Randomized Phase II Study of Cisplatin and Etoposide Versus Temozolomide and Capecitabine in Patients With Advanced Poorly Differentiated (G3) Non-Small Cell Gastrointestinal Neuroendocrine Carcinomas
Phase: PHASE2
Conditions: Gastric Neuroendocrine Carcinoma, Intestinal Neuroendocrine Carcinoma, Pancreatic Neuroendocrine Carcinoma
Sponsor: ECOG-ACRIN Cancer Research Group

 
EA2142 
1 
Randomized Phase II Study of Platinum and Etoposide 
versus Temozolomide and Capecitabine in Patients with 
Advanced G3 Non-Small Cell Gastroenteropancreatic 
Neuroendocrine Tumors including Poorly Differentiated 
Neuroendocrine Carcinomas and Well-Differentiated 
Neuroendocrine Neoplasms 
STUDY CHAIR: Jennifer Eads, M.D. 
STUDY CO-CHAIR: George Fisher, M.D., Ph.D. 
STUDY STATISTICIAN: Paul Catalano, Sc.D. 
PATHOLOGY CO-CHAIR: David Klimstra, M.D. 
IMAGING STATISTICIAN: Zheng Zhang, Ph.D. 
IMAGING CO-CHAIRS: Daniel L. Rubin, MD, MS 
 Terence Z. Wong, M.D., Ph.D. 
 Andrei Iagaru, M.D.  
GASTROINTESTINAL COMMITTEE CO-CHAIRS: Peter O’Dwyer, M.D. 
  Terence Z. Wong, M.D., Ph.D. 
Version Date:  January 23, 2020 
NCI Update Date:  November 6, 2015 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
US SITES ONLY  
 
November 6, 2015 
ALLIANCE / Alliance for Clinical Trials in Oncology  
Addendum #1- Prior to activation 
NRG / NRG Oncology 
 
Update #1- Prior to activation 
SWOG / SWOG 
 
Addendum #2 – 2/17 
 
 
Addendum #3 – 9/19 
NCTN GROUP STUDY CHAMPIONS 
 
Addendum #4 
ALLIANCE: Thorvardur R. Halfdanarson, MD 
 
 
NRG: Walid L. Shaib, MD 
 
 
SWOG: Heloisa Soares, MD 
 
 
 
Agents 
IND# 
NSC# 
Supply 
Cisplatin 
IND Exempt Study 
NSC 119875 
Commercially available 
Carboplatin  
IND Exempt Study 
NSC 241240 
Commercially available  
Etoposide 
IND Exempt Study 
NSC 141540 
Commercially available 
Temozolomide 
IND Exempt Study 
NSC 362856 
Commercially available 
Capecitabine 
IND Exempt Study 
NSC 712807 
Commercially available 
Rev. 2/17 
Rev. Add3 
Rev. Add3 

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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Rationale for Selected Approach and Trial Design .................................... 7 
1.2 
Population to be studied ........................................................................... 7 
1.3 
Selection of cisplatin and etoposide ......................................................... 8 
1.4 
Selection of temozolomide and capecitabine ......................................... 10 
1.5 
Rationale for proposed study .................................................................. 12 
1.6 
Selection of progression free survival as primary endpoint ................... 13 
1.7 
Clinical Relevance of Study ..................................................................... 13 
2. Objectives ......................................................................................................... 14 
2.1 
Primary Objectives .................................................................................. 14 
2.2 
Secondary Objectives .............................................................................. 14 
2.3 
Laboratory Research Objectives ............................................................. 14 
3. Selection of Patients ......................................................................................... 15 
3.1 
Eligibility Criteria ..................................................................................... 15 
4. Randomization Procedures ............................................................................... 19 
4.1 
Randomization ........................................................................................ 23 
4.2 
Eligibility Verification .............................................................................. 24 
4.3 
Stratification Factors ............................................................................... 24 
4.4 
Additional Requirements ........................................................................ 24 
4.5 
Instructions for Patients who Do Not Start Assigned Protocol Treatment26 
5. Treatment Plan ................................................................................................. 27 
5.1 
Administration Schedule ......................................................................... 27 
5.2 
Adverse Event Reporting Requirements ................................................. 29 
5.3 
Dose Modifications ................................................................................. 35 
5.4 
Supportive Care ....................................................................................... 47 
5.5 
Duration of Therapy ................................................................................ 48 
5.6 
Duration of Follow-up ............................................................................. 48 
6. Measurement of Effect ..................................................................................... 49 
6.1 
Antitumor Effect – Solid Tumors ............................................................. 49 
7. Study Parameters .............................................................................................. 57 
7.1 
Therapeutic Parameters .......................................................................... 57 
8. Drug Formulation and Procurement ................................................................. 59 
8.1 
Capecitabine............................................................................................ 59 
8.2 
Temozolomide ........................................................................................ 60 
8.3 
Cisplatin ................................................................................................... 62 
8.4 
Carboplatin .............................................................................................. 65 
8.5 
Etoposide ................................................................................................ 67 
9. Statistical Considerations .................................................................................. 70 
9.1 
Endpoints ................................................................................................ 70 

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9.2 
Revised statistical plan after Spring 2019 DSMC recommendation (July 
2019) ....................................................................................................... 70 
9.3 
Feasibility ................................................................................................ 72 
9.4 
Safety monitoring .................................................................................... 73 
9.5 
Study Monitoring .................................................................................... 73 
9.6 
Gender and Ethnicity (Revised for July 2019 amendment) .................... 73 
9.7 
Correlative Studies Statistics ................................................................... 74 
10. Imaging Study Submissions ............................................................................... 75 
10.1 Standard-of-Care Imaging Time Points and Minimum Preferred Phases75 
10.2 Images Submission .................................................................................. 75 
11. Specimen Submissions ...................................................................................... 76 
11.1 Submissions to the Central Biorepository and Pathology Facility (CBPF)76 
11.2 Shipping Guidelines ................................................................................. 77 
11.3 ECOG-ACRIN Sample Tracking System .................................................... 78 
11.4 Use of Specimens in Research ................................................................ 78 
11.5 Sample Inventory Submission Guidelines ............................................... 79 
12. Laboratory Research Studies ............................................................................ 80 
12.1 Central Diagnostic and Ki-67 Analysis (MANDATORY, INTEGRATED) ..... 80 
12.2 Research Studies ..................................................................................... 80 
12.3 Lab Data Transfer Guidelines .................................................................. 82 
13. Electronic Data Capture .................................................................................... 83 
14. Patient Consent and Peer Judgment ................................................................ 83 
15. References ........................................................................................................ 83 
Appendix I  Pathology Submission Guidelines ........................................................ 86 
Appendix II  Patient Thank You Letter ..................................................................... 90 
Appendix III  Patient Pill Calendar ........................................................................... 91 
Appendix IV  ECOG Performance Status ................................................................. 93 
Appendix V  Patient Drug Information Handout and Wallet Card .......................... 94 
 

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NCI Update Date: November 6, 2015 
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STUDY CHAIR 
ALLIANCE CHAMPION 
Jennifer Eads, MD  
University of Pennsylvania, Abramson Cancer 
Center 
3400 Civic Center Blvd 
South Pavilion, 10th Floor 
Philadelphia, PA 19104 
Phone: (215) 615-1725 
Fax: (215) 349-8551 
Email: jennifer.eads@uphs.upenn.edu 
Thorvardur R. Halfdanarson, MD 
Mayo Clinic 
200 First Street Southwest 
Rochester, MN 55905 
Phone: (507) 293-0462  
Fax: (507) 284-1803  
Email: halfdanarson.thorvardur@mayo.edu  
STUDY CO-CHAIR 
NRG CHAMPION 
George Fisher, M.D. 
Stanford University Medical Center 
269 Campus Drive, 
CCSR Building Room 1115 
Stanford, CA 94305 
Phone: (650) 723-9057 
Fax: (650) 725-9113 
Email: georgeaf@stanford.edu  
Walid L. Shaib, MD 
Emory University School of Medicine, 
Winship Cancer Institute of Emory University 
Clifton Campus 
1365-C Clifton Rd., NE 
Atlanta, GA 30322 
Phone: (404) 778-1900 
Fax: (404) 778-2177 
Email: wshaib@emory.edu  
 
STUDY CHAIR LIAISON (SCL) 
SWOG CHAMPION 
Maryann Redlinger RN, BSN, OCN 
Abramson Cancer Center, University of 
Pennsylvania 
3400 Civic Center Blvd, 12 South Pavilion #24 
Philadelphia, PA 19104 
Office: (215) 662-7452 
Cell: (267) 319-2078 
Fax: (215) 662-2417 
Email: Maryann.Redlinger@uphs.upenn.edu  
Heloisa Prado Soares, MD 
UNM Cancer Center 
1201 Camino de Salud Northeast 
Albuquerque, NM 87131 
Phone: (505) 925-0408 
Email: hsoares@salud.unm.edu  
 
 
Rev. 2/17 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
(Sign in at www.ctsu.org, and 
select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions on 
using the Oncology Patient Enrollment 
Network (OPEN) which can be accessed 
at https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
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 current 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) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or 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.  
The CTSU Web site is located at   https://www.ctsu.org 
 

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Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
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Schema 
Arm A1
Capecitabine 750 mg/m2 po every 12 hours 
(+/- 2 hours) days 1-14
Temozolomide 200 mg/m2 po daily days 10-14
Stratify
ECOG PS 0-1 vs. 
ECOG PS 2
GI vs. pancreatic NETS
R
A
N
D
O
M
I
Z
E
Arm B1
Cisplatin 25 mg/m2 IV daily days 1-3
Etoposide 100mg/m2 IV daily days 1-3
OR
Carboplatin target AUC of 5 on day 13
Etoposide 100mg/m2 IV daily days 1-3
Accrual: 80
Cycle: Arm A-28 days
Arm B-21 days
All doses are based on actual body weight.
Images and radiology report submissions are required. See Section 4.4.5 for submission instructions and Section 10 for outline. 
1. Treatment will continue until progression or unacceptable toxicity.
2. Capecitabine dose in mg/m2 is PER DOSE and this dose should be taken every 12 hours.
3. Please refer to Section 5.1.2 for specific dose for Carboplatin
 
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1. 
Introduction 
1.1 
Rationale for Selected Approach and Trial Design 
Neuroendocrine carcinomas of the GI tract, while increasing in incidence, are 
uncommon with an age-adjusted annual incidence of 3.65/100,000 according to 
the Surveillance, Epidemiology, and End Results (SEER) database. Amongst 
these tumors, those with a high-grade (G3) are rare and account for 
approximately 11% of all gastroenteropancreatic neuroendocrine tumors. These 
are aggressive carcinomas that typically present at a late stage and have a 
dismal median overall survival of only 10 months (1). To date, and even for the 
current standard of care regimen, no prospective trial has been conducted to 
guide treatment for this disease and current treatment recommendations are 
extrapolated from the small cell lung cancer literature. Data pertaining to 
histologic classification and tumor biology are also extremely limited making the 
care of patients with this disease entity a significant challenge. Prospective 
studies evaluating potential treatment options with associated correlative studies 
to better understand the histologic and molecular features of these carcinomas 
are therefore desperately needed. 
1.2 
Population to be studied 
The current WHO classification system defines G3 gastroenteropancreatic 
neuroendocrine carcinomas (NECs) as those with a Ki-67 of greater than 20% or 
a mitotic rate of > 20/10 high-powered fields (2). These are high grade malignant 
neoplasms that are histologically categorized as small cell, large cell or mixed 
neuroendocrine carcinomas with small cell carcinomas (accounting for 
approximately 35-43% of all lesions) being pathologically distinctive from the 
remaining classes of carcinomas (large cell or mixed neuroendocrine 
carcinomas) (3,4). Given the inclusion of a Ki-67 of greater than 20% up to 
100%, this encompasses a broad range of proliferative indices that may in fact 
be more reflective of a very heterogeneous group. The Ki-67 labeling index has 
not been specifically evaluated amongst these subsets of G3 
gastroenteropancreatic neuroendocrine carcinomas but amongst small cell lung 
cancer and neuroendocrine carcinomas of the lung it has been demonstrated 
that small cell lung cancer exhibits a significantly higher Ki-67 labeling index than 
large cell neuroendocrine carcinomas of the lung (5). Overall this would suggest 
that while all histologic subtypes are classified under one category (G3), small 
cell gastroenteropancreatic neuroendocrine carcinomas may be distinct from 
non-small cell gastroenteropancreatic neuroendocrine carcinomas. From a 
clinical standpoint, observations of heterogeneity within this population have also 
been made. In a study of patients with poorly differentiated 
gastroenteropancreatic neuroendocrine carcinomas (both small cell and non-
small cell included) it was reported that patients not responding well to platinum 
based therapy in the front-line setting (the current standard of care), often 
responded better to temozolomide based therapy, an agent used more for the 
treatment of well differentiated neuroendocrine tumors. Patients responding to 
temozolomide based therapy, while meeting the overall criteria for a 
neuroendocrine carcinoma, had Ki-67 levels in the lower end of the spectrum 
(less than 60%) and were noted to have tumor specimens that stained positive 
immunohistochemically for chromogranin A as well as positive octreotide scans 

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(6). These features all suggest a lesion that may be more aligned with a well 
differentiated neuroendocrine tumor. A subsequent retrospective evaluation of 
305 patients with poorly differentiated neuroendocrine carcinomas (again, both 
small cell and non-small cell histologies included) showed that using a Ki-67 of 
55% as a cutoff, patients in the lower Ki-67 range (20-54%) had a poorer 
response to platinum based therapy as compared to patients in the higher Ki-67 
range (55-100%), with response rates of 15% vs. 42% respectively. However 
patients in the lower Ki-67 range had an improved 30 month survival as 
compared to patients in the high Ki-67 range with 30 month survival rates of 23% 
and 7% respectively (4). These data suggest that although currently classified as 
one tumor type, G3 gastroenteropancreatic neuroendocrine carcinomas are 
heterogeneous and may warrant a different treatment approach, particularly 
carcinomas with non-small cell histology. It is important to note that while well-
differentiated pancreatic primaries and other gastrointestinal primaries are 
treated utilizing different treatment approaches. For G3 lesions of either 
gastrointestinal or pancreatic origin, the treatment approach is the same. 
1.3 
Selection of cisplatin and etoposide 
Historically, patients with G3 gastroenteropancreatic neuroendocrine carcinomas 
are treated similarly to patients with small cell lung cancer given the histologic 
similarities between these two diseases and this is reflected in the guidelines of 
the National Cancer Comprehensive Network (NCCN) (7). As a result, cisplatin 
and etoposide, the current standard front-line therapy for small cell lung cancer, 
is also the standard front-line treatment for patients with a G3 
gastroenteropancreatic neuroendocrine carcinoma. There have been no 
randomized prospective studies assessing cisplatin and etoposide in G3 
gastroenteropancreatic neuroendocrine carcinomas but this regimen has been 
evaluated in the front-line setting for treatment of G3 gastroenteropancreatic 
neuroendocrine carcinomas in two small studies (one prospective, n=18, one 
retrospective, n=41) with observed response rates of 42-67% and an associated 
overall survival ranging from 15-19 months (8,9). In addition to being small 
studies, the definition of a poorly differentiated carcinoma in these trials was not 
consistent with the criteria used today and likely included carcinomas with small 
cell histology. Even with limited data for platinum and etoposide for treatment of 
G3 gastroenteropancreatic neuroendocrine carcinomas, it is the standard of care 
and therefore will serve as the control arm for this study. 
1.3.1 
Clinical experience with cisplatin and etoposide (control arm) 
Current standard therapy for G3 gastroenteropancreatic 
neuroendocrine carcinomas is derived in large part from the small cell 
lung cancer literature and the NCCN (National Comprehensive 
Cancer Network) guidelines defer recommendations regarding 
treatment of G3 GI neuroendocrine carcinomas to the management of 
small cell lung cancer (7). Standard therapy for small cell lung cancer 
involves treatment with cisplatin and etoposide. A phase II study of 
VP-16 (etoposide) and cisplatin was conducted in 11 patients with 
limited stage and 20 patients with extensive stage small cell lung 
cancer. Of 17 evaluable patients with extensive disease, 29% 
achieved a complete response and an additional 59% achieved a 
partial response for an overall response rate of 88%. This was 

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associated with a median duration of response of 26 weeks and a 
median survival time of 39 weeks (10). A subsequent randomized 
phase III study of standard dose vs. high dose etoposide in 
combination with cisplatin for patients with extensive stage small cell 
lung cancer showed no improvement with higher doses of etoposide 
but confirmed excellent response rates, reporting a complete 
response rate of 22% and a partial response rate of 61% for an 
overall response rate of 83%. This was associated with a median 
overall survival of 11 months (11). A randomized phase III study of 
cisplatin and etoposide vs. cisplatin and irinotecan in patients with 
extensive stage small cell lung cancer showed a complete response 
rate of 9.1% and a partial response rate of 67.5% in the cisplatin and 
etoposide group for an overall response rate of 76.6%. This was 
associated with a median overall survival of 9.4 months (12). 
Additional randomized phase III studies have evaluated the role of 
cisplatin and etoposide in small cell lung cancer (13-15) with reported 
response rates of 44%, 63% and 57% respectively and associated 
median progression free survival of 4.6, 5.2 and 6.3 months 
respectively. Based on these data, cisplatin and etoposide has been 
established as the front-line regimen in the treatment of small cell lung 
cancer. 
To a lesser extent, cisplatin and etoposide have been evaluated in 
high grade GI neuroendocrine carcinomas and in none of these 
studies was the G3 definition applied. A phase II study of 18 patients 
with “anaplastic” neuroendocrine carcinomas reported an overall 
response rate of 67%, a median duration of regression of 8 months 
and a median overall survival of 19 months (8). The results of this 
study are limited by the use of both an outdated classification system 
and outdated response criteria. A retrospective study of 41 patients 
with a poorly differentiated neuroendocrine carcinoma reported a 
response rate of 42%, a progression free survival of 8.9 months and 
an overall survival of 15 months (9). In addition to being retrospective 
in nature, this study was limited by the inclusion of 21 (out of 41 total) 
patients with primary tumors involving the respiratory tract, 
mediastinum, head and neck or unknown primary site. A retrospective 
study of 258 patients with poorly differentiated neuroendocrine 
carcinomas of the GI tract treated with either cisplatin and irinotecan 
or cisplatin and etoposide reported a response rate of 27% and a 
median progression free survival of 4 months in the cisplatin and 
etoposide treated group (16). Finally, a retrospective study of 305 
patients with poorly differentiated gastroenteropancreatic 
neuroendocrine carcinomas reported a response rate of 31% and a 
median progression free survival of 4 months in 252 patients receiving 
platinum containing front-line therapy (4). When combined with the 
data in small cell lung cancer, these studies have served as the 
backbone supporting the use of cisplatin and etoposide in the 
treatment of poorly differentiated/G3 gastroenteropancreatic 
neuroendocrine carcinomas. Using these reported results, we have 
estimated a progression free survival of 6 months for the cisplatin and 
etoposide containing control arm of this study. 

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1.3.2 
Substitution of carboplatin for cisplatin 
Given the toxicities associated with cisplatin, carboplatin is standardly 
used as an acceptable alternative treatment per the Small Cell Lung 
Cancer NCCN guidelines (7). These two agents have been found to 
be equivalent in multiple studies including small phase II trials, a 
retrospective study and a meta-analysis (17-20). 
1.4 
Selection of temozolomide and capecitabine 
Temozolomide as a single agent has been evaluated in two phase II studies. 
When administered as second or third-line treatment to 28 patients with G3 
gastroenteropancreatic neuroendocrine carcinomas (as defined only by Ki-67 
greater than 20%, tumor histologic subtype not reported) a response rate of 0% 
and a median overall survival of 3.5 months were observed (10). Several other 
studies, however, have demonstrated response to a temozolomide based 
regimen in both poorly differentiated and well differentiated settings. When 
administered to 64 patients with relapsed sensitive or refractory small cell lung 
cancer, a response rate of 22% and a median overall survival of 5.8 months were 
observed (11). A retrospective evaluation of patients with G3 
gastroenteropancreatic neuroendocrine carcinomas treated with temozolomide 
+/- capecitabine +/- bevacizumab in the second-line setting showed a response 
rate of 33% and a median overall survival of 22 months (6), the best overall 
survival of any regimen evaluated in this disease type. A retrospective analysis of 
29 patients with neuroendocrine neoplasms who received temozolomide and 
capecitabine was recently conducted where primary sites included the pancreas 
(14 patients), gastrointestinal tract (5 patients), lung (8 patients) and unknown (2 
patients). Six of these patients had G3 lesions, 2 of which had a Ki-67 of 20-30%. 
Both of these patients had a partial response to therapy (12). Amongst patients 
with well differentiated pancreatic neuroendocrine tumors, a regimen of 
temozolomide and capecitabine appears very promising with a retrospective 
analysis of 30 patients receiving this treatment showing a response rate of 70% 
and a median progression free survival of 18 months (13). A small study 
reporting results in 28/38 planned patients with well differentiated neuroendocrine 
tumors (including 12 gastrointestinal carcinoid tumors and 11 pancreatic 
neuroendocrine tumors) receiving temozolomide and capecitabine demonstrates 
promising results; gastrointestinal carcinoids showed stable disease in 58%, a 
partial response in 33% and a complete response in 8% with a median 
progression free survival of > 22 months. In the pancreatic neuroendocrine tumor 
group, 55% showed stable disease, 45% had a partial response and median 
progression free survival was > 18.2 months (14). Also supporting the use of a 
temozolomide based regimen, a survey of international neuroendocrine experts 
conducted at the North American Neuroendocrine Tumor Society annual meeting 
in October, 2012 identified that of any regimen used for the second-line treatment 
of G3 gastroenteropancreatic neuroendocrine carcinomas, temozolomide and 
capecitabine was overwhelmingly the most popular at 41% of those surveyed. 
The next most commonly used regimens (streptozocin, irinotecan or platinum) 
had only 14% support comparatively. Clearly, the evidence base is scant and 
additional prospective study is required. 
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1.4.1 
Clinical experience with temozolomide and capecitabine 
Multiple small studies of a variety of chemotherapy regimens have 
been conducted in the second line setting for the treatment of small 
cell lung cancer with very few promising results. Investigated 
regimens include both single agent and combination regimens of 
paclitaxel, gemcitabine, irinotecan, temozolomide, carboplatin, 
capecitabine and oxaliplatin (26-37). Treatment with carboplatin and 
paclitaxel showed the most promising response rate of 45-83% 
however median overall survival with this regimen has ranged from 
only 5.3-7.9 months (31). Even fewer studies have evaluated poorly 
differentiated/G3 gastroenteropancreatic neuroendocrine carcinomas 
specifically. A retrospective analysis of 25 patients with poorly 
differentiated gastroenteropancreatic neuroendocrine carcinomas who 
received a temozolomide-based regimen following treatment with a 
platinum based therapy was conducted. Patients received 
temozolomide alone, temozolomide plus capecitabine or either of 
these regimens plus bevacizumab and were reported to have an 
overall response rate of 33% with an associated progression free 
survival of 22 months (6), a progression free survival superior to any 
other second line therapy in either small cell lung cancer or poorly 
differentiated gastroenteropancreatic neuroendocrine carcinomas. As 
such, despite being retrospective data, a temozolomide-based 
regimen is accepted by many in the neuroendocrine community (and 
is used in actual practice) as an appropriate treatment option for 
second-line therapy in poorly differentiated/G3 gastroenteropancreatic 
neuroendocrine carcinomas. A recent retrospective analysis of 29 
patients with neuroendocrine neoplasms who received temozolomide 
and capecitabine was recently conducted where primary sites 
included the pancreas (14 patients), gastrointestinal tract (5 patients), 
lung (8 patients) and unknown (2 patients). Six of these patients had 
G3 lesions, 2 of which had a Ki-67 of 20-30%. Both of these patients 
had a partial response to therapy. A total of 72% had either a partial 
response or stable disease, thereby demonstrating clinical benefit in 
patients with both poorly differentiated (G3) and well differentiated 
neoplasms (23). 
As previously described, the G3 neuroendocrine carcinoma subset is 
likely comprised of a heterogeneous group of tumors as it contains 
neoplasms with both small cell and non-small cell histology. 
Particularly amongst the non-small cell subgroup, it is hypothesized 
that many non-small cell neoplasms may behave more like a well-
differentiated tumor as many of the truly high grade, poorly 
differentiated carcinomas are often of small cell histology. In addition 
to demonstrating activity in poorly differentiated/G3 neuroendocrine 
carcinomas, temozolomide based regimens show promise in the well 
differentiated neuroendocrine tumors as well, particularly 
neuroendocrine tumors of the pancreas, which is also the most 
common site of origin amongst G3 gastroenteropancreatic 
neuroendocrine carcinomas (23, 38-40). In a phase II study of 29 
patients with GI neuroendocrine tumors (pancreatic neuroendocrine 
tumors, carcinoids and paragangliomas, 28 well differentiated and 1 
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poorly differentiated) treated with temozolomide and thalidomide, an 
overall response rate of 25% was observed (45% in pancreatic 
neuroendocrine tumors, 7% in carcinoids). After a median follow-up 
period of 26 months, progression free survival and overall survival 
could not be reported (38). A phase II study of temozolomide and 
bevacizumab reported a response rate of 15% (33% in pancreatic 
neuroendocrine tumors, 0% in carcinoids) with an associated median 
progression free survival of 11.0 months (14.3 months in pancreatic 
neuroendocrine tumors, 7.3 months in carcinoids) (40). A 
retrospective study of 30 patients with pancreatic neuroendocrine 
tumors receiving a combination of temozolomide and capecitabine 
showed a response rate of 70% with a median progression free 
survival of 18 months (24). Finally, a small study reporting results of 
28/38 planned patients with well differentiated neuroendocrine tumors 
(including 12 gastrointestinal carcinoid tumors and 11 pancreatic 
neuroendocrine tumors) receiving temozolomide and capecitabine 
demonstrates promising results; gastrointestinal carcinoids showed 
stable disease in 58%, a partial response in 33% and a complete 
response in 8% with a median progression free survival of > 22 
months. In the pancreatic neuroendocrine tumor group, 55% showed 
stable disease, 45% had a partial response and median progression 
free survival was >18.2 months (25). These data have established a 
temozolomide based regimen as a reasonable consideration in the 
treatment of well differentiated pancreatic neuroendocrine tumors and 
emerging data suggests that this regimen is efficacious in well 
differentiated neuroendocrine tumors of non-pancreatic origin as well. 
To date, no other systemic chemotherapy has shown antitumor 
activity against both well differentiated and poorly differentiated 
gastroenteropancreatic neuroendocrine neoplasms. 
1.5 
Rationale for proposed study 
Based on both pathologic and clinical evidence, we believe that despite being 
categorized as a single entity, G3 gastroenteropancreatic neuroendocrine 
carcinomas are a heterogeneous group of tumors that may not all be best served 
by treatment with the current standard, platinum and etoposide, particularly 
tumors with non-small cell histology. Amongst the non-small cell subgroup, 
features outlined above suggest that some of these carcinomas may behave 
more like a well differentiated neuroendocrine tumor. Based on evidence that 
temozolomide and capecitabine show clinical activity in both well differentiated 
and the G3 population of gastroenteropancreatic neuroendocrine 
tumors/carcinomas, as well as consensus amongst the neuroendocrine treatment 
community that a temozolomide based regimen is a favored treatment option for 
this population and is already in use by many physicians, a regimen of 
temozolomide and capecitabine appears to be the most promising and warrants 
further investigation within this population. We therefore aim to conduct a 
randomized phase II study evaluating platinum (cisplatin or carboplatin) and 
etoposide (standard therapy) vs. temozolomide and capecitabine for the 
treatment of advanced G3 gastroenteropancreatic neuroendocrine carcinomas of 
the non-small cell subtype. We further plan to prospectively collect tissue 
specimens and patient images to conduct correlative molecular and imaging 
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analyses that may also improve our understanding of the underlying biology of 
this disease. 
1.6 
Selection of progression free survival as primary endpoint 
Given the poor prognosis for this disease entity, overall survival was considered 
as a primary endpoint. However, we have chosen progression free survival as 
our primary endpoint for this study as it is anticipated that there will be a high rate 
of crossover to the opposite treatment arm at the time of disease progression, 
particularly with such limited treatment options for this disease. We will plan 
instead to evaluate overall survival as a secondary endpoint, the results of which 
will be more descriptive and exploratory in nature. 
1.7 
Clinical Relevance of Study 
Neuroendocrine tumors in general are rare and only 11% of them are 
neuroendocrine carcinomas categorized as a G3 lesion (1). As such, G3 
neuroendocrine carcinomas are an orphan disease that has not been well 
studied and to date, no prospective study has been conducted in this patient 
population to evaluate either standard therapy (platinum and etoposide) or any 
other regimen in the front-line setting under the current WHO classification 
system. Current recommendations for treatment of this disease are largely based 
on the small cell lung cancer literature and this is also reflected in the National 
Comprehensive Cancer Network (NCCN) guidelines (7). While there are 
similarities histologically between these two diseases, there are also likely many 
differences, particularly when considering tumors with non-small cell histology. 
Given the paucity of data regarding G3 gastroenteropancreatic neuroendocrine 
carcinomas, further studies are very much in need. 
While there are histologic similarities between small cell lung cancer and G3 
gastroenteropancreatic neuroendocrine carcinomas, only 35-43% of these 
tumors have small cell histology with the remaining being of large cell or mixed 
histology (3). As data for treatment of this disease is extrapolated from the small 
cell lung cancer literature, it is unclear that the current standard of care (platinum 
and etoposide) is truly the most appropriate treatment regimen, particularly 
amongst the non-small cell population. Additionally, as described above, the 
current classification system for G3 gastroenteropancreatic neuroendocrine 
carcinomas encompasses a broad range of Ki-67 levels. Recent retrospective 
clinical data suggests that Ki-67 may influence response to treatment and impact 
survival suggesting an underlying pathologic heterogeneity under the umbrella of 
one diagnosis (4), however this has not been prospectively evaluated. A clearer 
understanding of both the biology of these carcinomas as well as their response 
to the proposed regimens, using an updated classification system and in the 
context of a large, prospective, randomized study has great potential to result in 
findings that could be practice changing. 
This is the first attempt to conduct a prospective randomized study in G3 
gastroenteropancreatic neuroendocrine carcinomas. As this is a rare disease, the 
conduct of a subsequent phase III study would be unlikely. The results of this 
study would represent the largest clinical experience gained in the treatment of 
G3 gastroenteropancreatic neuroendocrine carcinomas and therefore would 
likely be practice changing, particularly for the non-small cell variety of G3 
gastroenteropancreatic neuroendocrine carcinomas. 
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2. 
Objectives 
2.1 
Primary Objectives 
2.1.1 
To assess the progression free survival (PFS) of platinum (cisplatin or 
carboplatin) and etoposide versus the PFS of temozolomide and 
capecitabine in patients with advanced G3 non-small cell 
gastroenteropancreatic neuroendocrine carcinomas. 
2.2 
Secondary Objectives 
2.2.1 
To assess the response rate (RR) of platinum (cisplatin or carboplatin) 
and etoposide versus the RR of temozolomide and capecitabine in 
patients with advanced G3 non-small cell gastroenteropancreatic 
neuroendocrine carcinomas. 
2.2.2 
To assess the overall survival (OS) of platinum (cisplatin or 
carboplatin) and etoposide versus the OS of temozolomide and 
capecitabine in patients with advanced G3 non-small cell 
gastroenteropancreatic neuroendocrine carcinomas. 
2.2.3 
To evaluate the toxicities associated with the combination of 
temozolomide and capecitabine and the combination of platinum 
(cisplatin or carboplatin) and etoposide, respectively, in patients with 
advanced G3 non-small cell gastroenteropancreatic neuroendocrine 
carcinomas. 
2.3 
Laboratory Research Objectives 
2.3.1 
To assess the impact of each treatment regimen on PFS, RR and OS 
based on Ki-67 index in patients with advanced G3 non-small cell 
gastroenteropancreatic neuroendocrine carcinomas. 
2.3.2 To assess the prognostic significance of well differentiated versus 
poorly differentiated non-small cell gastroenteropancreatic 
neuroendocrine tumors in relationship to survival and response to 
treatment.  
2.3.3 
To assess the agreement in Ki-67 status between that reported by 
institutional pathologist and that reported by central pathology review. 
 
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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, M) _______________________ 
Physician Signature and Date ___________________ 
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 
Patients must have a locally advanced and unresectable or metastatic 
gastroenteropancreatic neuroendocrine carcinoma that is either 
known or suspected to be of GI origin. Primary tumors arising from the 
lung, gynecologic organs or prostate are not permitted. 
3.1.2 
Patients must have pathologically/histologically confirmed tumor of 
non-small cell histology. 
3.1.3 
Patients must have a Ki-67 proliferative index of 20-100% OR at least 
10 mitotic figures per 10 high powered fields 
3.1.4 
Patients 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 within 4 weeks prior to 
randomization and must be acquired by multiphasic CT or contrast 
MRI.   
NOTE: 
PET-CT scans are allowed provided the CT portion of the 
exam is equivalent to a diagnostic CT scan and includes 
both oral and IV contrast. 
3.1.5 
Patients may not have had any prior systemic therapy (chemotherapy, 
targeted therapy, PRRT) for this malignancy. Prior somatostatin 
therapy is permitted. Prior palliative radiation is permitted but radiated 
lesions may not be used for measurement. 
3.1.6 
Patients may not have received any of the protocol agents within 5 
years prior to randomization.  
3.1.7 
Any prior surgeries must have been completed at least 4 weeks prior 
to randomization.  
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3.1.8 
Patients must be at least ≥ 18 years of age. 
3.1.9 
Patients must have an ECOG performance status of 0-2. 
3.1.10 
Patients may not be receiving any other investigational agents while 
on study treatment. 
3.1.11 
Patients may not be receiving Coumadin while on treatment. Other 
anticoagulants are allowed. 
3.1.12 
Patients must have normal organ and marrow function as definded 
below within less than or equal to 14 days prior to randomization: 
3.1.12.1 
Leukocytes ≥ 3,000/mm3 
Leukocytes ________ Date: ________ 
3.1.12.2 
Absolute neutrophil count ≥ 1,500/mm3 
Neutrophil count: ________ Date: ________ 
3.1.12.3 
Hemoglobin ≥ 9 g/dL 
Hemoglobin: ________ Date: ________ 
3.1.12.4 
Platelets ≥ 100,000/mm3 
Platelets: ________ Date: ________ 
3.1.12.5 
Total bilirubin ≤ institutional upper limit of normal (ULN) or 
≤ 1.5 X institutional ULN (if the patient has liver 
metastases). 
ULN: ________ Bilirubin: ________ Date: ________ 
3.1.12.6 
AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional ULN or (≤ 5 
X institutional ULN if the patient has liver metastases). 
ULN: ________ AST ________ Date: ________ 
ULN: ________ ALT ________ Date: ________ 
3.1.12.7 
Serum creatinine ≤ 1.5 X institutional ULN and creatinine 
clearance ≥ 60 ml/min 
ULN: ________ Creatinine: ________ Date: ________ 
NOTE: 
Creatinine Clearance must be calculated using 
the Cockcroft-Gault equation. 
3.1.13 
Patients must have a life expectancy of ≥ 12 weeks as determined 
clinically by the treating physician. 
3.1.14 
Patients with brain metastases (either remote or current) or presence 
of carcinomatous meningitis are not eligible 
3.1.15 
Patients with known DPD deficiency will be excluded as the use of 
capecitabine is contraindicated in these patients. 
3.1.16 
Patients must NOT have active or uncontrolled infection, symptomatic 
heart failure, unstable angina pectoris, cardiac arrhythmia or a serious 
psychiatric illness/social situation that would limit compliance with 
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3.1.17 
Patients with impaired decision making capacity may participate in the 
study if a legal authorized representative is available to consent. 
3.1.18 
Patients must NOT have a history of allergic reactions attributed to 
compounds of similar chemical or biochemical composition to 
cisplatin, carboplatin, etoposide, temozolomide or capecitabine. 
3.1.19 
Patients must NOT have absorption issues that would limit the ability 
to absorb study agents. 
3.1.20 
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: ____ 
3.1.21 
Patients with symptomatic peripheral vascular disease are not eligible. 
3.1.22 
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, superficial 
bladder 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 of disease: ________ 
3.1.23 
Women must not be pregnant or breast-feeding due to potential harm 
to the fetus from cisplatin, carboplatin, etoposide, 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 achieved menarche at some point 2) has 
not undergone a hysterectomy or bilateral oophorectomy; or 3) has 
not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 
consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female of child bearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.24 
Women of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of 
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contraception or to abstain from sexual intercourse for the duration of 
their participation in the study.  
3.1.25 
Patients must be able to swallow pills. 
3.1.26 
Patients must be able to tolerate CT or MR imaging including contrast 
agents as required for the treatment and the protocol. 
3.1.27 
Patients who are known to have HIV or are on combination 
antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions with cisplatin, carboplatin, etoposide, 
temozolomide, and/or capecitabine. In addition, these patients are at 
increased risk of lethal infections when treated with marrow-
suppressive therapy. Appropriate studies will be undertaken in 
patients receiving combination antiretroviral therapy when indicated. 
 
 
 
 
 
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 
Cancer Therapy Evaluation Program Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, Rave, or TRIAD OR acting as a 
primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In 
addition, IVRs and NPIVRs must list all clinical practice sites and Institutional Review 
Boards (IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Addition to a site roster; 

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• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval. 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 
participating organization (i.e., Alliance). Additional information is located on the CTEP 
website at https://ctep.cancer.gov/investigatorResources/default.htm. For questions, 
please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by emailing the email address above or calling 1-888-651-
CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 

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• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents:  
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a PO on the protocol. 
• 
Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of your screen 
• 
Enter the protocol number in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand, then select ECOG-ACRIN, 
and protocol number EA2142; 
• 
Click on Documents, select Site Registration, and download and complete the forms 
provided.  
NOTE: For sites under the CIRB initiative, IRB data will load automatically to the 
CTSU as described above. 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log on to the CTSU members’ website → 
Regulatory → Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
Required Protocol Specific Regulatory Documents 
1. 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. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 

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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 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site’s registration status on the members’ side of the CTSU website. 
• 
Log on to the CTSU members’ website 
• 
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 
NOTE: 
The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to randomization. 
Treatment should start within ten working days after randomization.  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 

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• 
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). 
• 
A diagnostic specimen is available for central pathology review. 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. 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 Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The 
Rave Home section displays a table providing summary counts of Total Delinquencies 
and Total Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules 
are available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the 
CTSU website. Staff that have Rave study access can access the Rave study data using 
a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
NOTE: 
Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization (LPO) for delinquent 
form details and reports to be available on the DQP. Site staff should contact 
the LPO Data Manager for their protocol regarding questions about Rave 
Calendaring functionality. 
4.1 
Randomization 
The following information will be requested for randomization: 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.1.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 

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• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
4.3 
Stratification Factors 
Patients will be stratified by the following factors to ensure balance between 
arms. 
4.3.1 ECOG PS 0-1 vs. ECOG PS 2  
4.3.2 
GI vs. Pancreatic NET 
4.4 
Additional Requirements 
4.4.1 
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. 
4.4.2 
Biological specimens are to be submitted as indicated in Section 11. 
4.4.3 
Medidata Rave is a clinical data management system being used for 
data collection for this trial/study. Access to the trial in Rave is 
controlled through the CTEP-IAM system and role assignments. To 
access Rave via iMedidata, site staff will need to be registered with 
CTEP and have a valid and active CTEP-IAM account; and assigned 
one of the following Rave roles on the relevant Lead Protocol 
Organization (LPO) or Participating Organization roster at the 
enrolling site: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), 
Rave SLA, or Rave Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. To the hold Rave CRA 
role or Rave CRA (Lab Admin) role, the user must hold a minimum of 
an AP registration type. To hold the Rave Site Investigator role, the 
individual must be registered as an NPIVR or IVR. Associates can 
hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 

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required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. If an eLearning is required and has not yet been 
taken, the link to the eLearning will appear under the study name in 
iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study 
in Rave will be granted, and a Rave EDC link will display under the 
study name. 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.4.4 
Imaging studies are to be submitted as indicated in Section 10 using 
TRIAD as indicated below. 
4.4.5 
Digital CT/MRI/PET Imaging Data Submission Using TRIAD  
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a 
secure method to transmit DICOM RT and other objects. TRIAD 
anonymizes and validates the images as they are transferred. 
TRIAD Access Requirements: 
• 
Site physics staff who will submit images through TRIAD will need 
to be registered with the Cancer Therapy Evaluation Program 
(CTEP) and have a valid and active CTEP Identity and Access 
Management (IAM) account, and be registered as an A, AP, 
NPIVR or IVR. Please refer to CTEP Registration Procedures of 
the protocol for instructions on how to request a CTEP-IAM 
account. 
• 
To submit images, site staff must hold the TRIAD Site User role 
on an NCTN or ETCTN roster. Individuals requiring a TRIAD Site 
User role should contact the person holding a primary role at the 
site for their affiliated NCTN or ETCTN roster.  
• 
All individuals on the Imaging and Radiation Oncology Core 
provider roster have access to TRIAD, and may submit images for 
credentialing purposes, or for enrollments to which the provider is 
linked in OPEN. 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with the proper user 
role, he/she will need to have the TRIAD application installed on 
his/her workstation to be able to submit images. TRIAD installation 

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documentation can be found by following this link 
https://triadinstall.acr.org/triadclient/   
This process can be done in parallel to obtaining your CTEP-IAM 
account username and password and RCR registration. 
If you have any questions regarding this information, please send an 
e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org or 1-
703-390-9858. 
4.5 
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 through Medidata 
Rave according to the schedule in the EA2142 Forms Completion Guidelines. 

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5. 
Treatment Plan 
NOTE:  
No therapies (investigational or commercial agents) other than those 
described below may be administered with the intent to treat the patient’s 
malignancy. No other investigational treatment may be given for any purpose 
while on study. 
NOTE: 
Patients whom have received prior somatostatin analogue therapy are 
permitted to stay on it if the treating physician feels that they are deriving 
clinical benefit from it for hormone mediated symptoms. 
NOTE: 
An assessment of drug-drug interactions between patient’s medication list 
and the assigned treatment should be conducted using updated package 
inserts prior to initiation of treatment. 
All doses are based on actual body weight. If there is a < 10% change in weight, keep 
the doses the same. If there is a ≥ 10% change in weight, a new dosing weight should 
be set and used for dose calculations. If the newly calculated weight results in no 
change to the dose (for oral agents only), the same dose may be used if felt to be 
indicated by the treating physician. 
5.1 
Administration Schedule 
5.1.1 
Capecitabine and Temozolomide —Arm A 
Cycle = 28 days (+/- 2 days) 
• 
Capecitabine 750 mg/m2 by mouth every 12 hours (+/- 2 hours) on 
days 1-14 
• 
Temozolomide 200mg/m2 by mouth once daily on days 10-14 
NOTE: 
Please refer to the Patient Pill Calendar in Appendix III. 
Patients are required to return their completed Patient Pill 
Calendar at each clinic visit. 
Premedication required: Ondansetron or an approved 5HT3 
antagonist should be used as a premedication 30-60 minutes prior to 
temozolomide. Other anti-emetics, anxiolytics, and analgesics may be 
provided at physicians’ discretion 
Continue treatment until patient develops disease progression (as 
defined by Section 6.1.4) or unacceptable toxicity  
Patients will need to be asked about other drugs they are taking at 
home such as OTC products, herbal medicines, tea, or other 
prescribed drugs. Patients should record this information on their Pill 
Calendar 
5.1.1.1 
Arm A Treatment Notes 
Monitor CBC and platelet count prior to drug 
administration.  
• 
The calculated total daily capecitabine dose by body 
surface area (BSA) will be used and treatement should 
be administered according to the following table Only 
500 mg tablets will be used:  
Rev. 2/17 
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Dose: 750 mg/m2 every 12 hours 
(or 1500 mg/m2/day) 
500 mg tabs 
Surface Area 
(m2) 
Total Daily Dose 
(mg) 
# tabs in 
AM 
# tabs in 
PM 
1.2-1.5 
2000 
2 
2 
1.51-1.83 
2500 
3 
2 
1.84-2.16 
3000 
3 
3 
2.17-2.5 
3500 
4 
3 
2.51-2.83 
4000 
4 
4 
• 
Capecitabine should be taken morning and night, with 
at least  12 hours (+/-2 hours) between each dose. 
Capecitabine pills should be swallowed with water 
within 30 minutes after a meal. Capecitabine pills may 
not be crushed. Capecitabine missed doses will not be 
made up and patients should not double-up on missed 
doses during treatment. 
• 
The temozolomide dose will be capped at 400 mg 
daily. The calculated dose by BSA will be rounded to 
the closest mg amount permitted within the confines of 
available pill sizes. Temozolomide should 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. 
5.1.2 
Cisplatin (or Carboplatin) and Etoposide—Arm B 
Cycle = 21 days (+/- 2 days) 
CBC will be monitored prior to day 1 of drug administration. 
Premedication with ondansetron (or other 5HT3 antagonist) and 
dexamethasone prior to each chemotherapy administration (days 1-3) 
is required. Additional antiemetics, analgesics and anxiolytics may be 
used per the discretion of the treating physician. Pre- and post- 
treatment hydration may be administered per institutional standards. 
If the treating physician chooses to use Aprepitant, when given 
once daily for 14 days as a 100 mg capsule with an oral contraceptive 
containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, this 
decreased the AUC of ethinyl estradiol by 43% and decreased the 
AUC of norethindrone by 8%. Women of childbearing potential using 
pregnancy contraception that includes ethinyl estradiol should not 
receive Aprepitant for the treatment of nausea/delayed emesis. 
Patients may change to a different method of contraception if they 
wish to use Aprepitant. 
• 
Cisplatin 25 mg/m2 daily x 3 days (days 1-3) to be administered 
per institutional guidelines. 

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OR 
• 
Carboplatin target AUC of 5 once on day 1 to be administered per 
institutional guidelines 
AND 
• 
Etoposide 100mg/m2 daily x 3 days (days 1-3) to be administered 
per institutional guidelines. 
Continue treatment until patient develops disease progression (as 
defined by Section 6.1.4) or unacceptable toxicity. 
NOTE: 
Treatment will be administered on an outpatient basis 
unless local institutional standard practice requires 
inpatient administration. 
NOTE: 
CALVERT FORMULA FOR CARBOPLATIN DOSING: 
Total Dose (mg) = (target AUC) x (GFR + 25) 
For the purposes of this protocol, the GFR is considered to be 
equivalent to the creatinine clearance. 
Round up any creatinine ≤ 0.6 mg/dL, to 0.6 mg/dL 
Glomerular Filtration Rate (GFR) Estimation: Calculated creatinine 
clearance of ≥ 50 cc/min using the Cockcroft-Gault formula: 
Males: 
(140 – Age in years) x Actual Body Weight in kg 
72 x Serum Creatinine (mg/dL) 
Females: Estimated creatinine clearance for males x 0.85 
With the Calvert formula, the total (final) dose of carboplatin is 
calculated in mg, not mg/m2. 
DO NOT exceed a dose of 150 mg per AUC or cap at 750 mg/AUC5. 
NOTE: 
Choice of platinum agent will be per treating physician 
discretion. Once a platinum agent is picked, no changes 
are allowed. 
5.2 
Adverse Event Reporting Requirements 
NOTE: 
Starting April 1, 2018, all expedited adverse events reporting through 
CTEP-AERS are required to use CTCAE v5, however, this study will 
continue to utilize CTCAE v4 for routine adverse event reporting in 
Rave and dose modifications. 
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 a trial using Medidata Rave.   
• 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
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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: Expected events are those that have been 
previously identified as resulting from administration of the agent. 
An adverse event is considered unexpected, for expedited 
reporting purposes, when either the type of event or the severity of 
the event is NOT listed in the protocol or drug package insert. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). The 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. 
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 (857-504-2900) 
• 
the FDA (1-800-FDA-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 
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documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
CTEP 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 EA2142 and outline 
the specific expedited adverse event reporting requirements for 
study EA2142.   

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5.2.5 
Steps to determine if an event is to be reported in an expedited 
manner 
 
Identify the type and grade of the event 
using CTCAE v5.0. 
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 
EA2142 
Commercial Agents:  Capecitabine, Temozolomide, Cisplatin, 
Carboplatin, and Etoposide 
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 
A death occurring while on study or within 30 days of the last dose of treatment requires both routine 
and expedited reporting, regardless of causality. Attribution to treatment or other cause must be 
provided. 
NOTE: A death due to progressive disease should be reported as a Grade 5 “Disease 
progression” under the System Organ Class (SOC) “General disorder and 
administration site conditions”.  Evidence that the death was a manifestation of 
underlying disease (e.g. radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted. 
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. 
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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. 
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 ECOG-ACRIN 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 ECOG-ACRIN 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 ECOG-ACRIN 
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5.3 
Dose Modifications 
5.3.1 
General 
Dose reductions will be based on current dose. If dose reduction is 
required, reduction is permanent. Missed doses will not be made up. 
No dose escalation is permitted for any of the study drugs.  
Dose will be modified for all drugs if there is ≥ 10% change in patient’s 
weight while on study. For oral agents, particularly capecitabine, a 
new dose calculation may result in the same number of pills to be 
administered due to rounding issues. 
Doses 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. 
Patients may receive a maximum of two dose reductions per agent. 
If a third reduction is required, the patient should discontinue all 
protocol treatment. However, for Arm A, patients may discontinue one 
agent due to toxicity and continue the other on-study.  
If different percentages of dose reductions for a specific drug are 
required because of two different types of toxicities, the greater 
percentage dose reduction should be undertaken. 
AEs determined to be unrelated to study treatment will not require 
dose reduction. 
NOTE: 
If patients have been off study treatment ≥ 4 weeks of 
next planned cycle start date, patients must 
discontinue protocol treatment. 
NOTE: 
Starting cycles early is prohibited due to safety purposes.  
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 
Capecitabine Dose Modifications 
Capecitabine will be initiated at 750 mg/m2 orally twice daily x 14 days 
on a 28-day treatment cycle. Dose should be calculated as a total 
daily dose of 1500mg/m2, then divided into two doses. 
For all capecitabine dose modifications, if the protocol indicated that 
the dose should be reduced for subsequent administrations, a 
reduction of at least 500 mg (of the total daily dose) should be 
implemented even if the calculation including the dose reduction 
results in the same number of pills as was originally administered 
(example: if treated originally at 2500 mg daily, only 2000 mg daily 
may be administered if a dose reduction was called for). 

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5.3.2.1 
Hematologic Toxicities 
ANC (/mm3) 
 
Platelets (/mm3) 
Modification 
< 1500/mm3 
and/or 
< 100,000/mm3 
Hold until ANC ≥ 1500/mm3 and 
platelets are ≥ 100,000/mm3, 
resume at 20% dose reduction 
≥ 1500/mm3 
and 
≥ 100,000/mm3 
No dose modification 
Mucositis, Diarrhea and Esophagitis 
** Adequate medical management for these conditions should be 
implemented before a dose modification is made for one of these 
symptoms** 
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 or 4 
Mucositis or esophagitis 
Hold until ≤ grade 1; resume at 
20% dose reduction 
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. 
5.3.2.2 
Hyperbilirubinemia 
If grade 3 or 4 hyperbilirubinemia occurs that is thought to 
be related to capecitabine, capcitabine should be held until 
the bilirubin improves to ≤ 3.0 x institutional ULN. 
For grade 3 toxicity, resume capecitabine at 75% of the 
original starting dose for the first incident, 50% of the 
original starting dose for the second incident, and 
discontinue treatment permanently for the third incident. If 
the patient has already had a dose modification for another 
toxicity, the new dose level should be used as the baseline 
for making these adjustments.  
For grade 4 toxicity, resume capecitabine at 50% of the 
original starting dose for the first incident and discontinue 
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patient has already had a dose modification for another 
toxicity, the new dose level should be used as the baseline 
for making these adjustments.   
5.3.2.3 
Non-hematologic Toxicity 
For other non-hematologic toxicities, dose reductions of 
capecitabine will be at the discretion of the investigator. A 
20% dose reduction must be performed with each 
subsequent reduction. A maximum of 2 dose reductions 
can be performed. 
5.3.3 
Temozolomide Dose Modifications 
• 
Dose reductions: For non-hematologic grade 3 and 4 AEs (except 
for nausea and vomiting as well as AEs unrelated to treatment) 
the dose should be reduced according to the Temozolomide Dose 
Level Table at the discretion of the investigator. Dose reductions 
for treatment day ANC and platelet counts should also be made 
according to the Dose Level Table below. Each dose reduction will 
be a 20% reduction from the prior level. 
• 
Discontinuation: Also, except for nausea and vomiting, if any of 
the same non-hematologic grade 3 and 4 AEs that are at least 
possibly related to temozolomide recur after two reductions for 
that AE, then temozolomide will be stopped. 
Temozolomide Dose Level Table 
Dose Level 
Dose in mg/m2 
0 
200 
-1 
160 
-2 
128 
* Note this is a 20% dose reduction with each dose level. 
5.3.3.1 
Hematologic Toxicity 
ANC (/mm3) 
 
Platelets (/mm3) 
% of Planned 
Temozolomide 
≥ 1500/mm3 
and 
≥ 100,000/mm3 
100% 
750-1499/mm3 
or 
50,000-99,999/mm3 
Hold* 
< 750/mm3 
or 
< 50,000/mm3 
Hold** 
* Upon recovery to ANC ≥ 1,500/mm3 and platelets to ≥ 
100,000/mm3, the dose level -1 will be administered (160 
mg/m2). Discontinue temozolomide dose if patients do not 
recover within ≤ 3 weeks. If patient was already receiving 
Temozolomide at the -1 dose level, reduce to the -2 dose (128 
mg/m2). 
** Upon recovery to ANC ≥ 1,500/mm3 and platelets to ≥ 
100,000/mm3, the dose level -2 will be administered (128 
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weeks. If patient was already receiving Temozolomide at the -
2 dose level, temozolomide should be discontinued. 
5.3.3.2 
Non-hematologic Toxicity 
For non-hematologic toxicities, dose reductions of 
temozolomide will be at the discretion of the investigator. 
Dose reductions must follow the Temozolomide Dose 
Level Table above. A maximum of 2 dose reductions can 
be performed. For patients with significant liver function 
abnormalities the benefits and risks of continuing treatment 
should be carefully considered. 
5.3.4 
Cisplatin or Carboplatin Dose Modifications 
• 
Dose reductions: For non-hematologic grade 3 and 4 AEs (except 
for nausea and vomiting as well as AEs unrelated to treatment) 
the dose should be reduced according to the Cisplatin/Carboplatin 
Dose Level Table at the discretion of the investigator. Dose 
reductions for treatment day (or within 2 days of treatment) ANC 
and platelet counts should also be made according to the Dose 
Level Table below. 
NOTE: 
The etoposide will be held if platinum is held until a 
decision is made to skip platinum for the current cycle so 
that all drugs are kept on the same schedule. 
• 
Discontinuation Also, except for nausea and vomiting, if any of the 
same non-hematologic grade 3 and 4 AEs that are at least 
possibly related to platinum recur after two reductions for that AE, 
then platinum will be stopped. 
• 
A patient’s protocol treatment will be discontinued if more than 2 
cumulative dose reductions are necessary or if patients are unable 
to restart platinum within 3 weeks of interruption. Dose reductions 
will be permanent. Missed doses will be made up once toxicity is 
resolved per guidelines below. 
• 
All toxicity grades below are described using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
Cisplatin Dose Level Table 
Dose Level 
Dose in mg/m2 (days 1-3) 
0 
25 
-1 
20 
-2 
16 
* Note this is a 20% dose reduction with each dose level. 
Carboplatin Dose Level Table 
Dose Level 
Dose in AUC (day 1) 
0 
5 
-1 
4 

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5.3.4.1 
Recommended Dose Modifications 
Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
BLOOD AND LYMPHATIC SYSTEM DISORDER 
Anemia 
Grade 1 (Hgb < LLN-10.0 g/dL) 
Maintain dose level. 
Maintain dose level. 
Grade 2 (Hgb < 10.0 g/dL - 8.0 g/dL) 
Maintain dose level. 
Maintain dose level. 
Grade 3 (Hgb < 8.0 g/dL); 
transfusion indicated 
Maintain dose level. 
Maintain dose level. 
Grade 4 (Life threatening 
consequences; urgent intervention 
indicated); related to study drugs  
Discontinue study treatment. 
Discontinue study treatment. 
ANC decreased (Neutropenia) 
Grade 1 (ANC < LLN - 1.5 x 
109/L) 
Maintain dose level. 
Maintain dose level 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain dose level. 
Maintain dose level 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, and no fever. 
Then: 
- If resolved in ≤ 7 days, then 
maintain dose level 
- If resolved in > 7 days, then 
maintain dose level and consider 
prophylactic growth factor support 
per ASCO guidelines 
- If second occurrence, then ↓ 1 
dose level for subsequent cycles. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, and 
no fever. Then: 
- If resolved in ≤ 7 days, then 
maintain dose level 
- If resolved in > 7 days, then 
maintain dose level and initiate 
prophylactic growth factor support 
per ASCO guidelines 
- If second occurrence, then ↓ 1 dose 
level for subsequent cycles. 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose of cisplatin until resolved 
to CTCAE ≤ Grade 1, then ↓ 1 dose 
level; additionally, consider 
prophylactic growth factor support 
per ASCO guidelines. 
Omit dose of carboplatin until 
resolved to CTCAE ≤ Grade 1, then 
↓ 1 dose level; additionally, consider 
prophylactic growth factor support 
per ASCO guidelines. 
Febrile neutropenia  
Grade 3 (ANC < 1.0 x 109/L, 
single temperature of > 38.3°C or 
a sustained temperature of ≥ 
38.0°C) 
Omit dose of cisplatin, then  
- If resolved by ≤ 7 days, then ↓ 1 
dose level and consider 
prophylactic growth factor support 
per ASCO guidelines. 
- If not resolved within 7 days 
despite appropriate management 
including full clinically indicated 
course of antibiotics, if indicated, 
discontinue patient from study 
treatment. 
Omit dose of carboplatin, then  
- If resolved by ≤ 7 days, then ↓ 1 
dose level and consider prophylactic 
growth factor support per ASCO 
guidelines. 
- If not resolved within 7 days despite 
appropriate management including 
full clinically indicated course of 
antibiotics, if indicated, discontinue 
patient from study treatment. 
Grade 4 
Discontinue study treatment. 
Discontinue study treatment. 
Platelet count decreased (Thrombocytopenia) 
Grade 1 (PLT < LLN - 75 x 109/L) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then maintain 
dose level  
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, then 
maintain dose level 
Grade 2 (PLT < 75 - 50 x 109/L) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then ↓ 1 dose 
level   
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, then 
↓ 1 dose level   
Grade 3 (PLT < 50 - 25 x 109/L ) 
Omit dose of cisplatin until resolved 
Omit dose of carboplatin until 

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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then then ↓ 
1 dose level.  
- If resolved in > 7 days, then 
discontinue study treatment. 
resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then then ↓ 
1 dose level.  
- If resolved in > 7 days, then 
discontinue study treatment. 
Grade 4 (PLT < 25 x 109/L ) 
Discontinue study treatment. 
Discontinue study treatment 
Bleeding 
Any bleeding (related to cisplatin or 
carboplatin) resulting in a 
transfusion requirement 
Omit dose of cisplatin until no 
further bleeding has been observed. 
Continuation of study treatment 
may be considered. 
Omit dose of carboplatin until no 
further bleeding has been observed. 
Continuation of study treatment may 
be considered. 
INVESTIGATIONS – RENAL  
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level. 
Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1 or baseline, 
then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then ↓ 1 
dose level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1 or 
baseline, then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then ↓ 1 
dose level. 
Grade ≥ 3 (> 3.0 x ULN) 
Discontinue study treatment. 
Discontinue study treatment 
INVESTIGATIONS – HEPATIC 
Blood Bilirubin b (for patients with Gilbert Syndrome these dose modifications apply to changes in direct bilirubin 
only)  
For patients with total bilirubin ≥ grade 3, a CT scan or equivalent imaging procedure to exclude disease progression 
or potential other liver disease should be performed. 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose level. 
Maintain dose level 
Grade 2 (>1.5 – 3.0 x ULN)  
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then ↓ 1 
dose level.  
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 
1, then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then 
↓ 1 dose level. 
Grade 3 (> 3.0 – 10 x ULN) or 
higher 
Discontinue study treatment. 
NOTE: If CTCAE Grade 3 or 4 
hyper-bilirubinemia is due 
to the indirect (non-
conjugated) component 
only, and hemolysis as the 
etiology has been ruled out 
as per institutional 
guidelines (e.g. review of 
peripheral blood smear and 
haptoglobin determination), 
then ↓ 1 dose level and 
continue treatment at the 
discretion of the 
Investigator. 
Discontinue study treatment. 
NOTE: If Grade 3 or Grade 4 
hyperbilirubinemia is due to 
the indirect (unconjugated) 
component only, and 
hemolysis as the etiology 
has been ruled out as per 
institutional guidelines (e.g., 
review of peripheral blood 
smear and haptoglobin 
determination), then ↓1 
dose level and continue 
treatment at the discretion 
of the investigator. 
AST or ALT 

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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
Grade 1 and 2 (up to 5.0 x ULN) 
Maintain dose level. 
Maintain dose level. 
Grade 3 (> 5.0 - 20.0 x ULN) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then ↓ 1 
dose level. 
Omit dose of carboplatin until 
resolved to Grade ≤1, then 
- If resolved in ≤ 7 days, then 
maintain dose level 
- If resolved in > 7 days, then ↓ 1 
dose level 
Grade 4 (> 20.0 x ULN) 
Discontinue study treatment. 
Discontinue study treatment 
NERVOUS SYSTEM DISORDERS 
Neurotoxicity 
Grade 1 
Maintain dose level. 
Maintain dose level. 
Transient Grade 2 that improves to 
grade 1 on the day of planned 
therapy 
Maintain dose level. 
Maintain dose level. 
Grade 2 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then ↓ 1 dose 
level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, then 
↓ 1 dose level. 
Grade ≥ 3 or second occurrence of 
Grade 2 
Discontinue study treatment. 
Discontinue study treatment. 
GI DISORDERS 
Diarrhea  
Grade 1 
Maintain dose level, but initiate anti-
diarrhea treatment as clinically 
indicated 
Maintain dose level, but initiate anti-
diarrhea treatment as clinically 
indicated 
Grade 2 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, including with 
appropriate management, then 
maintain dose level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, 
including with appropriate 
management, then maintain dose 
level. 
Grade 3 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, initiate anti-
diarrhea treatment, then 
- If resolved in ≤ 48 hours, maintain 
dose level. 
- If resolved in > 48 hours, then ↓ 1 
dose level. 
  
For 2nd occurrence of diarrhea 
CTCAE Grade 3 for > 48 hours 
despite the use of anti-diarrhea 
treatment, discontinue study 
treatment. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, 
initiate anti-diarrhea treatment, then 
- If resolved in ≤ 48 hours, maintain 
dose level. 
- If resolved in > 48 hours, then ↓ 1 
dose level. 
  
For 2nd occurrence of diarrhea 
CTCAE Grade 3 for > 48 hours 
despite the use of anti-diarrhea 
treatment, discontinue study 
treatment. 
Grade 4 
Discontinue study treatment. 
Discontinue study treatment. 
Nausea/Vomiting 
Grade 1 
Maintain dose level, but initiate anti-
emetic treatment. 
Maintain dose level, but initiate anti-
emetic treatment. 
Transient Grade 2 that improves 
to grade 1 on the day of planned 
therapy 
Maintain dose level. 
Maintain dose level. 

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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
Grade 2 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, initiate anti-
emetic treatment, then maintain 
dose level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, 
initiate anti-emetic treatment, then 
maintain dose level. 
Grade 3 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, initiate anti-
emetic treatment, then: 
- If resolved in ≤ 48 hours, maintain 
dose level. 
- If resolved in > 48 hours, then ↓ 1 
dose level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, 
initiate anti-emetic treatment, then: 
- If resolved in ≤ 48 hours, maintain 
dose level. 
- If resolved in > 48 hours, then ↓ 1 
dose level. 
Grade 4 
Discontinue study treatment. 
Discontinue study treatment. 
GENERAL DISORDERS 
Fatigue 
Grade 1 or 2 
Maintain dose level. 
Maintain dose level. 
Grade 3 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, maintain 
dose level. 
- If resolved in  7 days, discontinue 
patient from study treatment. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, maintain 
dose level. 
- If resolved in  7 days, discontinue 
patient from study treatment. 
Grade 4 
Discontinue study treatment. 
Discontinue study treatment. 
INFUSION REACTIONS 
Infusion reactions 
Grade 1 
(Transient flushing or rash, fever  
< 38 °C [<100.4 °F]; intervention 
not indicated) 
- Stop infusion 
- Treat per institutional guidelines.  
- May resume infusion (within 4 
hours of initial start of infusion) 
at 50% of previous under 
continuous observation. Ensure 
that there is a minimum 
observation period of 1 hour 
prior to restarting the infusion. 
- Maintain dose level. 
- If the AE recurs at the reinitiated 
slow rate of infusion, and despite 
oral pre-medication, then do not 
resume infusion. 
- Stop infusion 
- Treat per institutional guidelines.  
- May resume infusion (within 4 
hours of initial start of infusion) at 
50% of previous under continuous 
observation. Ensure that there is 
a minimum observation period of 
1 hour prior to restarting the 
infusion. 
- Maintain dose level. 
- If the AE recurs at the reinitiated 
slow rate of infusion, and despite 
oral pre-medication, then do not 
resume infusion. 
Grade 2 
(Intervention or infusion 
interruption indicated; responds 
promptly to symptomatic treatment 
[e.g., antihistamines, NSAIDS, 
narcotics]; prophylactic 
medications indicated for ≤24 hrs) 
- Stop infusion 
- Treat per institutional guidelines.  
- May resume infusion (within 4 
hours of initial start of infusion) 
at 50% of previous under 
continuous observation. Ensure 
that there is a minimum 
observation period of 1 hour 
prior to restarting the infusion. 
- Maintain dose level. 
- If the AE recurs at the reinitiated 
slow rate of infusion, and despite 
oral pre-medication, then do not 
- Stop infusion 
- Treat per institutional guidelines.  
- May resume infusion (within 4 
hours of initial start of infusion) at 
50% of previous under continuous 
observation. Ensure that there is 
a minimum observation period of 
1 hour prior to restarting the 
infusion. 
- Maintain dose level. 
- If the AE recurs at the reinitiated 
slow rate of infusion, and despite 
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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
resume infusion. 
resume infusion. 
Grade 3 
Prolonged [e.g., not rapidly 
responsive 
to symptomatic medication and/or 
brief interruption of infusion]; 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for clinical 
sequelae [e.g., renal impairment, 
pulmonary infiltrates]) 
- Discontinue infusion 
immediately 
- Treat per institutional guidelines.  
- Discontinue patient from study. 
- Discontinue infusion 
immediately 
- Treat per institutional guidelines.  
- Discontinue patient from study. 
Grade 4 (Life-threatening; urgent 
intervention indicated) 
- Discontinue infusion 
immediately 
- Treat per institutional guidelines.  
- Discontinue patient from study. 
- Discontinue infusion 
immediately 
- Treat per institutional guidelines.  
- Discontinue patient from study. 
OTHER ADVERSE EVENTS 
Grade 1 or 2 
 
 
Grade 3 
 
 
Grade 4 
Maintain dose level of cisplatin or carboplatin.  For intolerable grade 2 
toxicity, may omit dose of cisplatin or carboplatin until resolved. 
 
Omit dose of cisplatin or carboplatin until resolved to CTCAE Grade ≤ 1, 
then ↓ dose level of cisplatin or carboplatin. 
 
Discontinue study treatment. 
NOTE: All of the above are general guidelines.  The investigator may omit dose of drug, decrease dose level of 
drug, or remove any patient from study for any toxicity, if he/she believes that it is in the best interest of the 
patient. 
If a patient requires a dose delay of > 21 consecutive days of cisplatin or carboplatin then the patient must be 
discontinued from the study treatment. Patients who discontinue from the study for a study-related adverse event or 
an abnormal laboratory value must be followed at least once a week for 3 weeks and subsequently at 3-week 
intervals, until resolution or stabilization of the event, whichever comes first, unless stated otherwise. 
5.3.5 
Etoposide Dose Modifications 
• 
Dose reductions: For non-hematologic grade 3 and 4 AEs (except 
for nausea and vomiting as well as AEs unrelated to treatment) 
the dose should be reduced according to the Etoposide Dose 
Level Table at the discretion of the investigator. Dose reductions 
for treatment day (or within 2 days of treatment) ANC and platelet 
counts should also be made according to the Dose Level Table 
below. Each dose reduction will be a 20% reduction from the prior 
level. 
• 
Discontinuation: Also, except for nausea and vomiting, if any of 
the same non-hematologic grade 3 and 4 AEs that are at least 
possibly related to study treatment recur after reduction for that 
AE, then etoposide will be stopped. 
Etoposide Dose Level Table 
Dose Level 
Dose in mg/m2 (days 1-3) 
0 
100 

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Etoposide Dose Level Table 
-1 
80 
-2 
64 
* Note this is a 20% dose reduction with each dose level. 
5.3.5.1 
Hematologic Toxicity 
ANC (/mm3) 
 
Platelets (/mm3) 
Modification 
< 1500/mm3 
and/or 
< 100,000/mm3 
Hold until ANC ≥ 1500/mm3 
and platelets are ≥ 
100,000/mm3, resume at 
20% dose reduction* 
≥ 1500/mm3 
and 
≥ 100,000/mm3 
No dose modification 
*This table applies to day of treatment (or within 2 days of 
treatment) hematologic toxicities. 
* If ANC and platelet count recover within one week, resume 
therapy at 100%. If greater than 7 days to recovery, upon 
recovery to ANC ≥ 1,500/mm3 and platelets to ≥ 100,000/mm3, 
the dose level -1 will be administered (80 mg/m2). Discontinue 
etoposide dose if patients do not recover within ≤ 3 weeks. If 
patient was already receiving Etoposide at the -1 dose level, 
reduce to the -2 dose (64 mg/m2). 
If already receiving treatment at the -1 dose level, upon 
recovery to ANC ≥ 1,500/mm3 and platelets to  
≥ 100,000/mm3, the dose level -2 will be administered (64 
mg/m2). Discontinue dose if patients do not recover within 
≤ 3 weeks. If patient was already receiving Etoposide at 
the -2 dose level, treatment should be discontinued. 
Neutropenia or Febrile Neutropenia 
For nadir neutropenia in the absence of fever or with fever 
that is successfully treated by oral antibiotics, there will be 
no dose adjustment. Filgrastim, sargramostim, or 
pegfilgrastim are allowed and should be administered 
according to ASCO guidelines (54). For treatment delays 
due to chemotherapy toxicities of more than 7 days, 
Etoposide should be dose-reduced according to the 
Etoposide Dose Level Table for all subsequent cycles of 
chemotherapy. For neutropenic fever (ANC  
< 500/mm3) and temperature > 100.5F) requiring 
intravenous antibiotics, the doses of all chemotherapy 
drugs (cisplatin and etoposide) should be reduced by one 
dose level according to the Etoposide Dose Level Table 
and the Cisplatin Dose Level Table for the next cycle and 
all subsequent cycles. If counts to not recover within 4 
weeks, discontinue all protocol therapy. 

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Thrombocytopenia 
For grade 4 nadir platelet count decrease 
(thrombocytopenia) (platelets < 25,000/mm3), the dose of  
Etoposide should be reduced by one dose level according 
to the Etoposide Dose Level Table for the next cycle and 
for all subsequent cycles of chemotherapy. If counts do not 
recover within 4 weeks, discontinue all protocol therapy. 
Anemia 
No dose reduction will be made for anemia. Patients 
should be supported per the treating physician’s discretion. 
The use of blood transfusions for anemia will be allowed as 
indicated. The use of erythropoietin stimulating agents is 
not permitted. 
5.3.5.2 
Non-hematologic Toxicity 
Gastrointestinal Toxicity, Nausea and Vomiting 
All patients should receive antiemetics* to prevent nausea 
and vomiting. Steroids and 5-HT3 antagonists are required 
premedications but additional specific antiemetic therapy is 
left to the discretion of the treatment physician. If vomiting 
is severe, consider hospital admission and/or use of 
aprepitant if possible. Do not modify chemotherapy doses. 
* Aprepitant, when given once daily for 14 days as a 100 
mg capsule with an oral contraceptive containing 35 mcg 
of ethinyl estradiol and 1 mg of norethindrone, decreased 
the AUC of ethinyl estradiol by 43% and decreased the 
AUC of norethindrone by 8%. Women of childbearing 
potential using pregnancy contraception that includes 
ethinyl estradiol should not receive Aprepitant for the 
treatment of nausea/delayed emesis. Patients may 
change to a different method of contraception if they wish 
to use Aprepitant. 
Hepatotoxicity 
Bilirubin 
Etoposide* 
≤ 1.5 X ULN 
100% 
> 1.5 – 3.0 X ULN 
50% 
> 3.0 X - ≤ 5.0 ULN 
30% 
> 5 X ULN 
Hold** 
* Please note that the % dose administered is based on the 
original starting dose of etoposide (100 mg/m2). If patient is at 
dose level -1 or -2, % should be based on reduced dose the 
patient is currently on, not original dose. 
** For bilirubin greater than 5 X ULN it is recommended not to 
use etoposide for that cycle but this is at the discretion of the 
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up to 3 weeks until total bilirubin is ≤ 5 X ULN. The cisplatin 
dose should also be held if etoposide is held so that all drugs 
are kept on the same schedule. If bilirubin improves within 3 
weeks to ≤ 5 X ULN, then resume treatment and use reduced 
dose per table above. If bilirubin does not improve to ≤ 5 X 
ULN within 4 weeks, discontinue protocol therapy. 
Hypomagnesemia 
Hypomagnesemia is not an indication for stopping therapy. 
Oral or parenteral magnesium supplementation is indicated 
for serum magnesium levels < 1.5 mEq/L. 
Allergic Reactions 
Discontinue all protocol treatment promptly if ≥ grade 3 
anaphylaxis develops. 
Suggested Management of Allergic Reaction: 
In case of mild allergic symptoms (e.g., appearance of a 
localized or generalized pruritus), symptomatic treatment 
may be given (e.g., oral antihistamine or corticosteroids).  
Patient experiencing significant allergic reaction should be 
managed according to local institutional standards. A 
combination of corticosteroids, antihistamines, nebulized 
respiratory therapy with beta (2) agonists and isotonic fluid 
support should be employed as appropriate based on 
patient’s clinical condition. 
For Grade 3 or Grade 4 symptoms: (Grade 3: severe 
reaction; prolonged [i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion]; recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]; 
Grade 4: life-threatening; pressor or ventilatory support 
indicated): 
• 
Immediately discontinue chemotherapy infusion. Begin 
an i.v. infusion of normal saline and treat the subject as 
follows: Recommend bronchodilators, epinephrine 0.2 
to 1 mg of a 1:1,000 solution for subcutaneous 
administration, 0.3 mg of a 1:1,000 solution for 
intramuscular administration, or 0.1 to 0.25 mg of a 
1:10,000 solution slowly for i.v. administration, and/or 
diphenhydramine 50 mg i.v. with methylprednisolone 
100 mg i.v. (or equivalent), as needed. Subject should 
be monitored until the Investigator is comfortable that 
the symptoms will not recur. Cisplatin will be 
permanently discontinued. Investigators should follow 
their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor subject 
until recovery from symptoms. 

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Grade 3 or 4 Non-Hematologic Toxicity 
If patient develops grade 3 or 4 non-hematologic toxicity 
attributed to protocol therapy but not detailed above, hold 
all therapy. These can be restarted if the toxicity has 
resolved to < grade 1 by the time of the next treatment. 
Doses of Etoposide should then be reduced according to 
the Etoposide Dose Level Table (taking into consideration 
the treatment dose used in the prior cycle).  
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 or an equivalent 5HT3 antagonist is required as a 
premedication 30-60 minutes prior to temozolomide (Arm A). 
5.4.3 
Ondansetron or an equivalent 5HT3 antagonist and dexamethasone 
are required premedications prior to administration of platinum and 
etoposide (Arm B). 
5.4.4 
Hydration and/or diuresis for patients in Arm B is permitted and may 
be conducted per institutional guidelines. 
5.4.5 
In the event of platinum extravasation, apply a warm pack to reduce 
local discomfort and notify the treating physician of the extravasation. 
If indicated, restart peripheral IV in a larger vein. 
5.4.6 
For management of allergic reactions to cisplatin, see Suggested 
Management of Allergic Reactions under Section 5.3.5.2. 
5.4.7 
Patients must maintain adequate hydration and urinary output. 
Patients, on both arms, should be advised to increase oral fluid intake 
during treatment. 
5.4.8 
Aprepitant may be considered as an additional antiemetic for patients 
experiencing severe nausea and vomiting in Arm B. Caution with use 
of this medication should be considered as outlined in Section 5.1.2 in 
regard to female patients using oral contraceptive agents. All other 
antiemetic administration may be left to the discretion of the treating 
physician. 
5.4.9 
Appropriate supportive measures including Imodium and/or Lomotil 
should be implemented immediately to prevent dehydration should 
diarrhea develop. 
5.4.10 
The use of growth factors (filgrastim, sargramostim or pegfilgrastim) is 
permitted in both arms of the study and should be administered in 
accordance with ASCO guidelines (54). 
5.4.11 
The use of erythropoietin stimulating agents is NOT permitted. 
Anemia may be managed with blood transfusions as indicated. 
5.4.12 
Concomitant aminoglycoside antibiotic use should be avoided during 
platinum therapy until patient has fully recovered (i.e., at least 4 
weeks from last dose of platinum). 

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5.4.13 
Use of bisphosphonates or denosumab is allowed for patients with 
bone metastasis or hypercalcemia. 
5.4.14 
Anxiolytics and analgesics may be provided at physicians’ discretion.  
5.4.15 
Supplemental pyridoxine (vitamin B6) is contraindicated in patients 
receiving cisplatin and may not be administered in patients on Arm B. 
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 EA2142 Forms Packet. 
5.5.2 
Patient develops disease progression per Section 6.1.4. 
5.5.3 
Patient withdraws consent. 
5.5.4 
Patient experiences unacceptable toxicity  
5.5.5 
Non-protocol medical cancer therapies are administered. Localized 
surgical interventions or radiation intervention for a second primary 
malignancy may be permitted but should be discussed with the study 
chair prior to initiation. 
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 8 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) 

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as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area are not considered measurable. 
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 
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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.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
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 

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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 
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. 
FDG-PET 
The role of FDG-PET response in this disease requires additional 
study. As such, new lesions identified on FDG-PET imaging may not 
be used to determine disease progression. FDG-PET will be 
interpreted visually (uptake above mediastinal blood pool will be 
interpreted as positive). Standardized uptake values (SUV) will be 
recorded in identified lesions for purposes of evaluation of response to 
treatment. 
For correlative imaging studies, EORTC criteria will be used for the 
assessment of response to treatment by PET in solid tumors.  
1. Progressive metabolic disease (PMD) to be classified as an 
increase in FDG tumor SUV of greater than 25% within the tumor 
region defined on the baseline scan, visible increase in the extent 
of FDG tumor uptake (20% in the longest dimension) or the 
appearance of new FDG uptake in metastatic lesions. 
2. Stable metabolic disease (SMD) would be classified as an 
increase in tumor FDG SUV of less than 25% or a decrease of 
less than 15% and no visible increase in extent of FDG tumor 
uptake (20% in the longest dimension). 
3. Partial metabolic response (PMR) would be classified as a 
reduction of a minimum of 15 ± 25% in tumor FDG SUV after one 
cycle of chemotherapy, and greater than 25% after more than one 
treatment cycle. 
Reporting would need to be accompanied by adequate and 
disclosed reproducibility measurements from each centre. An 
empirical 25% was found to be a useful cut-off point, but there is a 
need for a reproducibility analysis to determine the appropriate 
cut-offs for statistical significance. A reduction in the extent of the 
tumor FDG uptake is not a requirement for partial metabolic 
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4. Complete metabolic response (CMR) would be complete 
resolution of FDG uptake within the tumor volume so that it was 
indistinguishable from surrounding normal tissue. 
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) 
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. 

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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. 
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 

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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). 
New effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
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/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the 
achievement of both measurement and confirmation 
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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  
1. Prestudy scans and x-rays used to assess all measurable or non-measurable 
sites of disease must be done within 4 weeks prior to randomization. 
2. Prestudy CBC (with differential and platelet count) and chemistries should be 
done ≤ 2 weeks before randomization. 
3. Pregnancy testing (if applicable) should be done within 2 weeks of 
randomization. 
 
Prior to 
Randomization 
(Baseline)1 
Day 1 of Each 
Treatment 
Cycle 
Every 8 
weeks 
Post 
Treatment9 
Tests and Observations 
 
 
 
 
Assessment of medical history2 
X 
X 
 
X 
Physical Examination2,13 
X 
X 
 
X 
Pulse, Blood Pressure2 
X 
X 
 
 
Height 
X 
 
 
 
Weight and BSA calculation2 
X 
X 
 
 
Performance Status2 
X 
X 
 
 
Tumor Measurements2 
X 
 
X 
X 
Adverse Events Assessment2 
X 
X 
 
X10 
Pill Count/Diary 
 
X11 
 
 
Laboratory and Imaging Studies 
 
 
 
 
CBC with Differential and Platelets3 
X 
X 
 
 
Serum Electrolytes and Liver Function Tests2,4 
X 
X 
 
 
Coagulation studies (PT, INR, aPTT) 
X 
X12 
 
 
Serum or Urine Pregnancy Test5 
X 
 
 
 
Radiographic Studies2,6 
X 
 
X 
X 
Image Submissions8 
X 
 
X 
 
Biological Specimen Submissions7. 
MANDATORY: Pre-trial FFPE tumor7 
X 
 
 
 
Peripheral Blood, ACD vacutainer 
X 
 
 
 
1. Baseline requirements must be assessed prior to randomization as outlined in Section 3. Blood tests 
must be performed ≤ 2 weeks prior to randomization. CT and/or MRI must be performed ≤ 4 weeks 
prior to randomization. 
2. After Cycle 1, the following assessments may be scheduled with a +/- 3 day window; Assessment of 
medical history, Physical Examination, Pulse and Blood Pressure, Weight/BSA calculation, 
Performance Status, Tumor Measurements, Adverse Events Assessment, Serum Electrolytes and 
Liver Function, Radiographic Studies, including Images. 
3. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb and Hct required 
for protocol therapy must be done < 24 hours prior to the treatment cycle. 
4. Serum Electrolytes and Liver Function Tests include Na+, K+, Cl-, bicarbonate, BUN, creatinine, 
glucose, Mg++, AST, ALT, alkaline phosphatase, total protein, albumin, total bilirubin and direct 
bilirubin. 
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5. All females of childbearing potential must have a negative [blood test or urine test] within 14 days 
prior to study registration to rule out pregnancy..  
6. CT of the chest, abdomen and pelvis. If only MRI of the abdomen and/or pelvis is available, this can 
be substituted for CT of the abdomen and/or pelvis but CT of the chest should still be obtained. 
Contrast agents should be administered unless otherwise contraindicated. PET-CTs can be used, so 
long as the CT portion is of the same diagnostic quality and includes IV and oral contrast. The same 
screening technique used at baseline should be used for all subsequent follow-up scans. Even 
though dosing schedules are different in the two treatment arms, radiographic imaging should be 
obtained every 8 weeks by calendar while on protocol treatment. 
7. Submit as outlined in Section 11. Mandatory diagnostic tumor tissue must be submitted for central 
diagnostic review and classification and ancillary laboratory research studies. Peripheral blood is to 
be submitted per patient consent.  Submit to within 4 weeks following randomization. 
8. Baseline and subsequent imaging studies should be submitted to the IROC Imaging Core Facility for 
central image banking < 4 weeks after each imaging time point. In addition to the CT/MRI scans, 
baseline and subsequent [18F]-FDG PET scans, 68Ga-PET scans and octreotide scans, if performed, 
should be submitted. 
9. After completion of protocol treatment, monitor for adverse events for 30 days following 
discontinuation of treatment. Monitoring for survival, and scans should be performed every 3 months 
until patient is 2 years from randomization. Monitoring for survival and scans should be completed 
every 6 months if patient is 3-5 years from randomization. Once the patient progresses, adverse 
event assessments and scans no longer need to be performed but patients should be followed for 
survival (every 3 months until 2 years from randomization, every 6 months if 3-5 years from 
randomization). 
10. Adverse Events Assessment is required 30 days after last dose of protocol therapy. 
11. Note this is only required for patients randomized to Arm A.  
12. Repeat coagulation studies only need to be followed in patients on anti-coagulant therapy and may 
be obtained within a +/- 3 day window along with serum electrolytes and liver function studies. 
13. Baseline physical exam should be performed within 14 days of randomization. 
 
Rev. Add3 
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8. 
Drug Formulation and Procurement 
Capecitabine, temozolomide, cisplatin and etoposide will all be obtained commercially. 
8.1 
Capecitabine  
8.1.1 
Other Names  
Xeloda 
8.1.2 
Classification  
Cytotoxic chemotherapy, anti-metabolite 
8.1.3 
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, bine 
to tyhmidylate 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. 
8.1.4 
Storage and Stability  
Capecitabine is supplied as biconvex, oblong film-coated pills, 
available as 500 mg pills (peach). Capecitabine is stored at 25 
degrees C, with excursions permitted to 15 to 30 degrees C. 
8.1.5 
Dose Specifics  
750 mg/m2 orally by mouth twice daily on days 1-14 (Arm A) 
The calculated total daily dose by body surface area (BSA) will be 
rounded down to the nearest 500 mg to allow doses using 500 mg 
pills. 
8.1.6 
Preparation  
Available as 500 mg pills 
8.1.7 
Route of Administration  
Capecitabine needs to be taken orally within 30 minutes after a meal 
8.1.8 
Incompatibilities  
N/A 
8.1.9 
Availability  
Commercially available 
8.1.10 
Side Effects  
Hematologic: anemia, neutropenia, thrombocytopenia 

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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, visual abnormalities 
Psychiatric: mood alteration, depression 
Pulmonary: dyspnea, cough, pharyngeal disorder, epistaxis, sore 
throat 
Vascular: venous thrombosis 
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, 
diarrhea, and hand-foot skin syndrome 
8.1.11.3 
Administer doses at least 12 hours (+/- 2 hours) apart. 
8.1.11.4 
Capecitabine pills should be swallowed with water within 
30 minutes after a meal. 
8.1.11.5 
Capecitabine pills may not be crushed. 
8.1.12 
References 
1. Capecitabine package insert 
8.2 
Temozolomide  
8.2.1 
Other Names  
Temodar 
8.2.2 
Classification  
Cytotoxic chemotherapy, alkylating agent 
8.2.3 
Mode of Action  
Temozolomide [8-carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-
4(3H)-one] (Temodar) is an imidazole tetrazinone compound 

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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. 
8.2.4 
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 degrees C (77F). Temozolomide 
should be stored at 20-25 degrees C (68-77F), excursions permitted 
between 15-30 degrees C (59-86F). 
8.2.5 
Dose Specifics  
200 mg/m2 by mouth once daily on days 10-14 (Arm A) 
The temozolomide dose will be capped at 400 mg daily and is 
available as 5, 20, 100, 140, 180, or 150 mg capsules. The calculated 
dose by body surface area (BSA) will be rounded down to minimize 
the number of pills required. 
8.2.6 
Preparation  
N/A 
8.2.7 
Route of Administration  
Oral 
8.2.8 
Incompatibilities  
N/A 
8.2.9 
Availability  
Commercially available 
8.2.10 
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 
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Infections: PCP infection 
Metabolic: hyperglycemia, liver or kidney abnormalities 
Neurologic: headache, somnolence, insomnia, blurred vision 
Oncologic: secondary malignancy 
Psychiatric: anxiety, depression 
8.2.11 
Nursing/Patient Implications  
8.2.11.1 
Monitor CBC and platelet count prior to drug 
administration. 
8.2.11.2 
Symptom management of expected nausea, vomiting, 
photosensitivity, and mucositis within ≤ 3 months prior to 
treatment. 
8.2.11.3 
Ondansetron (or other approved 5HT3 antagonist) will be 
given as a premedication to prevent nausea 30-60 minutes 
prior to the temozolomide dose. 
8.2.11.4 
Temozolomide should be taken at night by mouth after 
fasting from solid food for two hours. 
8.2.11.5 
Temozolomide pills must not be crushed and must be 
administered whole. 
8.2.11.6 
Temozolomide missed doses will not be made up, and 
patients should not double-up on missed doses during 
treatment. Do no repeat dose if vomiting occurs after dose 
is administered. 
8.2.11.7 
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. 
8.2.12 
References 
1. Temozolomide package insert 
8.3 
Cisplatin 
8.3.1 
Other Names  
Cisdiaminedichloroplatinum, Cis-diaminedichloroplatinum (II), 
diaminedichloroplatinum, cis-platinum, platinum, Platinol, Platinol-AQ, 
DDP, CDDP, DACP, NSC 119875. 
8.3.2 
Classification  
Cytotoxic chemotherapy, alkylating agent 
8.3.3 
Mode of Action  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. 
Other possible mechanism include chelation of DNA and binding to 
cell membranes thereby stimulating immune mechanisms. 
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8.3.4 
Storage and Stability  
Intact vials of cisplatin are stored at room temperature.  Solutions 
diluted with sodium chloride or dextrose are stable for up to 72 hours 
at room temperature.  Due to the risk of precipitation, cisplatin 
solutions should not be refrigerated. 
8.3.5 
Dose Specifics  
25 mg/m2 on days 1-3 of each cycle to be administered per 
institutional standard. Cycle length is 21 days (Arm B). 
8.3.6 
Preparation  
Cisplatin to be mixed per institutional standard. 
8.3.7 
Route of Administration  
Intravenous 
8.3.8 
Incompatibilities  
Amsacrine, cefepime, gallium nitrate, mesna, piperacillin, sodium 
bicarbonate, thiotepa. Cisplatin may react with aluminum with is found 
in some syringe needles or IV sets, forming a black precipitate. 
Compatibilities: 
Admixture: Amphotericin-B, aztreonam, carmustine, cefazolin, 
cephalothin, droperidol, etoposide, floxuridine, hydroxyzine, 
ifosphamide, leucovorin, magnesium sulfate, mannitol, potassium 
chloride. Y-site: Allopurinol, bleomycin chlorpromazine, cimetidine, 
cyclophosphamide, dexamethasone, diphenhydramine, doxapram, 
doxorubicin, famotidine, filgrastim, fludarabine, fluorouracil, 
furosemide, ganciclovir, heparin, hydromorphone, lorazepam, 
melphalan, methotrexate, methylprednisolone, metoclopramide, 
mitomycin, morphine, ondansetron, paclitaxel, prochlorperazine, 
ranitidine, sargramostim, vinblastine, vincristine, vinorelbine. 
Consult your pharmacist regarding specific concentrations. 
8.3.9 
Availability  
Commercially available as a mg/mL solution in 50 and 100 mg vials. 
8.3.10 
Side Effects  
Renal: A dose-related, cumulative renal tubular injury can occur; 
adequate hydration and diuresis usually minimize the risk. Salt-
wasting nephropathy and/or orthostatic hypotension with 
hyporeninemic hypoaldosteronism can occur in up to 10% of patients. 
Neurologic: A dose-related ototoxicity, manifested by high-frequency 
hearing loss and tinnitus occurs in about 30% of patients. 
Paresthesias, decreased vibratory, position, and touch sensations are 
less common; particularly at cumulative doses < 400 mg/m2. 
Hematologic: mild leukopenia and thrombocytopenia occur in 25-30% 
of patients, but are rarely dose-limiting; anemia is less common. A 
potentially fatal hemolytic uremic syndrome has been reported. 
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Gastrointestinal: severe, dose-limiting nausea and vomiting occur in 
almost 100% of patients unless adequate antiemetic prophylaxis is 
given. Even with successful prophylaxis of acute nausea a delayed 
(72-96 hour) reaction, requiring addition therapy may occur. Anorexia 
and taste changes may also occur. 
Hypersensitivity: allergic reactions are reported in up to 20% of 
patients. Symptoms include rash, facial edema, wheezing, 
hypotension and tachycardia. Severe anaphylaxis is rare. 
Other: electrolyte wasting (magnesium, potassium and sodium), 
papilledema, optic neuritis, retrobulbar neuritis, diarrhea, mouth sores, 
hair loss, dizziness, dehydration, nail changes, fatigue, fluid retention, 
chills, lowered white blood cell counts, rash, muscle aches, joint pain, 
headache, confusion, loss of coordination, difficulty swallowing, 
indigestion, blood clotting in veins, fainting, seizures, difficulty 
urinating. 
8.3.11 
Nursing/Patient Implications  
8.3.11.1 
Monitor CBC, platelet count, BUN and creatinine prior to 
drug administration. 
8.3.11.2 
Monitor for signs of ototoxicity or neurotoxicity. 
8.3.11.3 
Symptom management of expected nausea and vomiting. 
Ondansetron (or other 5HT3 antagonist) and 
dexamethasone will be given daily prior to chemotherapy 
administration. Additional antiemetics may be provided per 
physician discretion. 
If the treating physician chooses to use Aprepitant, when 
given once daily for 14 days as a 100 mg capsule with an 
oral contraceptive containing 35 mcg of ethinyl estradiol 
and 1 mg of norethindrone, this decreased the AUC of 
ethinyl estradiol by 43% and decreased the AUC of 
norethindrone by 8%. Women of childbearing potential 
using pregnancy contraception that includes ethinyl 
estradiol should not receive Aprepitant for the treatment of 
nausea/delayed emesis. Patients may change to a 
different method of contraception if they wish to use 
Aprepitant. 
8.3.11.4 
Pre- and post-treatment hydration may be administered 
per institutional standards. 
8.3.11.5 
Diuretics may be ordered as needed per physician 
discretion. 
8.3.11.6 
Use of granulocyte colony stimulating factors are 
permitted. 
8.3.11.7 
Observe for signs of allergic reaction. 
8.3.12 
References 
1. Alberts DS. Carboplatin versus cisplatin in ovarian cancer. Semin 
Oncol 1995;22 (5 Suppl 12):88-90. 
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2. Bonomi P. Platinum/etoposide therapy in non-small cell lung 
cancer. Oncology 1992;49 (Suppl 1):43-50. 
3. Dabholkar M, Reed E. Cisplatin. Cancer Chemother Biol 
Response Modifiers 1993;14:86-97. 
4. Fram RJ. Cisplatin and platinum analogues: recent advances. 
Curr Opin Oncol 1992;4:1073-9. 
5. Garrow GC, Johnson, DH. Treatment of "good risk" metastatic 
testicular cancer. Semin Oncol 1992;19:159-65. 
6. Markman M. Current status of intraperitoneal therapy for ovarian 
cancer. Curr Opinion Obstet Gynecol 1993;5:99-104. 
7. Ozols RF, et al. Advanced ovarian cancer. Dose intensity. Ann 
Oncol 1993; (4 Suppl 4):49-56. 
8. Saxman S. Salvage therapy in recurrent testicular cancer. Semin 
Oncol 1992;19:143-7. 
9. Wheeler RH, Spencer S. Cisplatin plus radiation therapy. J 
Infusional Chemother 1995;5:61-6. 
8.4 
Carboplatin 
8.4.1 
Other Names 
Paraplatin® 
8.4.2 
Classification 
Carboplatin (carboplatin injection) (platinum, diammine[1,1-
cyclobutanedicarboxylato(2-)-O,O’]-, (SP-4-2)) is a platinum 
coordination compound, used as an anti-neoplastic agent. It is a 
second-generation tetravalent organic platinum compound. It is a 
crystalline powder with the molecular formula of C6H12N2O4Pt and a 
molecular weight of 371.25. It is soluble in water at a rate of 
approximately 14 mg/mL, and the pH of a 1% solution is 5 to 7. It is 
virtually insoluble in ethanol, acetone, and dimethylacetamide. 
8.4.3 
Mode of Action 
Like cisplatin, carboplatin binds to DNA, thereby inhibiting DNA 
synthesis, in a cell cycle nonspecific manner. Carboplatin must first 
undergo activation to produce antineoplastic activity. Bidentate 
carboxylate ligands of carboplatin are displaced by water forming 
(aquation) positively charged platinum complexes, which bind to 
nucleophilic sites in DNA, such as the O-6 position on guanine. 
Carboplatin produces predominantly interstrand DNA crosslinks rather 
than DNA-protein crosslinks. Intrastrand crosslinks result from the 
formation of adducts between the activated platinum complexes of the 
drug and the N-7 atom (not exclusively) atom on guanine to produce 
1,2 intrastrand links between adjacent guanine molecules, between 
neighboring guanine and adenosine molecules, or between 
neighboring guanine molecules. Interstrand cross-linking within the 
DNA helix also occurs. Platinum adducts may inhibit DNA replication, 
transcription and ultimately cell division. 
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8.4.4 
Storage and Stability 
Store intact vials at room temperature at 25°C (77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Further 
dilution to a concentration as low as 0.5 mg/mL is stable at room 
temperature (25°C) for 8 hours in NS or D5W. Stability has also been 
demonstrated for dilutions in D5W in PVC bags at room temperature 
for 9 days; however, the manufacturer recommends use within 8 
hours due to lack of preservative. Multidose vials are stable for up to 
14 days after opening when stored at 25°C (77°F) following multiple 
needle entries. 
8.4.5 
Dose Specifics 
Carboplatin will be administered at AUC 5 IV on day 1 every 21 days 
(3 week cycles). 
Calvert Formula for Carboplatin (AUC) Dosing 
Total dose (mg) = target AUC (in mg/mL/minute) * GFR (in L/minute) 
+ 25] 
For the purposes of this protocol, the GFR is considered to be 
equivalent to the creatinine clearance. 
Glomerular Filtration Rate (GFR) Estimation: Calculated creatinine 
clearance of ≥ 50 cc/min using the Cockcroft-Gault formula: 
Males: 
(140 – Age in years) x Actual Body Weight in kg 
72 x Serum Creatinine (mg/dL) 
Females: Estimated creatinine clearance for males x 0.85 
With the Calvert formula, the total (final ) dose of carboplatin is 
calculated in mg, not mg/m2. 
8.4.6 
Preparation 
Manufacturer’s labeling states solution can be further diluted to 
concentrations as low as 0.5 mg/mL in NS or D5W; however, most 
clinicians generally dilute dose in either 100 mL or 250 mL of NS or 
D5W. Concentrations used for desensitization vary based on protocol. 
Hazardous agent; use appropriate precautions for handling and 
disposal. Needles or IV administration sets that contain aluminum 
should not be used in the preparation or administration of carboplatin; 
aluminum can react with carboplatin resulting in precipitate formation 
and loss of potency. 
8.4.7 
Route of Administration 
Intravenous 
8.4.8 
Incompatibilities 
Amphoterecin B chloesteryl sulfate complex. Aluminum reacts with 
carboplatin causing precipitate formation and loss of potency; 
therefore, needles or intravenous sets containing aluminum parts that 
may come in contact with the drug must NOT be used for the 
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8.4.9 
Availability 
Carboplatin (Bristol-Myers Oncology Division) is commercially 
available in 50, 150, and 450 mg vials. 
8.4.10 
Side Effects 
Hematologic: thrombocytopenia, neutropenia, leukopenia, anemia, 
more pronounced in patients with compromised renal function and 
heavily pretreated patients; may be cumulative. 
Gastrointestinal: nausea, vomiting, treatable with moderate doses of 
antiemetics. 
Dermatologic: rash, urticaria. 
Hepatic: abnormal liver function tests, usually reversible with standard 
doses. 
Neurologic: rarely peripheral neuropathy 
Renal: elevations in serum creatinine, BUN; electrolyte loss (Na, Mg, 
K, Ca). 
Other: pain, asthenia. 
8.4.11 
Nursing/Patient Implications 
8.4.11.1 
Monitor CBC and platelet count; nadir occurs at 
approximately day 21 with recovery by day 28-30. 
8.4.11.2 
Premedicate with antiemetics—evaluate effectiveness. 
Ondansetron (or other 5HT3 antagonist) and 
dexamethasone are required. 
8.4.11.3 
Monitor fluid status—maintain adequate hydration. Pre- 
and post-treatment hydration may be administered per 
institutional standards. 
8.4.11.4 
Assess skin/mucous membranes. 
8.4.11.5 
Assess for signs of peripheral neuropathy—coordination, 
sensory loss. 
8.4.12 
References 
1. Calvert AH, et al. Carboplatin dosage: Prospective evaluation of a 
simple formula based on renal function. J Clin Oncol 1989; 
7:1748-1756. 
2. Woloschuk DMM, Pruemer JM, Cluxton RJ. Carboplatin: A new 
cisplatin analog. Drug Intell Clin Pharm 1988; 22:843-849. 
3. Christian MC. Carboplatin. In: Principles and Practice of 
Oncology, PPO Updates 1989; 3(11):1-16. 
8.5 
Etoposide 
8.5.1 
Other Names  
VP-16, VePesid, VP-16-213, EPEG, epipodophyllotoxin, NSC # 
141540. 
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8.5.2 
Classification  
Cytotoxic chemotherapy, podophyllotoxin derivative. 
8.5.3 
Mode of Action  
Etoposide inhibits the enzyme topoisomerase II, nucleoside transport 
and incorporation, and causes DNA breakage. 
8.5.4 
Storage and Stability  
The injection should be stored at room temperature; the capsules 
must be refrigerated (2-8 degrees C). Following dilution in 0.9% 
sodium chloride or 5% dextrose to concentrations of 0.2-0.4 mg/mL 
the drug is chemically stable for 96 and 48 hours in the refrigerator 
and room temperature respectively (?). Bristol-Myers in-house data 
indicate that etoposide may be stable in 5% dextrose or normal saline 
for 24 hours (0.6 mg/mL), 4 hours (1 mg/mL), and 2 hours (2 mg/mL). 
8.5.5 
Dose Specifics  
100 mg/m2 on days 1-3 of each cycle per institutional standards. 
Cycle length is 21 days (Arm B). 
8.5.6 
Preparation  
Etoposide to be prepared per institutional standard. 
8.5.7 
Route of Administration  
Intravenous 
8.5.8 
Incompatibilities  
Etoposide is compatible with cisplatin 200mg/mL in D5½NS or NS for 
24 hours when protected from light. Addition of mannitol and/or 
potassium chloride reduces stability to 8 hours in NS, but remains 
stable for 24 hours in D5½NS in 5%; also compatible with cytarabine 
and daunorubicin. 
8.5.9 
Availability  
Commercially available 
8.5.10 
Side Effects  
Hematologic: leukopenia, dose-related, primarily granulocytopenia; 
nadirs within 7-14 days and recover within 20 days of administration; 
thrombocytopenia, uncommon; anemia. 
Dermatologic: alopecia is generally mild, reversible and is reported to 
occur in 20-66% of patients although some patients develop total 
baldness; rarely rash, rarely severe pruritus, rarely radiation recall 
reaction, phlebitis, local pain at injection site, rarely pigmentation. 
Gastrointestinal: nausea and vomiting, relatively uncommon, but more 
frequent with oral dosing; anorexia in 10-13% of patients; stomatitis, 
rarely with conventional doses, more common and more severe in 
patients who have received radiation to the head and neck and with 
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diarrhea, aftertaste, parotitis, dysphagia, and constipation occur 
rarely. 
Hypersensitivity: rarely anaphylaxis. 
Hepatic: hyperbilirubinemia and increase transaminase levels, usually 
mild, transient and more common in high dose protocols. 
Cardiovascular: transient hypotension, associated with rapid 
administration; rarely transient hypertension rarely; other 
cardiovascular events (e.g., congestive heart failure) thought to be 
related to large amounts of sodium chloride administered with the 
drug. 
Neurologic: peripheral neuropathy, somnolence, fatigue, headache, 
vertigo, transient cortical blindness (all rarely); transient confusion with 
high doses, perhaps due to the alcohol-containing vehicle. 
Other: rarely fever, muscle cramps, metabolic acidosis, 
hyperuricemia. 
8.5.11 
Nursing/Patient Implications  
8.5.11.1 
Monitor CBC and platelet count prior to drug 
administration. 
8.5.11.2 
Advise patient of possible alopecia. Instruct how to obtain 
wig, hairpiece, etc. 
8.5.11.3 
Observe for possible phlebitis at injection site or burning 
pain with infusion. 
8.5.11.4 
Monitor for rare anaphylactoid reaction. 
8.5.11.5 
Administer antiemetics as indicated. 
8.5.12 
References 
1. van Maanen JMS, et al. Mechanism of action of antitumor drug 
etoposide: A review. J Natl Cancer Instit 1988; 80:1526-1533. 
2. Stewart CF, Hampton EM. Stability of cisplatin and etoposide in 
intravenous admixtures. Am J Hosp Pharm 1989; 46:1400-1404. 
3. Seargeant LE, et al. In vitro stability and compatibility of 
daunorubicin, cytarabine and etoposide. Cancer Treat Rep 1987; 
71:1189-1192. 
4. Fleming RA, et al. Etoposide: An update. Clin Pharm 1989; 8:274-
293.  
5. O'Dwyer PJ, et al. Etoposide, current status of an active 
anticancer drug. N Engl J Med 1985; 312:692-7 
 

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9. 
Statistical Considerations 
9.1 
Endpoints  
Primary Endpoint; Progression-Free Survival  
Secondary Endpoint; Response Rate, Overall Survival, Toxicity  
9.2 
Revised statistical plan after Spring 2019 DSMC recommendation (July 2019) 
Sample size with power justification  
Accrual on this study has been lower than expected, averaging 1-2 patients per 
month. The ECOG-ACRIN DSMC reviewed this study in Spring 2019 and made 
the recommendation to modify the statistical plan to reduce the required power of 
the study to 80% in order to achieve a more realistic sample size and timeframe. 
Therefore, a total of 80 patients will now be the accrual target to achieve 78 
randomized eligible cases. The study seeks to establish an improvement in the 
primary endpoint, which is defined as a 67% improvement in median 
progression-free survival (PFS) from 6 months in the control arm (Arm B) to 10 
months in the experimental arm (Arm A). The study is now designed to have 80% 
power for this 40% reduction in the hazard rate with 71 PFS events at full 
information which is now expected to occur after 75 months of accrual and 7 
additional months of follow-up. The primary comparison remains a log-rank test 
at a one–sided significance level of 0.10. Under exponential distributions the 
hypothesized reduction corresponds to 1-year progression-free survival of 44% in 
Arm A versus 25% in Arm B. 
Analysis plan including plans for formal interim analysis 
The primary analysis set will include all randomized eligible patients. 
Progression-free survival (PFS) is defined as time from randomization to 
documented progression or death without progression. Patients without 
documented progression or death reported will be censored at the time of the last 
documented disease evaluation. In the secondary analyses, overall survival (OS) 
is defined as time from randomization to death from any cause, censoring cases 
who are alive at the date of last contact. Kaplan-Meier estimates will be used for 
event-time distributions. PFS and OS by arm will be compared using one-sided 
stratified log-rank tests. Stratified Cox’s proportional hazards models will be used 
to estimate hazard ratios. Response rate (complete response or partial response) 
and toxicity are also secondary endpoints. Response rate will be analyzed using 
a Fisher’s exact test at a one–sided significance level of 0.10. 
Patient demographics and disease characteristics will be compared using two-
sample t-tests or Fisher’s exact tests as appropriate. We will also conduct 
exploratory subset analyses with respect to PFS, OS, and response rate to 
evaluate the prognostic significance of Ki-67 with regard to these clinical 
endpoints. 
Toxicity will be evaluated among all treated patients regardless of eligibility and 
interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. With 39 eligible patients per arm, the study will have sufficient precision 
to provide 90% confidence interval on toxicity that will be no wider than 28%. For 
rare toxicities with 4% true probability, there will be 80% probability of observing 
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one or more toxicities on either treatment arm. 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 relatively large differences in adverse events. 
This study will include one interim analysis of PFS for efficacy at approximately 
48 months from the start of accrual (possibly near April 2020), which should 
correspond to 36 failures under the alternative hypothesis or 50% information 
time). A log rank test using an O’Brien-Fleming boundary will be conducted and 
under the alternative hypothesis there is probability of 0.29 that the efficacy 
boundary will be crossed. Regarding futility, if at the interim analysis the 
estimated hazard ratio for experimental/control is ≥1 the study will be reported as 
negative. If the estimated hazard ratio is less than 1 but the efficacy boundary is 
not crossed, the study will have its final analysis at 82 months of study. Results 
of the interim analysis will be presented to the ECOG-ACRIN Data Safety 
Monitoring Committee (DSMC) when appropriate. 
9.2.1 
Original statistical plan (prior to July 2019 amendment) 
9.2.1.1 
Sample size with power justification 
A total of 126 patients will be needed to accrue 120 
randomized eligible cases. The study seeks to establish an 
improvement in the primary endpoint, which is defined as a 
67% improvement in median progression-free survival 
(PFS) from 6 months in the control arm (Arm B) to 10 
months in the experimental arm (Arm A). The study is 
designed to have 90% power for this 40% reduction in the 
hazard rate with 120 eligible patients and 105 PFS events 
(at full information) which are expected to occur with 30 
months of accrual at 4 patients per month and 12 
additional months of follow-up, using a log-rank test at a 
one–sided significance level of 0.10. Under exponential 
distributions the hypothesized reduction corresponds to 1-
year progression-free survival of 44% in Arm A versus 25% 
in Arm B.  
9.2.1.2 
Analysis plan including plans for formal interim analysis  
The primary analysis set will include all randomized eligible 
patients. Progression-free survival (PFS) is defined as time 
from randomization to documented progression or death 
without progression. Patients without documented 
progression or death reported will be censored at the time 
of the last documented disease evaluation. In the 
secondary analyses, overall survival (OS) is defined as 
time from randomization to death from any cause, 
censoring cases who are alive at the date of last contact. 
Kaplan-Meier estimates will be used for event-time 
distributions. PFS and OS by arm will be compared using 
one-sided stratified log-rank tests. Stratified Cox’s 
proportional hazards models will be used to estimate 
hazard ratios. Response rate (complete response or partial 
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Response rate will be analyzed using a Fisher’s exact test 
at a one–sided significance level of 0.10.  
Patient demographics and disease characteristics will be 
compared using two-sample t-tests or Fisher’s exact tests 
as appropriate. We will also conduct exploratory subset 
analyses with respect to PFS, OS, and response rate to 
evaluate the prognostic significance of Ki-67 with regard to 
these clinical endpoints. 
Toxicity will be evaluated among all treated patients 
regardless of eligibility and interim analyses of toxicity are 
performed twice yearly for all ECOG-ACRIN studies. With 
63 patients per arm, the study will have sufficient precision 
to provide 90% confidence interval on toxicity that will be 
no wider than 22%. For rare toxicities with 2% true 
probability, there will be 75% probability of observing one 
or more toxicities in either treatment arm. For rare toxicities 
with 3% true probability, there will be 85% probability of 
observing one or more toxicities on either treatment arm. 
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 relatively large 
differences in adverse events.  
This study will include one interim analysis of PFS for 
efficacy at 20 months (10 months before the projected end 
of the accrual period, which should correspond to 57 
failures under the alternative hypothesis or 50% 
information time). A log rank test using an O’Brien-Fleming 
boundary will be conducted and under the alternative 
hypothesis there is probability of 0.42 that the efficacy 
boundary will be crossed. Regarding futility, if at the interim 
analysis the estimated hazard ratio for experimental/control 
is ≥1 the study will be reported as negative. If the 
estimated hazard ratio is less than 1 but the efficacy 
boundary is not crossed, the study will have its final 
analysis at 42 months of study time or 12 months post end 
of accrual. Results of the interim analysis will be presented 
to the ECOG-ACRIN Data Safety Monitoring Committee 
(DSMC) when appropriate. 
9.3 
Feasibility  
G3 gastroenteropancreatic neuroendocrine carcinomas are rare, accounting for 
approximately 11% of all neuroendocrine neoplasms. As such, a randomized trial 
in this patient population has never been conducted. Given the lack of data 
available and the rarity of this disease, the Neuroendocrine Task Force is 
committed to pursuit of a clinical trial in this patient population and this trial will be 
heavily promoted throughout the National Clinical Trials Network cooperative 
groups. As it is a rare disease, intergroup participation will be required to meet 
accrual goals. As there is no precedent providing an estimate of patients 
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many members of the Neuroendocrine Task Force for a preliminary estimate of 
feasibility. As all cooperative group sites would be able to participate, we 
anticipate that a greater number of patients than listed below will be available for 
the study. 
9.4 
Safety monitoring  
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. 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 5.2.  
9.5 
Study Monitoring  
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
obtained from the ECOG-ACRIN Operations Office - Boston. 
9.6 
Gender and Ethnicity (Revised for July 2019 amendment) 
Based on previous data from ECOG ACRIN neuroendocine trials the anticipated 
accrual in subgroups defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
2 
2 
Not Hispanic or Latino 
34 
44 
78 
Ethnic Category: Total of all subjects 
34 
46 
80 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
2 
2 
Black or African American 
5 
8 
13 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
29 
36 
65 
Racial Category: Total of all subjects 
34 
46 
80 
Rev. Add3 
Rev. Add4 

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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. 
9.7 
Correlative Studies Statistics  
9.7.1 
Pathology samples will be collected from all eligible patients. Ki-67 will 
be determined using immunohistochemical analysis and will be 
reported as a percentage ranging from 0-100%, based on counting at 
least 500 tumor cells in the regions with the highest labeling rate (“hot 
spots”) 
The primary analysis of Ki-67 will be to evaluate the interaction, if any, 
between Ki-67 as a continuous measure and treatment. Cox 
regression of logistic regression, as appropriate, will be used to 
identify whether the treatment effect varies by Ki-67 for PFS, OS, and 
RR. Subsequent analyses to identify “optimal” cutpoints from 
continuous Ki-67 measurement are considered exploratory.  
Receiver operating characteristics (ROC) analysis will also be 
performed to determine the optimal cutoff value in Ki-67 that defines 
patients with prolonged OS, where prolonged OS is defined as 
survival of at least 12 months. Hence in these analyses, survival will 
be considered as a binary endpoint. This optimal cutoff will serve for 
differentiating patients with features that are clinically more consistent 
with a well differentiated non-small cell gastrointestinal 
neuroendocrine tumor from the analysis set.  
For the series of Ki-67 values observed in the data, Youden’s index 
will be calculated and with the highest index we will identify the 
threshold that minimizes the false positive and false negative rates for 
best detecting prolonged OS. Optimal cutoff values of Ki-67 with 
respect to response to temozolomide and capecitabine will be 
determined in similar exploratory manner but the analysis will differ in 
that we will only include patients whose Ki-67 and response to 
temozolomide and capecitabine are available. Response to 
temozolomide and capecitabine is defined as complete response or 
partial response defined by RESIST 1.1 following initiation of therapy. 
Concordance between Ki-67 measured centrally versus registering 
institutions’ pathology assessments will also be investigated and 
reported. Intra-class correlation will be calculated to assess 
agreement amongst the two continuous measures. 
We will also assess the prognostic significance of well differentiated 
versus poorly differentiated non-small cell gastroenteropancreatic 
neuroendocrine tumors in relationship to survival and response to 
treatment in a similar manner, via Cox proportional hazard models for 
time to event endpoint and logistic regression for objective response. 
 

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10. 
Imaging Study Submissions 
Baseline standard of care images including a CT of the chest, abdomen and pelvis will 
be obtained for each patient. If octreotide scan (SPECT or SPECT/CT) , 68Ga-PET 
scans and 18F-FDG PET scans are done, it is requested that images be submitted. 
Subsequent CT scans of the chest, abdomen and pelvis will be obtained every two 
months. Additional octreotide scans, 68Ga-PET scans and 18F-FDG PET scans may also 
be obtained per physician discretion. As the radiographic characteristics of G3 
gastroenteropancreatic neuroendocrine carcinomas have not been extensively studied, 
building of a centralized bank of images will generate a resource upon which 
researchers may draw to ask further radiographic questions regarding this tumor type. 
This data set of serial images from approximately 80 patients with G3 
gastroenteropancreatic neuroendocrine carcinomas will serve as one of the largest NEC 
image banks. 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, 68Ga-PET 
scans, [18F] FDG-PET, perfusion CT, octreotide scan or any 
combination) of the chest, abdomen and pelvis including all phases 
completed will be submitted to the ACR Imaging Core Laboratory per 
Section 10.2 instructions. 
10.1.2 
Standard practice imaging studies for the trial per EA2142 procedures 
include: 
• 
Pre-treatment baseline scan for eligibility assessment. 
• 
Imaging studies during study-prescribed treatment—(e.g. CT 
scans or MRIs at every 8 week intervals). 
10.1.3 
Three-phase contrast-enhanced CT acquisition as outlined below is 
recommended. 
• 
Late arterial phase through the abdomen; 
• 
Portal venous phase through the abdomen and pelvis; 
• 
Delayed (equilibrium) phase through the abdomen at 3-4 minutes 
after contrast administration; 
• 
If performed per standard institutional practice, optional perfusion 
CT sequences of an area of interest may be performed if available 
at the participating institution. 
10.2 
Images Submission 
10.2.1 
See Section 4.4.5 for instructions.  
 
Rev. 2/17 
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11. 
Specimen Submissions 
Fixed paraffin-embedded tumor (mandatory) from core biopsy or surgery is to be 
submitted for central diagnostic review and, per patient consent, research studies. 
Peripheral blood (per patient consent) are also to be submitted for research. 
SAMPLE TRACKING SYSTEM (STS): All specimens submitted on this trial must be 
entered and tracked using the ECOG-ACRIN Sample Tracking System.  Any case 
reimbursements associated with specimen submissions to ECOG-ACRIN–designated 
laboratories will be determined only from data contained in STS. 
LABELING: Specimens are to be labeled clearly with the ECOG-ACRIN protocol 
number “EA2142”, patient initials, date and time of collection, and sample type. All 
sample submissions are to be accompanied with an STS shipping manifest. 
SHIPPING ACCOUNT: Samples shipped to the ECOG-ACRIN CBPF are to be shipped 
using the CBPF’s FedEx account using the FedEx On-Line Services. Access to the 
shipping account for specimen shipments to the ECOG-ACRIN CBPF at MD Anderson 
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 
11.1 
Submissions to the Central Biorepository and Pathology Facility (CBPF) 
The ECOG-ACRIN Central Biorepository and Pathology Facility (CBPF) is the 
receiving laboratory for all specimens submitted from patients participating in this 
trial. 
11.1.1 
Pathology Materials - MANDATORY 
Submission of pathology materials from all patients is mandatory. 
The required materials are to be submitted within four (4) weeks 
following randomization. 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 may render the patient’s data 
unevaluable. 
If these criteria cannot be met, please contact the ECOG-ACRIN 
Central Biorepository and Pathology Facility (CBPF) 
(eacbpf@mdanderson.org) to obtain alternative submission 
requirements. 
A. FFPE TUMOR TISSUE 
All of the following materials are to be submitted. If unavailable, 
please contact the CBPF and provide justification in STS.  
• 
One representative diagnostic fixed paraffin-embedded 
metastatic (or primary) tumor block, core biopsy or surgical 
specimen, if available. 
NOTE: 
If blocks are not available for submission, submit the 
following: 
• 
Mandatory: Two (2) H&E slides.  

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• 
Mandatory: Minimum of five (5) unstained charged 
slides 4 or 5 µm thick. 
• 
Additional materials from consenting patients: Two 
(2) 4mm cores, 15-25 unstained slides. 
• 
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, please indicate as 
such in the appropriate comment field in STS.   
B. FORMS 
• 
A copy of the surgical (if appropriate) and pathology reports 
• 
Immunologic studies, if available 
• 
Sample Tracking System Shipping Manifest 
11.1.2 Whole Blood, ACD vacutainer 
Blood is to be collected and submitted from patients who answer 
“Yes” to “I agree to have my samples collected and I agree that my 
samples and related information may be used for the laboratory 
studies described above.” 
This specimen is to be collected after randomization, but prior to start 
of treatment 
Draw one (1) 8-10mL ACD DNA vacutainers 
Ship at ambient with the tissue the day of collection. OR, freeze at  
≤ -70°C and ship on dry ice. If samples are frozen at -20°C ship on dry 
ice within 1 week of draw. 
NOTE: 
Glass vacutainers cannot be frozen, so if glass vacutainers 
are used, transfer peripheral blood to cryovials for freezing. 
11.2 
Shipping Guidelines 
The receiving laboratory is not available to receive shipments over holidays or 
weekends.  
The required initial diagnostic tumor tissue materials, reports and forms are to be 
submitted within four (4) weeks following patient randomization. It is requested 
that the blood samples be submitted with or prior to submission of the tissue.  If 
blood samples are frozen they must be shipped overnight on dry ice.  Tissue and 
blood must be packaged in a manner that the tissue cannot freeze. 
Samples from multiple patients may be batched and shipped together. All 
samples must be adequately labeled with protocol number, ECOG-ACRIN 
patient case number, and date of collection. 
Ship Frozen 
or ambient   

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Shipping Address 
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 
Tissue specimens shipped standard mail must utilize a “trackable” mechanism. 
For shipments utilizing FedEx, access to the shipping account for specimen 
shipments requires logging into fedex.com with an account issued by the ECOG-
ACRIN CBPF. 
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:  Additionally, 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-
acrin.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. Include site contact information on the 
form. Notify the laboratory of the shipment by faxing a copy of the completed 
form to the laboratory the day of shipping. Indicate the shipping tracking number 
and 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 
Testing of banked specimens will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved in 
accordance with National Clinical Trials Network (NCTN) policies. Tissue 

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specimens will be processed and distributed to investigators for the central 
diagnostic outlined in Section 11. 
Specimens from patients who consented to allow their specimens to be used for 
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. 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. Bloods and other products may be 
destroyed per protocol of the given lab, or they could be anonymized (stripped of 
all identifiers) and used for instrument calibration or other quality control 
measures which are not published or linked to the clinical trial. Tissue will be 
returned or stored indefinitely or return to the site upon request.  
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 
the ECOG-ACRIN Operations Office – Boston. 

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12. 
Laboratory Research Studies 
12.1 
Central Diagnostic and Ki-67 Analysis (MANDATORY, INTEGRATED) 
The pathologic diagnosis of G3 gastroenteropancreatic neuroendocrine 
carcinomas is difficult and diagnostic criteria can be variable between institutions. 
Therefore, a central pathology review will be conducted on tumor specimens of 
all patients participating in the study to confirm diagnosis. This will be a 
retrospective review to ensure that only patients meeting inclusion criteria are 
considered in the final statistical analysis. Any H&E slides made at the original 
institution of the patient will be requested along with other diagnostic slides 
including but not limited to Ki-67, chromogranin and synaptophysin. Pathology 
reports from the originating institution will also be obtained. Tissue samples will 
be assessed for tumor histology and mitotic index using standard H&E staining 
techniques. Ki-67 labeling rate will be evaluated using immunohistochemistry 
(see methods in Section 12.2.1 below). While institutional Ki-67 slides will be 
evaluated for comparison if available, all patients will have an unstained slide 
used for Ki-67 analysis. The Ki-67 will be determined by a manual count of at 
least 500-2000 cells performed on a printed photograph of the stained slide. In 
addition to manual scoring, computerized imaging analysis will also be conducted 
on each specimen. 
Marker 
Primary Ab 
Dilution 
Company 
Secondary Ab 
Dilution 
Ki-67 
Monoclonal 
1:100 
DAKO 
a-mouse 
1:200 
We will also conduct subset analyses with respect to PFS, OS, and response 
rate to evaluate the prognostic significance of Ki-67 with regard to these clinical 
endpoints. 
This diagnostic review will be performed under the direction of David Klimstra, 
MD at Memorial Sloan-Kettering Cancer Center.  
12.2 
Research Studies 
The following correlative studies are proposed research studies. At the time it is 
determined that these studies will be performed, a full correlative science 
proposal or amended protocol document with formal statistical analysis plan for 
the marker studies will be submitted to and reviewed by CTEP. 
12.2.1 
MGMT IHC and Promoter Methylation 
Immunohistochemistry: MGMT immunohistochemical evaluation will 
be performed using the Ventana Discovery XT platform. Ventana CC1 
standard pretreatment solution will be used. A monoclonal antibody 
against MGMT (Invitrogen) will be applied then Omni Map Polymer for 
16 minutes at a dilution of 1:150. A secondary anti-mouse antibody 
will be applied at a dilution of 1:200. Immunohistochemical expression 
of MGMT will be interpreted as “present” or “absent” where absent is 
classified as a complete absence of labeling in the face of positive 
staining in adjacent non-neoplastic cells, which serve as an internal 
positive control. 

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Marker 
Primary Ab 
Dilution 
Company 
Secondary Ab 
Dilution 
MGMT 
Monoclonal 
1:150 
Invitrogen 
a-mouse 
1:150 
MGMT Promoter Methylation: DNA will be extracted from formalin 
fixed paraffin embedded tissue using the DNeasy Tissue Kit (Qiagen, 
69506) and concentration assessed using a Nanodrop assay. Bisulfite 
conversion of genomic DNA will be performed using the Zymo EZ-
DNA Methylation-Direct Kit (Zymo Research, D5021), converting non-
methylated cytosines to uracuils while methylated cytosines remain 
resistant to conversion. Bisulfite converted genomic DNA will be 
subjected to PCR amplications followed by pyrosequencing using the 
PryoMark Q24 instrument and methylation status will be determined 
using the PyroMark Q24 software.  
12.2.2 
Molecular Profiling of Poorly Differenctiated (G3) 
Gastroenteropancreatic Neuroendocrine Tumors (INTEGRATED)  
Immunohistochemical staining will be performed on fixed paraffin 
embedded tumor tissue to evaluate the following reference gene set—
DAXX, ATRX, CDK4, mdm2, SSTR2, Rb, p53, and MGMT. Molecular 
profiles will then be correlated with pathologic features, clinical 
outcome data and radiographic data. 
Staining will be performed using the Ventana Discovery XT platform. 
The Ventana CC1 solution will be used for pretreatment followed by 
the Ventana DABMap Development Kit. The individual protocol may 
vary slightly depending on the antibody being evaluated. Primary 
antibodies (see table below) will be applied for 60 minutes at their 
respective dilutions. Secondary antibodies will be applied at a 1:200 
dilution for 60 minutes. An a-mouse secondary antibody will be used 
for monoclonal primary antibodies and an a-rabbit secondary antibody 
will be used for polyclonal primary antibodies. Immunohistochemical 
expression of each antibody will be scored on a semi-quantitative 
scale that includes the percentage of cells labeling and the intensity 
(0, 1+, 2+, 3+); the criteria to determine ultimate positivity will vary 
depending on the antibody.  
If availability issues in regard to slides available for studies become an 
issue, IHC studies to be conducted will be determined by the study 
team. 
Marker 
Primary Ab 
Dilution 
Company 
Secondary Ab 
Dilution 
ATRX 
Polyclonal 
1:500 
Sigma 
a-rabbit 
1:200 
DAXX 
Polyclonal 
1:100 
Sigma 
a-rabbit 
1:200 
CDK4 
Polyclonal 
1:5000 
Santa Cruz 
a-rabbit 
1:200 
mdm2 
Monoclonal 
1:500 
Calbiochem 
a-mouse 
1:200 
SSTR2 
Polyclonal 
1:100 
Abcam 
a-rabbit 
1:200 
Rb 
Monoclonal 
1:50 
LEICA 
a-mouse 
1:200 
p53 
Monoclonal 
1:500 
DAKO 
a-mouse 
1:200 

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12.3 
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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13. 
Electronic Data Capture 
Please refer to the EA2142 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. 
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Bosman FT, Carneiro F, Hruban RH et al. WHO Classification of Tumours of the 
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Shia J, Tang LH, Weiser MR, et al. Is nonsmall cell type high-grade neuroendocrine 
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26. Rocha-Lima CM, Herndon JE, Lee ME, et al. Phase II trial of irinotecan/gemcitabine 
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the irinotecan/gemcitabine doublet versus irinotecan monotherapy in previously 
treated patients with extensive stage small-cell lung cancer. Lung Cancer 
2009;65:187-191. 
28. Ohyanagi F, Horiike A, Okano Y, et al. Phase II trial of gemcitabine and irinotecan in 
previously treated patients with small-cell lung cancer. Cancer Chemother 
Pharmacol 2008;61:503-508. 
29. Schuette W, Nagel S, Juergens S, et al. Phase II trial of gemcitabine/irinotecan in 
refractory or relapsed small-cell lung cancer. Clin Lung Cancer 2005;7:133-137. 
30. Dongiovanni V, Buffoni, L, Berruti A, et al. Second-line chemotherapy with weekly 
paclitaxel and gemcitabine in patients with small-cell lung cancer pretreated with 
platinum and etoposide: a single institution phase II trial. Cancer Chemother 
Pharmacol 2006;58:203-209. 
31. Mori K, Kamiyama Y, Kondo T, et al. Pilot phase II study of weekly chemotherapy 
with paclitaxel and carboplatin for refractory or relapsed small-cell lung cancer. 
Cancer Chemother Pharmacol 2006;58:86-90. 
32. Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory 
or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. 
J Clin Oncol 2003;21:1550-1555. 
33. Hoang T, Kim K, Jaslowski A, et al. Phase II study of second-line gemcitabine in 
sensitive or refractory small cell lung cancer. Lung Cancer 2003;42:97-102. 
34. Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin (XELOX) 
suitable treatments for progressing low-grade and high-grade neuroendocrine 
tumours? Cancer Chemother Pharmacol 2007;59:637-642. 
35. Bergsland EK, Ko AH, Tempero M, et al. Phase II trial of FOLFOX plus 
bevacizumab in advanced, progressive neuroendocrine tumors. J Clin Oncol 2008; 
suppl, abstract 216. 
36. Ramalingam SS, Foster J, Gooding W, et al. Phase 2 study of irinotecan and 
paclitaxel in patients with recurrent or refractory small cell lung cancer. Cancer 
2010;116:1344-1349. 
37. Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel 
for relapsed and refractory small cell lung cancer. Anticancer Research 
2006;26:777-782. 
38. Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and 
thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 
2006;24:401-406. 
39. Ekeblad S, Sundin A, Tiensuu Janson E, et al. Temozolomide as monotherapy is 
effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer 
Res 2007;13:2986-2991. 
40. Kulke MH, Stuart K, Earle CC, et al. A phase II study of temozolomide and 
bevacizumab in patients with advanced neuroendocrine tumors. J Clin Oncol 
2006;24(18S):4044. 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
86 
Randomized Phase II Study of Platinum and Etoposide versus Temozolomide and 
Capecitabine in Patients with Advanced G3 Non-Small Cell Gastroenteropancreatic 
Neuroendocrine Carcinomas 
 
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 EA2142 
4. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
87 
Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG Pathology Coordinating Office: 
• Institutional Surgical Pathology Report 
• Pathology materials (see attached List of Required Material) 
• ECOG-ACRIN STS-generated Shipping Manifest  or ECOG-ACRIN Generic Specimen 
Submission Form (#2981) 
NOTE: 
All submissions must be logged and tracked via the ECOG-ACRIN Sample 
Tracking System (STS).  See Section 11.2 
All submitted materials must be labeled with the protocol trial, the trial-specific patient 
case ID, patient initials.  Sites accession numbers must be provided with the samples 
submitted. 
Pre-trial Diagnostic Materials 
1. Institutional pathology report, including immunological reports if available 
2. STS-generated shipping manifest 
3. Diagnostic tumor slides 
4. Representative tumor tissue block (metastatic preferred, primary accepted) 
NOTE: 
If a block is unavailable for submission, submit the following:  
• 
Mandatory: one (1) H&E, five (5) unstained slides 4µm thick  
• 
Additional materials requested: 15-20 slides, two (2) 4mm cores. 
Adequate patient identifying information must be included with every 
submission. It is strongly recommended that full patient names be 
provided. This information will be used only to identify patient materials. 
This will expedite any required communications with the institution 
(including site pathologists).   
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 Pathology Coordinating Office by 
telephone (312) 503-3385. 
 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
88 
MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA2142: Randomized Phase II 
Study of Platinum and Etoposide versus Temozolomide and 
Capecitabine in Patients with Advanced G3 Non-Small Cell 
Gastroenteropancreatic Neuroendocrine Carcinomas 
 
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 diagnostic review and 
research studies. 
Return 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 Central Biorepository and Pathology Facility at MD Anderson. 
Pathology materials submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies per patient consent.  Paraffin blocks will be returned upon 
request for purposes of patient management. 
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. 
Results of the diagnostic review will be distributed to you upon completion of the review. 
This review will be retrospective and will not impact patient participation in E2142.  
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at 844-744-2420 (713-745-4440 Local or 
International Sites) or email: eacbpf@mdanderson.org 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
89 
ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
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 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
90 
Randomized Phase II Study of Platinum and Etoposide versus Temozolomide and 
Capecitabine in Patients with Advanced G3 Non-Small Cell Gastroenteropancreatic 
Neuroendocrine Carcinomas 
 
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 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 participation of people like you in clinical trials, we will 
improve treatment and quality of life for those with your type of 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 ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
91 
Randomized Phase II Study of Platinum and Etoposide versus Temozolomide and 
Capecitabine in Patients with Advanced G3 Non-Small Cell Gastroenteropancreatic 
Neuroendocrine Carcinomas 
 
Appendix III 
 
Patient Pill Calendar 
NOTE:  This pill calendar is for patients randomized to Arm A ONLY.  
 
Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
2. If you forget, the missed pills will not be taken later. 
3. “Cap”- is an abbreviation for “Capecitabine” and “Tem” is an abbreviation for 
“Temozolomide” 
4. Please bring the bottle, any leftover pills, and your pill calendar to your next clinic 
visit.  
5. Please list any other drugs you are taking at home such as OTC products, herbal 
medicines, tea, or other prescribed drugs. 
6. When taking Capecitabine: 
• 
Take doses at least 12 hours (+/- 2 hours) apart. 
• 
Capecitabine pills should be swallowed with water within 30 minutes after a meal. 
• 
Capecitabine pills may NOT be crushed. 
7. When taking Temozolomide: 
• 
Ondansetron should be taken to prevent nausea 30-60 minutes prior to the 
temozolomide dose. 
• 
Temozolomide should be taken at night by mouth after fasting from solid food for 
two hours. 
• 
Temozolomide pills must not be crushed and must be administered whole. 
• 
Do not repeat dose if vomiting occurs after dose is administered. 
 
 
 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
92 
Patient Pill Calendar 
This is a calendar on which you are to record the time and number of pills you take each day. You should take your scheduled dose of 
each pill. Note the times and the number of pills that you take each day. If you develop any side effects, please record them and 
anything you would like to tell the doctor in the space provided. Bring any unused pills and your completed pill calendar to your doctor’s 
visits. 
Day 
Date 
Times pills taken 
Number of pills taken 
Use the space below to make notes about 
things you would like to tell the doctor 
(including unusual symptoms you experience, 
other medicine you have taken and anything 
else you think would be of interest.) 
 
Month 
Day 
Year 
AM 
PM 
AM 
PM 
1 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
2 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
3 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
4 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
5 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
6 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
7 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
8 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
9 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
10 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
Tem:  
Tem:  
11 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
Tem:  
Tem:  
12 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
Tem:  
Tem:  
13 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
Tem:  
Tem:  
14 
 
 
 
Cap: 
 
Cap: 
 
Cap:  
Cap:  
 
Tem:  
Tem:  
15-28 
 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
93 
Randomized Phase II Study of Platinum and Etoposide versus Temozolomide and 
Capecitabine in Patients with Advanced G3 Non-Small Cell Gastroenteropancreatic 
Neuroendocrine Carcinomas 
 
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. 

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
94 
Randomized Phase II Study of Platinum and Etoposide versus Temozolomide and 
Capecitabine in Patients with Advanced G3 Non-Small Cell Gastroenteropancreatic 
Neuroendocrine Carcinomas 
 
Appendix V 
 
Patient Drug Information Handout and Wallet Card 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, Temozolomide/Capecitabine.  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
These are the things that you as a healthcare provider need to know: 
Capecitabine interacts with Coumadin resulting in an increased tendency for bleeding. Patients 
participating in this clinical trial are not permitted to receive Coumadin 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
Temezolomide or capcitabine may interact with other drugs which can cause side effects. For 
this reason, it is very important to tell your study doctors of any medicines you are taking before 
you enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking 
any regular medicines, or if you start taking a new medicine while you take part in this study.  
When you talk about your current medications with your doctors, include medicine you buy 
without a prescription (over-the-counter remedy), or any herbal supplements such as St. John’s 
Wort.  It is helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions. You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in 
a clinical trial.  
These are the things that you and they need to know:  
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• 
Coumadin may interact with one of your study drugs. Do not start taking this medication 
while you are receiving study treatment as part of this clinical trial.  
• 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Your study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________

ECOG-ACRIN 
EA2142 
Cancer Research Group 
Version Date: January 23, 2020 
 
NCI Update Date: November 6, 2015 
95 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the 
experimental study drug _____________.  This 
clinical trial is sponsored by the NCI.  
__________________ may interact with drugs that 
are [processed by your liver, or use certain 
transport proteins in your body or affects the 
electrical activity of your heart].  Because of this, it 
is very important to: 
➢ Tell your doctors if you stop taking any medicines or 
if you start taking any new medicines. 
➢ Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) that you are taking part in a clinical 
trial. 
➢ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplement. 
__________________ interacts with a [specific liver 
enzyme called CYP______, transport protein, heart’s 
electrical activity (QTc prolongation], and must be 
used very carefully with other medicines that interact 
with [this enzyme, transporter, or agent].  
➢ Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care 
providers to review any medicines  and herbal 
supplements that are considered “[strong 
inducers/inhibitors or substrates of CYP______, or 
transporter; or affect the heart’s electrical 
activity.]”  
➢ Before prescribing new medicines, your regular health 
care providers should go to a frequently-updated 
medical reference for a list of drugs to avoid, or 
contact your study doctor.  
➢ Your study doctor’s name is  
_____________________________ and can be 
contacted at 
_________________________________.