A Randomized Phase II Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors
Phase: PHASE2
Conditions: Gastrinoma, Glucagonoma, Insulinoma, Islet Cell Carcinoma, Pancreatic Polypeptide Tumor, Recurrent Islet Cell Carcinoma, Somatostatinoma
Sponsor: ECOG-ACRIN Cancer Research Group

E2211 
 
1 
A Randomized Phase II Study of Temozolomide or 
Temozolomide and Capecitabine in Patients with 
Advanced Pancreatic Neuroendocrine Tumors 
STUDY CHAIR: Pamela L. Kunz, MD 
STUDY CO-CHAIRS: Halla S. Nimeiri, MD 
 Al B. Benson III, MD 
STUDY STATISTICIAN: Paul J. Catalano, ScD 
PATHOLOGY CO-CHAIR: Teri Longacre, MD 
LABORATORY STUDIES CO-CHAIR: Iris Schrijver, MD 
IMAGING CO-CHAIRS: Terry Wong, MD, PhD 
Daniel L. Rubin, MD, MS 
GASTROINTESTINAL COMMITTEE CO CHAIRS: Al Benson, MD 
 Terry Wong, MD, PhD 
ALLIANCE CO-CHAIR: Diane Reidy-Lagunes, MD 
SWOG CO-CHAIR: Jonathan Strosberg, MD 
Version Date:  June 29, 2015 
NCI Update Date:  April 29, 2015 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
US Sites only 
 
April 11, 2013 
ALLIANCE / Alliance for Clinical Trials in Oncology  
Addendum #1 - Incorporated Prior to Activation 
NRG / NRG Oncology Foundation, Inc 
 
Update #1 - Incorporated Prior to Activation 
SWOG / SWOG 
 
Addendum #2 – 2/14 
 
 
Addendum #3 – 6/14 
 
 
Update #2 – 5/15 
 
 
Addendum #4 – 7/15 
 
 
Agents 
IND# 
NSC# 
Supply 
Temozolomide 
N/A 
NSC 362856 
Commercially Available 
Capecitabine 
N/A 
NSC 712807 
Commercially Available 
Rev. 6/14 
Rev. 6/14 
Rev. 6/14 

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Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Rationale for selected approach and trial design ..................................... 7 
1.2 
Clinical relevance of study ........................................................................ 8 
1.3 
All relevant data that justify the use of the control and experimental 
arms........................................................................................................... 9 
1.4 
Rationale for Laboratory Research Studies ............................................. 10 
2. Objectives ......................................................................................................... 12 
2.1 
Primary Endpoints ................................................................................... 12 
2.2 
Secondary Endpoints ............................................................................... 12 
3. Selection of Patients ......................................................................................... 13 
3.1 
Eligibility Criteria ..................................................................................... 13 
4. Randomization Procedures ............................................................................... 17 
4.1 
Protocol Number ..................................................................................... 19 
4.2 
Investigator Identification ....................................................................... 20 
4.3 
Patient Identification .............................................................................. 20 
4.4 
Eligibility Verification .............................................................................. 20 
4.5 
Stratification Factors ............................................................................... 20 
4.6 
Additional Requirements ........................................................................ 20 
4.7 
Instructions for Patients who Do Not Start Assigned Protocol Treatment21 
5. Treatment Plan ................................................................................................. 22 
5.1 
Administration Schedule ......................................................................... 22 
5.2 
Adverse Event Reporting Requirements ................................................. 23 
5.3 
Dose Modifications ................................................................................. 27 
5.4 
Supportive Care ....................................................................................... 30 
5.5 
Duration of Therapy ................................................................................ 30 
5.6 
Duration of Follow-up ............................................................................. 30 
6. Measurement of Effect ..................................................................................... 31 
6.1 
Antitumor Effect – Solid Tumors ............................................................. 31 
7. Study Parameters .............................................................................................. 38 
7.1 
Therapeutic Parameters .......................................................................... 38 
8. Drug Formulation and Procurement ................................................................. 41 
8.1 
Temozolomide ........................................................................................ 41 
8.2 
Capecitabine............................................................................................ 43 
9. Statistical Considerations .................................................................................. 45 
9.1 
Expected Accrual Pattern ........................................................................ 45 
9.2 
Treatment Assignment ............................................................................ 45 
9.3 
Statistical Design and Efficacy Monitoring .............................................. 45 
9.4 
Safety Monitoring ................................................................................... 46 
9.5 
Gender and Ethnicity .............................................................................. 47 

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10. Imaging Studies ................................................................................................. 48 
10.1 Standard-of-Care Imaging Time Points and Minimum Preferred Phases48 
10.2 Images Submission .................................................................................. 48 
11. Specimen Submission Requirements ................................................................ 50 
11.1 Specimen Preparation Guidelines ........................................................... 50 
11.2 Shipping Procedures ............................................................................... 51 
11.3 ECOG-ACRIN Sample Tracking System .................................................... 52 
11.4 Use of Specimens in Research ................................................................ 53 
11.5 Sample Inventory Submission Guidelines ............................................... 53 
12. Laboratory Research Studies ............................................................................ 54 
12.1 Pathology Review .................................................................................... 54 
12.2 Evaluation of MGMT status by IHC ......................................................... 54 
12.3 Evaluation of MGMT status by promoter methylation ........................... 54 
12.4 Statistical Considerations ........................................................................ 55 
12.5 Lab Data Transfer Guidelines .................................................................. 55 
13. Electronic Data Capture .................................................................................... 56 
14. Patient Consent and Peer Judgment ................................................................ 56 
15. References ........................................................................................................ 56 
Appendix I  Pathology Submission Guidelines ........................................................ 58 
Appendix II  Patient Thank You Letter ..................................................................... 63 
Appendix III  Patient Pill Calendar ........................................................................... 64 
Appendix IV  ECOG Performance Status ................................................................. 67 
 

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NCI Update Date: April 29, 2015 
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STUDY CHAIR 
STUDY CO-CHAIR 
 
Pamela L. Kunz, MD 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305-5826 
P: 650-725-8738 
F: 650-498-4696 
E: pkunz@stanford.edu 
 
Halla Nimeiri, MD 
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University/Feinberg School of 
Medicine 
676 North St. Clair 
Suite 850 
Chicago, IL 60611 
P: 312-695-6180 
F: 312-695-6189 
E: hnimeiri@nmff.org 
 
 
 
 
ALLIANCE CO-CHAIR 
SWOG CO-CHAIR 
 
Diane Reidy-Lagunes, MD 
Memorial Sloan Kettering Cancer Center 
3300 E66th Street, Room 1034 
New York, NY 10065 
P: 646-888-4185 
F: 646-888-4257 
E: reigdyd@mskcc.org 
 
 
 
Jonathan Strosberg, MD 
Moffit Cancer Center, FOB 2nd Floor 
12902 Magnolia Dr. 
Tampa, FL 33612 
P: 813-745-6392 
F: 813-745-7229 
E: jonathan.strosberg@moffitt.org 
 
 
STUDY CHAIR LIAISON (SCL) 
 
 
Benjamin Priestley, MPH 
ECOG-ACRIN Clinical Research 
Coordinator 
800 Welch Road, MC5757 
Palo Alto, CA 94304 
P: 650-723-2990 
F: 650-724-4042 
E: ben.priestley@stanford.edu 
 
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient enrollment 
section of the protocol for instructions on 
using the Oncology Patient Enrollment 
Network (OPEN) which can be accessed 
at https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com... 
Data collection for 
this study will be 
done exclusively 
through Medidata 
Rave.  Please see 
the data submission 
section of the 
protocol for further 
instructions.  
The most recent version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related questions) contact the Study PI of 
the Coordinating Group. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website  
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org 
 
 
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Schema 
R
A
N
D
O
M
I
Z
E
Arm A1
Temozolomide 200 mg/m2 po QD days 1-5
CT scans every 3 cycles
Arm B1
Capecitabine 750 mg/m2 po BID days 1-14
Temozolomide 200 mg/m2 po QD days 10-14
CT scans every 3 cycles
Cycle = 28 days
All doses are based on actual body weight.
Stratify
Prior everolimus
Prior sunitinib
Concurrent octreotide
Accrual = 145
1. Treatment will continue for up to 13 cycles (approximately 1 year).
Long-term Follow-up
Long-term Follow-up
 

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1. 
Introduction 
1.1 
Rationale for selected approach and trial design 
Patients with advanced pancreatic neuroendocrine tumors (NETs) currently have 
few treatment options that yield objective radiographic tumor regression. Recent 
studies evaluating everolimus1 and sunitinib2 in this patient population have 
demonstrated prolongation of progression-free survival (PFS) compared to 
placebo, but overall tumor response rates (by RECIST) with these agents are 
less than 10%.  
Historical studies reporting the highest response rates (RRs) and longest PFS 
intervals include regimens with cytotoxic chemotherapy. In an initial randomized 
study of 106 patients, Moertel et al. reported activity associated with the 
combination of streptozocin and doxorubicin in patients with advanced islet-cell 
tumors.3 The RR associated with this regimen was reported to be 69% and PFS 
was 20 months. However, because of the use of non-standard response criteria, 
the true objective radiologic response rate was likely much lower. Retrospective 
series have reported overall response rates of 6-39% and PFS of 4-18 months 
associated with streptozocin-based regimens in pancreatic NETs.4-6 While clearly 
associated with activity, the combination of streptozocin and doxorubicin is also 
associated with considerable toxicity, including myelosuppression, asthenia, and 
renal insufficiency, precluding its routine use in this disease. 
Recent retrospective series and small, prospective phase II studies, described 
below, suggest that temozolomide is similarly active but less toxic than 
streptozocin-based therapy in patients with pancreatic NETS. Furthermore, like 
streptozocin, temozolomide is an alkylating agent that induces methylation at the 
O6 position of guanine, suggesting that expression of the DNA repair enzyme 
methyl guanine methyltransferase (MGMT) may correlate with treatment 
response to temozolomide. Based on these studies, temozolomide-based 
therapy is listed on NCCN guidelines and is included in the Medicare 
compendium for use in pancreatic NETs. There is, nevertheless, little consensus 
on the optimal temozolomide regimen to use in patients with pancreatic NETs, 
nor has temozolomide been evaluated prospectively in a multi-institutional setting 
in patients with advanced pancreatic neuroendocrine tumors.  
The proposed study will provide prospective data on response rates and 
progression-free survival associated with temozolomide or temozolomide in 
combination with capecitabine, and will also assess the relative efficacy of these 
two regimens. The study further explores whether, as has been shown in 
glioblastoma, MGMT deficiency as determined by promoter methylation and 
immunohistochemistry, predicts response in patients with pancreatic NETs 
treated with these regimens.  
We propose a multi-institutional randomized study of temozolomide administered 
with or without capecitabine in advanced pancreatic neuroendocrine tumor 
patients (using dosing as per the Strosberg regimen16). The principal objective of 
the study will be to evaluate PFS associated with temozolomide alone or 
temozolomide and capecitabine in patients with advanced pancreatic 
neuroendocrine tumors.  Secondary objectives will be to assess the tumor 
response rates, overall survival, and toxicity associated with these regimens. A 

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correlative study will assess whether MGMT deficiency is associated with 
temozolomide response. 
1.2 
Clinical relevance of study  
Streptozocin-based therapy was associated with a survival benefit in one 
randomized study of pancreatic NETs3 and is currently the only FDA-approved 
cytotoxic agent for use in this disease. However, because of its potential for 
toxicity and production shortage, its use in pancreatic NETs is not widespread. 
Both retrospective and small, prospective studies suggest that temozolomide-
based regimens are an active and potentially less toxic oral alternative to 
streptozocin-based therapy in pancreatic NETs. Based on these studies, 
temozolomide is increasingly used for this indication and is included in both 
NCCN guidelines and the Medicare compendium.  
There have been no prospective studies evaluating the antitumor activity of 
temozolomide alone in patients with neuroendocrine tumors. Similarly, the 
current common use of a temozolomide/capecitabine combination regimen is 
based on data from a 30-patient, retrospective, single-institution series; the 
temozolomide/capecitabine regimen has not been formally evaluated in a 
prospective phase II study. A need to formally evaluate the activity of 
temozolomide in pancreatic neuroendocrine tumors, and to compare single agent 
vs. combination therapy in this disease was highlighted in the NCI 
Neuroendocrine Tumor Clinical Trials Planning Meeting (CTPM). 
The currently proposed study responds to this recommendation. We note that 
temozolomide alone is considered the reference arm for this study, despite the 
absence of prospective data for this combination in neuroendocrine tumors. We 
considered several alternative options in making this decision. Ideally, a placebo 
arm would be used as a reference, as was done in the RADIANT 3 and sunitinib 
randomized studies. However, a placebo was not considered appropriate or 
feasible in light of the fact that temozolomide is included in treatment compendia 
based on retrospective and small prospective series demonstrating antitumor 
activity. A streptozocin control arm was not considered feasible based on toxicity 
concerns, as well as, concerns regarding drug supply. A control arm of 
everolimus or sunitinib was considered; however, there was little enthusiasm for 
directly comparing a cytotoxic chemotherapy regimen to a targeted agent. 
Indeed, a current treatment paradigm is starting with targeted therapy in most 
patients, and using a cytotoxic regimen as a salvage therapy. A goal of this study 
is to establish clear prospective data for two promising cytotoxic regimes and to 
gain a preliminary assessment of their relative activity.  
Additionally, preliminary data described in the correlative section of this proposal 
suggest that the anti-tumor activity of temozolomide is associated with the DNA 
repair enzyme MGMT. The identification of biomarkers predictive of tumor 
response was an additional recommendation of the Neuroendocrine Tumor 
CTPM. Data derived from studies in glioblastoma strongly suggest a correlation 
between MGMT silencing and response to temozolomide-based therapy, as does 
retrospective data in pancreatic neuroendocrine tumors. The correlative 
component of this study will assess whether MGMT promoter methylation status 
is associated with the activity of temozolomide-based therapy. A positive 
association could provide justification for the use of MGMT expression as a 

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determinant for which pancreatic neuroendocrine tumor patients should receive 
temozolomide-based treatment. 
1.3 
All relevant data that justify the use of the control and experimental arms 
Antitumor activity associated with temozolomide in neuroendocrine tumors has 
been reported in a number of retrospective series. In a retrospective series of 36 
patients treated with temozolomide monotherapy, tumor regression was 
observed in 31% of bronchial carcinoid tumors and 8% of pancreatic 
neuroendocrine tumors; median time to progression (TTP) was 7 months for all 
patients.7  In a series of 97 patients, 18 of 53 patients with pancreatic NETs 
(34%) achieved a partial or complete response to temozolomide-based 
therapies; median PFS was 13.6 months for those patients.8  A third 
retrospective series of 21 patients treated with temozolomide monotherapy 
demonstrated responses in 25% of pancreatic NETs, median PFS was 9.1 
months.9 
Temozolomide has additionally been investigated prospectively in small phase II 
studies of patients with neuroendocrine tumors, though always in combination 
with other agents.  In an initial study, 29 patients with metastatic neuroendocrine 
tumors were treated with a combination of temozolomide, administered at a dose 
of 150 mg/m2 for 7 days, every other week, and thalidomide at doses of 50 to 400 
mg daily; this combination was associated with objective tumor responses in 5/11 
patients.  Median PFS was not reached.10  A subsequent phase II study 
evaluated the combination of temozolomide and bevacizumab in 34 patients with 
neuroendocrine tumors (15 pancreatic, 19 carcinoid).11  Patients received 
temozolomide, 150 mg/m2/day po for 7 days every other week, and 
bevacizumab, 5 mg/kg IV every other week. Due to anticipated lymphopenia, 
patients also received prophylaxis with trimethoprim/sulfamethoxazole (1 DS 
tablet q MWF). Objective tumor responses were observed in 33% of patients with 
pancreatic neuroendocrine tumors with median PFS of 14.3 months for these 
patients (M Kulke, personal communication).  In a third prospective study a 
regimen of temozolomide and everolimus was associated with an overall tumor 
response rate of 35% in patients with advanced pancreatic NET, median PFS 
was not reported.12   
Interestingly, pre-clinical and early clinical evidence suggest that capecitabine 
may be synergistic with temozolomide.13,14  In a series of 17 patients with 
pancreatic NETs, combination therapy with temozolomide and capecitabine was 
associated with a tumor response rate of 59%, median PFS was not reported.15  
A recent single-institution retrospective study by Strosberg et al. reported 
response rates of 70% and a median PFS of 18 months in 30 patients with 
advanced pancreatic NETs16.  In this study, temozolomide was administered at a 
dose of 200 mg/m2 days 10-14, and capecitabine was administered at a dose of 
750 mg/m2 BID d1-14. The combination and specific dosing schedules reported 
were very well tolerated with only 4 patients experiencing grade 3 or 4 adverse 
events (anemia, thrombocytopenia, elevated AST and elevated ALT).  The most 
common grade 1 and 2 adverse events were fatigue, nausea, myelosuppression 
and hand-foot syndrome. Based on this study, the combination of temozolomide 
and capecitabine has become popular and commonly used in patients with 
advanced pancreatic neuroendocrine tumors.  

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Taken together, these prospective and retrospective studies suggest that 
temozolomide-based therapy is comparable to streptozocin-based regimens and 
might reasonably be expected to be associated with an overall median PFS of 7-
14 months in patients with advanced pancreatic NET. To date, no prospective 
studies have evaluated the antitumor activity of temozolomide alone in pancreatic 
neuroendocrine tumors, nor have any prospective studies formally evaluated the 
combination of temozolomide and capecitabine in this setting. As noted above, 
despite the absence of prospective data, temozolomide alone is considered a 
reference arm in this study based on the strength of prior retrospective and 
limited prospective data demonstrating activity with temozolomide containing 
regimens in this setting, and the inclusion of temozolomide in treatment 
compendia. Strong historical control data from the placebo arms of the 
randomized studies of everolimus (showing a PFS of 5.5 months)1 and sunitinib 
(showing a PFS of 4.5 months)2 should provide a reasonable basis for 
assessment of the antitumor activity associated with temozolomide alone. 
Additionally, these two regimens have never been formally compared.  
The proposed study will compare the temozolomide/capecitabine combination 
(as reported by Strosberg and colleagues), in which temozolomide is 
administered during a 28 day cycle at a dose of 200 mg/m2 days 10-14 of 28 day 
cycles and capecitabine is administered at a dose of 750 mg/m2 BID days 1-14 of 
28 day cycles, to single agent temozolomide. We note that prior prospective 
studies of temozolomide have used a dose-intense regimen of 150 mg/m2 for 7 
days, administered every other week, but that this regimen has been associated 
with significant lymphopenia and need for prophylaxis. To reduce this risk, and to 
facilitate comparison with the combination regimen, we have elected to use a 
single-agent temozolomide regimen of 200 mg/ m2 days 1-5 of a 28-day regimen 
in our study. We further plan to limit the total duration of treatment to 13 cycles 
(approximately 1 year). 
1.4 
Rationale for Laboratory Research Studies 
1.4.1 
Evaluation of MGMT status by Immunohistochemistry (IHC) 
Temozolomide is an alkylating agent initially developed as an oral and 
more easily tolerated alternative to dacarbazine. The cytotoxic effect 
of temozolomide has been attributed to its ability to induce DNA 
methylation at the O6 position of guanine. Methylation of guanine 
results in DNA mismatch, ultimately resulting in apoptosis and tumor 
cell death.17 The sensitivity of tumor cells to alkylating agents, 
including temozolomide, has been associated with decreased levels 
of the DNA repair enzyme, O6-methylguanine DNA methyltransferase 
(MGMT), which, through its ability to restore DNA to its normal form, 
can prevent chemotherapy-induced cell death.18 Decreased levels of 
MGMT have been associated with clinical benefit and enhanced 
survival in melanoma and glioblastoma patients treated with 
temozolomide.19-23 
In a study by Kulke, et al., 97 archival neuroendocrine tumors 
specimens were evaluated for MGMT deficiency by 
immunohistochemistry.8 Among 37 pancreatic neuroendocrine tumors 
evaluated, 19 (51%) were MGMT deficient. Non-functional tumors 
included similar proportions of MGMT intact and MGMT deficient 

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tumors. Three of 10 insulinomas were MGMT deficient; both 
gastrinomas and the single evaluated glucagonoma were also MGMT 
deficient. In contrast, MGMT was present in all 60 carcinoid tumors 
(20 typical bronchial carcinoids, 20 atypical bronchial carcinoids and 
20 small intestine carcinoids) evaluated.   Among 21 patients with 
evaluable tumor tissue who had also received treatment with 
temozolomide, 4 of 5 patients with MGMT-deficient tumors (all 
pancreatic NETs) and 0 of 16 patients with MGMT-intact tumors 
responded to treatment (p=0.001). 
1.4.2 
Evaluation of MGMT status by Promoter Methylation 
The clinical utility of assessing MGMT promoter methylation status 
was first demonstrated in patients with gliomas. Gliomas are the most 
common primary brain tumors. Grade IV gliomas, also known as 
glioblastoma multiforme (GBM) are highly malignant tumors that 
account for almost a third of primary brain tumors in adults. Patients 
with gliomas that exhibited promoter methylation of the MGMT gene 
showed modestly longer survival after treatment with alkylating 
chemotherapeutics than patients whose gliomas did not show MGMT 
promoter methylation.  Clinical trials to evaluate the use of MGMT 
promoter methylation to predict response to alkylating agents have 
also been designed for patients with acute myeloid leukemia, 
neuroendocrine tumors, and other cancers. 
The mechanisms of MGMT regulation in neuroendocrine tumors 
remain unknown. Silencing of the MGMT gene by CpG island 
promoter methylation is a common mechanism of MGMT regulation in 
other tumor types. In patients with glioblastoma, MGMT promoter 
methylation is associated with improved survival and benefit from 
temozolomide.22,24 Limited studies of CpG island methylation in 
neuroendocrine tumors however, have found either no significant 
difference in MGMT promoter methylation rates between carcinoid 
and pancreatic neuroendocrine tumors, or higher rates of promoter 
methylation in carcinoid tumors compared to pancreatic 
neuroendocrine tumors.25,26 
Further studies to evaluate whether promoter methylation is a 
common MGMT silencing mechanism in neuroendocrine tumors, and 
whether promoter methylation correlates with immunohistochemical 
absence of MGMT, are warranted. 

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2. 
Objectives 
2.1 
Primary Endpoints 
2.1.1 
To evaluate PFS associated with temozolomide alone or 
temozolomide and capecitabine in patients with advanced pancreatic 
neuroendocrine tumors.  
2.2 
Secondary Endpoints 
2.2.1 
To evaluate response rates (RR) associated with temozolomide alone 
or temozolomide and capecitabine treatment in patients with 
advanced pancreatic neuroendocrine tumors. 
2.2.2 
To evaluate overall survival (OS) associated with temozolomide alone 
or temozolomide and capecitabine in patients with advanced 
pancreatic neuroendocrine tumors.  
2.2.3 
To evaluate the toxicity associated with temozolomide alone or 
temozolomide and capecitabine treatment in patients with advanced 
pancreatic neuroendocrine tumors. 
2.2.4 
To evaluate the usefulness of MGMT status (by IHC and promoter 
methylation) for predicting response in pancreatic neuroendocrine 
tumor patients treated with either temozolomide or temozolomide and 
capecitabine. 
2.2.5 
To bank radiology images for evaluation of quality, reproducibility, and 
compliance with CT methodology. 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F) _______________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Patient must have histologically or pathologically confirmed locally 
unresectable or metastatic low or intermediate grade pancreatic 
neuroendocrine tumor, excluding small cell carcinoma. 
3.1.2 
Patient must have measurable disease by RECIST 1.1 criteria as 
defined in Section 6.1.2. Baseline measurements and evaluations of 
all sites of disease must be obtained ≤ 4 weeks prior to randomization 
and must be acquired by multiphasic CT or contrast MRI. 
3.1.3 
 Patient must have documented disease progression, and date of last 
documented disease progression must be within 12 months from date 
of randomization. 
3.1.4 
Patient must not have received prior temozolomide, DTIC, 
capecitabine, or 5-FU therapy. 
3.1.5 
Prior everolimus and/or sunitinib therapy is allowed, so long as it was 
discontinued ≥ 4 weeks prior to randomization. 
3.1.6 
Concurrent somatostatin analogues are allowed provided that the 
patient 1) has been on a stable dose (+/- 10mg) for 8 weeks and 2) 
has documented disease progression on that dose. 
3.1.7 
Chemoembolization is allowed if ≥ 4 weeks from study entry. There 
are 3 possible scenarios: 
3.1.7.1 
If patient has hepatic disease only: they need to have 
progressed in the liver since chemoembolization and have 
measureable disease by RECIST 1.1 in order to be 
eligible. 
3.1.7.2 
If patient has hepatic and extrahepatic disease: they will 
need to have progressed inside OR outside the liver and 
_____
_____
Rev. 6/14 
Rev. 6/14 
Rev. 7/15 
_____
_____
_____

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have measureable disease by RECIST 1.1 in order to be 
eligible. 
3.1.8 
Patients may not be receiving any other investigational agents while 
on study treatment. 
3.1.9 
Patients may not be receiving Coumadin while on treatment.  Other 
anticoagulants are allowed. 
3.1.10 
Patients must have normal organ and marrow function as defined 
below within ≤ 14 days prior to randomization: 
3.1.10.1 
Leukocytes ≥ 3,000/mm3 
Leukocytes________ Date:________ 
3.1.10.2 
Absolute neutrophil count ≥ 1,500/mm3 
Neutrophil count:_______ Date:________ 
3.1.10.3 
Hemoglobin ≥ 9 g/dL 
Hemoglobin:________ Date:________ 
3.1.10.4 
Platelets ≥ 100,000/mm3 
Platelets: _________ Date:________ 
3.1.10.5 
Total bilirubin ≤ institutional upper limit of normal (ULN) or 
≤ 1.5 X institutional ULN (if the patient has liver 
metastases). 
ULN: _________ Bilirubin:_________ Date:________ 
3.1.10.6 
AST(SGOT)/ALT(SGPT) ≤ 3 X institutional ULN or (≤ 5 X 
institutional ULN if the patient has liver metastases).  
ULN: _________ AST_________ Date:________ 
ULN: _________ ALT_________ Date:________ 
3.1.10.7 
Serum Creatinine ≤ 1.5 X institutional ULN  
ULN: _________ Creatinine:_________ Date:________ 
3.1.11 
Patient must be at least 18 years of age. 
3.1.12 
Patient must have ECOG performance status 0-1. 
3.1.13 
Patient must have life expectancy ≥ 12 weeks. 
3.1.14 
Patients with either clinically apparent central nervous system 
metastases or carcinomatous meningitis are ineligible. 
3.1.15 
Patients must NOT have active or uncontrolled infection or serious 
medical or psychiatric illness. 
3.1.16 
Patients must NOT have history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to 
temozolomide or capecitabine. 
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
_____
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3.1.17 
Patient must NOT have absorption issues that would limit the ability to 
absorb study agents.  
3.1.18 
Patients with a history of the following within ≤ 12 months of study 
entry are not eligible. 
• 
Arterial thromboembolic events: Yes____ Date:______ No:_____ 
• 
Unstable angina: Yes_____ Date:_____ No:_____ 
• 
Myocardial Infarction: Yes_____ Date:______ No:______ 
3.1.19 
Patients with symptomatic peripheral vascular disease are not eligible. 
3.1.20 
Patients must NOT have previous or concurrent malignancy.  
Exceptions are made for patients who meet any of the following 
conditions: 
• 
Non-melanoma skin cancer, in situ cervical cancer, or breast 
cancer in situ. 
OR 
• 
Prior malignancy completely excised or removed and patient has 
been continuously disease free for > 5 years. 
OR 
• 
Prior malignancy cured by non-surgical modalities and patient has 
been continuously disease free for > 5 years. 
Date of last evidence disease:___________ 
3.1.21 
Women must not be pregnant or breast-feeding due to potential harm 
to fetus from temozolomide and/or capecitabine. 
All females of childbearing potential must have a blood test or urine 
study within ≤ 2 weeks prior to randomization to rule out pregnancy. A 
female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female of childbearing potential? ______ (Yes or No)  
Date of blood test or urine study: _________________ 
3.1.22 
Women of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of 
contraception or to abstain from sexual intercourse for the duration of 
their participation in the study. Should a woman become pregnant 
while participating in this study, she should inform her treating 
physician immediately. If a man impregnates a woman while 
participating in this study, he should inform his treating physician 
immediately.  
_____
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3.1.23 
Patient must be able to swallow pills. 
3.1.24 
Patient must be able to tolerate CT or MR imaging including contrast 
agents as required for their treatment and the protocol. 
 
 
 
 
 
 
Physician Signature 
 
Date 
 
OPTIONAL: This signature line is provided for use by institutions wishing to use the 
eligibility checklist as source documentation. 
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4. 
Randomization Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU) 
IRB Approval: 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU member web site by entering credentials 
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at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically 
load to RSS. 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E2211 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E2211 
• 
Click on the Site Registration Documents link 
Requirements for E2211 site registration: 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB) 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
FAX: (215) 569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Required Protocol Specific Regulatory Documents 
1.  CTSU Regulatory Transmittal Form. 
2.  Copy of IRB Informed Consent Document. 
NOTE:  Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
consent document must be justified in writing by the investigator and 
approved by the IRB. 
3.  A.  CTSU IRB Certification Form. 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
Or 
C.  IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 

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• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patients must not start protocol treatment prior to randomization. 
Treatment should start within ten working days after randomization.  
Patient randomization can occur only after pre-treatment evaluation is complete, 
eligibility criteria have been met, and the study site is listed as ‘approved’ in the CTSU 
RSS. Patients must have signed and dated all applicable consents and authorization 
forms.   
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at <https://eapps-
ctep.nci.nih.gov/iam/index.jsp>) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.  
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
randomization and treatment information. Please print this confirmation for 
your records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.   
The following information will be requested: 
4.1 
Protocol Number  
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4.2 
Investigator Identification  
4.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2 
Investigator’s name (NCI number) 
4.2.3 
Cooperative Group Credit 
4.2.4 
Credit Investigator 
4.2.5 
Protocol specific contact information 
4.3 
Patient Identification  
4.3.1 
Patient’s initials (first and last) 
4.3.2 
Patient’s Hospital ID and/or Social Security number 
4.3.3 
Patient demographics 
4.3.3.1 
Gender 
4.3.3.2 
Birth date 
4.3.3.3 
Race 
4.3.3.4 
Ethnicity 
4.3.3.5 
Nine-digit ZIP code 
4.3.3.6 
Method of payment 
4.3.3.7 
Country of residence 
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3.   
4.5 
Stratification Factors 
Patients will be stratified according to the following factors for purposes of 
balancing arms: 
4.5.1 
Prior everolimus:  Yes v. No 
4.5.2 
Prior sunitinib:  Yes v. No 
4.5.3 
Concurrent octreotide:  Yes v. No 
4.6 
Additional Requirements  
4.6.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.6.2 
The IRB-approved consent must allow patients the option to provide 
specimens to for use in undefined future research.   
4.6.3 
Biological samples to be submitted as indicated in Section 11.  
4.6.4 
Imaging studies are to be submitted as outlined in Section 10. 
4.6.5 
Data collection for this study will be done exclusively in Medidata 
Rave. Study staff will receive an invitation to join the study in Rave 
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after evidence of IRB approval is submitted to RSS. Access to the trial 
in Rave is granted through the iMedidata application to all persons 
with the appropriate roles in RSS after IRB approval is obtained. To 
access iMedidata/Rave the site user must have an active CTEP IAM 
account (https://eapps-ctep.nci.nih.gov/iam). In addition, site users 
that are a member of ECOG-ACRIN must have the mapped ECOG-
ACRIN roles or explicit Rave roles (Rave CRA, Read-Only, Site 
Investigator) in RSS at the enrolling site. Site users that are not 
members of ECOG-ACRIN must have the Rave roles on the CTSU 
roster at the enrolling sites. The Site Administrator or Data 
Administrator at the enrolling site may assign the appropriate roles 
from the Site Roles tab on the CTSU website. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent study 
invitation e-mails from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be listed in the upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave 
accounts will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on 
the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.7 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E2211 Forms Completion Guidelines. 

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5. 
Treatment Plan 
5.1 
Administration Schedule 
One cycle = 28 days 
All doses are based on actual weight. If there is a < 5% change in Body Surface 
Area (BSA), keep the doses the same. If there is a ≥ 5% change in BSA, a new 
dosing weight and BSA should be set and used for dose calculations. 
• 
Temozolomide 
• 
The temozolomide dose will be capped at 400 mg daily. The calculated 
dose by BSA will be rounded down to minimize the number of capsules 
required. The treating investigator should use their best judgment to meet 
these guidelines.  
• 
Temozolomide sould be taken by mouth at night after fasting from solid 
food for two hours. Temozolomide capsules must not be crushed and 
must be administered whole.  
• 
Temozolomide missed doses will not be made up and patients should not 
double-up on missed doses during treatment.  
• 
Ondansetron or other anti-emetic is strongly suggested as a 
premedication 30-60 minutes prior to temozolomide. Otherwise, anti-
emetics, anxiolytics, and analgesics may be provided at physicians’ 
discretion.  
• 
Capecitabine 
• 
The calculated total daily capecitabine dose by BSA will be rounded down 
to allow doses using 500 mg tablets. Investigators should approximate 
the calculated dose based on the pill size available while rounding down 
to minimize the number of capsules required. The treating investigator 
should use their best judgment to meet these guidelines.  
• 
Capecitabine should be taken morning and night, with at least 8 hours 
between each dose. Capecitabine tablets should be swallowed with water 
within 30 minutes after a meal.  
• 
Capecitabine missed doses will not be made up and patients should no 
double-up on missed doses during treatment.  
NOTE:  
Monitor CBC and platelet count prior to drug administration. 
5.1.1 
ARM A 
Temozolomide 200 mg/m2 po QD days 1-5 
Repeat cycles every 28 days  
Maximum duration of treatment 13 cycles (approximately 1 year) 
5.1.2 
ARM B 
Capecitabine 750 mg/m2 po BID days 1-14 
Temozolomide 200 mg/m2 po QD days 10-14 
Repeat cycles every 28 days  
Maximum duration of treatment 13 cycles (approximately 1 year) 
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5.2 
Adverse Event Reporting Requirements   
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
Routine reporting:  Adverse events are reported in a routine manner 
at scheduled times during the trial using Medidata Rave.  
Expedited reporting:  In addition to routine reporting, certain adverse 
events must be reported in an expedited manner for timelier 
monitoring of patient safety and care. The following sections provide 
information and instructions regarding expedited adverse event 
reporting. 
5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution:  An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
Unlikely 
The AE is doubtfully related to treatment 
Possible 
The AE may be related to treatment 
Probable 
The AE is likely related to treatment 
Definite 
The AE is clearly related to treatment 
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.   
• 
Expectedness:  Any adverse event, the type or severity of which 
is consistent with the current investigator’s brochure, product 
label, and/or the protocol document 
5.2.3 
Reporting procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
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In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) 
• 
the FDA (800-332-1088) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Determination of reporting requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including: 
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
the relationship to the study treatment (attribution) 
• 
the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol E2211 and outline 
the specific expedited adverse event reporting requirements for 
study E2211. 
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5.2.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner 
 
 
Identify the type and grade of the event 
using CTCAE v4.0 
Determine if the event is related to the 
protocol treatment (attribution) 
With this information, review the chart in 
Section 5.2.6 to determine if event is 
reportable via CTEP-AERS 
Refer to footnote b in Section 5.2.6 
to determine if the event meets the 
protocol specific reporting 
requirements for this study. If so, 
report the event via CTEP-AERS 
Is the event 
reportable? 
No 
Yes 
Report the 
event via 
CTEP-AERS 
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 

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5.2.6 
Expedited Reporting Requirements for Arms A and B on protocol 
E2211 
Commercial Agents:  Temozolomide and Capecitabine 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only – (Arms A and B) 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any 
death that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or 
definitely to the treatment must be reported within 7 calendar days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported via CTEP-
AERS within 7 calendar days of learning of the event.  For instructions on how to 
specifically report these events via CTEP-AERS, please contact the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497. This will need to be discussed on a case-by-case 
basis. 
5.2.7 
Other recipients of adverse event reports and supplemental data 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company, if applicable.    
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.8 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave. 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1.  Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
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3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form 
5.3 
Dose Modifications  
5.3.1 
General 
Initial doses of capecitabine will be based on BSA (i.e. 750 mg /m2 po 
BID). Initial doses of temozolomide will be based on BSA, unless over 
the 400 mg cap in which case 400 mg will be used as the total daily 
dose. 
If BSA-based dose is used for a patient, dose reductions for weight 
change or toxicity will be based on the total daily dose (see 
Capecitabine and Temozolomide Dose Table). 
If temozolomide cap is used, dose reductions for weight change will 
only be made if recalculated dose is less than 400 mg. If 
temozolomide cap is used, dose reductions for toxicity will be based 
on the total daily dose. 
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If dose reduction is required, reduction is permanent. Missed doses 
will not be made up. 
Dose will be modified for all drugs if there is a ≥ 5% change in 
patient’s BSA while on study. 
If multiple toxicities are seen, the dose administered in a subsequent 
cycle should be based on the most severe toxicity experienced in the 
current cycle.  
For Arm B, patients may discontinue one agent due to toxicity and 
continue the other on-study. 
AEs determined to be unrelated to study treatment will not require 
dose reduction.  
***NOTE: 
If patient has been off treatment for any reason > 4 
weeks from next planned cycle start date, patient must 
discontinue protocol treatment. 
All toxicity grades below are described using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of 
the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov). 
5.3.2 
Temozolomide Dose Modifications 
The dose of temozolomide will be determined according to (1) non-
hematologic AEs during the previous cycle, as well as (2) the lowest 
ANC and platelet counts during that cycle. 
• 
Dose reductions: For non-hematologic grade 3 AEs (except for 
nausea and vomiting as well as AEs unrelated to treatment) the 
dose should be reduced according to the Temozolomide 
Hematologic and Other Toxicities charts below. Dose reductions 
for treatment day ANC and platelet counts should also be made 
according to the Hematologic chart below. No dose escalation of 
temozolomide is permitted 
• 
Discontinuation: For patients who require more than 2 dose 
reductions, temozolomide will be permanently discontinued.  For 
any non-hematologic drug-related grade 4 AEs that does not 
resolve within the allowed 4 weeks, then temozolomide treatment 
will be permanently discontinued.  Also, except for nausea and 
vomiting, if any of the same non-hematologic grade 3 AEs that are 
at least possibly related to study treatment recur after reduction for 
that AE, then temozolomide will be stopped. 
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Hematologic Toxicity 
ANC (/mm3) 
 
Platelets 
(/mm3) 
% of Planned Temozolomide 
≥ 1500/mm³ 
and 
≥ 100,000/mm3 
100% 
500-
1499/mm³ 
or 
40,000-
99,999/mm3 
Hold* until ANC ≥ 1500/mm3 and PLT ≥ 
100,000/mm3; resume at 20% dose reduction. 
< 500/mm³ 
or 
< 40,000/mm3 
Hold** until ANC ≥ 1500/mm3 and PLT ≥ 
100,000/mm3; resume at 40% dose reduction. 
* Two total dose reductions are permitted before temozolomide will be discontinued. 
** One dose reduction is permitted before temozolomide will be discontinued. 
Other Toxicity 
For other hematologic toxicities not included in the table above and 
non-hematologic toxicities, dose reductions of temozolomide will be at 
the discretion of the investigator. A maximum of 2 dose reductions 
can be performed in increments of 20% or a single dose reduction of 
40%. For patients with significant liver function abnormalities the 
benefits and risks of continuing treatment should be carefully 
considered. 
5.3.3 
Capecitabine Dose Modifications 
Capecitabine will be initiated at 750 mg/m2 PO BID x 14 days on a 28-
day cycle. 
Two total dose reductions are permitted before capecitabine will be 
discontinued. Each dose reduction will be a 20% reduction from the 
prior level. 
Hematologic Toxicities 
ANC (/mm3)  
Platelets (/mm3) 
Modification 
< 1500/mm³ AND/OR < 100,000/mm³ 
Hold until ANC ≥ 1500/mm3 and 
PLT ≥ 100,000/mm3; resume at 
20% dose reduction 
≥ 1500/mm³ 
AND 
≥ 100,000/mm³ 
No dose modification 
Mucositis, Diarrhea or Esophagitis 
Grade Toxicities/Symptoms 
Modification 
1 
Mucositis, esophagitis, 
or diarrhea 
No dose modification 
2 
Diarrhea 
No dose modification 
2 
Mucositis, or 
esophagitis 
Hold until ≤ grade 1 and resume at 20% dose 
reduction 
3 
Diarrhea 
Hold until ≤ grade 1; resume at 20% dose reduction 
3/4 
Mucositis or esophagitis Hold until ≤ grade 1; resume at 20% dose reduction 
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Palmar – Plantar Erythrodysesia Syndrome (Hand and Foot Rash) 
Grade 
Modification 
1 
No dose modification 
2 
Hold until symptoms resolve to grade 0 or 1. 
Resume at 20% dose reduction. 
≥ 3 
Hold until symptoms resolve to grade 0 or 1. 
Resume at 20% dose reduction. 
Other Toxicity 
For other hematologic toxicities not included in the tables above and 
non-hematologic toxicities, dose reductions of capecitabine will be at 
the discretion of the investigator. A maximum of 2 dose reductions 
can be performed in increments of 20%. 
5.4 
Supportive Care  
5.4.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.4.2 
Ondansetron is required as a premedication 30 minutes prior to 
temozolomide. Otherwise, anti-emetics, anxiolytics, and analgesics 
may be provided at physicians’ discretion. 
5.5 
Duration of Therapy  
Patients will receive protocol therapy unless: 
5.5.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E2211 Forms Completion Guidelines. 
5.5.2 
Patient withdraws consent. 
5.5.3 
Patient experiences unacceptable toxicity. 
5.5.4 
Non-protocol cancer therapies are administered.  
5.5.5 
Disease progression per protocol criteria or death. 
5.5.6 
Patient completes 13 cycles of therapy (approximately 1 year of 
treatment). 
5.6 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated and for survival for 5 years from the date of randomization. All patients 
must also be followed through completion of all protocol therapy. 

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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response 
every 12 weeks.  In addition to a baseline scan, confirmatory scans should also 
be obtained 4 weeks following initial documentation of objective response. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before 
randomization. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the 
definitions stated below. 
(NOTE: 
Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment.  The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 

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with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area are measurable if they demonstrate recent evidence 
of progression. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected.   
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum 
of the diameters will be used as reference to further characterize any 

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objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before randomization. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
in diameter as assessed using calipers (e.g., skin nodules).  In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up 
must be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 

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scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed.   
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.  Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin 
Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 

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6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm. 
(NOTE: 
The appearance of one or more new lesions is 
also considered progression, See Section 
6.1.4.3). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 8 weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (<10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 

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When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on 
the basis of change in non-target disease in the face of SD 
or PR of target disease will  
therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease:  i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or b) 
there is new pathological confirmation that it is disease 
(regardless of size).  
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease progression or 
initiation of non-protocol therapy (taking as reference for 
progressive disease the smallest measurements recorded 
since the protocol treatment started).  The patient’s best 
response assignment will depend on the achievement of 
both measurement and confirmation criteria. 

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For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target Lesions 
New Lesions* Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
≥ 4 wks. Confirmation 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 8 wks. from study entry 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
  PD** 
Yes or No 
   PD*** 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
6.1.4.5 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 8 weeks. 

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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
7.1.1 
To be completed within 14 DAYS before randomization: 
• 
All blood work, including pregnancy test. 
7.1.2 
To be completed within 28 DAYS before randomization: 
• 
CT or MRI should be performed. 
 
≤ 4 weeks Prior to 
Randomization 
Day 1 of each 
cycle4 
Every 3 cycles  
End of 
Treatment12 
Post Treatment to 5 
years from study entry1 
Tests & Observations 
 
 
 
 
 
History and Progress Notes4 
X 
X 
 
X 
X 
Physical Examination4 
X 
X 
 
X 
X 
Pulse, Blood Pressure4 
X 
X 
 
 
 
Weight/BSA4 
X 
X 
 
 
 
Performance Status4 
X 
X 
 
 
 
Tumor Measurements4 
X 
 
X 
X 
 X7 
Adverse Event Assessment 
 
X 
 
X 
X 
Laboratory Studies 
 
 
 
 
 
CBC, Diff, Platelets4 
 X6 
X 
 
 
 
Serum Electrolytes and Chemistry2,4 
 X6 
X 
 
  X12 
 
Tumor markers11,4,13 
 X6 
 
X 
 
 
Pregnancy Test (serum or urine HCG) 
 X3 
 
 
 
 
CT Scan and/or MRI 4,5,10,13 
X 
 
X 
X 
 X7 
Specimen Submissions 
 
 
See Sections 11 and 12 
MANDATORY: Tumor Tissue FFPE8 
X 
 
 
 
 
Peripheral blood, ACD or EDTA tube9 
X 
 
 
 
 
1. Monitor for survival every 3 months until patient is two years from randomization, then every 6 months until patient is 5 years from randomization. 
Follow-up is no longer required after patient is more than 5 years from randomization. Once the patient progresses, adverse event assessments 
no longer need to be performed. 
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6/14 
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2. Serum electrolytes: Na+, K+, bicarbonate, Cl, BUN, creatinine, glucose; total bilirubin, SGOT(AST), SGPT(ALT), alkaline phosphatase, albumin, 
total protein, calcium. Serum electrolytes and chemistry must be done within 1 week of start of Cycle 1 and ≤ 72 hours prior to each subsequent 
treatment cycle. 
3. Within 2 weeks of randomization for women of childbearing potential. 
4. Labs and physical exam must be done within 1 week of start of Cycle 1. After Cycle 1, Day 1, the start of each treatment cycle may be scheduled 
up to three days after the expected Day 1 of that cycle. History and Progress Notes; Physical Examination; Pulse, Blood Pressure; Weight/BSA; 
Performance Status; CBC, Diff, Platelets; Serum Electrolytes and Chemistry, and Adverse Event Assessment must be done ≤ 72 hours prior to 
each treatment cycle.  
5. If only MRI of the abdomen and/or pelvis is available, this can be substituted for CT of abdomen and/or pelvis, but CT of chest should still be 
obtained. Copies of all standard-of-care imaging studies are to be submitted to the American College of Radiology Imaging Network (ACRIN) and 
the ACR Imaging Core Lab as outlined in Section 10. 
6. Must be done within 2 weeks prior to randomization. 
7. Post treatment scans will be performed every 3 months for 3 years from randomization and every 6 months between 3-5 years from 
randomization. The collection of tumor markers is encouraged at this time, but not required. Once there is confirmation of progression, scans and 
tumor measurements no longer have to be performed. 
8. Representative tumor tissue (block preferred) and related pathology reports are to be submitted for central diagnostic review and classification 
and defined research studies within 4 weeks following randomization as outlined in Section 11. Failure to submit the required materials may 
render the case unevaluable but will not impact patient participation in the trial. 
9. Research blood sample may be collected at any time during the trial, although prior to start of treatment is preferred. EDTA may be used if ACD 
not available. Submit from patients who answer “Yes” to “I agree to provide additional blood for research” as outlined in Section 12. 
10. Imaging instructions: All standard-of-care imaging studies (including CT, MRI, PET, perfusion CT, or any combination) of the abdomen and pelvis 
will be submitted to ACRIN via the ACR Imaging Core Lab per Section 10.2 instructions. Submission of chest images is optional. Preferably, a 
minimum of three (3) image phases will be submitted (see below): 
Preferred: 
• 
Late arterial phase through the abdomen 
• 
Portal venous phase through the abdomen and pelvis 
• 
Delayed (equilibrium) phase through the abdomen at 3 to 4 min after contrast administration.   
If performed per standard institutional practice: 
• 
Perfusion CT sequences of an area of interest is optional and should be performed according to site specific specifications if available at 
the participating institution. 
11. Tumor markers: Chromogranin A and Neuron Specific Enolase (NSE) are required at baseline and every 3 cycles.  Other tumor markers may be 
done at the investigator’s discretion and based on patient symptoms (i.e. glucagon, insulin, VIP, pancreatic polypeptide, gastrin). Continued 
collection of tumor markers is encouraged during the follow-up period. 
12. End of Treatment assessments and labs must be performed within 4 weeks after patient’s last date of protocol treatment. CT scan and/or MRI 
performed within 30 days of the last date of protocol treatment do not need to be repeated at End of Treatment. 
Rev. 6/14 
Rev. 2/14,  
6/14 
Rev. 6/14 
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13.  After randomization, the CT scan or MRI, Tumor Measurements, and Tumor Markers will be completed every 3 cycles. Should the 3 cycle interval 
be delayed or extended, the next interval scan and tumor markers should be completed no more than 16 weeks from previous scan (≤ 4 weeks 
from planned scan date). 
 
Rev. 6/14 

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8. 
Drug Formulation and Procurement 
Both temozolomide and capecitabine will be obtained commercially. 
8.1 
Temozolomide 
8.1.1 
Other Names  
Temodar 
8.1.2 
Classification  
Cytotoxic chemotherapy, alkylating agent 
8.1.3 
Mode of Action  
Temozolomide [8-carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-
4(3H)-one] (Temodal) is an imidazole tetrazinone compound 
developed by Schering-Plough for use as an antineoplastic agent.  
TMZ is a prodrug that spontaneously hydrolyzes to 5-(3-
methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), which is also the 
active metabolite of dacarbazine. Dacarbazine, however, requires 
hepatic metabolism for formation of this metabolite, which results in 
variable levels.  TMZ is stable at an acidic pH, allowing oral 
absorption, and has a broad biodistribution. 
Temozolomide is not directly active but undergoes rapid 
nonenzymatic conversion at physiologic pH to the reactive compound 
5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of 
DNA. Alkylation (methylation) occurs mainly at the O6 and N7 
positions of guanine. 
8.1.4 
Storage and Stability  
As a solid, temozolomide is thermally stable and does not decompose 
when exposed to light. In solution, temozolomide undergoes rapid 
hydrolysis in a basic environment. The product label recommends 
storage at room temperature 25°C (77°F).  Temozolomide should be 
stored at 20-25°C (68-77°F), excursions permitted between 15-30°C 
(59-86°F).  
8.1.5 
Dose Specifics  
ARM A: 200 mg/m2 po QD on days 1-5 
ARM B: 200 mg/m2 po QD on days 10-14 
The temozolomide dose will be capped at 400 mg daily and is 
available as 5, 20, 100, 140, 180, or 250 mg capsules.  The calculated 
dose by body surface area (BSA) will be rounded down to minimize 
the number of pills required. 
8.1.6 
Preparation  
N/A 

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8.1.7 
Route of Administration  
Oral 
8.1.8 
Incompatibilities  
N/A 
8.1.9 
Availability  
Commercial supply 
8.1.10 
Side Effects  
Hematologic: anemia, neutropenia, thrombocytopenia, aplastic 
anemia. 
Constitutional: fatigue, anorexia, weight loss 
Dermatologic: rash, pruritus, Stevens-Johnson-Syndrome 
Gastrointestinal:  nausea, vomiting, constipation, diarrhea, abdominal 
pain, stomatitis, dysphagia 
Infections:  PCP infection 
Metabolic: hyperglycemia, liver or kidney abnormalities 
Neurologic:  headache, somnolence, insomnia, blurred vision 
Oncologic: secondary malignancy 
Psychiatric:  anxiety, depression 
8.1.11 
Nursing/Patient Implications  
8.1.11.1 
Monitor CBC and platelet count prior to drug 
administration.   
8.1.11.2 
Symptom management of expected nausea, vomiting, 
photosensitivity, and mucositis within ≤ 3 months prior to 
treatment. 
8.1.11.3 
Ondansetron will be given as a premedication to prevent 
nausea 30-60 minutes prior to the temozolomide dose.  
8.1.11.4 
Temozolomide should be taken by mouth after fasting from 
solid food for two hours.  
8.1.11.5 
Temozolomide tablets must not be crushed and must be 
administered whole.  
8.1.11.6 
Temozolomide missed doses will not be made up, and 
patients should not double-up on missed doses during 
treatment. Do not repeat dose if vomiting occurs after dose 
is administered.  
8.1.11.7 
 Liver function tests should be performed after each 
treatment cycle.  For patients with significant liver function 
abnormalities the benefits and risks of continuing 
temozolomide should be carefully considered. 

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8.1.12 
References  
1. Temozolomide package insert.  
8.2 
Capecitabine 
8.2.1 
Other Names  
Xeloda 
8.2.2 
Classification  
Cytotoxic chemotherapy, anti-metabolite 
8.2.3 
Mode of Action  
Capecitabine is a fluoropyrimidine carbamate that is an orally active 
prodrug of 5-fluorouracil.  Normal cells, as well as tumor cells, 
metabolize 5- fluorouracil into 5-fluoro-2’deoxyuridinemonophosphate 
(FdUMP) and 5-fluorouridine triphosphate (FUTP). Both are 
metabolites that cause cell injury by two different mechanisms.  
FdUMP and the folate factor, N5-10-methylenetetrahydrofolate, bind 
to thymidylate synthase (TS) to inhibit the formation of thymidylate. 
This deficiency of thymidylate causes cell cycle division to halt. This is 
because thymidylate is necessary for thymidine triphosphate 
production, which is essential for DNA synthesis.  FUTP works by 
incorporating itself into transcription in place of uridine triphosphate 
therefore interfering with RNA transcription and protein synthesis. 
8.2.4 
Storage and Stability  
Capecitabine is supplied as biconvex, oblong film-coated tablets, 
available as 500 mg tablets (peach).  Capecitabine is stored at 25oC, 
with excursions permitted to 15 to 30 oC.   
8.2.5 
Dose Specifics  
ARM A: None 
ARM B: 750 mg/m2 po BID on days 1-14 
The calculated total daily dose by body surface area (BSA) will be 
rounded down to the nearest 500 mg allow doses using 500 mg 
tablets.    
8.2.6 
Preparation  
N/A 
8.2.7 
Route of Administration  
Oral 
8.2.8 
Incompatibilities  
N/A 
8.2.9 
Availability  
Commercial supply 
8.2.10 
Side Effects  

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Hematologic: anemia, neutropenia, thrombocytopenia  
Cardiovascular: Edema, venous thrombosis 
Constitutional: fatigue, pyrexia, swelling in hands, feet or abdomen, 
pain, chest pain 
Dermatologic: hand-foot syndrome, dermatitis, skin discoloration, 
alopecia 
Gastrointestinal:  diarrhea, nausea, vomiting, stomatitis, abdominal 
pain, gastrointestinal motility disorder, constipation, taste disturbance, 
upper GI inflammatory disorders, gastrointestinal hemorrhage, ileus 
Hepatic:  hyperbilirubinemia 
Infections:  bacterial or viral 
Metabolic: appetite decreased, dehydration 
Musculoskeletal:  back pain, arthralgia 
Neurologic:  peripheral sensory neuropathy, headache, dizziness, 
insomnia 
Ocular:  eye irritation, vision abnormal 
Psychiatric:  mood alteration, depression 
Pulmonary:  dyspnea, cough, pharyngeal disorder, epistaxis, sore 
throat 
Vascular:  venous thrombosis 
8.2.11 
Nursing/Patient Implications  
8.2.11.1 
Monitor CBC and platelet count prior to drug 
administration.   
8.2.11.2 
Administer doses at least 8 hours apart. 
8.2.11.3 
Symptom management of expected nausea, vomiting, 
diarrhea, and hand-foot skin syndrome. 
8.2.11.4 
Capecitabine tablets should be swallowed with water within 
30 minutes after a meal.   
8.2.11.5 
Capecitabine tablets are allowed to be crushed. 
8.2.12 
References  
1. Capecitabine package insert 

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9. 
Statistical Considerations 
9.1 
Expected Accrual Pattern 
While neuroendocrine tumors (NETs) are relatively rare in the population, the 
absence of standard treatment options has led to significant interest and rapid 
accrual to clinical trials in this disease in recent years.  For example, the recently 
completed industry-sponsored RADIANT3 study accrued 410 patients with 
pancreatic NETs over a period of 21 months from 18 countries (83 sites) for an 
overall accrual rate of 19 patients per month.  CALGB 80701, a randomized 
study of everolimus with or without bevacizumab in patients with advanced 
pancreatic NET opened in October 2010 and has accrued over 70 patients, with 
a current accrual rate of approximately 6 per month. CALGB 80701 targets a 
similar population to the currently proposed study and will likely complete accrual 
within the next year. Assuming participation of several cooperative groups within 
the U.S., we similarly expect to enroll approximately 6 patients per month to this 
trial.  Accrual is expected to be complete within 2 years from study activation. 
9.2 
Treatment Assignment 
Patients will be randomized with equal probability to treatment with single agent 
temozolomide or the combination of temozolomide and capecitabine using a 
stratified permuted blocks algorithm with stratification based on prior treatment 
with everolimus (Yes vs No), prior treatment with sunitinib (Yes vs No) and 
concurrent administration of octreotide (Yes vs No). 
9.3 
Statistical Design and Efficacy Monitoring 
The primary endpoint of this trial is progression-free survival (PFS). Patient 
assessments will be made every 3 months. 
This study will require a minimum of 138 patients (or a maximum of 145 patients 
to allow for 5% ineligibility) to be accrued at the rate of roughly 6 patients per 
month. With 23 months of accrual time and 13 months of follow-up (3 years total 
study time), this trial will have at least 81% power to detect a difference in 
median PFS between the treatment arms of 9 versus 14 months (hazard ratio of 
0.64) using a two-sided log-rank test at the overall 0.20 significance level. The 
assumption of 9 months for the temozolomide arm is based on historical data of 
temozolomide alone and temozolomide-based regimens as described in the 
introduction. The assumption of 14 months for the combination arm is based a 
goal of improving treatment by 55% (which conservatively approximates the 
Strosberg PFS data of 18 months). 
There will be two log-rank tests conducted, an interim analysis at 76% 
information (at 80 PFS events, projected to occur just after the end of the accrual 
period at 26 months) and a final analysis at 100% information (105 PFS events), 
projected to occur at 3 years from the start of accrual. The overall type I error will 
be controlled using an O’Brien-Fleming boundary function. Using this boundary, if 
the repeated two-sided 95% confidence interval on the hazard ratio does not 
contain the target alternative hazard ratio of 0.64, consideration will be given to 
declaring the study negative and reporting the results. If the interim log-rank test 
is positive, the study can be reported early before the projected end of the follow-
up period. 

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Response rate (RR) will be a secondary endpoint. RR will be defined by revised 
RECIST criteria version 1.1 and include complete responses and partial 
responses. Prior studies of single agent temozolomide suggest that the response 
rate associated with single-agent temozolomide is 8-24%; however, overall 
response rates associated with other temozolomide-based regimens in this 
disease are between 30-40%. For the purposes of this study, we assume that 
single agent temozolomide will be associated with a response rate of 33%. 
Retrospective series of temozolomide/capecitabine have reported response rates 
of 59-70% in advanced pancreatic neuroendocrine tumors. 
With 138 patients there will be at least 80% power to detect an absolute 
difference of 20% in the objective response rates (for example, between 33% 
and 53% true response rates) using a two-group Fisher’s exact test at an overall 
two-sided 20% significance level. In addition, within each arm, a 90% confidence 
interval on the true objective response rate will be no wider than 21 percentage 
points. Overall survival will also be a secondary endpoint but power for overall 
survival comparisons will be limited. 
9.4 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Expedited reporting of certain adverse events is required through the 
CTEP-AERS system, which is monitored continuously with formal notifications 
monthly of unexpected grade 4 and 5 events. Formal comparison of toxicity rates 
between the arms is not a goal of this trial and the sample size will provide 
sufficient power for detecting only relative large difference in adverse events. 
With at least 69 patients per treatment arm, a 90% confidence interval on any 
adverse event rate will be no wider than 21 percentage points and there is at 
least 87% probability of observing one or more rare events (3% true probability) 
in either treatment arm. 
Reports of these analyses are sent to the ECOG-ACRIN Principal Investigator or 
Senior Investigator at the participating institutions. Expedited reporting of certain 
adverse events is required, as described in Section 5. 
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9.5 
Gender and Ethnicity  
Based on previous data from the neuroendocrine stratum of ECOG study E4298 
the anticipated accrual in subgroups defined by gender and race/ethnicity is as 
follows:  
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
3 
6 
Not Hispanic or Latino 
69 
70 
139 
Ethnic Category: Total of all subjects 
72 
73 
145 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
3 
3 
6 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
69 
70 
139 
Racial Category: Total of all subjects 
72 
73 
145 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 

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10. 
Imaging Studies 
ECOG-ACRIN plan to bank CT images collected during the course of the study at the 
central ACR Imaging Core Laboratory. This data set of serial images from more than 
130 patients with pancreatic NETs will serve as one of the largest NET image banks. For 
the ECOG-ACRIN E2211 trial, we plan to evaluate specific clinical data elements to 
associate images with treatment milestones and use these images to retrospectively 
evaluate internal imaging consistency methodologies, such as quality of images 
received, reproducibility, and compliance. In the future, the de-identified image bank may 
be used for additional research, such as retrospective reviews of disease or software 
validation. Patient identifiers will never be included in future research and no patients will 
be named in publications related to future research. 
10.1 
Standard-of-Care Imaging Time Points and Minimum Preferred Phases 
10.1.1 
All standard-of-care imaging studies (including CT, MRI, PET, 
perfusion CT, or any combination) of the abdomen and pelvis, 
including all phases completed, will be submitted to ACRIN per 
Section 10.2 instructions. Submission of chest images is optional. 
10.1.2 
Standard practice imaging studies for the trial per E2211 procedures 
include:  
• 
Pre-treatment baseline scan for eligibility assessment; 
• 
Imaging studies during study-prescribed treatment—(e.g. CT 
scans or MRIs at the completion of cycles 3, 6, 9, and 12 
(approximately every 12 weeks). 
• 
Follow-up imaging studies—e.g. CT scans or MRIs approximately 
every 3 months for 3 years from randomization and 6 months for 
3-5 years from randomization or until disease progression. 
10.1.3 
Preferably, a minimum of three (3) image phases will be submitted 
(see below), as well as any perfusion CT sequences that may be 
performed as standard institutional practice: 
• 
Preferred: 
• 
Late arterial phase through the abdomen; 
• 
Portal venous phase through the abdomen and pelvis; 
• 
Delayed (equilibrium) phase through the abdomen at 3 to 4 
min after contrast administration; 
• 
If performed per standard institutional practice: 
• 
Perfusion CT sequences of an area of interest is optional and 
should be performed according to site specific specifications if 
available at the participating institution. 
10.2 
Images Submission 
10.2.1 
For TRIAD Submission: The preferred image transfer method is via 
TRIAD, a software application that ACRIN provides for installation on 
a site’s PC. One or several computers of choice within the institutional 
“firewall” and on the institutional network may be equipped with 
TRIAD software; Internet access is also required. The TRIAD 
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application can then be configured as a DICOM destination on either 
scanner(s) and/or PACS system for direct network transfer of study 
related images into the TRIAD directory. When properly configured, 
the TRIAD software anonymizes, encrypts, and performs a lossless 
compression of the images before they are transferred to the ACRIN 
image archive in Philadelphia. Once equipment-readiness has been 
determined, imaging personnel from ACRIN will coordinate installation 
and training for the software. 
For more information, contact: TRIAD-support@phila.acr.org or call 
215-940-8820. 
10.2.2 
For Submission Via Media: In the event that the transfer of image data 
is not available via TRIAD, images may also be sent on a CD/DVD-
ROM to the ACRIN core lab for transfer to the image archive. All 
image data submitted to the ACRIN core lab must be in DICOM 
format. 
10.2.3 
The Imaging Transmittal Worksheet (ITW) must accompany all image 
submissions. PDF versions of the transmission worksheets, along 
with completion and submission instructions, are available on the 
ACRIN website. 
10.2.4 
Images may be mailed to: 
American College of Radiology Imaging Network 
ACR Imaging Core Laboratory 
Attn: E2211 
1818 Market Street 16th Floor 
Philadelphia, PA 19103 

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11. 
Specimen Submission Requirements 
Diagnostic material from previously collected tissue (core biopsy or surgical specimen 
preferred over FNA) must be submitted for central diagnostic review and classification 
and for laboratory research studies. These studies are defined in Section 12. Peripheral 
blood is to be submitted from consenting patients for future research studies. 
All specimens submitted on this trial must be entered and tracked using the ECOG-
ACRIN Sample Tracking System (see Section 11.3). Any case reimbursements 
associated with specimen submissions to ECOG-ACRIN – designated laboratories will 
be determined only from data contained in STS. 
Specimens are to be labeled clearly with the ECOG-ACRIN protocol number “E2211”, 
patient initials, date and time of collection, and sample type. 
11.1 
Specimen Preparation Guidelines 
11.1.1 
Tissue Samples 
Submission of pathology materials from all patients is mandatory. 
The submitting pathologist and clinical research associate should 
refer to Appendix I (Pathology Submission Guidelines) for guidelines 
and summary of submission requirements. Failure to submit the 
required materials for the central pathology review may render case 
unevaluable but will not impact patient participation in the trial. 
The following materials are to be submitted within four (4) weeks 
following randomization: 
• 
All original stained diagnostic slides. 
NOTE: 
These slides will be returned to the site upon 
completion of the review which is retrospective and will 
be performed in batches. If the return of these slides is 
to be expedited: 
1. Contact the repository to discuss expedited review.  
They may request that materials be held until 
requested.  
2. Upon submission, indicate need for expedited 
review in the appropriate comment field in STS.   
3. If submission is delayed, a copy of the pathology 
report must be submitted and it is requested that 
the delay or inability to submit the materials be 
indicated in STS. 
• 
One representative diagnostic formalin-fixed paraffin-embedded 
tumor block, core biopsy or surgical specimen preferred. 
NOTE: 
If a block is unavailable for submission, submit the 
following: 
• 
Twenty (20) unstained slides 4µm thick 
• 
Two (2) 4mm cores. 
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If these criteria cannot be met, please contact the ECOG-ACRIN 
Central Biorepository and Pathology Facility 
(eacbpf@mdanderson.org) to obtain alternative submission 
requirements. 
• 
Forms:  
• 
A copy of the surgical (if appropriate) and pathology reports 
and Immunologic studies (if available). If tissue submissions 
are delayed, reports are still required to be submitted following 
registration. 
• 
Sample Tracking System Shipping Manifest 
11.1.2 
Peripheral Blood, ACD or EDTA  
Blood specimens are to be submitted for future research studies from 
patients who answered “yes” to “I agree to provide additional blood for 
research.” 
Samples are not to be drawn until after patient has been randomized 
to treatment.  Although collection prior to start of protocol treatment is 
preferred, the sample may be drawn at any time during study 
participation. 
• 
Draw blood into two 10mL ACD or EDTA tubes. Invert gently eight 
to ten times to thoroughly mix the blood and anti-coagulant. 
• 
Specimen may be shipped at ambient temperature the day of 
collection or frozen (at < -70ºC preferred). If frozen, specimens 
collected in glass vacutainers must be transferred to sterile 
cryovials prior to freezing. Plastic vacutainers may be frozen 
directly. 
11.2 
Shipping Procedures  
All sample submissions are to be accompanied with an STS shipping manifest. 
11.2.1 
Submission Schedule 
The receiving laboratory is not available to receive shipments over 
holidays or weekends.  Therefore, samples are only to be shipped via 
overnight courier Sunday through Thursdays (excluding a day before 
a holiday). 
11.2.1.1 
The required initial diagnostic tumor tissue materials are to 
be submitted within four (4) weeks following patient 
randomization. 
11.2.1.2 
Peripheral blood samples from multiple patients may be 
batched and shipped together.  The samples are to be 
shipped as follows: 
• 
Samples shipped at ambient are to be shipped with a 
cool pack. If collected Monday – Thursday then ship 
day of collection.  Samples collected on Friday or a 
weekend are to be placed in a refrigerator and shipped 
Monday. 
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• 
Frozen samples are to be shipped on dry ice (5 lbs. 
minimum). Samples batched in a regular freezer are to 
be shipped within a month following the draw.  
Samples stored at < -70ºC may be shipped on a 
quarterly basis. 
11.2.2 
Shipping Address 
Samples are to be shipped using the CBPF’s FedEx account using 
the FedEx On-Line Services. 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
Access to the shipping account for specimen shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can now only be 
obtained by logging into fedex.com with an account issued by the 
ECOG-ACRIN CBPF. For security reasons, the account number will 
no longer be given out in protocols, over the phone, or via email. If 
your site needs to have an account created, please contact the 
ECOG-ACRIN CBPF by email at eacbpf@mdanderson.org 
11.3 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important:  Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software.  A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu.  
Study Specific Notes 
Generic Specimen Submission Form (#2981v2) will be required only if STS is 
unavailable at time of sample submission. Notify the laboratory of the shipment 
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by Faxing a copy of the completed form to the laboratory. Indicate the 
appropriate Lab on the submission form: 
• 
ECOG-ACRIN CBPF 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
11.4 
Use of Specimens in Research 
Pathology materials will be distributed to investigators for the central diagnostic 
review and laboratory research studies defined in Section 12.  
Specimens from patients who consented to allow their specimens to be used for 
future ECOG-ACRIN-approved research studies will be retained in an ECOG-
ACRIN-designated central repository.  For this trial, specimens will be retained at 
the ECOG-ACRIN Central Biorepository and Pathology Facility. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microassays (TMAs). DNA 
and plasma (if appropriate) will be isolated from the submitted peripheral blood 
samples. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request.  
If future use is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. Pathology materials may be 
retained for documentation purposes or returned to the site.  All other specimens 
will be destroyed per guidelines of the respective repository 
11.5 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory.  
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office – Boston on a monthly basis in an electronic format defined by 
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12. 
Laboratory Research Studies 
Submission of tumor tissue for central review and research studies is mandatory (see 
Section 11). Representative tumor tissue samples will be processed and routed by the 
ECOG-ACRIN CBPF for use in the studies described below.  The results of these 
studies are for the purposes of the trial only and will not be returned to the site or 
reported to the patient. 
Priority of tissue use: 
1. Pathology Review 
2. MGMT status by IHC 
3. MGMT status by promoter methylation 
12.1 
Pathology Review 
The appropriate representative tumor tissue samples will be forwarded to Teri 
Longacre, MD for central diagnostic review and classification to confirm the 
diagnosis of low or intermediate grade pNET.  This is a retrospective review to 
determine the evaluability of the patient’s data for data analysis. The results of 
the review are for the purpose of the trial only and will not be returned to the site. 
12.2 
Evaluation of MGMT status by IHC 
Mouse monoclonal antibody to MGMT will be used (1:25 dilution; clone MT 3.1; 
Lab Vision), a biotinylated secondary antibody (mouse IgG), and then avidin-
horseradish peroxidase (Vectastain Elite ABC Kit; Vector Laboratories) according 
to the manufacturer’s instructions. Immunohistochemical MGMT expression will 
be scored as either ‘‘intact’’ or ‘‘deficient’’ in tumor cells using a prospective 
classification scheme. Tumors will be scored as ‘‘intact’’ when there is nuclear 
staining for MGMT in any tumor cells. Tumors will be scored as ‘‘deficient’’ when 
there is a complete absence of nuclear staining for MGMT in all tumor cells. Non-
neoplastic cells (lymphocytes, stromal cells, and endothelial cells) served as an 
internal positive control in all tissue sections.  We will additionally use an external 
tissue array control slide with known negative tumor.  
The assay will be performed in a CLIA certified lab under the direction of Teri 
Longacre, MD at Stanford University. 
12.3 
Evaluation of MGMT status by promoter methylation 
DNA is purified from formalin-fixed paraffin embedded and then treated with 
bisulfite. Bisulfite treatment chemically converts unmethylated cytosines to uracil 
but does not affect methylated cytosine. Two PCR reactions are then performed 
using primers corresponding to bisulfite modified (unmethylated) or unmodified 
(methylated) MGMT promoter sequence. The products of the PCR reaction are 
analyzed by agarose gel electrophoresis.  Methylation-specific PCR performed 
on paraffin-embedded tissue specimens is dependent on tissue quality and 
quantity. It is important that there is little tissue necrosis since amplification could 
otherwise be compromised. It is to be expected to frequently see amplification of 
both methylated and unmethylated MGMT promoter sequences in the same 
specimen, which likely represents heterogeneity among tumor cells and/or the 
presence in the specimen of non-neoplastic cells. Presence of promoter 
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methylation, which causes epigenetic silencing of the MGMT gene, a DNA repair 
gene on chromosome 10q26, is a positive predictive factor for chemotherapeutic 
response to alkylating agents.   
The assay will be performed in a CLIA certified lab under the direction of Iris 
Schrijver M.D at Stanford University. 
12.4 
Statistical Considerations 
From prior correlative studies in ECOG-ACRIN it is expected that about 75% of 
cases will provide tissue amenable to MGMT evaluation, accounting for samples 
not obtainable and assay yield among obtainable samples. From earlier studies 
in pancreatic neuroendocrine tumors it is also anticipated that the MGMT-
deficiency rate is roughly 50% and MGMT-deficient tumors are expected to be 
associated with higher levels of objective tumor response to temozolomide based 
therapy. Assuming that the overall response rate is 41% (across both treatment 
arms, under the alternative hypothesis) and that roughly 104 eligible patients with 
samples are available, there will be at least 80% power to detect an absolute 
difference in response rates of 29% (for example, 55% versus 26% in the 
MGMT-deficient versus MGMT-intact groups, respectively) using a two-sided 5% 
level Fisher's exact test. If the true difference in response rates between MGMT-
deficient and MGMT-intact tumors is larger, power will be higher (for example 
90% power for a difference in response rates of 57% versus 24%) and if the 
overall treatment response rate is closer to the null hypothesis (overall 33% 
response rate in both arms), there will be at least 85% power for the same level 
of absolute response rate difference, 29%, between the MGMT-deficient versus 
MGMT-intact groups. The evaluation of MGMT by IHC and promoter methylation 
and correlation with progression-free and overall survival will be exploratory in 
nature.  Furthermore, statistical power for MGMT deficiency by treatment arm 
interactions will be limited given the relatively small size of this trial and these 
analyses will also be exploratory. 
12.5 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office – Boston 1 week after these cut-off 
dates 

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Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
56 
13. 
Electronic Data Capture 
Please refer to the E2211 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
14. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
15. 
References 
1. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine 
tumors. N Engl J Med 2011;364:514-23. 
2. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of 
pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501-13. 
3. Moertel C, Lefkopoulo M, Lipsitz S, Hahn R, Klaassen D. Streptozocin-doxorubicin, 
stretpozocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell 
carcinoma. N Engl J Med 1992;326:519-23. 
4. Kouvaraki M, Ajani J, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the 
treatment of patients with locally advanced and metastatic pancreatic endocrine 
carcinomas. J Clin Oncol 2004;22:4762-71. 
5. Cheng P, Saltz L. Failure to confirm major objective antitumor activity ofr 
streptozocin and doxorubicin in the treatment of patients with advanced islet cell 
carcinoma. Cancer 1999;86:944-8. 
6. McCollum AD, Kulke MH, Ryan DP, et al. Lack of efficacy of streptozocin and 
doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 
2004;27:485-8. 
7. Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in 
treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 
2007;13:2986-91. 
8. Kulke MH, Hornick JL, Frauenhoffer C, et al. O6-methylguanine DNA 
methyltransferase deficiency and response to temozolomide-based therapy in 
patients with neuroendocrine tumors. Clin Cancer Res 2009;15:338-45. 
9. Maire F, Hammel P, Faivre S, et al. Temozolomide: a safe and effective treatment for 
malignant digestive endocrine tumors. Neuroendocrinology 2009;90:67-72. 
10. Kulke M, Stuart K, Enzinger P, et al. Phase II study of temozolomide and thalidomide 
in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006;24:401-6. 
11. Kulke M, Stuart K, Earle C, et al. A phase II study of temozolomide and bevacizumab 
in patients with advanced neuroendocrine tumors. PROC ASCO 2006:A4044. 
12. Kulke M, Blaszkowsky L, Zhu A, et al. Phase I/II study of everolimus (RAD001) in 
combination with temozolomide (TMZ) in patients (pts) with advanced pancreatic 
neuroendocrine tumors (NET). Gastrointestinal Cancers Symposium 2010: Abstr 223 
2010. 

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Cancer Research Group 
Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
57 
13. Fine R, Fogelman D, Schreibman S. Effective Treatment of Neuroendocrine Tumors 
With Temozolomide and Capecitabine. Journal of Clinical Oncology, ASCO Annual 
Meeting Proceedings Vol 23, No 16S, Part I of II (June 1 Supplement): 4216 2005. 
14. Murakami J, Lee YJ, Kokeguchi S, et al. Depletion of O6-methylguanine-DNA 
methyltransferase by O6-benzylguanine enhances 5-FU cytotoxicity in colon and oral 
cancer cell lines. Oncology reports 2007;17:1461-7. 
15. Isacoff W, Moss R, Pecora A, Fine R. Temozolomide/capecitabine therapy for 
metastatic neuroendocrine tumors of the pancreas. A retrospective review. J Clin 
Oncol, 2006 ASCO Annual Meeting Proceedings 2006;18S:A14023. 
16. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and 
temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 
2010. 
17. Liu L, Gerson SL. Targeted modulation of MGMT: clinical implications. Clin Cancer 
Res 2006;12:328-31. 
18. Gerson SL. Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 
2002;20:2388-99. 
19. Middleton MR, Lunn JM, Morris C, et al. O6-methylguanine-DNA methyltransferase 
in pretreatment tumour biopsies as a predictor of response to temozolomide in 
melanoma. Br J Cancer 1998;78:1199-202. 
20. Chinot OL, Barrie M, Fuentes S, et al. Correlation between O6-methylguanine-DNA 
methyltransferase and survival in inoperable newly diagnosed glioblastoma patients 
treated with neoadjuvant temozolomide. J Clin Oncol 2007;25:1470-5. 
21. Brandes AA, Tosoni A, Cavallo G, et al. Correlations between O6-methylguanine 
DNA methyltransferase promoter methylation status, 1p and 19q deletions, and 
response to temozolomide in anaplastic and recurrent oligodendroglioma: a 
prospective GICNO study. J Clin Oncol 2006;24:4746-53. 
22. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from 
temozolomide in glioblastoma. N Engl J Med 2005;352:997-1003. 
23. Friedman HS, McLendon RE, Kerby T, et al. DNA mismatch repair and O6-
alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly 
diagnosed malignant glioma. J Clin Oncol 1998;16:3851-7. 
24. Paz MF, Yaya-Tur R, Rojas-Marcos I, et al. CpG island hypermethylation of the DNA 
repair enzyme methyltransferase predicts response to temozolomide in primary 
gliomas. Clin Cancer Res 2004;10:4933-8. 
25. Arnold CN, Sosnowski A, Schmitt-Graff A, Arnold R, Blum HE. Analysis of molecular 
pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system. 
Int J Cancer 2007;120:2157-64. 
26. Chan AO, Kim SG, Bedeir A, Issa JP, Hamilton SR, Rashid A. CpG island 
methylation in carcinoid and pancreatic endocrine tumors. Oncogene 2003;22:924-
34. 
 

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Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
58 
A Randomized Phase II Study of Temozolomide or Temozolomide and Capecitabine in 
Patients with Advanced Pancreatic Neuroendocrine Tumors 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. 
Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. 
Instructional memo to submitting pathologists 
3. 
List of Required Materials for E2211 
4. 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
Rev. 5/15 

ECOG-ACRIN 
E2211 
Cancer Research Group 
Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
59 
Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
Instructions: 
1. 
Submitted materials must be adequately labeled, including:  
Patient's name (last, first) 
Protocol number 
Protocol case number (the patient's ECOG-ACRIN sequence number 
Institution  
2. 
 Complete blank areas of the pathologist's instructional memo and forward it, 
along with the List of Required Material and, if used, the Generic Specimen 
Submission Form, to the appropriate pathologist.  
3. 
The pathologist should return the required pathology samples and surgical 
pathology reports, along with the completed ECOG-ACRIN Generic Specimen 
Submission Form (#2981). If any other reports are required, they should be 
obtained from the appropriate department at this time. 
4. 
Keep a copy of the submitted documents and the StS-generated shipping 
manifest for your records.  
5. 
Double-check that ALL required forms, reports and pathology samples are 
included in the package to the Central Biorepository and Pathology Facility. (See 
appropriate List of Required Material.)  
Pathology specimens submitted WILL NOT be processed by the Central 
Biorepository and Pathology Facility until all necessary items are received. 
Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International 
Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate 
any problems in meeting the pathology material submission deadline of one 
month, contact the Pathology Coordinator at the ECOG-ACRIN Central 
Biorepository and Pathology Facility by telephone 844-744-2420 or by email at 
eacbpf@mdanderson.org. 
Rev. 5/15 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
60 
List of Required Material 
E2211: A Randomized Phase II Study of Temozolomide or Temozolomide and 
Capecitabine in Patients with Advanced Pancreatic Neuroendocrine Tumor 
Pre-Treatment 
1. 
Institutional pathology report (must be included with EVERY pathology 
submission). 
2. 
Institutional surgical report (if surgical materials are submitted) and 
immunological studies reports (if performed) 
3. 
ECOG-ACRIN Sample Tracking System (STS) generated shipping manifest 
4. 
Required path materials. 
• 
All original stained diagnostic slides. 
NOTE: 
These slides will be returned to the site upon completion of the 
review which is retrospective and will be performed in batches. If 
the return of these slides is to be expedited: 
1. Contact the repository to discuss expedited review.  They may 
request that materials be held until requested.  
2. Upon submission, indicate need for expedited review on the 
638 form AND in the appropriate comment field in STS.   
3. If submission is delayed, a copy of the applicable reports (#2 
and #3 above) must be submitted and it is requested that the 
delay to submit the materials be indicated in STS. 
• 
One representative diagnostic formalin-fixed paraffin-embedded tumor 
block, core biopsy or surgical specimen preferred. 
NOTE: 
If a block is unavailable for submission, submit the following: 
• 
Twenty (20) unstained slides 4µm thick 
• 
Two (2) 4mm cores. 
I f these criteria cannot be met, please contact the ECOG-ACRIN Central 
Biorepository and Pathology Facility (CBPF)(eacbpf@mdanderson.org) to 
obtain alternative submission requirements. 
NOTE: 
Since blocks are being used for laboratory studies, in some 
cases the material may be depleted, and, therefore, the block 
may not be returned. 
 
Rev. 6/14 
Rev. 6/14 
Rev. 5/15 

 
61 
MEMORANDUM 
TO:  
_________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
___________________________________ 
SUBJECT: 
Submission of Pathology Materials for E2211: A Randomized Phase II 
Study of Temozolomide or Temozolomide and Capecitabine in 
Patients with Advanced Pancreatic Neuroendocrine Tumor) 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by ______________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for pathology review and 
laboratory research studies. 
Keep a copy of the submission for your records and return, the surgical pathology 
report(s), the slides and/or blocks and any other required material (see List of Required 
Material) to the Clinical Research Associate (CRA). The CRA will forward all required 
pathology material to the ECOG-ACRIN ACRIN Central Biorepository and Pathology 
Facility. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies.  Paraffin blocks will be returned for purposes of patient 
management upon written request.  The original stained diagnostic slides will be 
returned upon completion of the review. 
Please note: Since blocks are being used for laboratory studies, in some cases 
the material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at 844-744-2420 or by email at 
eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 
Rev. 5/15 

ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
62 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 
Rev. 5/15 

ECOG-ACRIN 
E2211 
Cancer Research Group 
Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
63 
A Randomized Phase II Study of Temozolomide or Temozolomide and Capecitabine in 
Patients with Advanced Pancreatic Neuroendocrine Tumors 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

ECOG-ACRIN 
E2211 
Cancer Research Group 
Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
64 
A Randomized Phase II Study of Temozolomide or Temozolomide and Capecitabine in 
Patients with Advanced Pancreatic Neuroendocrine Tumors 
 
Appendix III 
 
Patient Pill Calendar 
 
 
Pill Calendar Directions 
1. Take your scheduled dose of each pill as instructed by your doctor. 
2. If you forget to take the pills, the missed pills will not be taken later. 
3. Complete the appropriate calendar based on the arm you are assigned to (Arm A or 
Arm B). 
4. Note the number of pills you take each day. If you develop any side 
effects/symptoms, please record them in the appropriate spot on your calendar. If 
you take any medication other than temozolomide or capecitabine, note them in the 
appropriate spot on your calendar. 
5. Do not take study medication on a day that has “XXXXX” on the calendar. 
6. Please bring the empty bottle(s), any leftover pills and your pill calendar to your next 
clinic visit. 
 
 
Rev. 7/15 

ECOG-ACRIN 
E2211 
Cancer Research Group 
Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
65 
E2211 Patient Pill Calendar – Arm A 
 
 
Patient ID:___________                                          Cycle #:____________ 
Dose:  Take _____________# of capsules once daily 
Cycle 
Day 
Date 
Temozolomide 
Time 
Notes 
 
MM/DD/YY 
# of Capsules 
Taken 
XX:XX 
PM 
Note any symptoms/side effects you 
experience or any medications you take 
besides Temozolomide. 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
XXXXX 
XXXXX 
 
7 
 
XXXXX 
XXXXX 
 
8 
 
XXXXX 
XXXXX 
 
9 
 
XXXXX 
XXXXX 
 
10 
 
XXXXX 
XXXXX 
 
11 
 
XXXXX 
XXXXX 
 
12 
 
XXXXX 
XXXXX 
 
13 
 
XXXXX 
XXXXX 
 
14 
 
XXXXX 
XXXXX 
 
15 
 
XXXXX 
XXXXX 
 
16 
 
XXXXX 
XXXXX 
 
17 
 
XXXXX 
XXXXX 
 
18 
 
XXXXX 
XXXXX 
 
19 
 
XXXXX 
XXXXX 
 
20 
 
XXXXX 
XXXXX 
 
21 
 
XXXXX 
XXXXX 
 
22 
 
XXXXX 
XXXXX 
 
23 
 
XXXXX 
XXXXX 
 
24 
 
XXXXX 
XXXXX 
 
25 
 
XXXXX 
XXXXX 
 
26 
 
XXXXX 
XXXXX 
 
27 
 
XXXXX 
XXXXX 
 
28 
 
XXXXX 
XXXXX 
 

ECOG-ACRIN 
E2211 
Cancer Research Group 
Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
66 
E2211 Patient Pill Calendar – Arm B 
 
 
Patient ID:___________Cycle #:__________ Dose: Take _____# of Temozolomide capsules once 
daily Dose:  Take _____# of Capecitabine tablets twice daily 
Cycle 
Day 
Date 
Capecitabine 
Times 
Temozolomide 
Time 
Notes 
 
MM/DD/YY 
# of Tablets 
Taken 
XX:XX 
AM/PM 
# of Capsules 
Taken 
XX:XX 
PM 
Note any symptoms/side effects 
you experience or any 
medications you take besides 
Capecitabine or Temozolomide. 
1 
 
XXXXX 
XXX 
 
2 
 
XXXXX 
XXX 
 
3 
 
XXXXX 
XXX 
 
4 
 
XXXXX 
XXX 
 
5 
 
XXXXX 
XXX 
 
6 
 
XXXXX 
XXX 
 
7 
 
XXXXX 
XXX 
 
8 
 
XXXXX 
XXX 
 
9 
 
XXXXX 
XXX 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
16 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
17 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
18 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
19 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
20 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
21 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
22 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
23 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
24 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
25 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
26 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
27 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 
28 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
 

ECOG-ACRIN 
E2211 
Cancer Research Group 
Version Date: June 29, 2015 
 
NCI Update Date: April 29, 2015 
67 
A Randomized Phase II Study of Temozolomide or Temozolomide and Capecitabine in 
Patients with Advanced Pancreatic Neuroendocrine Tumors 
 
Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.