy ............................................................................................................... 19 
4.2.4.1.  Treatment Planning Specifications………………………………………………..20 
4.2.4.2.  Critical Structure Tolerance .................................................................................... 23 
4.2.4.3.  Radiotherapy Toxicity…………………………………………………………….24 
4.3.  Other concomitant treatment......................................................................................... 23 
4.4  Dose modification and management of toxicity ............................................................ 24 
        4.4.1.  Adjuvant Chemoradiation…………………………………………………………...25 
        4.4.2.  Toxicities/Dose Adjustments during Adjuvant Therapy (radiation)………………..26 
        4.4.3.  Adjuvant Maintenance Chemotherapy……………………………………………...26 
5.0  Evaluation of patients: Dose limiting toxicities ..................................................................... 27 
6.0  CRITERIA FOR DISCONTINUATION/WITHDRAWAL OF INFORMED CONSENT. . 28 
7.0   Study calendar ....................................................................................................................... 29 
8.0  MEASUREMENT OF EFFECT………………………………………………………31 
8.1 
Definitions................................................................................................................. 30 
8.2 
Monitoring for recurrence ......................................................................................... 30 
9.0.  ADVERSE EVENTS ............................................................................................................ 30 
9.1.  Adverse Event and Reporting Definitions………………………………………………….31 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
Version: July 13, 2016 
 
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9.2.  Reporting of Serious Treatment Emergent Adverse Events to Genentech…………………32 
9.3.  MedWatch 3500A Reporting Guidelines…………………………………………………..32 
9.4.  Assessing Causality………………………………………………………………………...33 
10.0.  STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................... 32 
10.1.  Study design/endpoints ............................................................................................... 32 
10.2.  Sample size/accrual rate .............................................................................................. 33 
        10.2.1.  Analysis of Primary Endpoints…………………………………………………….34 
        10.2.2.  Analysis of Secondary Endpoints………………………………………………….34 
10.3.  Reporting and exclusions .................................................................................................... 34 
10.3.1.  Evaluation of Response………………………………………………………………….35 
11.0.   TRIAL MANAGEMENT .................................................................................................. 35 
11.1.  Audits and inspections ................................................................................................ 35 
11.2.  Changes to the protocol .............................................................................................. 35 
11.3.  Ethics........................................................................................................................... 35 
11.4.  Procedures in case of an overdose…………………………………………………...36 
11.5.  Procedures in case of pregnancy ................................................................................. 35 
        11.6.  Trial Monitoring……………………………………………………………………..36 
REFERENCES…………………………………………………………………………………..38 
APPENDIX A ............................................................................................................................... 40 
Performance Status Criteria 
APPENDIX B ............................................................................................................................... 41 
Further Guidance on the Definition of a Serious Adverse Event (SAE)  
APPENDIX C……………………………………………………………………………………43 
EORTC - Quality of Life Assessments 
APPENDIX D ............................................................................................................................... 50 
Further Guidance on the Assessment of Casuality 
APPENDIX E……………………………………………………………………………………52 
SKCCC Clinical Trial Monitoring Program 
APPENDIX F 
Adverse Events with Possible Relationship to Erlotinib………………………………………...68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
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1. OBJECTIVES 
 
This is a phase II study of erlotinib in combination with chemoradiation and adjuvant 
chemotherapy in patients with resected pancreatic cancer. 
 
The objectives of the trial are: 
 
Primary 
 
 
1. To seek preliminary evidence of antitumor activity (progression free survival) of 
Erlotinib in combination with standard adjuvant chemoradiation and chemotherapy in 
patients with resected adenocarcinoma of the pancreas. 
 
Secondary  
 
 
1. To characterize the toxicity profile of Erlotinib in combination with adjuvant 
chemoradiation in patients with resected pancreatic cancer. 
 
2. To evaluate the quality of life of patients receiving Erlotinib based chemoradiation 
prior to treatment (after surgery), one month following treatment and every 3-4 
months thereafter. 
 
3. To seek preliminary evidence of antitumor activity (overall survival) of Erlotinib in 
combination with standard adjuvant chemoradiation and chemotherapy in patients 
with resected adenocarcinoma of the pancreas. 
 
 
2.0  INTRODUCTION: 
 
2.1. Background 
 
2.1.1. Pancreatic Cancer 
 
Pancreatic cancer remains a devastating disease.  In 2008, approximately 38,000 patients will be 
diagnosed with pancreatic cancer and 35,000 will die of their disease(1). At the time of 
diagnosis, 80% of patients have locally advanced or advanced disease for which no curative 
therapy exist.  Seventy to eighty percent of patients treated with curative intent will recur in the 
first two years after surgical resection and will succumb to their disease (2, 3).  The most recent 
outcome update from the Johns Hopkins Hospital series (N=616) showed that the median (21.2), 
2-year (43.9%), and 5-year (20.1%) were still poor despite aggressive management with adjuvant 
5-FU based chemoradiation(4).  The standard of treatment for patients with advanced disease or 
for those who recur after surgical resection is single agent gemcitabine.  In phase III studies, 
treatment with gemcitabine resulted in a response rate of ≈ 5 %, a median survival less than 6 
months, and a 1-year survival of 18 % (5).  New therapeutic strategies are clearly needed in this 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
Version: July 13, 2016 
 
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disease. The Pancreatic Cancer Research Group at Johns Hopkins has pioneered novel treatments 
for patients with resectable pancreatic cancer including different regimens of chemoradiation as 
well as allogeneic vaccines (2)(6).   
 
2.1.2.  EGFR as a Target for Anticancer Drug Development(7).  
 
The epidermal growth factor receptor (EGFR) is a member of a large family of growth factor 
receptor tyrosine kinases that share a common structure composed of an extracellular ligand 
binding domain, a short transmembrane domain, and an intracellular domain that has tyrosine 
kinase activity.  Binding of the cognate ligand, for example, EGF or transforming growth factor 
(TGFα) to the extracellular domain of EGFR initiates a signal transduction cascade that can 
influence many aspects of tumor cell biology; these include growth, survival, metastasis, and 
angiogenesis, as well as tumor cell sensitivity to chemotherapeutic and radiotherapeutic drugs.  
Tyrosine phosphorylation provides docking sites on the EGFR for recruitment of proteins that 
are either direct substrates for EGFR-mediated phosphorylation, or adaptor proteins that link the 
receptor to a cascade of “downstream” biochemical reactions, for example, the ras-raf-MAPK-
fos pathway, which drives tumor cell proliferation. Several studies have described amplification 
of the EGFR gene, mutations of the EGFR gene and overexpression of the EGFR surface protein 
in a number of tumor types, including up to 80% of pancreatic cancer. Thus EGFR is an 
attractive target in developing new treatments for cancer. Currently, several agents targeting the 
EGFR pathway have been approved for lung cancer (gefitinib and erlotinib) and colon cancer 
(erbitux).   
 
2.1.3.  Erlotinib (Tarceva®) (8) 
 
Erlotinib (Tarceva®) is an oral quinazoline derivative that is a signal transduction inhibitor of the 
epidermal growth factor receptor (EGFR) tyrosine kinase.  It has been developed as an oral 
antitumor agent and has been shown to have human antitumor activity in numerous preclinical 
and clinical trials.  Erlotinib is currently approved for the treatment of patients with 
chemotherapy refractory non-small cell lung cancer. Details about this agent can be found in the 
package insert. 
 
In phase I clinical trials, Erlotinib resulted in dose dependant diarrhea and cutaneous toxicity as 
the more relevant side effects.  The maximum tolerated dose of the agent administered on a daily 
continuous basis was 150 mg.  At this dose level, erlotinib was well absorbed resulting in plasma 
levels above the minimum concentration needed to inhibit the EGFR in preclinical models.  In 
addition, evidence of dose dependent antitumor inhibition of the EGFR was documented in serial 
skin biopsies (9).    
 
2.1.4.  Targeting the EGFR in Pancreatic Cancer 
 
The rationale to target the EGFR in pancreatic cancer is provided by preclinical and clinical 
studies.  In preclinical models, administration of erlotinib to pancreatic cancer xenograft resulted 
in tumor growth inhibition as well as apoptosis (10).  In addition,  preclinical investigations have 
shown that the combination of inhibitors of the EGFR with chemotherapy results in increased 
antitumor activity in preclinical models of pancreatic cancer (11).  In clinical trials, the anti 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
Version: July 13, 2016 
 
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EGFR antibody erbitux resulted in 12% response rate in patients with EGFR positive pancreatic 
cancer in combination with gemcitabine (12).  Importantly, a recent randomized phase III 
clinical trial in which we participated demonstrated a superior survival in patients with advanced 
pancreatic cancer treated with gemcitabine in combination with erlotinib when compared with 
gemcitabine alone (13).  This study is relevant for several reasons:  a) is the first study to show 
that a targeted agent has activity in pancreatic cancer after a large number of negative trials;  b) 
showed that EGFR targeted agents combined with chemotherapy are superior to chemotherapy 
alone.  This study led to the regulatory approval of erlotinib in patients with pancreatic cancer.   
 
2.1.5.  Rationale for adjuvant chemoradiation in pancreatic cancer.  
 
The optimal postoperative treatment of patients with resected pancreatic cancer is still debatable.   
Based on the results of a trial conducted under the auspices of the GITSG that compare adjuvant 
chemoradiation with 5-Fluorouracil and radiation therapy versus control and that showed a 
survival improvement in treated patients.  Chemoradiation has been accepted as the standard of 
care in the USA.  The GITSG study has been criticized for different reasons including the small 
sample size.  Subsequent studies have been controversial with regards to the overall impact of 
chemoradiation in patients with pancreatic cancer.  More recent trials have actually shown that 
chemotherapy is the superior treatment modality in this situation.  Once again, methodological 
flaws limit the acceptability of these results (2)(14). 
 
The Johns Hopkins Hospital is one of the most experienced centers in the treatment of patients 
with pancreatic cancer.  Phase II studies conducted for over the last decade in which different 
chemotherapy regimens were combined with radiation therapy have resulted in a median survival  
of ≈ 20 months which is comparable to the best results obtained using other strategies (4).  More 
recently, chemoradiation has been used as a platform to add innovative vaccine strategies 
developed at Hopkins (6).  While there are several regimens available, our standard approach has 
been a combination of infusional 5-FU administered concurrently with radiation therapy and 
gemcitabine.  This regimen is the control arm of the RTOG 9704 phase III studies which has 
completed enrollment and was recently reported(15). 
 
 
2.1.6.  Rationale for Capecitabine (XelodaTM) in patients with pancreatic cancer.  
 
Capecitabine (XelodaTM) is an oral pro-drug that is absorbed unchanged in the GI tract and 
subsequently undergoes a series of enzymatic conversions into 5-FU in tumor cells. It has been 
approved for use in patients with metastatic breast and colon cancer, and is being investigated in 
numerous other tumor types.  Its activity is felt to be similar to continuous infusion 5-FU, since 
sustained blood levels are maintained with twice-daily oral dosing.  The recommended oral dose 
is 2500 mg/m2 in two divided doses twelve hours apart for 14 days, followed by a 7-day rest 
period.  Several randomized trials have shown that this dose of capcitabine was comparable to 5-
FU/leucovorin in patients with advanced or metastatic colorectal cancer (16). Capecitabine either 
alone or in combination with leucovorin has several advantages including improved response 
rates, favorable toxicity profiles, and convenience.  However, no significant differences in 
overall survival, median duration of response, and median time to disease progression were seen 
(17). More recently, capecitabine has demonstrated superior survival as compared to single agent 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
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5-FU and leucovorin in the adjuvant setting in patients with colorectal cancer.  In pancreatic 
cancer, single agent capecitabine resulted in 7-8 % objective response rate and a 24% clinical 
benefit response (18).  
 
In addition to simulating continuous infusion 5-FU, which has been shown to be superior to 
bolus dosing in the post-operative setting, capecitabine has several properties that may enhance 
its selectivity for tumor cells.  Capecitabine has been shown to selectively upregulate thymidine 
phosphorylase (TP), which releases 5-FU from 5’FUDR in the final enzymatic step of 
conversion from Capecitabine to 5-FU, in tumor cells (19).  Following administration of 
Capecitabine, 5-FU levels are on average 3 times higher in tumor tissue than in surrounding 
healthy tissue (20).  Correlation between tumor susceptibility to Capecitabine and the 
TP:dihydropyrimidine dehydrogenase (DPD, which catabolizes 5-FU to its metabolite 
dihydrofluorouracil) ratio has been shown (21). 
 
Based on preclinical data, using Capecitabine combined with radiation therapy has several 
theoretical advantages.  Radiation may increase the activity of Capecitabine by increasing levels 
of thymidine phosphorylase (TP) in tumor cells (19).  Clinical trials have been conducted with 
Capecitabine combined with radiation therapy in patients with rectal cancer. A phase I dose-
finding trial of Capecitabine combined with pelvic radiotherapy (50.4 Gy) showed the MTD to 
be 1000 mg/m2 BID, with the recommended phase II dose being 825 mg/m2 BID (22).  A phase 
II trial combining neoadjuvant Capecitabine 825 mg/m2 BID, leucovorin 20 mg/ m2/day, and 
radiation (50.4 Gy), followed by surgery 6 weeks later, has also been published showing 
acceptable toxicities (23).  The combination is being further investigated in several phase III 
trials. Similarly, the combination of capecitabine with radiation therapy has been frequently used 
at doses of 800 mg/m2 BID in patients upper GI malignancies with good tolerability (24). 
 
2.1.7.  Rationale for adding Erlotinib to Capecitabine and radiation therapy 
 
The combination of inhibitors of the EGFR with chemotherapy and radiation therapy is attractive 
because the antiproliferative effects of these different therapeutic modalities are, in general, 
synergistic.  The combination of an EGFR inhibitor with radiation therapy is particularly 
appealing.  There is preclinical data indicating that one of the mechanisms by which tumor cells 
became resistant to the apoptotic and antiproliferative effects of radiation therapy is through 
paracrine activation of the EGFR by TGFα, which is released after radiation exposure. Inhibition 
of the EGFR has been demonstrated in preclinical models to block the antiapoptotic effects of 
TGF alpha shedding and to restore the apoptotic response of tumor cells to radiation (25).  In 
addition, inhibition of the EGFR also been shown to increase TP in human cell lines, which 
suggests additive activity when combined with Capecitabine.  Preliminary results from a trial 
combining another EGFR inhibitor increased the conversion of capecitabine to 5-fluorouracil 
and augmented 5-FU AUC0-∞ (unpublished data Laheru, Hidalgo, and Rudek). While these are 
all preclinical studies, they all show mechanisms by which combining inhibition of the EGFR, 
Capecitabine, and radiation may have potent and selective antitumor activity. 
 
 The initial portion of this protocol enrolled 12 patients which combined erlotinib, capecitabine 
and radiation therapy.  A planned interim analysis of the first 6 patients who completed the 
course of adjuvant chemoradiation while on study showed increased fatigue and gastrointestinal 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
Chemotherapy in Patients with Resectable Pancreatic Cancer 
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complaints with oral daily capecitabine 800mg/m2 bid, erlotinib 150 mg daily, and concurrent 
radiation. The capecitabine dosage was thus adjusted to 800mg/m2 PO bid to be administered on 
a “5 days on/ 2 days on” regimen with erlotinib changed to 100 mg daily.  With this regimen, the 
subsequent 6 patients have successfully completed the chemoradiation portion of the protocol 
successfully without any serious adverse events.  The next 34 patients will be treated per this 
regimen to make a total of 40 subjects enrolled. 
 
 
 
3.0  ELIGIBILITY CRITERIA 
 
 
3.1.  Inclusion criteria 
 
1. Resection of a stage I/II pancreatic adenocarcinoma of the pancreas (R0/R1) and a 
candidate to receive postoperative adjuvant chemoradiation.  R2 (acroscopic 
resection) based on the surgeons operative note will be excluded from the study. 
2. Aged 18 years or older. 
3. ECOG performance status < 1.  
4. The effects of Erlotinib and Capecitabine on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
5. Patients must have normal organ and marrow function as defined below: 
 
 leukocytes  
 
 
 
 
>3,000/μl 
 absolute neutrophil count  
>1,500/μl 
 platelets  
 
 
 
 
>100,000/μl 
 total bilirubin  
 
 
 
≤ 2 mg/dL  
 AST(SGOT)/ALT(SGPT) 
≤ 5 X institutional upper limit of normal 
 creatinine  
 
 
 
 
≤ 2 mg/dL  
aPTT   
 
 
 
 
 
< 40 seconds,  
PT  
 
 
 
 
 
 
<2 seconds more than ULN. 
 
6. Provision of written informed consent 
7. Patients must have a working knowledge of English in order to complete the quality 
of life questionnaires. Patients that do not meet this requirement will be exempt from 
the QoL assessment, but remain eligible for all other components of the study. 
 
 
3.2.  Exclusion criteria 
 
1. Known severe hypersensitivity to Erlotinib any of the excipient of this product.  
Hypersensitivity to Capecitabine, doxifluridine, or 5-FU. 

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2. Other coexisting malignancies or malignancies diagnosed within the last 5 years, with 
the exception of basal cell carcinoma, non-invasive early stage bladder cancer (<T1), 
and cervical cancer in situ. 
3. Uncontrolled, intercurrent illness including (but not limited to) ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.   
4. Concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, 
or St John's Wort.  Careful monitoring of PT/INR must be done for patients taking 
Warfarin. 
5. Incomplete healing from previous oncologic or other major surgery. 
6. Gastrointestinal tract disease resulting in an inability to take oral medication.  
7. Pregnant women are excluded from this study because Erlotinib is an epidermal 
growth factor inhibitor with the potential for teratogenic or abortifacient effects based 
on the data suggesting that EGFR expression is important for normal organ 
development.  Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with Erlotinib, breastfeeding 
should be discontinued if the mother is treated with Erlotinib. Capecitabine is also 
potentially teratogenic and its metabolites can be found in breast milk. 
8. Patients with known AIDS or who are HIV-positive on anti-retroviral therapy are 
excluded since patients’ immune deficiency are at increased risk of lethal infection 
when treated with marrow-suppressive therapy, and interactions between Erlotinib and 
anti-retroviral therapy are unknown.  If patients have known risk factors of HIV they 
should be tested based on the discretion of the treating oncologist. 
9. Any evidence of clinically active interstitial lung disease (patients with chronic stable 
radiographic changes who are asymptomatic need not be excluded). 
10. Previous radiation to the abdomen. 
11. Previous chemotherapy for pancreatic cancer. 
 
4.0.  TREATMENT 
4.1.  Overview 
 
This combination of therapies, while not previously tested together, is not expected to cause 
excessive toxicity based on the results of several phase I and II trials.  As discussed above, a 
phase I dose-finding trial of Capecitabine combined with simultaneous irradiation of 50.4 Gy 
over 5 weeks found the MTD to be 1000 mg/m2 BID (2000 mgm2 daily total) there where no 
grade 3 toxicities observed (22).  This dose was also well-tolerated in a phase II trial combining 
Capecitabine and radiation (23).  In upper GI malignancies, doses of 1600 mg/m2 of 
Capecitabine are well tolerated.   Trials combining Erlotinib and radiotherapy are just beginning 
to accrue, with no excessive toxicity yet reported. Finally, Erlotinib has been combined with 
chemotherapy at standard doses without excess toxicity beyond that seen with chemotherapy 
alone.   
 
This study is a phase II trial of erlotinib in combination with chemoradiation in patients with 
stage I/II adenocarcinoma of the pancreas who are candidates for adjuvant chemoradiation.  
 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
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Eligible patients will receive adjuvant treatment with erlotinib 100 mg plus Capecitabine 800 
mg/m2 PO BID (5 days on/ 2 days off) and External Beam Radiation Therapy (EBRT) to the 
tumor bed plus adjacent lymph nodes at doses of 50.4 Gy in 28 fractions after surgery.  For 
patients with close or positive margins after resection, they will be able to receive 54.0 Gy over 
30 fractions.  Approximately 4-8 weeks after the conclusion of chemoradiation, it is 
recommended patients will continue treatment with 4 cycles of gemcitabine 1000 mg/m2 days 1, 
8, and 15 every 28 days plus erlotinib 100 mg/daily.  
 
 
Schema 
 
 Adjuvant Chemoradiation followed by Adjuvant Chemotherapy” 
 
 
Chemoradiation:  
• Baseline collection of EORTC QLQ C-30/ PAN26 QOL 
• Capecitabine 800 mg/m2 PO BID (1600 mg/m2 total) (5 days on/2 days off regimen) AND 
• Erlotinib 100 mg PO QD (1 hour prior to Capecitabine) (both given daily without 
interruption) AND 
• Radiotherapy 50.4 Gy delivered over 28 fractions (or 54 Gy delivered over 30 fractions for 
patients with close or positive margins after resection) 
(Mon-Fri)  
. 
 
 
 
 
 
 
 
 
Four to Eight weeks of recovery from toxicity.  
 
 
 
 
 
  
 
 
Adjuvant: 
• Gemcitabine  1000 mg/m2 D1,8, and 15 every 28 days x 4 cycles 
• Erlotinib 100 mg PO QD x 4 months 

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4.2.  Treatment Products Description 
 
4.2.1.  Erlotinib 
 
Erlotinib will be provided by Genentech and storage and administered as per package insert 
instructions.  
 
4.2.1.1.  Treatment schedule of Erlotinib 
Erlotinib will be self-administered to all patients enrolled in the study. During the treatment 
period, patients will receive single-agent erlotinib 100 mg/day.  Tablets should be taken at the 
same time each day with 200 mL of water at least 1 hour before or 2 hours after a meal.  Patients 
who are unable to swallow tablets may dissolve the tablets in distilled water for administration. If 
a patient forgets to take a dose, the last missed dose should be taken as soon as the patient 
remembers, as long as it is at least 12 hours before the next dose is due to be taken.  The daily 
treatment schedule will be resumed the next day with the patient taking the next scheduled dose. 
4.2.1.2.  Duration of Erlotinib  
 
Discontinue only if indicated by the protocol, disease progression, unacceptable/unmanageable 
drug-related adverse events occur or the study is closed. 
 
4.2.1.3.  Expected Toxicities with Erlotinib  
 
To date, thousands of cancer patients have received Erlotinib at doses of 100-150 mg/day.  
Common adverse events associated with Erlotinib administration include rash and diarrhea.  
Other common adverse events include nausea/vomiting, stomatitis, headache, and fatigue.  
A common toxicity is a papular, pustular rash manifesting most often on the face and upper 
trunk. The rash may be associated with erythema, pain, pruritus, dryness, and less commonly, 
stomatitis, keratitis and nail bed changes.  Wearing of contact lenses while receiving Erlotinib 
therapy is not recommended.  The incidence of diarrhea can be as high as 50%.  The median time 
to onset of skin rash was 8 days and median time to occurrence of first diarrheal symptom was 9 
days.  
There have been infrequent reports of serious interstial lung disease (ILD) in patients receiving 
Erlotinib for treatment of NSCLC or other advanced solid tumors.  The overall incidence of ILD 
in Erlotinib-treated patients from all studies (including uncontrolled studies and studies with 
concurrent chemotherapy) is approximately 0.6%.  Included in this rate of ILD are reported 
diagnoses of pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative 
bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, and lung infiltration, 
irrespective of investigator assessed causality.  Most of the cases were associated with 
confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, 
preexisting parenchymal lung disease, metastatic lung disease, or pulmonary infections. Other 
serious and non-serious adverse events have been reported, and details are provided in the 
package insert.  

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Reversible renal impairment has been reported in association with dehydration associated with 
nausea, vomiting, and diarrhea.  There have been rare reports of renal failure in patients 
receiving Erlotinib in combination with platinum-containing chemotherapy regimens. Febrile 
neutropenia has been reported in patients receiving concomitant chemotherapy.   
Gastrointestinal perforation (including fatalities) has been reported in patients receiving 
TARCEVA. Patients receiving concomitant anti-antiogenic agents, corticosteroids, NSAIDs, 
and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular 
disease are at increased risk. Permanently discontinue TARCEVA in patients who develop 
gastrointestinal perforation. 
Bullous, blistering and exfoliative skin conditions have been reported, including cases suggestive 
of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal. 
Interrupt or discontinue TARCEVA treatment if the patient develops severe bullous, blistering or 
exfoliating conditions. 
Ocular disorders: Corneal perforation or ulceration have been reported during use of TARCEVA. 
Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis 
have been observed with TARCEVA treatment and are known risk factors for corneal 
ulceration/perforation. Interrupt or discontinue TARCEVA therapy if patients present with 
acute/worsening ocular disorders such as eye pain. 
Erlotinib is both protein bound (92%–95%) and metabolized by hepatic cytochromes CYP3A4 
and CYP3A5 and pulmonary cytochrome CYP1A1.  Therefore, a potential for drug–drug 
interaction exists when Erlotinib is co-administered with drugs that are highly protein bound or 
that are CYP3A4 inhibitors/inducers.   
Co-administration of Erlotinib with an inhibitor of CYP3A4 metabolism (ketoconazole, 200 mg 
po BID for 5 days) resulted in increased exposure to Erlotinib as measured by an 86% increase in 
median Erlotinib AUC and a 69% increase Cmax, compared with administration of Erlotinib 
alone. 
Induction of CYP3A4 metabolism by a known enzyme inducer (rifampin, 600 mg po QD for 7 
days) resulted in a 69% decrease in the median Erlotinb AUC, compared with administration of 
Erlotinib alone.  However, the effect of rifampin on Cmax was negligible.   
International normalized ratio (INR) elevations and/or bleeding events have been reported in 
some cancer patients taking warfarin while on Erlotinib.  Patients taking warfarin or other 
warfarin-derivative anticoagulants should be monitored regularly for changes in prothrombin 
time or INR. 
For a comprehensive summary of possible adverse events associated with Erlotinib,  please see 
Appendix F 
4.2.1.4  Management of erlotinib toxicity 
 
The following guidelines for holding/discontinuation for erlotnib treatment will be used: 

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Version: July 13, 2016 
 
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Criteria and Guidelines for Management  
of Erlotinib-Related Toxicities 
NCI-CTCAE (v 3.0) Grade 
Erlotinib Management 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg at first 
onset, followed by 2 mg q 2–4 
hours until free of diarrhea for 12 
hours) 
Grade 2 
None 
(Dose interruption of erlotinib  
is necessary if diarrhea 
persists over 48–72 hours 
despite optimal medical 
management) 
Loperamide (4 mg at first onset, 
followed by 2 mg q 2–4 hours until 
diarrhea free for 12 hours) 
Grade  3 
Hold Erlotinib  
Interrupt erlotinib until resolution 
to Grade ≤1, and then restart. If 
toxicity does not recover within a 
week after erlotinib has been 
stopped it should be discontinued 
for that phase of treatment.  If this 
toxicity occurs during the 
maintenance phase then erlotnib 
will be permanently discontinued. 
Grade 4 
Discontinue study treatment. 
 
Pulmonary Events if possibly ILD 
All Grades 
Temporarily interrupt 
erlotinib pending the 
diagnostic evaluation.  If the 
pulmonary adverse event is 
assessed as related to erlotinib 
, discontinue the patient from 
study treatment. 
Unexplained dyspnea, either new or 
progressive, should be aggressively 
evaluated.   
Rash 
Tolerable rash 
None 
Any of the following:  minocycline 
a, topical tetracycline, topical 
clindamycin, topical silver 
sulfadiazine, diphenhydramine, oral 
prednisone (short course) at 
discretion of investigator 
Intolerable rash 
Consider interruption if 
unresponsive to symptomatic 
management.   
Manage as described above. If rash 
does not resolve to grade 1 within 
one week after erlotinib is held,  
erlotinib will be discontinued until 
the maintenance phase.  If this 
toxicity occurs during the 
maintenance phase then erlotnib 
will be permanently discontinued. 
Grade 4 
Discontinue study treatment. 
Manage as described above 

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a Recommended dose:  200 mg po bid (loading dose) followed by 100 mg po bid for  
7–10 days. 
 
 Permanently discontinue TARCEVA in patients who develop gastrointestinal perforation. 
 
Interrupt or discontinue TARCEVA treatment if the patient develops severe bullous, blistering or 
exfoliating conditions. 
Interrupt or discontinue TARCEVA therapy if patients present with acute/worsening ocular 
disorders such as eye pain. 
 
4.2.2.  Capecitabine 
 
Detailed information regarding Capecitabine can be found in the package insert. Capecitabine 
will be obtained from commercial sources. Capecitabine will be given by oral administration 
twice daily concurrently with chemoradiation. Dosing will be as follows: 
 
Capecitabine (XelodaTM) trial treatment 
Treatment 
Strength 
Daily Dose 
Tablets per dose 
Capecitabine 
(XelodaTM) 
150 mg, 
500 mg 
tablets 
 
800 mg/m2 PO BID on “5 days on/ 2 days off” 
regimen 
 
Dependent on 
BSA (m2) 
(see dosing table) 
 
Capecitabine tablets should be taken within 30 minutes after the end of a meal and swallowed 
with water.  On study days where both Erlotinib and Capecitabine are given, it is recommended 
that Erlotinib be taken 60 minutes prior to Capecitabine. 
 
The following tables serve as a general guide for Capecitabine dosing.  Exact dose amounts for 
individual patients should be determined by the study investigator. 
 
Capecitabine Dosing 800 mg/m2 BID  
*Total daily dose calculated on mg/m2 for the median value and rounded to the nearest 100 mg 
 
4.2.2.1.  Expected Toxicities with Capecitabine.  
 
 
Capecitabine dose level = 800 mg/m2 
Number of tablets to be taken at each dose 
(Morning and evening) 
Surface Area 
(m2) 
Daily Dose (mg)* 
Each Dose               Dose 
 
150 mg tablet 
 
500 mg tablet 
1.16 – 1.43 
1100                        2200 
4 
1 
1.44 – 1.71 
1300                        2600 
2 
2 
1.72 – 1.95 
1500                        3000 
0 
3 
1.96 – 2.23 
1700                        3400 
8 
1 
>2.24 
1900                        3800 
6 
2 

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The most common side effects of Capecitabine are (by system): 
GI: diarrhea, nausea, vomiting, stomatitis, abdominal pain, upset stomach, constipation, loss of 
appetite, and dehydration. 
Skin: hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, 
painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss. 
Systemic: tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, 
and muscle pain), trouble sleeping, and taste problems. 
 
See Package Insert for details.  Dose adjustments will be made as outlined below.  
 
4.2.3  Gemcitabine 
 
Gemcitabine (difluorodeoxycytidine) is a pyrimidine antimetabolite, which is an analogue of 
deoxycytidine. It was initially synthesized as a potential antiviral drug but selected for anticancer 
development because of its activity in in-vivo and in vitro tumors. Gemcitabine should be stored, 
reconstituted and administered according to the manufacturer’s recommendation.  
 
Gemcitabine will be obtained from commercial sources. Vials: 200 mg white, lyophilized 
powder in a 10 mL size sterile single use vial (No. 7501) NDC 0002-7501-01 1 g white, 
lyophilized powder in a 50 mL size sterile single use vial (No. 7502) NDC 0002-7502-01 Store 
at controlled room temperature (20° to 25°C) (68° to 77°F). The USP has defined controlled 
room temperature as "A temperature maintained thermostatically that encompasses the usual and 
customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic 
temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 
30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses." 
 
 
4.2.3.1  Gemcitabine Treatment Schedule 
 
Gemzar should be administered by intravenous infusion at a dose of 1000 mg/m2 once weekly for 
3 weeks followed by 1 week of rest. The standard infusion is 30 minutes.  
 
The recommended diluent for reconstitution of Gemzar is 0.9% Sodium Chloride Injection 
without preservatives. Due to solubility considerations, the maximum concentration for Gemzar 
upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may 
result in incomplete dissolution, and should be avoided. To reconstitute, add 5 mL of 0.9% 
Sodium Chloride Injection to the 200 mg vial or 25 mL of 0.9% Sodium Chloride Injection to the 
1 g vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL 
which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for 
the 200 mg vial or 1.3 mL for the 1 g vial). The total volume upon reconstitution will be 5.26 mL 
or 26.3 mL, respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of 
gemcitabine, respectively. The appropriate amount of drug may be administered as prepared or 
further diluted with 0.9% Sodium Chloride Injection to concentrations as low as 0.1 mg/mL. 
Reconstituted Gemzar is a clear, colorless to light straw-colored solution. After reconstitution 
with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 
3.3. The solution should be inspected visually for particulate matter and discoloration, prior to 

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administration, whenever solution or container permit. If particulate matter or discoloration is 
found, do not administer. When prepared as directed, Gemzar solutions are stable for 24 hours at 
controlled room temperature 20° to 25°C (68° to 77°F) [See USP]. Discard unused portion. 
Solutions of reconstituted Gemzar should not be refrigerated, as crystallization may occur. The 
compatibility of Gemzar with other drugs has not been studied. No incompatibilities have been 
observed with infusion bottles or polyvinyl chloride bags and administration sets. Unopened 
vials of Gemzar are stable until the expiration date indicated on the package when stored at 
controlled room temperature 20° to 25°C (68° to 77°F). Caution should be exercised in handling 
and preparing Gemzar solutions. The use of gloves is recommended. If Gemzar solution contacts 
the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the 
mucosa with copious amounts of water. Although acute dermal irritation has not been observed 
in animal studies, two of three rabbits exhibited drug-related systemic toxicities (death, 
hypoactivity, nasal discharge, shallow breathing) due to dermal absorption. Procedures for 
proper handling and disposal of anti-cancer drugs should be considered.  
 
4.2.3.2  Expected Toxicities with Gemcitabine 
 
Gemzar can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and 
anemia, and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored 
for myelosuppression during therapy. Hemolytic-Uremic Syndrome (HUS) has been reported 
rarely with the use of Gemzar. Gemzar is a Pregnancy Category D drug. Gemzar can cause fetal 
harm when administered to a pregnant woman. Gemcitabine is embryotoxic causing fetal 
malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 
1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal 
malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in 
rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was 
characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. 
There are no studies of Gemzar in pregnant women. If Gemzar is used during pregnancy, or if 
the patient becomes pregnant while taking Gemzar, the patient should be apprised of the 
potential hazard to the fetus.  
 
 
4.2.4  Radiotherapy 
 
Radiation will be administered by the Department of Radiation Oncology at Johns Hopkins, 
either in the Weinberg Building of the Sydney Kimmel Comprehensive Cancer Center at John 
Hopkins (SKCCC), or at the SKCCC Greenspring facilities.  All patients will be simulated for 
radiation therapy at SKCCC. 
 
Patients will receive 50.4 Gy given in 28 fractions (1.8 Gy/fraction) daily for 5 ½ weeks.  
Patients with close or positive margins after resection may receive up to 54.0 Gy given in 30 
fractions.  Treatment will be directed at the tumor bed as well as at hepatic, duodenal, celiac, and 
superior mescenteric artery and periaortic lymph node sites at the same craniocaudal levels using 
conformal 3-D radiation therapy or intensity-modulated radiation therapy (IMRT).   
 

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4.2.4.1  Treatment Planning Specifications 
 
Patient positioning for radiation therapy: 
 
During radiation therapy simulation and treatment, all patients will be positioned supine with 
their arms raised above their heads. This will enable the entry of radiotherapy beams from lateral 
directions. A thoracic immobilization board with hand grips will be used to minimize 
interfractional motion.  
 
Equipment:  
 Greater than or equal to 10 MV photons should be used.  The 
minimal acceptable SAD is 100 cm. 
 
Dose-Time Factors:  
 All radiation fields should be treated daily with all external beam 
schemes. 
 
Radiation Fields: 
 Radiation fields include the large field-primary tumor bed plus 
lymph nodes.  A 3-D conformal or IMRT approach is required and 
will be most appropriate to minimize bowel, spinal cord, liver and 
kidney dose.  The preoperative primary tumor extent (as defined by 
preoperative imaging and operative findings, PET/CT images, and 
surgical clip placement, if performed) must be covered with a 
margin from the field edge of 1.5-2.0 cm, as detailed below in 
Large Fields and in the Field Edges table.  In addition, the 
local/regional and para-aortic lymph nodes adjacent to the lower 
thoracic and upper abdominal vertebral bodies are to be included.  
Inclusion of the hepaticojejunostomy site is also recommended.   
 
Large Fields: 
 As general guidelines, the edges of the large fields are defined as 
follows (these field edges may be adjusted if 3-D conformal or 
IMRT planning is used, however adequate coverage with full dose 
radiation must be confirmed with a dose volume histogram (DVH): 
 
 
 
 
 
a) Superior edge: intervertebral space T10-T11 or mid T11. 
b) Inferior edge: intervertebral space L3-L4, depending on the 
preoperative studies. 
c)  Right edge: encompassing the preoperative position of the 
pancreatic duodenum (per preoperative studies). 
d) Left edge: a margin of 2 cm from the preoperative primary 
tumor extent or 2 cm from the left edge of the vertebral bodies, 
whichever is more lateral. 

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e) Posterior edge: should split the anterior vertebral bodies in half.  
See Field Diagrams. 
f) Anterior edge: 1.5-2.0 cm anterior to anterior aspect of the 
primary tumor as defined on preoperative CT scan, and at least 
2.5-3.0 cm anterior to the anterior edge of the vertebral bodies, 
whichever is most anterior, (or 1.5-2.0 cm anterior to nodal 
volumes as reconstructed from CT scan information and 
outlined on simulator films (recommended, but not required). 
 
Boost Fields: 
 A single field reduction at 45 Gy is required, encompassing only 
the preoperative primary tumor volume, with a field edge margin 
of 1.5-2.0 cm on all fields. 
Field Edges:  
 The Target Volume is equivalent to the large field and boost field, 
as defined in Radiation Fields and outlined in Field Diagrams. 
 
 
 
Lateral Fields 
Per 
Protoc
ol 
Variation      
Acceptable 
Deviation   
Unacceptable 
A) Length 
Same as AP/PA fields 
 
B) Distance from 
anterior aspect of 
primary tumor 
1.5-2 cm 
0.5-3 cm 
<0.5 or >3 cm 
C) Distance from 
remaining aspect of 
primary tumor 
2-3 cm 
1-4 cm 
<1 or >3 cm 
D) Posterior edge 
mid-
vertebral 
bodies 
+/-1 cm from 
mid-vertebral 
bodies 
<1 or >3 cm 
E) Anterior edge relation 
to vertebral body 
3.5-4 cm 
2.5-5 cm 
<2.5 or >5 cm 
AP/PA Field(s) 
Per 
Protocol 
Variation      
Acceptable 
Deviation   
Unacceptable 
A) Length 
Inclusive of 4-5 vertebral 
bodies 
<4 or >5 vertebral 
bodies 
B) Distance from 
primary tumor 
1.5-2 cm 
1-3 cm 
< 1 or >3 cm 
C) Distance from 
vertebral body* 
2 cm 
1-3 cm 
< 1 or >3 cm 

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F) Anterior edge relation 
to nodal volumes (if 
reconstructed from 
CT and outlined on 
simulator films) 
1.5-2 cm 
1-3 cm 
<1 or >3 cm 
 
Boost Fields 
Per 
Protocol 
Variation      
Acceptable 
Deviation   
Unacceptable 
Distance from primary 
tumor 
1.5-2 cm 
1-3 cm 
<1 or >3 cm 
*May be included at the level of hepaticojejunostomy, if this is included. 
NOTE: The above will be reviewed in the context of kidney sparing/shielding as required in 
Critical Structure Tolerance and Treatment Breaks. 
 
Physical Parameters 
 
Beam Energy: 
 Megavoltage equipment is required, with nominal photon 
energies >10 MV. 
Treatment Distance: 
Minimum treatment distance to skin for SSD techniques or 
isocenter for SAD techniques should be at least 100 cm. 
 
Simulation Films: 
 Must undergo prospective quality assurance and evaluation 
as per Boost Fields and Field Edges during routine quality 
assurance conference. 
Localization Films:  
 Obtain for each treatment field per week. 
Isodose Distribution: 
Will be reviewed during the routine quality assurance 
conference.  All plans which include the isodose 
distribution will be stored in IMPAC in the Johns Hopkins 
Department of radiation oncology.  The dose delivered to 
the target volume must not deviate from the doses specified 
in Treatment Fields/Radiation Dose by more than 5 
percent in either direction.  Variations will be scored as per 
Dose Changes. 
Dose Specifications: 
Doses will be specified as follows: 
For an arrangement of three or more intersecting beams: at 
intersection of the central ray of the beams. 
 
Other / complex treatment arrangements: at the center of 
the target volume.   
 

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4.2.4.2.  Critical Structure Tolerance 
 
Small Bowel /Liver:  
Efforts should be made to exclude the small bowel and 
liver as much as possible by utilizing megavoltage beams 
and multiple shaped ports.  The liver must not have >50% 
of its volume receiving >30 Gy. 
Spinal Cord:  
 The spinal cord dose will be limited to <40 Gy by use of 
posterior blocking in the lateral field(s). 
 
Kidneys:   
 The equivalent of one kidney should receive <18 Gy or at 
least the equivalent of two-thirds of one kidney must be 
spared from the radiotherapy fields.  If only a single 
functioning kidney is present, at least 2/3 of the functioning 
kidney must be excluded from any radiation port. 
 
4.2.4.3.  Radiotherapy toxicity 
 
Common toxicities of radiotherapy include diarrhea, dermatitis, fatigue, nausea, alopecia in 
involved fields, and sterility (females are more likely to be left sterile than males).  Uncommon 
toxicities include intestinal obstruction and/or intestinal bleeding requiring surgery. 
 
4.3.  Other concomitant treatment 
 
Any patients who require ophthalmic surgery during the course of the trial will be temporarily 
withdrawn.  Concomitant use of medications known to affect the conductive system, such as 
beta-blockers, calcium channel blockers, or digoxin, is allowed under investigator supervision.  
concomitant use of the following drugs is NOT allowed: phenytoin, carbamazepine, rifampicin, 
phenobarbital or St John's Wort; these drugs induce CYP3A4 and may decrease levels of 
Erlotinib. Concomitant use of CYP3A4 inhibitors (eg, itraconazole) may result in increased 
levels of Erlotinib. This exposure may be clinically relevant, as adverse experiences are related 
to dose and exposure. 
 
Coadministration of drugs that cause significant sustained elevations in gastric pH greater than or 
equal to 5 may reduce plasma concentrations of Erlotinib, and therefore may reduce efficacy. 
 
International normalized ratio (INR) elevations, bleeding, or both events have been reported in 
some patients taking warfarin.  Patients taking warfarin should be monitored regularly for 
changes in prothrombin time (PT) or INR. 
 
Systemic retinoids should not be given because of theoretical concerns about negatively affecting 
the Erlotinib mechanism of action.  Systemic steroids are discouraged for the treatment of skin 
toxicities.  Patients who are taking steroids for reasons other than skin toxicity at trial entry may 
continue treatment.  
 

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Other medication, which is considered necessary for the patient’s safety and well being, may be 
given at the discretion of the investigator(s). 
 
4.4  Dose modification and management of toxicity 
 
4.4.1  Adjuvant Chemoradiation 
 
Several toxicities of Capecitabine, radiation, and Erlotinib overlap. These include diarrhea, 
nausea and vomiting and skin toxicity. Dose modifications for Erlotinib are described in table 
4.4.2.  Capecitabine will be held at the first occurrence of a grade 2 toxicity, then dose-reduced at 
a second occurrence of a grade 2 toxicity, and held/dose-reduced for first occurrence of grade 3 
or greater toxicities (see table 4.4.2).  Therapy will be interrupted until the grade 2 or greater 
toxicity abates to grade 1. Subsequently a dose adjustment will be made unless it is the first 
occurrence of a grade 2 toxicity where the dose will remain the same.  With the second 
occurrence of grade 2 or greater toxicity, therapy will be interrupted and subsequently restarted 
at reduced dose level.  With a third occurrence, dosing will be interrupted and subsequently 
restarted at another dose reduction, and will be discontinued if a grade 3 toxicity recurs.  It will 
also be discontinued if a grade 4 toxicity occurs at any time.  Patients whose toxicity does not 
recover after holding the drug for a maximum of 2 weeks will be removed from the study.   
 
Capecitabine dosing (on 5 days on/ 2 days off regimen): 
 
 
 
 
 
Starting dose = 800 mg/m2 po BID (1600 mg/m2 daily) 
 
 
 
 
Dose level –1 = 25% dose reduction 
 
 
 
 
Dose level –2 = 50% dose reduction 
   
Since toxic syndromes of severe diarrhea in the setting of neutropenia have been observed with 
5-FU based therapy, both Capecitabine and Erlotinib will be held in cases where grade 2 or 
greater diarrhea is observed in the setting of a rapidly declining ANC (or grade 3 or 4 
neutropenia). 
 
This is presented in tabular form below.  Note that if radiation therapy is interrupted for toxicity, 
Erlotinib will be stopped for the duration of radiation therapy and will be resumed in the 
maintenance phase of treatment if appropriate. 

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4.4.2 Toxicities/dose adjustments during adjuvant therapy (radiation) 
NCI Grade 
% of planned Capecitabine dosef 
Erlotinib  
Radiation 
Grade 0-1  
100% 
Current dose 
Current dose 
Grade 2 a 
 
 
 
1st appearance 
Hold then return to current dose b 
Current dose 
Current dose 
2nd appearance Hold then reduce by 25% b 
Hold, then 
current dose b 
Current dose 
3rd appearance 
Hold then reduce by 50% b 
Discontinue 
Hold x 1 wk c 
4th appearance Discontinue 
Discontinue 
Hold x 2 wks c 
Grade 3 a 
 
 
 
1st appearance 
Hold then reduce by 25% b 
Hold, then 
current dose b 
Current dose e 
2nd appearance Hold then reduce by 50% b 
Discontinue 
Hold x 1 wk c 
3rd appearance 
Discontinue 
Discontinue 
Hold x 2 wks c 
Grade 4 
Discontinue permanently, or hold 
then reduce to 50% of previous 
level d 
Discontinue d 
Hold x 2 wks c, d 
a Except nausea/vomiting (unless patient is on antiemetic therapy), diarrhea (unless patient is on medical therapy), 
and neutropenia.  Grade >2 skin toxicity will be treated according to the likely cause.  CTC grade 2, 3, or 4 
diarrhea with rapidly or precipitously declining absolute neutrophil count (ANC), or at same time as 
neutropenia CTC grade 3 or 4.  Erlotinib and Capecitabine should be discontinued for up to a maximum of 14 
days until the ANC is ≥ 0.5 × 109/L, the diarrhea resolves, or the diarrhea has decreased in severity to CTC grade 1. 
b Upon recovery to grade 1 or less within two weeks of stopping (with prophylaxis where possible).  Missed doses of 
Erlotinib and Capecitabine will not be made up. 
c Holding of radiation will be at the discretion of the treating radiation oncologist; missed dosing will be made up at 
the discretion of the treating radiation oncologist.  If radiation therapy is interrupted due to toxicity, erlotinib 
treatment will be stopped for the duration of radiation therapy and will be resumed in the adjuvant stage of therapy 
(with capecitabine), if appropriate. 
d All grade 4 discontinuations and/or toxicities will be reviewed by investigator and IRB to determine if patients 
may continue on study with appropriate dose adjustment. 
e Radiation will be continued unless toxicity is possibly related to radiation treatment; for example, diarrhea, or 
dermatitis over the radiation area. 
f Capecitabine and erlotinib dose adjustment will not be applied for lymphopenia (Grade 2 or above) 
 
4.4.3  Adjuvant Maintenance Chemotherapy 
 
Adjuvant chemotherapy consists of gemcitabine and erlotinib.  Management for Erlotinib 
toxicities will be as detailed below (Table 4.4.3).   For gemcitabine, dose adjustments will be 
based on the hematological and non-hematological toxicity of the drug and be monitored at the 
discretion of the treating oncologist.  Weekly doses of gemcitabine will not be made up. Weekly 
dose management of Erlotinib are as follows: 
 
Table 4.4.3 
Toxicity 
Grade 
Erlotinib management* 
Guideline for management 
Keratitis 
1 
None 
No intervention 
  
2 (if < 14 days) 
None** 
Preservative-free artificial 
  
2 (if >14 days) 
Hold until recovery to < grade 
tears, ointments, and/or 
other 

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26
  
  
1 
therapies as clinically 
  
> 3 
Hold until recovery to < grade 
indicated, with a follow-up 
  
  
1  
examination within 2 weeks 
Diarrhea 
1 
None 
No intervention 
  
2 
None** 
Loperamide (4 mg at first 
  
> 3 (despite optimal 
use 
Hold until recovery to < grade  onset, followed by 2 mg every 
  
of loperamide) 
1  
2–4 hrs until diarrhea free for 
  
  
  
12 hrs) 
Rash 
1 
None 
No intervention 
  
2 
None** 
Any of the following: 
  
> 3 
Hold until recovery to < grade  monocycline, topical tetra- 
  
  
1  
cycline or clindamycin, 
  
  
  
topical silver sulfadiadize, 
  
  
  
diaphenhydramine, oral 
  
  
  
prednisone (short course) 
Bilirubin 
> 3 X ULN 
Hold until grade < 2  
  
  
  
  
Liver  
> 5 X ULN 
Hold until grade < 2  
  
transaminase 
  
  
Signs   
  
Hold pending diagnosis 
Patient should be thoroughly 
and symptoms 
  
Permanently discontinue if  
evaluated, closely monitored, 
of Interstitial 
  
diagnosis is confirmed and 
and supported as clinically 
Pneumonitis 
  
considered possibly related 
to OSI-774 
indicated. 
  
  
  
Other toxicity 
> 2 prolonged 
clinically 
Hold until recovery to <  
Treatment as appropriate 
  
significant toxicity 
grade 1  
  
  
  
  
* If no recovery after 2 weeks of holding drug, patients should go off 
study. 
  
** If dose has been previously held for grade 2 rash or diarrhea, and grade 2 symptoms recur, OR if the  
Patient finds the symptoms unacceptable, hold dose until recovery to < grade 1  
  
  
Additional information for erlotinib: 
  
1.) GI perforation: In the event of bowel perforation, patient should be removed from erlotinib therapy  
2.) Ocular AEs: Erlotinib should be interrupted for acute/worsening eye pain and should be discontinued 
in patients with persistent inflammation or severe eye surface damage. 
  
 
 
Patients who develop grade 3-4 toxicity at any time during the study will be dose reduced by 25 
% upon recovery and for the rest of the study.  Patients who develop recurrent grade 3-4 toxicity 
can be further dose reduce by 50 % for the remaining treatments.  Patients with a third episode of 

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27
toxicity despite 2 dose reduction will be removed from the study permanently. Patients who 
missed (due to toxicity) more than 3 scheduled doses of gemcitabine will be removed from the 
study.   Erlotinib will be held if patients develop any signs of ILD during the maintenance phase 
of treatment unless it is determined by the treating physician to not be related to the drug. 
 
 
Toxicities 
 
Gemcitabine Dose Adjustment 
ANC 
> 1000 cell/uL 
100 % dose 
750-999 cells/uL 
50 % dose 
< 750 cells/uL 
Hold 
Platelets 
> 100,000 cells/uL 
100 % dose 
75,000-99,999 cells/uL 
50 % dose 
< 75,000 cells/uL 
Hold 
Non Hematologic Toxicity 
Grade 0 -1 
100 % 
 
Grade 2 - 4 
Hold 
 
 
 Assessment of quality of life: Quality of life will be assessed using The European Organization 
for Research and Treatment in Cancer quality of life core cancer questionnaire with the 
pancreatic cancer module (EORTC QLQ C-30/ PAN26).  The European Organization for 
Research and Treatment in Cancer Quality of Life Questionnaire (EORTC QOL-C30) is a 
multidimensional, 30-item questionnaire which assesses five functional scales (physical, role, 
cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting), a 
global health /QOL scale, as well as 6 single items (26)(27).  The EORTC QLQ-PAN26 
supplements the core questionnaire with 26 items specific for patients with pancreatic cancer 
(28)(29). The instrument will be administered in English to eligible patients. Questionnaires will 
be self-reported by the patient at the times outlined in the calendar.  Questionnaires should be 
administered prior to the patient being seen by the doctor.  Questions can be read verbatim to 
patients who are blind or illiterate. For QoL assessment, the primary outcome will be the change 
in overall QoL score from baseline at 12 months. Changes in QoL from baseline to other time 
points, and on subscales of both instruments, are secondary endpoints.  
 
5.0  Evaluation of patients: Dose limiting toxicities 
 
Each patient will be evaluated for toxicity weekly during the chemoradiation segment of the 
protocol and monthly for the maintenance phase of the treatment. Further enrollment will be held 
if two or more patients of each cohort of six experience any of the following dose limiting 
toxicities (DLTs): 
 
-Grade 3 or higher nonhematologic toxicity according to CTCAE version 3.0 ocurring 
despite optimal supportive care, if applicable. 
-grade 4 neutropenia (ANC <500) for 5 or more days 
-febrile neutropenia 
-platelet count <25,000/mm3 
-grade 3 or higher cutaneous toxicity 
 

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Version: July 13, 2016 
 
28
 
 
6.0  CRITERIA FOR DISCONTINUATION/WITHDRAWAL OF INFORMED 
CONSENT. 
 
 
Patients may be discontinued from trial treatment and assessments at any time, at the discretion 
of the investigator(s). Specific reasons for discontinuing a patient from this trial are the 
following: 
 
-Objective local or distant progression of disease  
-Patient lost to follow-up (ie, dropouts) 
-Unacceptable toxicity 
-Protocol noncompliance 
-Withdrawal of consent 
-Development of intercurrent illness  
-Inability to return to Johns Hopkins monthly during the maintenance phase of treatment. 
 
If the reason for withdrawal from the trial is the death of the patient, the 2 options for 
categorizing withdrawal are either progressive disease or an adverse event (AE; more than 1 AE 
may be documented as a reason for withdrawal).  Only 1 event will be captured as the cause of 
death.  Note that death is an outcome and not an AE.  
 
All deaths that occur within the trial period or within 30 days after administration of the last dose 
of trial drug must be reported primarily for the purposes of serious adverse event (SAE) 
reporting; however, deaths due unequivocally to progression are not SAEs.  All trial treatment-
related toxicities and SAEs must be followed up until resolution or until, in the criteria of the 
investigator, is unlikely to resolve. 
 
All patients who have new or worsening CTCAE grade 3 or 4 laboratory values at the time of 
withdrawal must have additional testing performed, and the results must be recorded in the 
patients’ medical records.  These patients should be followed up until the laboratory values have 
returned to CTCAE grade 1 or 2 or until 30 days after the date of withdrawal (whichever comes 
first), unless these values are not likely to improve because of the underlying disease.  In these 
cases, the investigators must record their opinions in the patients’ medical records.  Laboratory 
abnormalities should not be reported as adverse events unless any criterion for a SAE is fulfilled, 
the laboratory abnormality causes the patient to discontinue from the study, or the investigator 
insists the abnormality should be reported as an AE.   
 
After withdrawal from treatment, patients must be followed up for existing AEs for 30 calendar 
days after administration of the last dose of trial drug.  All SAEs occurring during that period 
must be reported to FDA and must be followed up until resolved, unless in the investigator’s 
opinion the condition is unlikely to resolve because of the patient’s underlying disease. 
 
 
 
 

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7.0   Study calendar 
 
 
 
Screening 
 
Chemo/XRT 
Day 16 
Weekly 
During 
Chemo/XRT 
Before the 
start of 
maintenance 
Cycle #1  
 
Before the 
start of 
maintenance 
Cycle #2  
 
 
Before the 
start of 
maintenance 
Cycle #3 
 
 
Before the 
start of 
maintenance 
Cycle #4 
 
 
Follow-
up 
every 
3-4 
Months 
x 2 
years8  
Informed 
consent1 
X 
 
 
 
 
 
 
 
Medical 
history 
X2 
 
X 
X 
X 
X 
X 
X 
Physical 
exam 
X2 
 
X 
X 
X 
X 
X 
X 
ECOG 
performance 
status 
X2 
 
X 
X 
X 
X 
X 
X 
CA 19-9 
X2 
 
 
X 
X 
X 
X 
X 
Chemistry 
panel3 
X2 
 
X 
X 
X 
X 
X 
X 
Hematology4 X2 
 
X 
X 
X 
X 
X 
X 
PT/PTT 
X2 
 
 
 
 
 
 
 
CT scan5 
X2 
 
 
X 
 
X 
 
X 
QOL 
Questionnaire 
X 
 
 
X  
 
X 
 
X 
Erlotinib  
 
X 
X 
 
X 
X 
X 
X 
 
Xeloda 
 
X 
X 
 
 
 
 
 
Gemcitabine 
 
 
 
X 
X 
X 
X 
 
Radiation 
 
X 
X 
 
 
 
 
 
 
 
1 To be obtained prior to ANY study-SPECIFIC procedure. 
2 Within 4 week prior to initiation of chemoradiation. Section 4.3 details use of concomitant medications.  
3 Creatinine, total bilirubin, AST, ALT, alkaline phosphatase, LDH, Ca, K, Na, albumin, total protein. 
4 Hemoglobin, hematocrit, platelets, WBC with differential. 
5 CT of the chest, abdomen and pelvis with IV and oral contrast.  Pancreas protocol (thin slices through the 
pancreas).  Outside CT scans acceptable but must be submitted for review. 
6 Day 1= Day that Erlotinib/Xeloda/radiation began 
7 Maintenance chemotherapy will begin 4-8 weeks after completion of chemoradiation, when patient has been 
deemed by investigator to be sufficiently recovered from chemoradiation.   It is recommended that patients 
receive a total of 4 cycles of gemcitabine (1000 mg/m2 weekly 3 doses per month) with daily erlotinib (100 
mg/m2).  During this period patients have the option of being treated closer to home but must return to Hopkins 
once a month for follow-up.  Gemcitabine/erlotinib administration should include appropriate hematologic, 
chemistry, and electrolyte monitoring as determined by the patient’s oncologist, in consulatation with the 
gemcitabine and erlotinib package inserts 
(http://www.gene.com/gene/products/information/pdf/tarceva-prescribing.pdf and http://pi.lilly.com/us/gemzar.pdf 
At this time all outside records including labs and clinic notes must be submitted to Johns Hopkins for review. Only 
grade 3 and above AE’s will be collected during this maintenance phase of treatment (M1-M4). SAE’s will be 
reported according to institutional guidelines set by Johns Hopkins.  Erlotinib will be obtained from the 
Hopkins pharmacy prior to chemoradiation and monthly during M1-M4.  It is required that patients return for a 
follow-up visit and restaging within 6 weeks of completion of their maintenance therapy (even if the duration is 
shorter than 4 cycles). 

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8 Follow-up visits – Following the maintenance phase of therapy patients will be followed every 3 months for 2 
years.  After 2 years patients will be seen every 6 months for 3 years for a total follow-up of 5 years per 
standard of care. As in the maintenance phase of the trial only grade 3 AEs will be collected.  SAE’s will be 
reported according to institutional guidelines set by Johns Hopkins.   
 
8.0  MEASUREMENT OF EFFECT 
 
The primary clinical endpoint is time to progression determined as the time elapsed from surgical 
resection to development of tumor recurrence, either local or distant.   
  
8.1 Definitions 
 
Time to progression refers to the time period between surgical resection and detection of 
recurrence by either clinical exam or radiological exam. Every effort should be made to biopsy 
suspected disease in order to confirm recurrence.   Any recurrence within the pancreatic area will 
be classified as local recurrence; any failure outside the pancreatic area will be recorded as 
distant recurrence. 
 
8.2 Monitoring for recurrence 
 
Upon the completion of adjuvant treatment, patients will undergo post-treatment monitoring for 
5 years.  The following will comprise follow-up: 
 
- History/Exam within 1-3 weeks upon completion of maintenance chemotherapy then every 3 
months for 2 years, then every 6 months thereafter; further visits as dictated by patient 
symptoms. 
-  CBC, tumor markers, chemistry panel every 3 months for 5 years (total). 
-  Abd/Pel CT every 3 months for 2 years, then every 6 months for 3 more year. 
-  Quality of life questionnaire per the study calendar. 
 
Upon detection of local or distant recurrence, patients are off-study; however every attempt will 
be made to follow patients until death to determine the secondary objective of overall survival. 
 
9.0.  ADVERSE EVENTS 
 
9.1.  Adverse Event and Reporting Definitions 
 
In the event of an adverse event the first concern will be for the safety of the subject.   
 
Investigators are required to report to Genentech Drug Safety ANY serious treatment 
emergent adverse event (STEAE) as soon as possible.   
 
A STEAE is any sign, symptom or medical condition that emerges during erlotinib treatment or 
during a post-treatment follow-up period that (1) was not present at the start of erlotinib 
treatment and it is not a chronic condition that is part of the patient’s medical history, OR (2) was 
present at the start of erlotinib treatment or as part of the patient’s medical history but worsened 

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in severity and/or frequency during therapy, AND that meets any of the following regulatory 
serious criteria: 
 
• Results in death  
• Is life-threatening  
• Requires or prolongs inpatient hospitalization  
• Is disabling  
• Is a congenital anomaly/birth defect  
• Is medically significant or requires medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
9.2.  Reporting of Serious Treatment Emergent Adverse Events to Genentech 
 
All treatment emergent SAEs should be recorded on a MedWatch 3500A Form and faxed to: 
 
Genentech Drug Safety Fax:  
650-225-4682 or 650-225-4683 
 
 
(Please use the safety reporting fax cover sheet included in the IST start-up binder for your fax 
transmission) 
 
AND: 
 
To the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Clinical Research 
Office.  
 
9.3.  MedWatch 3500A Reporting Guidelines 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500A form: 
 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-up information:   
 

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Additional information may be added to a previously submitted report by any of the 
following methods: 
 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e. D.O.B., initials, subject number), protocol description and number, if assigned, suspect 
drug, brief adverse event description, and notation that additional or follow-up information is 
being submitted  (The subject identifiers are important so that the new information is added 
to the correct initial report.) 
 
Occasionally, Genentech may contact the reporter for additional information, clarification or 
current status of the subject for whom an adverse event was reported.  For questions regarding 
STEAE reporting, you may contact the Genentech Drug Safety representative noted above. 
 
9.4.  Assessing Causality: 
 
Investigators are required to assess whether there is a reasonable possibility that Tarceva caused 
or contributed to an adverse event.  The following general guidance may be used. 
Yes: 
if the temporal relationship of the clinical event to Tarceva administration makes a causal 
relationship possible, and other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event. 
 
No: 
if the temporal relationship of the clinical event to Tarceva administration makes a causal 
relationship unlikely, or other drugs, therapeutic interventions or underlying conditions provide a 
sufficient explanation for the observed event. 
 
10.0.  STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
 
10.1.  Study design/endpoints 
 
This is a phase II study of Erlotinib in combination with chemoradiation and adjuvant 
chemotherapy in patients with resected pancreatic cancer.  The objectives of the trial are: 
 
 
Primary 
 
 
1. To seek preliminary evidence of antitumor activity (progression free survival) of 
erlotinib in combination with standard adjuvant chemoradiation and chemotherapy in 
patients with resected adenocarcinoma of the pancreas. 
 
 
Secondary  

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1. To characterize the toxicity profile of erlotinib in combination with adjuvant 
chemoradiation in patients with resected pancreatic cancer. 
 
2. To evaluate the quality of life of patients receiving erlotinib based chemoradiation 
prior to treatment (after surgery), one month following treatment and every 3-4 
months thereafter. 
 
3. To seek preliminary evidence of antitumor activity (overall survival) of erlotinib 
in combination with standard adjuvant chemoradiation and chemotherapy in 
patients with resected adenocarcinoma of the pancreas. 
 
 
10.2.  Sample size/accrual rate 
 
This is a phase II study evaluating the addition of Erlotinib to 5-FU based chemoradiation and 
maintenance (gemcitabine and erlotinib) chemotherapy in patients with resectable 
adenocarcinoma of the pancreas.   
 
 
The principal endpoint is to estimate the progression free survival for this patient population.  
The table below shows the power to detect various differences in progression free survival for 
those treated with erlotinib in combination with standard adjuvant chemoradiation and 
chemotherapy versus the standard treatment for N=40 and two-sided type I error of 5%.  The 
expected median progression free survival time with 5-FU based chemoradiation alone for an 
accrual time of 18 months and follow-up period of 60 months is 12 months.   
 
Power 
Median Progression Free 
Survival Difference 
(months) 
0.46 
0.73 
0.89 
0.96 
4  
6 
8 
10 
 
We have 89% power to detect an 8 month improvement in progression free survival for those 
who receive treatment with N=40. 
 
We expect to enroll 2-4 patients per month, with accrual completed in approximately 14-18 
months. 
 
10.2.1.  Analysis of primary endpoints 
 
Progression free survival will be calculated as the time from surgery to the time of disease 
progression.  Median and overall survival will be estimated and 95% confidence intervals 
will be reported using Kaplan-Meier methods.   
 

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34
10.2.2.  Analysis of secondary endpoints 
 
Toxicity will be evaluated using the NCI Common Toxicity Criterion for Adverse Events 
Version 3.0.  Toxicities requiring dose-reduction are described in section 4.4.  The 
frequency of toxicities per organ system and grade will be summarized, including time of 
onset.  All patients who receive at least one dose of Erlotinib will be included in the toxicity 
analysis.  Patients who began treatment, patients who are evaluable, and all who required 
dose reductions will be documented.  The toxicity profile of erlotinib will be characterized 
weekly in patients as mild or severe.  The percentage of mild and severe toxicities will be 
reported separately with 95% confidence intervals.  Individual patients’ toxicity profiles 
(frequency of severe reactions) of the course of the entire study will also be summarized. 
 
To determine health related quality of life (QoL) changes following this treatment regimen. 
For the EORTC QLQ-C30 and QLQ-PAN26, summation results will be reported by 
subscale. Analysis will be performed using paired t tests/paired ANOVA against baseline 
values with a 0.05 level of significance (2 tailed). The primary endpoint for QoL assessment 
is 12 months.   
 
 
We estimate that 30 patients will have complete data for analysis of this (QOL) 
secondary endpoint. This conservative estimate of sample size should provide 
adequate power accounting for additional dropouts.  
 
 The overall survival will be calculated as the time from surgery to the time of death.  
Median and overall survival will be estimated and 95% confidence intervals will be 
reported using Kaplan-Meier methods.   
 
10.3.  Reporting and exclusions 
 
10.3.1.  Evaluation of response  
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  All of the patients who met the 
eligibility criteria should be included in the main analysis of the outcome parameters. Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion from the analysis 
of the response rate.  All conclusions should be based on all eligible patients.  Subanalyses may 
then be performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.).  However, these subanalyses may not serve as the 
basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding 
patients from the analysis should be clearly reported.   
 
 

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11.0.   TRIAL MANAGEMENT 
 
11.1.  Audits and inspections 
 
Authorized representatives of Genentech, a regulatory authority, or an Institutional Review 
Board (IRB) may visit the center to perform audits or inspections, including source data 
verification.  The purpose of an Genentech audit or inspection is to systematically and 
independently examine all trial related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, Good Clinical Practice (GCP), and any applicable regulatory requirements.  The 
investigator should contact Genentech immediately if contacted by a regulatory agency about an 
inspection at his or her center. 
 
11.2.  Changes to the protocol 
 
If it is necessary for the trial protocol to be amended, the amendment or a new version of the trial 
protocol must be notified to or approved by the IRB.  If a protocol amendment requires a change 
to a particular center’s Written Informed Consent Form, then the IRB must be notified.  
Approval of the revised Written Informed Consent Form by the IRB is required before the 
revised form is used. 
 
Genentech’s willingness to supply Study Drug is predicated upon the review of the protocol.  
The Investigator agrees to provide prior written notice to Genentech of any modifications to the 
protocol or informed consent. 
 
11.3.  Ethics 
 
The principal investigator(s) is also responsible for providing the IRB with reports of any serious 
adverse events from any other trial conducted with the investigational product.  The trial will be 
performed in accordance with Good Clinical Practice. 
 
11.4.  Procedures in case of overdose 
 
There is currently no known antidote for Erlotinib. The treatment of AEs associated with 
overdose should be supportive and for the underlying adverse symptoms.  To date, no patient has 
experienced an overdose with Erlotinib.  
 
11.5.  Procedures in case of pregnancy 
 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under trial may have interfered with the effectiveness of a contraceptive 
medication.  However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, normal birth or congenital abnormality) must be followed up and documented even 
if the patient was discontinued from the trial. 
 

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36
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 
handled as SAEs.  All outcomes of pregnancy must be reported to Genentech on the pregnancy 
outcomes report form. 
 
11.6.  Trial monitoring 
 
The SKCCC Clinical Trial Monitoring Program (revision 6/16/05) is attached in appendix E.  As 
a phase II IND exempt investigator initiated trial, this trial is assigned a “level 1” plan in the 
clinical trial monitoring program. Trial Monitor Evaluation and Reporting will be done by the 
SKCCC Clinical Research Review Committee (CRC). 
 
Trial progress will be discussed at the Johns Hopkins GI Clinical Trial Program weekly meeting, 
which includes the protocol principal investigator, study coordinator(s), data manager(s), sub-
investigators (as appropriate), collaborators (as appropriate), and biostatisticians (as appropriate) 
involved with the conduct of the protocol.  During these meetings matters related to the 
following will be discussed:  safety of protocol participants, validity and integrity of the data, 
enrollment rate relative to expectation, characteristics of participants, and retention of 
participants, adherence to protocol (potential or real protocol violations), data completeness, and 
progress of data for objectives. 
 
 
 

Phase II Study of Erlotinib (Tarceva™ ) Combined with Chemoradiation and Adjuvant 
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Version: July 13, 2016 
 
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12. Xiong HQ, Rosenberg A, LoBuglio A, et al. Cetuximab, a monoclonal antibody targeting the 
epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic 
cancer: A multicenter phase II trial. J Clin Oncol 2004;22:2610-6.  
13. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with 
gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the national 
cancer institute of canada clinical trials group. J Clin Oncol 2007;25:1960-6.  

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14. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and 
chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200-10.  
15. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before 
and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: 
A randomized controlled trial. JAMA 2008;299:1019-26.  
16. Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous 
fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal 
cancer: Results of a randomized phase III study. J Clin Oncol 2001;19:2282-92.  
17. Cassidy J, Twelves C, Van Cutsem E, et al. First-line oral capecitabine therapy in metastatic 
colorectal cancer: A favorable safety profile compared with intravenous 5-
fluorouracil/leucovorin. Ann Oncol 2002;13:566-75.  
18. Cartwright TH, Cohn A, Varkey JA, et al. Phase II study of oral capecitabine in patients with 
advanced or metastatic pancreatic cancer. J Clin Oncol 2002;20:160-4.  
19. Sawada N, Ishikawa T, Sekiguchi F, et al. X-ray irradiation induces thymidine phosphorylase 
and enhances the efficacy of capecitabine (xeloda) in human cancer xenografts. Clin Cancer Res 
1999;5:2948-53.  
20. Schuller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumor 
following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 
2000;45:291-7.  
21. Ishikawa T, Sekiguchi F, Fukase Y, et al. Positive correlation between the efficacy of 
capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine 
dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 1998;58:685-90.  
22. Dunst J, Reese T, Sutter T, et al. Phase I trial evaluating the concurrent combination of 
radiotherapy and capecitabine in rectal cancer. J Clin Oncol 2002;20:3983-91.  
23. Kim JS, Kim JS, Cho MJ, et al. Preoperative chemoradiation using oral capecitabine in 
locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2002;54:403-8.  
24. Vaishampayan UN, Ben-Josef E, Philip PA, et al. A single-institution experience with 
concurrent capecitabine and radiation therapy in gastrointestinal malignancies. Int J Radiat 
Oncol Biol Phys 2002;53:675-9.  
25. Bianco C, Tortora G, Bianco R, et al. Enhancement of antitumor activity of ionizing radiation 
by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase 
inhibitor ZD1839 (iressa). Clin Cancer Res 2002;8:3250-8.  
26. Groenvold M, Klee MC, Sprangers MA, et al. Validation of the EORTC QLQ-C30 quality of 
life questionnaire through combined qualitative and quantitative assessment of patient-observer 
agreement. J Clin Epidemiol 1997;50:441-50.  

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27. Aaronson NK, Ahmedzai S, Bergman B, et al. The european organization for research and 
treatment of cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst 1993;85:365-76.  
28. Fitzsimmons D, Johnson CD. Quality of life after treatment of pancreatic cancer. 
Langenbecks Arch Surg 1998;383:145-51.  
29. Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality of 
life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the 
QLQ-C30 in patients with pancreatic cancer. EORTC study group on quality of life. Eur J 
Cancer 1999;35:939-41.  
 
 

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APPENDIX A 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 

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APPENDIX B 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
 
Life threatening 
 
“Life threatening” means that the patient was at immediate risk of death from the adverse event 
as it occurred or it is suspected that use or continued use of the product would result in the 
patient’s death.  “Life threatening” does not mean that had an adverse event occurred in a more 
severe form it might have caused death (ie, hepatitis that resolved without hepatic failure). 
 
Hospitalization 
 
Outpatient treatment in an emergency room is not in itself a serious adverse event, although the 
reasons for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered adverse events if the illness or 
disease existed before the patient was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study. 
 
Important medical event or medical intervention 
 
Medical and scientific judgment should be exercised in deciding whether a case is serious in a 
situation where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.  Examples of such events are: 
 
· Angioedema not severe enough to require intubation but requiring iv hydrocortisone treatment 
· Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with N-
acetylcysteine 
· Intensive treatment in an emergency room or at home for allergic bronchospasm 
· Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or convulsions 
that do not result in hospitalization 
· Development of drug dependency or drug abuse 
 
Disease Progression 
Any events or hospitalization that are unequivocally due to progression of disease must not be 
reported as a serious adverse event. 
 
 
 
 
 
 
 
 

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Appendix C 
 
 
 
EORTC QLQ-C30 
EORTC QLQ-PAN26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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45
 
 

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Appendix C 
 
 
EORTC QLQ-PAN26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D 
 
Further Guidance on the Assessment of Casuality 
 
The following factors should be considered when deciding if there is a “reasonable possibility” 
that an adverse event (AE) may have been caused by the investigational product. 
 
· Time course of events and exposure to suspect drug:  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of suspect drug? 
· Consistency with known drug profile:  Was the AE consistent with the previous knowledge 
of the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological 
class?  OR could the AE be anticipated from its pharmacological properties? 
· De-challenge experience:  Did the AE resolve or improve on stopping or reducing the dose of 
the suspect drug? 
· No alternative cause:  The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors. 
· Re-challenge experience:  Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped?  AstraZeneca would not normally recommend or support a re-
challenge. 
· Laboratory tests:  Has a specific laboratory investigation confirmed the relationship? 
 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
 
In contrast, there would not be a “reasonable possibility” of causality if none of the above criteria 
apply or where there is evidence of exposure and a reasonable time course but any de-challenge 
(if performed) is negative or ambiguous or there is another more likely cause of the AE.  In 
difficult cases, other factors could be considered such as: 
· Is this a recognized feature of overdose of the drug? 
· Is there a known mechanism? 
 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this. 
  
 
 

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APPENDIX E 
 
 
 
 
 
 
 
SIDNEY KIMMEL COMPREHENSIVE CANCER 
CENTER AT JOHNS HOPKINS 
 
DATA AND SAFETY MONITORING PROGRAM 
(Revised 6/16/2005)

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TABLE OF CONTENTS 
 
1. 
BACKGROUND ................................................................................................................. 53 
1.1. NIH Principles of Monitoring Data and Safety ............................................ 53 
1.2. National Cancer Institute’s Definition of a Clinical Trial ......................... 53 
2. 
MONITORING THE PROGRESS OF TRIALS AND THE SAFETY OF PARTICIPANTS .............. 54 
2.1. SKCCC Data and Safety Monitoring Plan .................................................... 54 
2.2. Institutional Oversight and Responsibilities for Monitoring of Clinical 
Trials 56 
2.2.2. Clinical Research Review Committee (CRC) .............................................. 56 
2.2.3. Institutional Review Board .............................................................................. 57 
2.2.4. Internal Data Monitoring .................................................................................. 57 
2.2.5. External Data Monitoring................................................................................. 57 
2.2.6. Quality Assurance Auditing............................................................................. 58 
2.2.7. Data And Safety Monitoring Committee ....................................................... 59 
2.2.8. Medical Expert Committee .............................................................................. 61 
2.2.9. Data and Safety Monitoring Board ................................................................ 61 
3. 
COMPLIANCE WITH PROBLEM/EVENT REPORTING REQUIREMENTS ............................. 63 
3.3. Reporting Guidelines followed at SKCCC ........................................................ 64 
4. 
MULTI-SITE CLINICAL TRIALS ........................................................................................ 64 
Appendix A: Review of Reportable Protocol Events ................................................ 65 
Appendix B: Review of Amendments ........................................................................... 66 
Appendix C: SKCCC Multi-Center Guidelines ............. Error! Bookmark not defined. 
END NOTES .............................................................................. Error! Bookmark not defined. 
 

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1. BACKGROUND 
 
NIH policy requires that grantees have in place procedures for the data and 
safety monitoring of clinical trials1.  This is to ensure the safety of participants, 
the validity and integrity of the data, and the appropriate termination of trials for 
which significant benefits or risks have been uncovered or for which, it appears 
that the trial cannot be concluded successfully.  The NIH DSM policy covers 
clinical trials of all phases funded by the NIH.  The Sidney Kimmel 
Comprehensive Cancer Center (SKCCC) Institutional Data and Safety Monitoring 
Plan (DSMP) was developed to comply with the NIH policies, the NCI’s Essential 
Elements of a Data and Safety Monitoring Plan for Clinical Trials Funded by the 
NCI guidance document2, and FDA regulations for monitoring IND trials.   
 
1.1. NIH Principles of Monitoring Data and Safety 
 
1.1.1. All clinical trials require monitoring.  Data and safety monitoring is 
required for all types of clinical trials, including physiologic, toxicity, 
and dose-finding studies (phase I); efficacy studies (phase II); 
efficacy, effectiveness and comparative trials (phase III), etc. 
 
1.1.2. Monitoring should be commensurate with risks.  The method and 
degree of monitoring needed is related to the degree of risk 
involved.  A monitoring committee is usually required to determine 
safe and effective conduct and to recommend conclusion of the trial 
when significant benefits or risks have developed or the trial is 
unlikely to be concluded successfully.  Risk associated with 
participation in research must be minimized to the extent practical.  
 
1.1.3. Monitoring should be commensurate with size and complexity.  
Monitoring may be conducted in various ways or by various 
individuals or groups, depending on the size and scope of the 
research effort.  These exist on a continuum from monitoring by the 
principal investigator or NIH program staff in a small phase I study to 
the establishment of an independent data and safety monitoring 
board for a large phase III clinical trial. 
 
 
1.2. National Cancer Institute’s Definition of a Clinical Trial 
 
1.2.1. The NCI operational definition of a clinical trial is a prospective study 
involving human subjects designed to answer specific questions 
about the effects or impact of particular biomedical or behavioral 
interventions; these may include drugs, treatments, devices, or 
behavioral or nutritional strategies.  Participants in these trials may 
be patients with cancer or people without a diagnosis of cancer but 
at risk for it. 
  

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1.2.2. In the area of molecular or imaging diagnostics, the NCI considers a 
study to be a clinical trial if it uses the information from the 
diagnostic test in a manner that somehow affects medical decision-
making for the study subject.  In this way, the information from the 
diagnostic may have an impact on some aspect of outcome, and 
assessment of this impact may be a key goal of the trial.  By 
contrast, studies that do not use information from the diagnostic test 
in any manner that can affect the outcome of study subjects, but 
whose objective is only the gathering of data on the characteristics 
of a new diagnostic approach, are not clinical trials and are not 
covered by this DSM policy, unless performing the diagnostic test 
itself imposes some risk on study subjects.  
 
1.2.3. Behavioral clinical trials include interventions whose goals are to 
increase behaviors (e.g. cancer screening, physical activity, fruits 
and vegetable intake), eliminate or reduce behaviors (e.g., smoking, 
sun exposure) and/or improve coping and quality of life (e.g., among 
cancer survivors) and reduce the negative sequelae of treatment.  
Interventions may pertain to cancer prevention, early detection, 
treatment, and survivorship.  Observational studies and those that 
do not test interventions are not clinical trials.  
 
 
2. MONITORING THE PROGRESS OF TRIALS AND THE SAFETY OF PARTICIPANTS 
 
2.1. SKCCC Data and Safety Monitoring Plan 
 
2.1.1. Outlines the general process for data and safety monitoring, 
including institutional oversight and review procedures important to 
assure and document compliance.  This Plan is comprised of graded 
oversight mechanisms that comply with NIH/NCI and FDA 
standards.   
 
2.1.2. Monitoring for clinical trials is a continuous, ongoing review of the 
conduct of the trial, including adherence to study design and 
documentation of appropriate reporting of protocol events.  The 
responsibilities for monitoring are shared between the Assistant 
Director for Clinical Research, Clinical Research Review Committee 
(CRC), SKCCC Data and Safety Monitoring Committee (DSMC), 
Data and Safety Monitoring Board (DSMB), SKCCC CRO Quality 
Assurance Program or Sponsor, and the PI. 
 
2.1.3. All clinical trials at SKCCC are required to have a Data and Safety 
Monitoring section in the protocol.  If a clinical trial does not have a 
specific mechanism defined in the protocol for data and safety 
monitoring, the principal investigator of each trial is required to 
define a specific clinical research trial monitoring system 
commensurate with the risks and complexity of the proposed trial.  

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2.1.4. The SKCCC DSMP utilizes a graded monitoring system as shown in 
Table 1 below.  Level 1 is designed for low risk/low complexity trials, 
while Level 4 is designed for high risk/high complexity trials including 
phase III trials.  The level of monitoring must be included in the 
protocol for review and subsequent approval by the SKCCC Clinical 
Research Review Committee (CRC), the Institutional Review Board 
(IRB) and, if applicable, the NCI.  
 
2.1.5. In all four levels, primary internal data monitoring is performed by 
the principal investigator.  A principal investigator leads a team of 
data managers and research nurses assigned to the trial.  The 
principal investigator reviews the data on a regular basis and 
internally monitors the trial performance in a timely manner.  PI 
monitoring is an essential element of all clinical trials.  
 
2.1.6. An external data monitor is recommended for higher risk trials.  
Level 2, 3 and 4 monitoring plans involve an external monitoring 
process.  Such monitoring may be performed by the SKCCC CRO 
Quality Assurance program monitors or contracted through an 
external Clinical Research Organization.  In addition to data 
monitoring, all trials covered under the SKCCC DSMP receive 
periodic quality assurance audits under the SKCCC CRO Auditing 
Guidelines.  Level 1 monitored trials receive an audit after the first 
subject is enrolled.  Subsequent audits are scheduled periodically 
(usually annually) as long as the trial remains open for accrual.  
Level 2, 3 & 4 monitored trials are audited at the end of the first year 
and then periodically every one to three years.  Monitoring and 
auditing reports are reviewed by the DSMC, Medical Expert 
Committee and/or the DSMB.  
 
2.1.7. It is the responsibility of the DSMC, Medical Expert Committee, 
and/or the DSMB to make recommendations to the PI, Assistant 
Director for Clinical Research and IRB concerning continuation or 
conclusion of the trial. 
 

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Table: 1 
SKCCC DSMP Schema 
 
Level 1 
Level 2 
Level 3 
Level 4 
Risk  
of Trial 
Low – Medium 
Medium – High 
High 
High 
Complexity  
of Trial 
Low – Medium 
Low – High 
Medium – High 
High 
Internal 
Monitoring 
Performed by 
PI and Study 
Staff 
PI and Study 
Staff 
PI and Study 
Staff 
PI and Study 
Staff 
External 
Monitoring 
Performed by 
None 
CRO QA 
Program or 
External  
CRO QA 
Program or 
External  
CRO QA 
Program or 
External  
SKCCC CRO 
Auditing  
All clinical trials are audited under the SKCCC CRO Auditing 
Guidelines 
 
Data and 
Safety 
Monitoring 
Oversight 
DSMC 
DSMC 
DSMC and 
Medical Expert 
Committee A 
DSMC and 
DSMB B  
Trial Type 
Phase I, II, Behavioral, & Nutritional may select 
Level 1, 2, or 3 
Required for 
Phase III 
 
JH Investigator sponsored IND/IDE  
must use Level 2, 3 or 4  
A When there is conflict between the DSMC and Medical Expert Committee, the 
DSMC will have final decisional authority. 
B When there is conflict between the DSMC and DSMB, the DSMB will have final 
decisional authority. 
 
 
2.2. Institutional Oversight and Responsibilities for Monitoring of Clinical 
Trials  
 
2.2.1. The Assistant Director for Clinical Research (ADCR) has overall 
responsibility for data and safety monitoring of clinical trials 
conducted at the SKCCC.  The ADCR appoints the Chair and all 
members of both Clinical Research Review Committee (CRC) and 
the Data and Safety Monitoring Committee (DSMC). 
 
2.2.2. Clinical Research Review Committee (CRC) 
 
2.2.2.1. The Clinical Research Review Committee is charged with 
ensuring that protocols meet the Center’s standards for 
Scientific Merit, Scientific Priority, and Adequate Scientific 
Progress as well as ensuring the inclusion of women and 

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minorities and children in research.  The CRC is also 
responsible for approving the monitoring plan for each 
study. 
 
2.2.2.2. CRC membership includes physicians from various Center 
programs, biostatisticians, epidemiologists, and a patient 
advocate. 
 
2.2.2.3. Clinical trials are reviewed by the CRC in a two-stage 
process.  First, protocols are reviewed all necessary 
sections are present, adequate, consistent, and complete.  
Then the study is sent to the full CRC where it receives a 
review as described in Section 1) a).  After discussion, each 
member votes on the protocol. 
 
2.2.2.4. Once studies are approved by the CRC they are forwarded 
to the IRB for review 
 
2.2.3. Institutional Review Board 
 
2.2.3.1. The Johns Hopkins Medicine Institutional Review Boards 
(JHM IRBs) are responsible for protecting the rights and 
welfare of the human subjects of research conducted by 
faculty and staff at Johns Hopkins Institutions.  The JHM 
IRBs review all human subject research projects conducted 
by Hopkins faculty and staff.  
 
2.2.3.2. Monitoring plans are reviewed and approved for each study 
by the IRB.   
 
2.2.4. Internal Data Monitoring 
 
2.2.4.1. The PI has the primary responsibility for continuous internal 
monitoring for safety, protocol compliance and identification, 
grading, coding and required reporting of all anticipated and 
unanticipated protocol events/problems.  This responsibility 
is usually shared between the PI, research nurse and data 
manager.  The PI is ultimately responsible for grading and 
attribution of all events. 
 
2.2.5. External Data Monitoring 
 
2.2.5.1. The SKCCC CRO Quality Assurance Program is 
responsible for external data monitoring.  Alternately, the 
Sponsor/PI may use external agency for data monitoring.  
For example, CTEP uses Theradex for Phase I studies. 
 

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2.2.5.2. Monitoring visits occur at least annually; but may be as 
frequent as monthly for rapidly accruing and/or high-risk 
trials.  Monitoring occurs for 100% of subjects enrolled on 
the trial. 
 
2.2.5.3. During routine monitoring visits, the following are generally 
reviewed: 
(1) Accrual 
(2) Consent forms 
(3) Eligibility 
(4) Data completeness 
(5) Data timeliness 
(6) Data accuracy 
(7) Anticipated and unanticipated protocol event/problem 
identification, grading, attribution and appropriate 
reporting 
 
2.2.5.4. Following a monitoring visit, a report is prepared and sent to 
the PI, study staff and DSMC for review. 
 
2.2.5.5. Monitoring SOPs and guidelines have been developed for 
use, when the external monitor is the SKCCC CRO Quality 
Assurance Program. 
 
2.2.6. Quality Assurance Auditing  
  
2.2.6.1. The Quality Assurance Program is responsible for ensuring 
protocol compliance and the validity and integrity of data for 
all Institutional and Externally Peer Reviewed clinical trials.  
This is accomplished through a comprehensive auditing 
program.  The level of oversight is commensurate with the 
risk, size and complexity of the clinical trial.  Auditors are 
well trained in the diseases for which they are auditing. 
 
2.2.6.2. Two types of audits are routinely performed 
 
2.2.6.2.1. Early audits are scheduled after the first subject 
has been enrolled.  The focus is protocol 
compliance.  Findings are reviewed with the PI 
and study staff.  
 
2.2.6.2.2. Periodic audits generally occur annually.  In 
addition to a full administrative/regulatory review, 
three to six subject's research records and 
corresponding source documents are reviewed.   
 
2.2.6.3. Areas of concentration for audits are: 

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(1) Timely submission of continuing review reports, 
amendments, and reportable protocol events 
(2) Accrual 
(3) Valid signed consent forms 
(4) Eligibility 
(5) Data Quality 
(6) Treatment administration 
(7) Response / Outcome Assessment 
(8) Anticipated and unanticipated protocol event/problem 
identification, grading, attribution and appropriate 
reporting 
(9) Study Drug/Instrument Accountability 
 
2.2.6.4. Audit findings are reviewed with the PI and study staff and a 
final report is sent to the DSMC and/or DSMB for review 
and approval. 
 
2.2.7. Data And Safety Monitoring Committee 
 
2.2.7.1. The DSMC is charged with ensuring the safety of 
participants and the validity and integrity of the data and the 
appropriate termination of studies for which significant 
benefits or risks have been uncovered.  The Committee is 
responsible for continuous, ongoing review of the conduct 
of the trial, including adherence to study design and 
documentation of appropriate monitoring and reporting of 
protocol events.  Inherent in this process is the goal of 
enhancing the quality of the research by providing the 
investigator with constructive criticism.  The DSMC 
membership includes physicians from various Center 
Programs and representatives from biostatistics, data 
management, nursing, and quality assurance.    
 
2.2.7.2. DSMC members may not have a conflict of interest with any 
aspect of the trials they monitor.  Members must abstain 
from voting and making recommendations for any trial 
where they are an investigator or have a conflict of interest.  
Conflict of interest is defined and managed by the Johns 
Hopkins University Conflict of Interest Policy.  
 
2.2.7.3. The DMSC reviews: 
 
2.2.7.3.1. Reportable anticipated and unanticipated 
protocol events/problems. The DSMC Chair or 
designee and QA manager meet at least two 
times per month to review all events that were 
submitted to the CRO. 

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(1) Events that may be potentially significant are 
referred to the DSMC for full review while 
non-significant events are reviewed in a 
summary format by the DSMC. 
(2) With respect to subject safety, the Chair may 
place a temporary hold on any trial pending 
full DSMC review 
(3) The DSMC may recommend any of the 
following: 
(a) No action 
(b) Request further information/follow-up by 
PI 
(c) Temporary hold on accrual 
(d) Termination of the trial with required 
reporting to appropriate regulatory 
agencies 
(4) A Flow Diagram for the reportable protocol 
events/problems review process is outlined 
in Appendix A 
 
2.2.7.3.2. Protocol Amendments 
(1) The DSMC Chair or designee and QA 
manager meet at least two times per month 
to review all amendments that were 
submitted to the CRO. 
(2) Administrative or minor amendments do not 
receive any further consideration by the 
DSMP committees 
(3) Amendments that may significantly impact 
the scientific merit of the trial are referred to 
the CRC for review 
(4) Amendments that may have a significant 
impact on subject safety are referred to the 
full DSMC for review 
(5) With respect to subject safety, the Chair may 
place a temporary hold on any trial pending 
full DSMC review 
(6) The DSMC may recommend any of the 
following: 
(a) No action 
(b) Request further information/follow-up by 
PI 
(c) Temporary hold on accrual 
(d) Termination of the trial with required 
reporting to appropriate regulatory 
agencies 
(7) Flow Diagrams for the Amendment review 
process is outlined in Appendix B 

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2.2.7.3.3. Audit and Monitoring Reports 
(1) Quality Assurance manager presents a 
synopsis of audit and monitoring findings 
and recommendations 
(2) The auditor and/or monitor will be present to 
answer any questions from the Committee  
(3) Committee members may: 
(a) Accept report as is 
(b) Recommend QA change report 
(c) Add, reclassify or delete deficiencies 
 
(4) Committee members vote on final outcome: 
(a) Acceptable 
(b) Acceptable with actions 
(i) Require a Quality Improvement Plan 
(ii) Re-audit at a specified time frame for 
compliance 
(c) Not acceptable 
(i) Close the trial with required reporting 
to appropriate regulatory agencies 
(ii) Require a Quality Improvement Plan 
(iii) Re-audit at a specified time frame for 
compliance 
 
2.2.8. Medical Expert Committee 
 
2.2.8.1. In some clinical trials, the expected outcome may be difficult 
to assess.  This may require oversight by a group with 
greater expertise in a specific medical area than the DSMC 
can provide, but less extensive than a DSMB.  In such 
cases, the protocol must specify procedures for an expert 
medical monitoring process which entail: 
2.2.8.1.1. Membership of Monitoring Group 
2.2.8.1.2. Content of Review 
2.2.8.1.3. Authority of Committee 
2.2.8.1.4. Review and reporting frequency 
2.2.8.1.5. Reporting Requirements 
 
2.2.8.2. In general, the Medical Expert Committee uses data 
reported by the internal data monitoring process and the 
external monitor. 
2.2.8.3. If the DSMC and the Medical Expert Committee have 
differing recommendations, the DSMC will have final 
decisional authority 
 
2.2.9. Data and Safety Monitoring Board 
 

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2.2.9.1. SKCCC has a DSMB available for investigators to utilize.  An 
investigator may assemble a DSMB specific to the trial.  The 
DSMB membership must be approved by the CRC, IRB and 
NCI. 
2.2.9.2. The DSMB is charged with monitoring and evaluating three 
aspects of clinical trials.  These Include: 
 
2.2.9.2.1. Safety:  By reviewing interim toxicity data for a trial 
in order to assure the continuing safety of subjects 
 
2.2.9.2.2. Efficacy:  By reviewing interim analyses of 
outcome data, prepared by the study statisticians 
to assure that the data are consistent with 
identifying an important clinical efficacy. 
 
2.2.9.2.3. Study Progress:  By reviewing outcome data, to 
assure that the study can be completed in a 
reasonable time frame to be of significant clinical 
relevance. 
 
2.2.9.3. The DSMB Membership will include voting and nonvoting 
members.  The core DSMB must include five members.  
These should include at least one experienced oncologist, a 
statistician and a lay representative.  Members should be 
selected based upon their expertise, experience, reputation 
for objectivity, knowledge of clinical trial methodology and 
absence of a significant conflict of interest.  Members may 
not have a conflict of interest with any aspect of the trials 
they monitor.  Conflict of interest is defined by the Johns 
Hopkins University Conflict of Interest Policy.  The DSMB will 
meet at least twice annually or more frequently as dictated 
by the requirements of clinical trials under its supervision.  
Data review dates should be selected so that the committee 
can prepare a report for the continuing review of supervised 
trials. 
 
2.2.9.4. The formal meeting of the DSMB for each trial shall consist 
of three parts.  The first part is an open session in which 
members of the clinical team, including the principal 
investigator and trial statisticians are available to review data 
with the DSMB.  Outcome results must not be discussed 
during this open session.  Following the open session, the 
DSMB may hold a closed session including members of the 
board and appropriate members of the coordinating center 
and the statistician handling the trial.  The third phase of 
each meeting is an executive session involving only voting 
DSMB members and may be held to allow the DSMB to 
discuss general conduct of the trial and all outcome results, 

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including toxicities, adverse events, and other protocol 
events/problems, to develop recommendations, and to take 
votes as necessary.  The DSMB recommendation and the 
SKCCC action plan, if any, will be forwarded together to the 
IRB, NIH, FDA and sponsor as appropriate, providing the 
opportunity for their opinions and recommendations.  In no 
cases will the DSMB recommendations be taken as binding, 
provided reasons for an alternative course of action are 
endorsed by the CRC and investigator. 
 
2.2.9.5. Following each study review, the DSMB will recommend 
either: 
2.2.9.5.1. Continuation of the trial as is using the current 
protocol and statistical plan. 
 
2.2.9.5.2. Continuation of the project with modifications as 
outlined by the board 
 
2.2.9.5.3. Immediate suspension of the trial for safety 
reasons with a recommended plan of follow-up to 
minimize subject harm. 
 
2.2.9.5.4. Placing a clinical hold on a trial.  Subjects may 
continue on their assigned treatments until 
clarifications requested by the board are resolved. 
 
2.2.9.5.5. Termination of the trial because of 1) treatment 
effectiveness demonstrated earlier than expected 
(“early stopping”), 2) futility of further accrual to 
meet the trials goal, 3) discovery of new 
information that precludes completion of the trial, 
or 4) structural problems in trial execution that are 
not amenable to correction. 
 
 
3. COMPLIANCE WITH PROBLEM/EVENT REPORTING REQUIREMENTS 
 
3.1. Problems and Events include: on-site and off-site adverse events, injuries, 
side effects, breaches of confidentiality, or other problems that may occur 
any time during or after the research study 
 
3.2. Reporting of problems/events involving risk to participants or others in all 
clinical trials at SKCCC is conducted in accordance with all appropriate 
federal regulations and guidelines as well as Institutional policies and 
guidelines.  In addition, problem/event reporting procedures are specified in 
detail in each protocol, depending upon the type of study, the severity of the 
problem/.event, the study sponsor, and the existence of an IND/IDE. 
 

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3.3. Reporting Guidelines followed at SKCCC 
 
3.3.1. NCI 
3.3.1.1. 
CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements3  
3.3.1.2. 
NCI, Data and Safety Monitoring Guidelines4 
 
3.3.2. FDA 
3.3.2.1. 
Information for FDA-Regulated Industry5 
3.3.2.2. 
21 CFR 312.32 IND Safety Reports6 
3.3.2.3. 
21 CFR 812.150 IDE Safety Reports7 
 
3.3.3. Johns Hopkins Institutional Review Board (JHM IRB) 
3.3.3.1. 
Protocol Event And Protocol Deviation Reporting 
Requirements8 
 
3.3.4. Western Institutional Review Board (WIRB) 
3.3.4.1. 
WIRB Protocol Deviations & Violations / Unanticipated 
Problems Reporting System9  
 
 
4. MULTI-SITE CLINICAL TRIALS 
 
Principal Investigators from the SKCCC may invite Investigators from other 
institutions to participate in a clinical trial.  In these cases, the Principal 
Investigator is ultimately responsible for the conduct of the trials at all 
participating sites, and is required to establish a Coordinating Center to manage 
all trial related documents and data.  The SKCCC Coordinating Center SOPs and 
Operations Manual were developed to assist investigator when they are 
responsible for the coordinating center of a clinical. 
 
The Operations Manual is available in Appendix C.  The manual describes the 
processes and oversight that SKCCC coordinating centers have in place for 
collecting and reporting AEs to all necessary regulatory agencies and co-
investigators at participating institutions. 
 
 
 

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Appendix A: Review of Reportable Protocol Events 
 
Full DSMC 
Committee
Principal 
Investigator
Institutional 
Review 
Board
DSMC Chair
Substantial
Increased
Risk
Expedited DSMC 
Committee
No 
Increased 
Risk
Flow Diagram: Review of Reportable Protocol Events at 
                                   Sidney Kimmel Comprehensive Cancer Center
Please Note: Copies of Reportable Events will be held in the CRO for DSMC Review.  Originals will be 
forwarded to the IRB for parallel review.  DSMC / CRO will notify the IRB of any recommended action.
Clinical Research 
Office
DSMC
Recommendations
(If any)
 

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Appendix B: Review of Amendments 
No increased risk
No substantial 
change to 
scientific merit
Flow Diagram: Amendment Reviews at 
                                                                Sidney Kimmel Comprehensive Cancer Center
Please Note:  Copies of amendments will be held in the CRO for Committee Review.  Originals will be 
forwarded to the IRB for parallel review. DSMC / CRO will notify the IRB of any recommended action.
Full DSMC 
Committee
Principal 
Investigator
Institutional 
Review 
Board
DSMC Chair
Clinical Review 
Committee (CRC)
Substantial
increased
risk
Expedited DSMC 
Committee
Clinical Research 
Office
Substantial change
to scientific merit
Comments
Recommendations
Comments
Recommendations
Approve or
Disapprove
 

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1 http://grants.nih.gov/grants/guide/notice-files/not98-084.html, and 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html 
 
2 http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1 
 
3 NCI Reporting Guidelines at http://ctep.gov/reporting 
 
4 http://cancertrials.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines/page5 
 
5 http://www.fda.gov/oc/industry/default.htm 
 
6 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32 
 
7 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=812.150 
 
8 http://irb.jhmi.edu/Guidelines/Event_Deviation_Reporting.html 
 
9 http://www.wirb.com/shell.php?content=content/inv_adverse_events