Clinical trial NCT01124695
Conditions: Breast Cancer Stage IV Breast Cancer
Keywords: estrogen receptor-positive breast cancer progesterone receptor-positive breast cancer recurrent breast cancer stage IV breast cancer
Sponsor: ECOG-ACRIN Cancer Research Group
Start date: 2011-01-07; Completion date: 2022-12-01
Enrollment: 124 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate may fight cancer by blocking the use of estrogen by tumor cells.

PURPOSE: This phase II trial is studying how well tamoxifen citrate works in patients with metastatic or recurrent breast cancer.

Detailed description:
OBJECTIVES:

Primary

* To correlate CYP2D6 (Cytochrome P450 2D6) score (0 vs 1-2) and progression-free survival (PFS)

Secondary

* To correlate CYP2D6 score (0 vs 1 vs 2) and PFS
* To correlate CYP2D6 score (0 vs 1-2) and the proportion of these patients who are progression-free at 6 months.
* To correlate endoxifen concentration with response
* To correlate CYP2D6 with response
* To correlate the presence of candidate estrogen receptor (ESR) 1 and 2 variant alleles, UDP-glucuronosyltransferases (UGT) 7, sulfotransferases (SULT) 1A1, other candidate genes and biomarkers to PFS and other tamoxifen related outcomes

OUTLINE: This is a multicenter study.

Patients receive oral tamoxifen citrate once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicities.

Blood, plasma, and tissue samples are collected periodically for laboratory studies.

After completion of study therapy, patients are followed up every 3-6 months for 5 years.

Arms: arm 1: Patients receive oral tamoxifen citrate once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicities.
Interventions: intervention 1: tamoxifen
Intervention descriptions: intervention 1: PO

Protocol documents:
Prot_SAP_000.pdf: 
E3108 
 
1 
A Phase II Prospective Trial Correlating Progression Free 
Survival with CYP2D6 Activity in Patients with Metastatic 
Breast Cancer Treated with Single Agent Tamoxifen 
STUDY CHAIR: Vered Stearns, M.D. 
STUDY CO-CHAIR: Bryan Schneider, M.D. 
STUDY STATISTICIAN: Anne O’Neill, M.S. 
COMMITTEE CHAIR: George W. Sledge, Jr., M.D. 
DEVELOPMENTAL THERAPEUTICS AND 
LABORATORY CO-CHAIR: 
 
David A. Flockhart, M.D., Ph.D. 
CALGB CO-CHAIR: Minetta Liu, M.D. 
SWOG CO-CHAIR: Caroline Lohrisch, M.D., FRCPC 
NCCTG CO-CHAIR: Matthew P. Goetz, M.D. 
Version Date:  May 1, 2014 
NCI Update Date:  March 25, 2015 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
NRG / NRG Oncology Foundation, Inc 
 
September 21, 2010 
Cancer Trials Support Unit (CTSU)* 
 
Addendum #1 – Incorporated Prior to Activation 
SWOG / SWOG  
 
Addendum #2 – 5/11 
ALLIANCE / Alliance for Clinical Trials in Oncology  
Addendum #3 – 8/12 
NCIC-CTG / NCIC Clinical Trials Group 
 
Addendum #4 – 5/14 
*This study is supported by the NCI Cancer Trials 
Support Unit (CTSU). Institutions not aligned with 
ECOG-ACRIN will participate through the CTSU 
mechanism. 
 
Update #1 - 3/15 
 
 
 
 
 
 
 
 
 
 
Rev. 5/14 


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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Hormone Treatment Recommendations in Breast Cancer ....................... 7 
1.2 
Pharmacogenetics of Tamoxifen Response .............................................. 8 
1.3 
Genetic Predictors of Other Tamoxifen-Associated Outcomes .............. 13 
2. Objectives ......................................................................................................... 15 
2.1 
Primary Objective .................................................................................... 15 
2.2 
Secondary Objectives .............................................................................. 15 
3. Selection of Patients ......................................................................................... 16 
3.1 
Eligibility Criteria ..................................................................................... 16 
4. Registration Procedures .................................................................................... 20 
4.1 
Protocol Number ..................................................................................... 23 
4.2 
Investigator Identification ....................................................................... 23 
4.3 
Patient Identification .............................................................................. 23 
4.4 
Eligibility Verification .............................................................................. 23 
4.5 
Additional Requirements ........................................................................ 23 
4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment24 
5. Treatment Plan ................................................................................................. 25 
5.1 
Administration Schedule ......................................................................... 25 
5.2 
Adverse Event Reporting Requirements ................................................. 25 
5.3 
Dose Modifications ................................................................................. 28 
5.4 
Supportive Care ....................................................................................... 29 
5.5 
Duration of Therapy ................................................................................ 29 
5.6 
Duration of Follow-up ............................................................................. 29 
6. Measurement of Effect ..................................................................................... 30 
6.1 
Antitumor Effect – Solid Tumors ............................................................. 30 
7. Study Parameters .............................................................................................. 38 
7.1 
Therapeutic Parameters .......................................................................... 38 
7.2 
Biological Sample Submissions ............................................................... 40 
8. Drug Formulation and Procurement ................................................................. 41 
8.1 
Tamoxifen ............................................................................................... 41 
9. Statistical Considerations .................................................................................. 44 
9.1 
Gender and Ethnicity .............................................................................. 45 
10. Pathology Review .............................................................................................. 46 
10.1 Pathological materials from the primary tumor and metastatic site, 
when available, should be submitted for banking for future studies. .... 46 
10.2 Materials Required For This Protocol ..................................................... 46 
10.3 Shipping Procedures ............................................................................... 47 
10.4 ECOG-ACRIN Sample Tracking System .................................................... 47 
10.5 Banking .................................................................................................... 48 


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11. Correlative Studies ............................................................................................ 49 
11.1 The main goal of the study is to correlate the presence of genetic 
polymorphism, tamoxifen metabolites, and benefit from the drug. ...... 49 
11.2 Sample Submission Schedule – Tamoxifen Metabolites (Mandatory) ... 50 
11.3 Methods .................................................................................................. 51 
11.4 Banking .................................................................................................... 51 
11.5 Sample Inventory Submission Guidelines ............................................... 51 
11.6 Lab Data Transfer Guidelines .................................................................. 52 
12. Records to Be Kept ............................................................................................ 53 
13. Patient Consent and Peer Judgment ................................................................ 53 
14. References ........................................................................................................ 53 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) - [Deleted in Addendum #4] ............................................................ 55 
Appendix II  Pathology Submission Guidelines ....................................................... 56 
Appendix III  Patient Thank You Letter .................................................................... 61 
Appendix IV  Medication Diary for Tamoxifen ........................................................ 62 
 


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STUDY CHAIR 
Vered Stearns, MD 
Bunting-Blaustein Cancer Research Building 
1650 Orleans Street, Room 145 
Baltimore, MD 21231-1000 
Phone: 443-287-6489 
Fax: 410-614-4073 
Email: vstearn1@jhmi.edu 
 
STUDY CO-CHAIR 
STUDY CHAIR LIAISON (SCL) 
Bryan P. Schneider, MD 
Indiana Cancer Pavilion 
535 Barnhill Drive, RT473 
Indianapolis, IN 46202 
Phone: 317-274-6473 
Fax: 317-274-8022 
Email: bpschnei@iupui.edu 
Stacie Jeter 
Bunting-Blaustein Cancer Research Building 
1650 Orleans Street, Room 186 
Baltimore, MD 21231-1000 
Phone: 410-614-6138 
Fax: 410-614-9421 
Email: sjeter1@jhmi.edu 
Page 410-283-6006 for « patient in office » 
questions only. 
 
SWOG CO-CHAIR  
CALGB CO-CHAIR 
Caroline Lohrisch, MD, FRCPC 
Medical Oncology 
Vancouver Cancer Centre, BCCA 
600 W. 10th Aveenue 
Vancouver, BC V5Z 4E6 
Phone: 604-877-6000, Ext. 2740 
Fax: 604-877-0585 
Email: clohrisch@bccancer.bc.ca 
Minetta Liu, M.D. 
Lombardi Comprehensive Cancer Center 
Georgetown University Hospital 
3800 Reservoir Rd. NW 
Washington, DC 20007-2113 
Phone: 202-444-6377 
Fax: 202-444-9429 
Email: liumc@georgetown.edu 
 
NCCTG CO-CHAIR 
Matthew P. Goetz, M.D. 
Mayo Clinic 
200 First Street S.W. 
Rochester, MN 55905 
Phone: 507-284-4857 
Fax: 507-284-1803 
Email: goetz.matthew@mayo.edu 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data  directly to the 
Lead Cooperative Group unless 
otherwise specified in the protocol: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN)  
which can be accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations Office - 
Boston, 
FSTRF, 900 Commonwealth Avenue 
Boston, MA 02215 
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal mail 
(preferred), however fax is accepted. 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions.   
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’ websiteis 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 clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please review the 
CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website 
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev. 
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Schema 
Tamoxifen 
20 mg PO 
daily1
Continue 
Tamoxifen1
1. Open label tamoxifen 20 mg PO daily until progression, unacceptable toxicities or any other condition outlined in 
Section 5.5.
2. Collection of Baseline blood for the mandatory research studies should be done prior to protocol treatment 
(preferred), but may be done at the end of Cycle 3 visit. Additional blood is to be submitted at the end of Cycle 3 
and at the end of treatment. See Section 7.2 and 11.
R
E
G
I
S
T
R
A
T
I
O
N
1 cycle = 28 days
Accrual = 240
Cycle 1 and higher
2
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1. 
Introduction 
Tamoxifen remains the most common endocrine intervention prescribed to women with 
all stages of hormone receptor positive breast cancer or to decrease the incidence of the 
disease. Recent data suggest that genetic variants in the cytochrome P450 2D6 
(CYP2D6) gene or inhibition of the enzyme result in altered metabolic profile and 
reduced efficacy. The overall goal of this clinical trial is to determine whether variants in 
CYP2D6 influence progression free survival and other outcomes in women with 
metastatic breast cancer, and to explore the role of other genetic variants. 
Hypotheses: 
Breast cancer patients with a CYP2D6 score of 0 (poor metabolizers) will have a 
reduced progression-free survival compared to those with a score of 1 or 2 (intermediate 
or extensive metabolizers, respectively, Hazard ratio 1.89 for poor metabolizer relative to 
extensive or intermediate metabolizer based on Mayo Clinic investigators).  
Fewer breast cancer patients with a CYP2D6 score of 0 will be progression-free at 6 
months compared to those with a score of 1 or with a score of 2. Furthermore, 
participants with higher endoxifen concentration will have improved time to progression 
compared to those with lower concentration. 
We have observed significant correlation between ESR variants and tamoxifen-induced 
hot flashes. A correlation between ESR and tamoxifen efficacy has never been tested. 
We hypothesize that candidate variants in ESR1 and ESR2 may influence time to 
progression. In addition, other genes that are important in tamoxifen’s metabolism have 
not been well-studied. Candidates include: ESR1 PvuII, ESR1 XbaI, and ESR2-02, UGT, 
and SULT1A1. 
1.1 
Hormone Treatment Recommendations in Breast Cancer  
Despite the increase in breast cancer prevalence in recent years, disease 
specific mortality has declined. The improvement in survival has been attributed 
both to early diagnosis and to optimal local and systemic therapies, especially 
adjuvant endocrine treatments. While for people with hormone receptor positive 
breast cancer, the most common drug prescribed worldwide is tamoxifen. In the 
adjuvant setting, tamoxifen is prescribed for a total of five years based on 
cumulative data suggesting that five years of tamoxifen was better than two 
years but ten years were not better than five. More recently aromatase inhibitors 
have been introduced to the treatment of postmenopausal women and are now 
commonly administered for five years instead of tamoxifen or in a sequential 
manner following two to three years of tamoxifen for a total of five years or in the 
extended adjuvant setting for five years following five years of tamoxifen. 
National guidelines recommend that most postmenopausal women should be 
offered aromatase inhibitors in one of these settings. However, tamoxifen 
remains the drug of choice for premenopausal women and for men. Clinical trials 
comparing tamoxifen alone to the addition of ovarian suppression to tamoxifen or 
ovarian suppression and aromatase inhibitors in premenopausal women are still 
ongoing and results regarding the efficacy of each of those treatments and long 
term safety are not currently available. Therefore, ovarian suppression or 
aromatase inhibitors should generally not be used in premenopausal women 
outside of clinical trials unless tamoxifen is contraindicated.  


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Recommendations for adjuvant systemic therapy are based on estimates of risk 
of subsequent recurrence for an individual person as well as the risk for 
treatment related toxicity. Overall it is thought that the benefits of tamoxifen 
outweigh the potential risks for a population. However, it is well recognized that 
not all breast cancer patients will enjoy the same benefits from identical 
treatments. Several tumor characteristics may predict who may benefit from 
tamoxifen, for example high expression of estrogen receptor and progesterone 
receptor (ER/PR) is associated with a higher likelihood of benefit from tamoxifen 
compared to the presence of only one of these receptors, and no benefit is 
expected in the absence of hormone receptors. Only 50% of women with ER/PR 
expressing tumors will benefit from hormonal interventions. Other specific or 
aggregate tumor characteristics may predict response and are under extensive 
investigation. 
1.2 
Pharmacogenetics of Tamoxifen Response 
Host characteristics may also play an important role in predicting response to 
specific agents or treatments but have not been extensively studied. The recent 
sequencing of the human genome and new high throughput technologies have 
led to a greater appreciation of the role that pharmacogenetics and host factors 
may play as predictors of drug response. If so, assessment of host factors prior 
to initiation of specific agents may become standard practice. Recent 
pharamcogenetic data have demonstrated that tamoxifen metabolism, and 
perhaps efficacy, can be affected by polymorphisms in CYP2D6 or due to 
interactions with drugs that inhibit the encoded enzyme. Prospective studies that 
included both genotype and metabolite data are not available. The overall goal of 
the proposal is to determine whether CYP2D6 status, other candidate genes, and 
tamoxifen metabolism influence outcomes of patients with metastatic breast 
cancer. 
COBRA (Consortium On Breast Cancer Pharmacogenomics) investigators 
reported that women who have been on chronic adjuvant tamoxifen therapy and 
have been prescribed the strong CYP2D6 inhibitor such as paroxetine had a 
marked reduction in concentration of the active tamoxifen metabolite endoxifen. 
This metabolite is present in very low concentrations in the blood, however, it has 
100 fold greater affinity to the estrogen receptor compared to the parent drug 
tamoxifen and may be therefore a very important metabolite of tamoxifen 
determining drug efficacy. Endoxifen’s potency is similar to another metabolite 4-
hydroxy tamoxifen, however it is present in 5-7 fold greater concentration 
compared to the latter metabolite (1-3). Based on the pharmacogenetic and 
metabolic studies of tamoxifen, the North Central Cancer Treatment Group 
(NCCTG)/Mayo Clinic and COBRA investigators determined CYP2D6 genotype 
through extracting DNA from formalin-fixed paraffin-embedded archival tumor 
specimens of 190 post-menopausal women who received 5 years of tamoxifen 
20 mg daily through a prospective, phase III trial. Women with two CYP2D6*4 
variant alleles (poor metabolizers) had a worse outcome compared to those with 
one variant (intermediate metabolizers) and those with two wild-type alleles 
(extensive metabolizers) (4, 5). In addition, women who have taken a CYP2D6 
inhibitor had also experienced a worse disease free survival. Overall survival was 
not affected. A recent update with an extended follow-up and a more 
comprehensive genotype analysis of these original patients showed a hazard 
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ratio of 4.0 in relapse-free time among poor metabolizers relative to extensive 
metabolizers. 
Since this initial report, several other datasets have been evaluated and results 
have been published, however most include archival tissue or mixed populations 
of women who may have received chemotherapy, different duration of tamoxifen 
therapy, and different menopausal status (6-9). The data are summarized briefly 
below and  in table 1 (10). 
Several groups reported a correlation between CYP2D6 variants and reduced 
tamoxifen efficacy (Table 1). German investigators evaluated the predictive value 
of genetic variants of CYP2D6, CYP2C19, and three other cytochrome P450 
enzymes for tamoxifen treatment outcome. Tamoxifen-treated patients carrying 
the CYP2D6 alleles that are associated with impaired formation of antiestrogenic 
metabolites including *4, *5, *10, *41, had significantly more recurrences of 
breast cancer, shorter relapse-free periods and worse event-free survival rates 
compared with carriers of functional alleles. Interestingly, patients with the 
CYP2C19 high enzyme activity promoter variant *17 had a more favorable clinical 
outcome than carriers of *1, *2, and *3 alleles (11). In a Korean cohort, the 
authors reported that CYP2D6 status influenced tamoxifen metabolism in the 
adjuvant setting, and response to the treatment in the metastatic setting in 
women with or without variants in the gene (12). Results from 67 Japanese 
patients revealed similar results (13). Finally, in the Italian chemoprevention 
study, women who received tamoxifen who were CYP2D6*4/*4 carriers had a 
higher likelihood of developing breast cancer (14). At the same time, three large 
studies have not demonstrated an association (7, 8, 15). 
Of note, CYP2D6 does not appear to be a prognostic marker in breast cancer. In 
one cohort, samples were obtained from women who did not receive systemic 
therapy. A significant correlation was not observed between genotypes and 
tumor size, nodal status, histologic grade, or ER status. In the women who did 
not receive tamoxifen, there was no association between metabolizer status and 
outcome (P = 0.37) (11). 


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Table 1. Summary of studies to date correlating CYP2D6 variants with clinical outcome, [modified from (10)] 
Author 
Year 
Setting and Study 
Summary 
Patients: Number 
and  Characteristics 
CYPD2D6 
variants 
Other 
Genotypes 
Comments& 
Outcomes 
Goetz 
2005 (4) 
Adjuvant. 
Retrospective review 
of participants in a 
prospective study. 
256 
Post-menopausal.  
ER-positive. 
*4, *6 
CYP3A5*3 
 
CYP2D6*4/*4 vs other: 
RFS HR 1.85, P=0.176. 
DFS HR 1.86, P=0.089. 
No association found with 
CYP3A5*3 
Goetz 
2007 (5) 
Adjuvant. 
Retrospective Same 
cohort as Goetz 
2005. 
190 
Post-menopausal. 
ER-positive. 
*4, *6 
 
13 patients on 
inhibitors 
PM vs other: 
TTR HR 1.91, P=0.034. 
RFS HR 1.74, P= 0.017. 
Wegman 
2005 (15) 
Adjuvant. 
Retrospective review 
of participants in a 
prospective study.  
226 
Post-menopausal.  
Some received CT. 
Not exclusively HR+. 
*4 
SULT1A1*1,*2 
Tamoxifen 
40mg/d x 2 yrs 
CYP2D6*4 carrier 
Lower risk of recurrence RR 
0.28, P=0.0089. 
SULT1A1*1,*2  
No association found 
SULT1A1*1/*1 
Lower risk of recurrence RR 
0.48, P=0.0074. 
CYP2D6*4 and/or 
SULT1A1*1/*1 
Lower risk of distant recurrence 
RR 0.38, P= 0.0041. 
Wegman 
2007 (8) 
Adjuvant. 
Retrospective 
677 
Post-menopausal  
HR+  
*4 
CYP3A5*3, 
SULT1A1*1,*2 
and 
UGT2B15*1,*2 
Tamoxifen 
40mg/d x 2 or 5 
yrs (until 1994) 
or 20mg/d   
(after 1994) 
CYP2D6*4/*4 vs CYP2D6*1 or 
*1/*1: 
improved DFS  
P= 0.04 and 0.05 
CYP3A5*3,SULT1A1*1*2 and  
UGT2B15*1,*2  
No association found 
CYP3A5*3/*3, Tam 5 ys, 
improved RFS 
HR 0.20, P=0.002. 


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Nowell 
2005 (7) 
Adjuvant. 
Retrospective 
337 
Pre- and Post- 
menopausal 
162 on tam 
175 no tam 
*4 
SULT1A1*1,*2 
and 
UGT2B15*1,*2 
Tamoxifen 
treatment details 
not provided 
CYP2D6*4 vs other in Tam-
treated Hazard Ratios: 
OS 0.77, 95% CI 0.32-1.81 
SULT1A1*2: 
Trend towards increased 
recurrence of disease with 
increasing alleles 
Patients on tam with both 
UGT2B15*2 and SULT1A1*2 
had decreased OS Hazard ratio 
4.4, 95% CI 1.17-16.55 
Schroth 
2007 (11) 
Adjuvant. 
Retrospective 
 
486 
Pre- and post-
menopausal.  
-206 HR+  received 
Tam  
-280 received CT or 
no therapy 53.8% of 
whom were HR+. 
*4,*5,*10,*
4 
CYP2C19*2,*3,*
17 
CYP2B6 
CYP2C9*2,*3 
CYP3A5*3 
Tamoxifen 
treatment details 
not provided 
Tam-treated PM vs other  
RFS HR 2.24, P=0.02. 
EFSR HR 1.89, P=0.02. 
CYP2C19*17 vs other CPY2C19 
alleles: 
HR for RFT 0.45; 95% CI, 0.21-
0.92 P = .03 
Lim 2007 
(12) 
Adjuvant. 
Prospective. Also 
includes a 
prospective 
metastatic cohort. 
211 
Pre- and post-
menopausal. 
HR+.  
-190 adjuvant 
-21 metastatic 
*5,*10 
 
Pregnane X 
receptor (PXR) 
Tamoxifen 
treatment details 
not provided 
20mg/d for at 
least 8 weeks 
before 
pharmaco-
kinetic studies 
CYP2D6*10/*10 
lower concentration of Tam 
metabolites  
P<0.0001. 
More often found among non-
responders than responders 
100% vs 50%, P=0.0186. 
Median TTP 5 vs 21.8 ms, 
P=0.0032 
No correlation found between 
PXR variants and metabolite 
concentrations 


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Xu 2008 
(16) 
Adjuvant. 
Retrospective Also 
include a prospective 
cohort. 
152 
Pre- and post-
menopausal women 
receiving Tam. 
-141 no Tam. 
 
37 women on Tam 
10 mg/d for >4 
weeks 
*10, 
 
 
Tamoxifen 
20mg/d for 
retrospective 
analysis 
10mg/d for >4 
weeks for 
prospective PK 
studies. No 
patients were 
co-prescribed 
inhibitors 
Tam-treated: CYP2D*10/10 vs 
CYP2D6*10/*1 or 1/*1:  
DFS HR 4.7, P=0.04. 
 
CYP2D6*10/10 
Lower concentration of Tam 
metabolites, P=0.04. 
Kiyotani 
2008 (13) 
Adjuvant. 
Retrospective 
67 
Pre-and post-
menopausal. HR+ 
Tam monotherapy. 
*4,*5,*6,*1
0,*21,*41 
 
 
CYP2D6*10/*10 vs *1/*1 : 
Recurrence OR 16.63, 
P=0.0057. 
RFS  
CYP2D6*10/*10 vs *1/*1 or 
*1/*10 : P=0.0031 or P=0.0010. 
Newman 
2008 
 (17)        
 
Adjuvant. 
Retrospective 
 
115  
Familial breast 
cancer 
-47 BRCA1+ 
-68 BRCA2+ 
*3, *4, *5, 
*41 
 
Tamoxifen 
20mg/d x 
median of 4 yrs.  
 
Inhibitors co-
prescribed in 4 
patients only  
Cox HR for overall low CYP2D6 
activity group adjusted for nodal 
status :  
BCR 2.1, P=0.14 
RFS 1.9, P=0.19 
OS 2.5, P=0.17 
BRCA2 and low CYP2D6 activity 
vs BRCA2 and normal CYP2D6 
activity: 
OS 6.9yrs vs 28.1yrs P=0.008 
Bonanni 
2006 (14) 
Chemo-prevention. 
Retrospective 
47 
Enrolled in a 
prospective study 
32 alleles,  
classifying 
to PM, IM, 
EM UM.  
 
Tam 20 mg/d x 
5 yrs vs placebo 
x 5 yrs 
Increased risk of PM vs others to 
develop breast cancer, P=0.035. 
Comments&: 1) Tamoxifen was administered at 20 mg/day for 5 years unless otherwise specified; 2) concomitant medication information was not 
available unless otherwise specified 
HR+ = hormone receptor positive, HR = hazard ratio, OR = odds ratio, ER = estrogen receptor, RFT = relapse free time, CT = chemotherapy, RFS 
= relapse free survival, OS = overall survival, DFS = disease free survival, Tam = tamoxifen, mg/d = milligrams per day, yrs = years. BCR = breast 
cancer recurrence, PM = poor metabolizer, IM = intermediate metabolizer, EM = extensive metabolizer, UM = ultrametabolize 


ECOG-ACRIN 
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The table highlights some of the shortcomings with studies performed to date 
and the difficulties interpreting results. The majority of studies were retrospective 
and only a few included women previously enrolled in a single prospective trial. 
More then one dose or schedule of tamoxifen may have been studied, and not all 
women had tumors that were hormone receptor positive. Indeed, a recent 
preliminary report from the International Tamoxifen Consortium at the San 
Antonio Breast Cancer Symposium (December 2009) failed to show a correlation 
between CYP2D6 status and long-term outcomes. 
Ideally, a prospective study of adjuvant tamoxifen should be conducted to 
compare long term outcomes of people with or without variants. However, due to 
the widespread use of aromatase inhibitors in postmenopausal women, the most 
common population affected by the disease, such a trial will be very difficult to 
conduct. While there are many ongoing attempts to evaluate datasets from large 
studies that have already been completed, these sets do not include tamoxifen 
metabolite information and most include only paraffin blocks, thus not allowing for 
complex pharmacogenetic profiling. An alternative is to evaluate progression-free 
survival and other outcomes in the metastatic setting. Therefore we propose a 
phase II study in patients who are candidates for tamoxifen treatment in the 
metastatic setting with either no prior therapy or with prior aromatase inhibitor 
therapy and will compare outcomes in those with and without variants in the 
CYP2D6 gene.  
In addition, only a few studies attempted to evaluate the influence of variants in 
other candidate genes on drug efficacy and prospective analysis is lacking.  We 
will study other candidate genes and will also explore whole genome analysis. 
1.3 
Genetic Predictors of Other Tamoxifen-Associated Outcomes 
Genetic variants in genes responsible for tamoxifen’s pharmacokinetics (eg 
CYP2D6) and pharmacodynamics (eg ESR) may also influence drug-related 
secondary benefits and adverse events. 
For example, in the COBRA prospective tamoxifen pharmacogenomics study, an 
association was initially observed between ESR1 XbaI genotype and baseline 
low-density lipoprotein (LDL) and total cholesterol. The XbaI genotype was also 
associated with tamoxifen-induced change in total cholesterol (post-menopause) 
and triglycerides and HDL (pre-menopause). The tamoxifen-induced change in 
triglycerides was also associated with the ESR2 genotype (rs#4986938) (18). 
The analysis in the initial cohort was carried out by PCR followed by restriction-
enzyme digestion. After reanalysis using more robust TaqMan assays, the 
findings related to ~10% of the genotypes for the ESR1 XbaI SNP were revised. 
For the other genotypes (i.e., ESR1 PvuII, ESR2, and CYP2D6), the results were 
nearly identical to those in the previous study. Upon reanalysis, previously 
reported associations between the ESR1 Xba1 genotypes and baseline 
triglyceride and LDL cholesterol levels were no longer observed emphasizing the 
need for additional study (19). 
Other studies reported correlation with ESR and events such as hot flashes and 
deep venous thromboses (DVT). In the prospective COBRA tamoxifen study, 
baseline hot flash score was significantly associated with both the ESR1 XbaI 
(rs#9340799) and PvuII (rs#2234693) genotypes (20). The combined haplotype 
analysis indicated that for an increase in one copy of the CG haplotype, the 
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subjects had a 2.5-fold higher baseline hot flash score. In addition, an ESR2 SNP 
(rs#4986938) was associated with a decreased risk of developing tamoxifen-
induced hot flashes (OR 0.12; 95% CI, 0.04-0.41; P = .0001). When the PvuII 
and the ESR2 genotypes were combined, they were also significantly associated 
with the tamoxifen-induced hot flash score. In a retrospective study conducted in 
collaboration between COBRA and with investigators at the Marshfield Clinic, the 
ESR1 XbaI SNP (rs#9340799) was significantly associated with tamoxifen-
induced DVTs(21). The hazard ratio for patients with at least one G allele was 
3.47. 
 


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2. 
Objectives 
2.1 
Primary Objective 
To correlate CYP2D6 score (0 vs. 1+2) and progression-free survival. 
2.2 
Secondary Objectives 
2.2.1 
To correlate CYP2D6 score (0 vs. 1 vs. 2) and progression-free 
survival. 
2.2.2 
To correlate CYP2D6 score (0 vs. 1 + 2) and proportion of patients 
who are progression-free at 6 months. 
2.2.3 
To correlate endoxifen concentration with response. 
2.2.4 
To correlate CYP2D6 score with response. 
2.2.5 
To correlate the presence of candidate estrogen receptor (ESR) 1 and 
2 variant alleles, UGT7, SULT1A1, other candidate genes and 
biomarkers to progression-free survival and other tamoxifen related 
outcomes. 
 
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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 registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria 
3.1.1 
Must have estrogen and/or progesterone receptor positive 
histologically confirmed adenocarcinoma of the breast. Receptor 
status may be based on any time during treatment prior to study 
registration, and from any site (i.e. primary recurrent, or metastatic). 
3.1.2 
Patients must have measurable or non-measurable Stage III/locally 
advanced or metastatic carcinoma of the breast where surgery is not 
possible, as defined in Section 6.1.1. Lesions must be evaluated 
within 4 weeks prior to registration. 
3.1.3 
Age ≥ 18 years. 
3.1.4 
Women must not be pregnant or breast-feeding due to harmful effects 
of tamoxifen. 
Breast feeding? ________  (Yes or No) 
NOTE: 
All females of childbearing potential must have a blood test 
within 2 weeks prior to registration to rule out pregnancy. A 
female of childbearing potential is any woman, regardless 
of sexual orientation or whether they have undergone tubal 
ligation, who meets the following criteria: 
1) Has not undergone a hysterectomy or bilateral oopherectomy; 
Or  
2) Has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female of child bearing potential? ______ (Yes or No) 
_____
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Date of pregnancy test: ___________________ 
3.1.5 
Women of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of non-
hormonal contraception. Acceptable contraception includes barrier 
methods (e.g., condoms or diaphragm) or intrauterine devices or IUDs 
(these may include low-dose hormones at the discretion of the Study 
Chair). 
3.1.6 
ECOG performance status of 0-2. 
3.1.7 
Systemic Therapy 
3.1.7.1 
Patients who have received agents that modulate or 
downregulate the estrogen receptor for breast cancer 
prevention (e.g. tamoxifen, raloxifene, fulvestrant)  or bone 
health (raloxifene) are eligible if they were on treatment for 
at least 6 months, did not have a diagnosis of breast 
cancer on the medication, and have discontinued the 
agents 6 months prior to study registration. 
3.1.7.2 
Adjuvant Setting  
3.1.7.2.1 
Chemotherapy or trastuzumab or 
bevacizumab in the adjuvant setting is 
allowed but must have been completed at 
least 4 weeks prior to study registration. 
Other prior non-hormonal investigational 
agents in the adjuvant setting must have 
completed at least 4 weeks prior to study 
registration and should be discussed with 
the study PI. 
3.1.7.2.2 
Prior aromatase inhibitors (e.g. anastrozole, 
letrozole, exemestane, aminoglutethamide) 
are allowed in the adjuvant setting. 
The following treatments (3.1.7.2.3 and 
3.1.7.2.4) are allowed provided that the 
patient must have discontinued the agents 6 
months prior to study registration: 
3.1.7.2.3 
Prior tamoxifen as adjuvant treatment is 
allowed as long as the patient did not have 
disease relapse or progression while on 
adjuvant tamoxifen or within 4 weeks of last 
dose.  
3.1.7.2.4 
Patients who have received other agents 
that modulate or downregulate the estrogen 
receptor (e.g. raloxifene, fulvestrant) in the 
adjuvant setting are eligible if they were on 
treatment for at least 6 months prior to 
disease progression in the locally advanced 
or metastatic setting.  
_____
_____
_____
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_____
Rev. 5/11, 8/12 
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_____
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3.1.7.3 
Locally Advanced or Metastatic Setting  
3.1.7.3.1 
Patients must not have had more than 2 
lines of non-hormonal treatment in the 
locally advanced or metastatic setting, 
including trastuzumab (Herceptin), 
bevacizumab, or other agents; treatment in 
the locally advanced or metatastic setting 
must have been completed at least 2 weeks 
prior to study registration. 
3.1.7.3.2 
Prior aromatase inhibitors (e.g. anastrozole, 
letrozole, exemestane, aminoglutethamide) 
are allowed in the locally advanced or 
metastatic setting. 
3.1.7.3.3 
Prior tamoxifen is not allowed in the locally 
advanced or metastatic setting.   
3.1.7.3.4 
Patients who have received other agents 
that modulate or downregulate the estrogen 
receptor (e.g. raloxifene, fulvestrant) in the 
locally advanced or metastatic setting are 
eligible if they were on treatment for at least 
6 months and must have discontinued these 
agents 6 months prior to study registration 
3.1.8 
Non-protocol concurrent hormonal therapy is not allowed. 
3.1.9 
Concurrent chemotherapy is not allowed. 
3.1.10 
Patients, must have adequate hematologic and renal function at the 
discretion of the treating physician and hepatic function as defined by 
the following within 4 weeks prior to registration: 
3.1.10.1 
Total bilirubin ≤ 1.5 x upper limit of normal 
Total bilirubin: ____________ ULN:_____________ 
Date of Test:  ____________ 
3.1.10.2 
SGPT (ALT) ≤ 2.5 x upper limit of normal OR ≤ 5 x upper 
limit of normal if liver metastases. 
ALT:  ____________ ULN:_____________ 
Date of Test:  ____________ 
3.1.10.3 
 SGOT (AST) ≤ 2.5 x upper limit of normal OR ≤ 5 x upper 
limit of normal if liver metastases. 
AST:  ____________ ULN:_____________ 
Date of Test:  ____________ 
3.1.11 
Patients with a history of central nervous system metastasis are 
allowed provided they have been treated (surgery, radiation, or 
radiosurgery) at least 4 weeks prior to initiating study drug and do not 
require medication(s) to control symptoms. Patients with known 
leptomeningeal disease are not eligible. 
_____
_____
_____
Rev. 5/11 
_____
Rev. 8/12 
_____
_____
_____
_____
_____
_____
_____
_____
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Rev. 8/12 
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3.1.12 
Patients may receive concurrent radiation therapy to painful sites of 
bony disease or areas of impending fracture as long as the radiation 
therapy is initiated prior to study entry and sites of measurable and 
non-measurable disease outside the radiation therapy port are 
available to follow. Patients who have received prior radiation therapy 
must have recovered from toxicity of the prior radiation therapy.  
3.1.13 
Patients must not take the following medications that are strong to 
moderate inhibitors of CYP2D6 and may alter tamoxifen metabolism: 
paroxetine (Paxil), fluoxetine (Prozac), buproprion (Wellbutrin) and 
quindine (Cardioquin) within 2 weeks of registration.  
3.1.14 
Patients must not suffer from medical or psychiatric conditions that 
would interfere with protocol compliance, the ability to provide 
informed consent, or assessment of response or anticipated toxicities. 
3.1.15 
Patients must be disease-free of prior invasive malignancies for ≥ 5 
years with the exception of curatively-treated basal cell or squamous 
cell carcinoma of the skin or carcinoma in situ of the cervix. 
3.1.16 
Patients may not initiate bisphosphonate or denosumab therapy while 
receiving treatment on this study. Patients who have begun receiving 
bisphosphonate or denosumab therapy prior to registration may 
continue at the same intervals used prior to study registration.  
3.1.17 
Patients must be disease-free of prior invasive malignancies for ≥ 5 
years with the exception of curatively-treated basal cell or squamous 
cell carcinoma of the skin or carcinoma in situ of the cervix. 
3.1.18 
Patients may not initiate bisphosphonate therapy while receiving 
treatment on this study. Patients who have begun receiving 
bisphosphonate therapy prior to registration may continue at the same 
intervals used prior to study registration. 
 
_____
Rev. 5/11 
_____
_____
_____
_____
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Rev. 5/11, 8/12 
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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU member web site by entering credentials 
at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically 
load to RSS. 
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Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E3108 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E3108 
• 
Click on the Site Registration Documents link 
Requirements for E3108 site registration: 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via 
the NCI CIRB) 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS.  
CTSU Regulatory Office 
 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
FAX: (215) 569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Required Protocol Specific Regulatory Documents 
1. CTSU Regulatory Transmittal Form. 
2. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
consent document must be justified in writing by the investigator 
and approved by the IRB. 
3. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 


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• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within three working days after registration. 
 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at <https://eapps-
ctep.nci.nih.gov/iam/index.jsp>) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data . OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
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The following information will be requested: 
4.1 
Protocol Number  
4.2 
Investigator Identification  
4.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2 
Investigator’s name (NCI number) 
4.2.3 
Cooperative Group Credit 
4.2.4 
Credit Investigator 
4.2.5 
Protocol specific contact information 
4.3 
Patient Identification  
4.3.1 
Patient’s initials (first and last) and chart number 
4.3.2 
Patient’s Social Security number and/or Hospital ID 
4.3.3 
Patient demographics 
4.3.3.1 
Sex 
4.3.3.2 
Birth date (mm/yyyy) 
4.3.3.3 
Race 
4.3.3.4 
Ethnicity 
4.3.3.5 
Nine-digit ZIP code 
4.3.3.6 
Method of payment 
4.3.3.7 
Country of residence 
4.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 3.  An 
eligibility checklist has been appended to the protocol.  A confirmation of 
registration will be forwarded by the ECOG-ACRIN Operations Office - Boston. 
4.5 
Additional Requirements  
4.5.1 
Patients must provide a signed and dated, written informed consent 
form. 
4.5.2 
Pathological materials should be submitted as indicated in Section 10 
for banking per patient consent. 
NOTE:  
Please submit block from primary tumor and, when 
available, from metastatic site. 
4.5.3 
Whole blood must be submitted for genotype verification as indicated 
in Section 11. Plasma must be submitted for the laboratory studies 
outlined in Section 11. 
NOTE: 
ECOG-ACRIN requires that biological samples submitted 
from patients participating in E3108 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking 
System (STS).  See Section 10.4. 


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4.6 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E3108 Forms Packet. Document the reason for not starting 
protocol treatment on the off-treatment form. Also report the date and type of the 
first non-protocol treatment that the patient receives on the Non-Protocol Therapy 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
1 cycle = 28 days 
Open label tamoxifen 20 mg PO (single dose) daily until progression, 
unacceptable toxicities, or any other condition outlined in Section 5.5.  
5.2 
Adverse Event Reporting Requirements  
5.2.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E3108 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
5.2.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: 
Identify the type of event: The descriptions and grading 
scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) will be utilized for AE 
reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP 
website (http://ctep.cancer.gov). 
Step 2: 
Grade the event using the NCI CTCAE version 4.0. 
Step 3: 
Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
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Step 4: 
Determine the prior experience of the adverse event. 
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 only, when either the type of event or 
the severity of the event is NOT listed in:  
• 
Arm A – the drug package insert or protocol  
Step 5: 
Review Section 5.2.6 for E3108 and/or ECOG-ACRIN 
specific requirements for expedited reporting of specific 
adverse events that require special monitoring.   
NOTE: 
For general questions regarding expedited reporting 
requirements, please contact the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP's Adverse Event Reporting System (CTEP-AERS). CTEP's 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) 
• 
the FDA (800-332-1088) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
When to report an event in an expedited manner 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.2.6. 
NOTE: 
Adverse events that meet the reporting requirements in 
Section 5.2.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
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requirements in Section 5.2.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
5.2.5 
Other recipients of adverse event reports 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
5.2.6 
Expedited reporting for commercial agents 
Commercial reporting requirements are provided below. The 
commercial agent used in arm A of this study is Tamoxifen. 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only –Arm A 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution.  
NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed possibly, 
probably, or definitely to the treatment must be reported within 7 calendar days of learning of 
the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar 
days of learning of the event.  For instructions on how to specifically report these events via 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 301-897-
7497.  This will need to be discussed on a case by case basis. 
Thromboembolic events: Any grade 3 or higher thromboembolic event must be reported via CTEP-AERS 
within 7 calendar days of learning of the event, regardless of attribution or 
expectedness. 
Secondary endometrial cancer: Any confirmed diagnosis of secondary endometrial cancer must be 
reported via CTEP-AERS within 7 calendar days of learning of the event, 
regardless of relationship to protocol treatment.  In addition, a completed 
Second Primary Form must be submitted to the ECOG-ACRIN Operations 
Office - Boston within 30 days of diagnosis. 
5.2.7 
Reporting of Other Second Primary Cancers 
All cases of second primary cancers that occur following treatment on 
NCI-sponsored trials must be reported to ECOG-ACRIN: 
• 
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: 
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1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis 
• 
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. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under treatment related secondary malignancy 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
NOTE: 
The Second Primary Form and the CTEP-AERS report should not be 
used to report recurrence or development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-sponsored study, 
the Second Primary Form must be submitted for the most recent trial. 
ECOG-ACRIN must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no longer 
required by the protocol, no follow-up data should be submitted via 
CTEP-AERS or by the Second Primary Form. 
5.3 
Dose Modifications  
NOTE: 
If tamoxifen administration is held for any reason, patient can remain 
on study for up to 7 days. If tamoxifen administration is held for > 7 
days, patient will be considered off-treatment. 
NOTE: 
Tamoxifen dose reductions are not allowed. 
All toxicities should be graded according to 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. The CTCAE version 4.0 can be found on the CTEP website 
(http://ctep.cancer.gov). 
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5.4 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
Patients receiving bisphosphonate therapy prior to beginning this trial may 
continue at the same intervals used prior to entering the study. Bisphosphonate 
therapy may not be initiated while being treated on this trial. 
Patients must not take the following medications that are strong to moderate 
inhibitors of CYP2D6 and may alter tamoxifen metabolism: paroxetine (Paxil), 
fluoxetine (Prozac), buproprion (Wellbutrin), and quindine (Cardioquin) 2 weeks 
prior to registration or at any time while on-study.  
5.5 
Duration of Therapy  
Patients will receive protocol therapy unless: 
5.5.1 
Progressive disease by RECIST criteria. See Section 6.1. 
5.5.2 
Severe toxicity at discretion of the treating physician (including 
thromboembolic disease, endometrial cancer).  
5.5.3 
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 E3108 Forms Packet. 
5.5.4 
Patient withdraws consent. 
5.5.5 
If tamoxifen is held for > 7 days. 
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 registration.  For patients 
who remain on-treatment, treatment data will be collected for 5 years from the 
date of registration 
 
 


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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients’ disease should be evaluated according 
to the schedule in Section 7. If a patient’s disease responds, a confirmatory scan 
must be performed at least 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 registration. 
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 
of the diameters will be used as reference to further characterize any 


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objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers.  All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before registration. 
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. 
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 


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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). 
The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease.  
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. To be assigned a status of 
complete response, changes in tumor measurements must 
be confirmed by a repeat assessment performed no less 
than four weeks after the criteria for response is met. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. To be assigned a status of partial response, 
changes in tumor measurements must be confirmed by a 
repeat assessment performed no less than four weeks 
after the criteria for response is met. 
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 12 weeks. 
6.1.4.2 
Evaluation of Non-Target Lesions 
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Complete Response (CR) 
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis) 
NOTE: 
If tumor markers are initially above the upper 
normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (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 on-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 


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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 
criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Best 
Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
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 > 12 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 
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For Patients with Only Non-Measurable Disease (i.e., Non-Target 
Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD 
is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
6.1.5 
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 12 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 registration. 
2. Prestudy CBC (with differential and platelet count) should be done ≤ 4 weeks prior to registration.  
3. All required prestudy chemistries, as outlined in Section 3, should be done ≤ 4 weeks prior to registration.  
NOTE: 
1 cycle = 28 days 
 
Pre-Study 
End of 
Cycles 1 
and 29 
End of 
Cycle 39 
Every 3 
cycles (after 
cycle 3) 9 
At 
discontinuation 
of treatment10 
Post treatment 
up to 5 years 
from study 
entry 
≤ 4 weeks 
prior to 
registration 
≤ 2 weeks 
prior to 
registration 
Height 
X 
 
 
 
 
 
 
History, Physical Exam, ECOG PS, 
Vital signs, Weight 
X 
 
X 
X 
X 
X 
X3 
Concomitant Medications 
X 
 
X 
X 
X 
 
X8 
CBC1 
X 
 
 
X 
X 
X 
 
Bilirubin, SGOT (AST), SGPT (ALT) 
X 
 
 
X 
X 
X 
 
Lipid profile11 
X 
 
 
X 
 
 
 
HCG 2 
 
X 
 
 
 
 
 
Bone scan 
X6 
 
 
X6 
X6 
 
X6,8 
Tumor assessment by PE 
X 
 
 
X 
X 
X 
X8 
Tumor assessment by CT or MRI7 
X 
 
 
X 
X 
X 
X8 
Research blood submissions5 
X4 
 
 
X 
 
X 
 
1. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct. 
2. All females of child-bearing potential must have a blood or urine test within 2 weeks prior to registration to rule out pregnancy. 
3. Every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry. No specific requirements if 
patient is more than 5 years from study entry. 
Rev. 5/11 
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4. It is strongly encouraged that the whole blood collected for the genotype verification is collected prior to protocol treatment, but may be 
collected at the end of cycle three (3) if unable to collect at baseline.  
5. Refer to Sections 7.2 and 11 for submission instructions. 
 
6. Baseline bone scan required in all patients; repeat in follow-up as clinically indicated. 
NOTE: 
If bone scan done within 6 months prior to registration showed no evidence suggesting bone metastases and no clinical indication 
of skeletal pain or other evidence suggesting bone metastases, a repeat baseline bone scan is not required.   
7. CT or MRI of chest/abdomen/pelvis are required at baseline. Those tests required to follow known site(s) of disease should be repeated at the 
end of Cycle 3 and then every 3 cycles during treatment and according to the follow up schedule if off treatment, until first progression of 
disease. 
NOTE: 
If CT or MRI of chest and/or abdomen/pelvis done within 6 months prior to registration showed no evidence of disease in the 
area(s) and no clinical indication suggesting new metastases, full re-staging including all areas is not required; however, ensure 
that disease is evaluable per RECIST requirements (Section 6). 
8. Concomitant medication and tumor assessments are to be done up to (and including) the assessment which shows first progression of 
disease. If patient discontinues treatment due to reasons other than disease progression, concomitant medication and tumor assessments 
should be performed until disease progression on the following schedule: Every 3 months if patient is < 2 years from study entry, every 6 
months if patient is 2-5 years from study entry. No specific requirements if patient is more than 5 years from study entry. 
9. All tests should be performed at the end of the cycle. A +/- 7 day window will be allowed in case of scheduling problems. 
10. Repeat any test not done within the prior 28 days. 
11. Lipid profile should be fasting. 
 
 
Rev. 8/12 
Rev. 8/12 
Rev. 5/11,  
8/12 
Rev. 5/11,  
8/12 
Rev. 5/11 
Rev. 5/11 
Rev. 5/11 
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7.2 
Biological Sample Submissions  
1. Pathological materials should be submitted for banking as outlined in Section 
10 per patient consent. 
2. Whole blood and plasma must be submitted as outlined in Section 11 for 
CYP2D6 status and tamoxifen and metabolite levels. 
NOTE: 
It is required that biological sample submissions be logged into the 
ECOG-ACRIN Sample Tracking System (STS) (see Section 10.4) 
for purposes of monitoring compliance. 
NOTE: 
An informed consent must be signed prior to the use of any 
samples for any laboratory study or banking.  
Rev. 8/12 
 
Pre-Study1 
End of 
Cycle 
Three (3) 
Off-
Treatment 
Submit to: 
 
Block from Primary Tumor 
X 
 
 
ECOG-ACRIN 
Central 
Biorepository and 
Pathology Facility 
 
Block from Metastatic Site 
(when available) 
X 
 
 
Rev. 8/12 
Plasma (one (1) 6mL sodium 
heparin green top tube)* 
 
X 
X 
Rev. 8/12 
Whole Blood (one (1) 8-10mL 
EDTA purple top tube - K3)* 
X2 
 
 
Indiana University 
School of Medicine 
* Mandatory 
1. Baseline, prior to treatment. 
2. Whole blood is strongly encouraged to be collected at baseline, prior to 
treatment, but may be collected at the end of cycle three (3) if unable to 
collect at baseline. 
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8. 
Drug Formulation and Procurement 
8.1 
Tamoxifen 
8.1.1 
Other Names  
Nolvadex, tamoxifen citrate, NSC# 180973 
8.1.2 
Classification  
Hormone antagonist (antiestrogen). 
8.1.3 
Mode of Action  
Tamoxifen and its metabolites possess antiestrogenic activity due to 
their ability to compete with estradiol for binding to receptors in the 
cells of tumors that contain high amounts of estrogen receptors (such 
as breast cancer). The estrogen receptor complex is translocated 
from the cytoplasm of cancer cells to the nucleus where it reduces 
DNA synthesis and cellular responses to estrogen. Tamoxifen also 
displays mild estrogenic activity and induces secretion of transforming 
growth factor beta (TGF-beta), which has inhibitory effects on many 
types of epithelial cells. 
8.1.4 
Storage and Stability  
Tamoxifen is stored at room temperature protected from light. 
8.1.5 
Dose Specifics  
20 mg PO daily (as a single dose) 
8.1.6 
Preparation  
Not applicable, tablet is ready for administration. 
8.1.7 
Route of Administration  
Oral. 
8.1.8 
Incompatibilities  
Tamoxifen is a potent inhibitor of hepatic cytochrome P450 mixed 
function oxidases (MFO). The effect of tamoxifen on the metabolism 
and excretion of other drugs requiring MFO for activation is unknown. 
Phenobarbital decreased tamoxifen serum level significantly in one 
patient. Concomitant bromocriptine therapy has been shown to 
elevate serum tamoxifen levels Tamoxifen may potentate the 
anticoagulant effects of warfarin. 
8.1.9 
Availability / How Supplied 
Tamoxifen is commercially available in 10 mg and 20 mg tablets. 
8.1.10 
Side Effects  
1. 
Hematologic: Thrombocytopenia, usually mild and transient, 
leukopenia, anemia. 
2. 
Dermatologic: Rash, erythema. 


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3. 
Gastrointestinal: Nausea, vomiting, anorexia (may lead to weight 
loss), diarrhea or constipation, distaste for food. 
4. 
Genitourinary: Vaginal bleeding or discharge, menstrual 
changes (amenorrhea, menstrual irregularities), pruritus vulvae. 
5. 
Hepatic: Increased liver enzymes, cholestasis, increased 
bilirubin, and fatty changes in the liver. 
6. 
Neurologic: Depression, dizziness, lightheadedness, headache, 
confusion, lassitude, and syncope. 
7. 
Cardiovascular: Hot flashes, thrombophlebitis, 
thromboembolism, pulmonary embolism, fluid retention and 
edema. Thrombotic events, DVT, clotting factor abnormalities. 
8. 
Ocular: Retinopathy, corneal opacity, slight increased risk of 
cataracts; corneal scarring and retinal changes have been 
reported. 
9. 
Metabolic: Hypercalcemia. 
10. Other: Tumor "flare" may occur in the first month of therapy, 
manifested as an increase in tumor-related symptoms, such as 
bone pain, increase in tumor size, erythema. Weight gain, fluid 
retention, and edema. 
11. Effects in pregnancy: classified as Category D; women should 
not become pregnant while taking tamoxifen. 
12. Secondary cancers: Tamoxifen increases the risk for uterine 
cancer and the possibility of death from this disease. Patients 
receiving tamoxifen should have routine gynecologic exams and 
report any menstrual irregularities, abnormal vaginal bleeding, 
changes in vaginal discharge and/or pelvic pain or pressure. 
Tamoxifen may possibly increase the risk for gastrointestinal 
cancers. 
8.1.11 
Nursing/Patient Implications  
1. 
Monitor carefully for tumor flare reactions. 
2. 
Teach patients and families to recognize signs and symptoms of 
hypercalcemia. 
3. 
Advise patient of potential vaginal bleeding and menstrual 
changes, hot flashes. 
4. 
Teach patients and families to recognize the signs and 
symptoms of thromboembolic events, namely deep vein 
thrombosis (DVT) and pulmonary embolism (PE). 
NOTE: 
A patient medication diary is available in Appendix IV to 
monitor tamoxifen administration. 


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8.1.12 
References  
Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern 
Med 1988; 109:219-228. 
Love RR. Tamoxifen therapy in primary breast cancer: Biology, 
efficacy and side effects. J Clin Oncol 1989; 7:803-815. 
Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat 
Rep 1978; 62:315-320. 
Lipton A, Harvey HA, Hamilton RW. Venous thrombosis as a side 
effect of tamoxifen treatment. Cancer Treat Rep 1984; 68:887-889. 
Please see tamoxifen package insert for more information. 


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9. 
Statistical Considerations 
The primary purpose of this study is to evaluate whether patients with blood samples 
with CYP2D6 score of 0 (poor metabolizer) have a reduced progression-free survival 
(PFS) relative to patients with samples with a CYP2D6 score of 1 or 2 (intermediate and 
extensive metabolizers, respectively). A total of 240 patients will be enrolled in this 
study. Assuming a monthly accrual of 10 patients, 24 months of accrual is needed. The 
below calculations assume that 85% (204/240) of the patients enrolled have samples 
where a CYP2D6 score of 0, 1, or 2 can be assigned. 
CYP2D6 SCORING 
We will use a scoring system that has been recently modified from Gaedigk et al (18) to 
include known CYP2D6 variants and inhibitors:  
CYP2D6 Allele 
Points Assigned/Allele 
*1, *1xN, *2, *2xN, *35 
1 
*9, *10, *17, *41 
0.5 
*3, *4, *5, *6, *11 
0 
Medication 
Points Adjustment 
Paroxetine, Fluoxetine , Bupropion 
-2 
Sertraline, Duloxetine, Citalopram, 
Escitalopram, Celecoxib, 
Diphenhydramine, Chlorpheniramine 
-1 
Venlafaxine 
-0 
An overall comparison of patients with scores CYP2D6=0 vs. CYP2D6= 1 or 2 with 
respect to progression-free survival will be made. It is estimated that approximately 10% 
will have a score=0, 40% with a score=1 and 50% with a score=2. A hazard ratio (HR) 
greater than 1.95 or 2 is of interest to influence change in practice. The table below 
shows the HRs that can be detected with 80% power when all patients have been 
followed at least 3 months and disease in 180/204 (88%) has progressed. A log-rank 
test with a 2-sided 5% type I error rate will be used for the comparison.  
Hazard Ratios that can be detected with 80% power 
Prevalence of patients with CYP2D6 Score=0 
8% 
 
10% 
 
12% 
2.09 
 
1.95 
 
1.86 
For example, if 10% of the patients have samples with a CYP2D6 score=0, there is 80% 
power to detect a hazard ratio of 1.95 (comparing score=0 to score=1 or 2).  
Due to the disproportionate expected percentage of poor vs. intermediate and extensive 
metabolizers, Cox proportional hazards models will be used to estimate the effect of 
CYP2D6 score with respect to PFS while adjusting for possible confounding factors such 
as prior AI use and other biomarkers that are being assessed in this study, to assess the 


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effect of prior AI use and other biomarkers alone with respect to PFS, and to test for 
interactions between the various baseline factors with respect to PFS. 
Due to the low estimated percentage of patients with a CYP2D6 score =0, a stopping 
rule is incorporated into this design. If the rate of accrual of poor metabolizers is less 
than 8% or less than 1 patient with a CYP2D6 score=0 per month in the first 18 months 
that the study is open, the study will be suspended for further evaluation of feasibility. 
The distribution of progression-free survival for the patients with a CYP2D6 score=0, 1, 
and 2 will be estimated using the Kaplan Meier method. Best overall response rate will 
be summarized as a proportion overall and within patients with a CYP2D6 score=0 vs. 
1+2 and within score=0, 1, and 2. Proportion progression-fee at 6 months will be 
summarized overall and within patients with CYP2D6 score=0 vs. 1+2, and within score= 
0, 1, and 2. Endoxifen levels will be summarized descriptively overall and within 
responders and non-responders. Comparisons between responders and non-responders 
with respect to endoxifen levels will be explored using a Wilcoxon rank sum test. 
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. 
9.1 
Gender and Ethnicity  
Based on previous data from E1103, the anticipated accrual in subgroups 
defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
13 
 
13 
Not Hispanic or Latino 
227 
 
227 
Ethnic Category: Total of all subjects 
240 
 
240 
Racial Category 
American Indian or Alaskan Native 
0 
 
0 
Asian 
4 
 
4 
Black or African American 
44 
 
44 
Native Hawaiian or other Pacific 
Islander 
 
 
 
White 
192 
 
192 
Racial Category: Total of all subjects 
240 
 
240 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
 


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10. 
Pathology Review 
NOTE:  
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (STS).  An 
STS shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.4.  
10.1 
Pathological materials from the primary tumor and metastatic site, when 
available, should be submitted for banking for future studies. 
The clinical investigator and the submitting pathologist have the responsibility for 
submitting pathology materials for banking. When a patient is registered to 
receive protocol therapy, the submitting pathologist and clinical research 
associate should refer to Appendix II (Pathology Submission Guidelines) which 
provides the following: 
10.1.1 
Instruction Sheet from ECOG-ACRIN Central Biorepository and 
Pathology Facility providing details for the Submission of Pathology 
Materials. 
10.1.2 
Memorandum to the submitting pathologist from Stanley Hamilton, 
M.D., chair, ECOG-ACRIN Laboratory Science and Pathology 
Committee, providing details for the Submission of Pathology 
Materials. 
10.1.3 
A list of required materials. 
10.2 
Materials Required For This Protocol 
10.2.1 
Forms 
• 
A copy of the surgical pathology report 
• 
Immunologic studies, if available 
• 
Sample Tracking System Shipping Manifest Form (see Section 
10.4) 
• 
If STS is unavailable, complete ECOG-ACRIN Generic 
Specimen Submission Form (#2981). Please identify the 
clinical status of the submitted material (i.e., pretreatment as 
opposed to remission and relapse).  Please log information 
into STS once accessible. 
In addition to the surgical pathology report, if immunologic studies 
have been performed at the home institution, it is necessary that 
these be forwarded as well.  
10.2.2 
Pathology Sample Submissions  
• 
Original diagnostic paraffin embedded primary tumor block and 
block from metastatic site (when available). 
NOTE: 
If unable to submit blocks submit fifteen (15) 5-micron 
sections on uncharged slides or contact the CBPF for 
alternatives at 1-844-744-2420 or 
eacbpf@mdanderson.org. 
NOTE: 
Submit only from patients who have consented to banking. 
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10.3 
Shipping Procedures  
Log the samples into the ECOG-ACRIN Sample Tracking System (STS) the day 
of shipment. If the STS is unavailable, an Generic Specimen Submission Form 
(#2981) must be submitted with the samples. Once STS is available, retroactively 
log the shipment into STS, using the actual collection and shipping dates.   
10.3.1 
Submission Schedule  
The pathology samples should be submitted within one month of 
patient registration. 
10.3.2 
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 Boulevard 
Houston, TX 77030 
Toll Free Phone: 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.   
NOTE: 
A copy of the completed submission form will be sent to 
the Operations Office by the CBPF. 
10.4 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS).  The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important:  Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software.  A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize 
yourself with the software prior to using the system. 
A shipping manifest form must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu. 
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10.4.1 
Study Specific Notes 
An Generic Specimen Submission Form (#2981) will be required only 
if STS is unavailable at time of sample submission. Indicate the 
appropriate Lab ID # on the submission form: 
• 
0001 = ECOG-ACRIN CBPF 
• 
0149 = Indiana University School of Medicine 
• 
Retroactively enter all collection and shipping information when 
STS is available. 
10.5 
Banking  
Blocks/slides submitted will be retained at the ECOG-ACRIN Central 
Biorepository for use in future ECOG-ACRIN approved studies. 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. 


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11. 
Correlative Studies 
NOTE:  
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System.  An STS 
shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.4.  
11.1 
The main goal of the study is to correlate the presence of genetic polymorphism, 
tamoxifen metabolites, and benefit from the drug. 
11.1.1 
Sample Submission Schedule – Genotype Verification (Mandatory) 
Whole blood must be collected at baseline, prior to treatment (strongly 
encouraged), but may be collected at the end of cycle three (3) if 
unable to collect at baseline. 
All questions regarding sample collection, preparation and shipping 
should be sent to: Anne Nguyen, Tel: 317-630-8795, Pager: 317-312-
1314, Fax: 317-630-8185, Email: annnguye@iupui.edu 
11.1.2 
Sample Preparation Guidelines  
Label blood samples with ECOG-ACRIN Protocol Number (E3108), 
ECOG-ACRIN Five Digit Sequence Number, Collection Date and 
Collection Time. 
Whole Blood, EDTA purple top tube (Pharmacogenomics) 
• 
Draw 8-10mL of blood into one (1) EDTA (purple top) vacutainer 
tube. 
• 
Pipette whole blood into two (2) cryotubes of 4-5mL each. 
• 
Freeze and store samples at -70°C or lower until time of shipment. 
11.1.3 
Shipping Procedures 
Log the samples into the ECOG-ACRIN STS the day of shipment.  If 
the STS is unavailable, an ECOG-ACRIN Generic Specimen 
Submission Form (#2981) must be submitted with the samples.  Once 
STS is available, retroactively log the shipment into STS, using the 
actual collection and shipping dates. 
Frozen blood samples should be shipped the day after collection. Ship 
blood samples overnight on dry ice. Blood samples collected on 
Thursday or Friday should be shipped the following Monday.  
Ship to: 
Anne Nguyen  
Indiana University School of Medicine 
Division of Clinical Pharmacology 
1001 West 10th Street 
WD Myers Bldg., W7123 
Indianapolis, IN 46202 
Tel: 317-630-8795 
Pager: 317-312-1314 
Fax: 317-630-8185 
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Email: annnguye@iupui.edu  
An STS shipping manifest form must be generated and shipped with 
all sample submissions.   
Samples should not be shipped on Friday or the day before an 
observed holiday. 
11.2 
Sample Submission Schedule – Tamoxifen Metabolites (Mandatory) 
Plasma must be collected at the following time points: 
• 
End of Cycle 3 
• 
Off Treatment 
Questions pertaining to sample collection and shipment can be directed to 
Adekunle Raji at the CBPF at 1-844-744-2420 or araji@mdanderson.org. 
(International sites should contact Raji for special processing and shipping 
instructions.) 
11.2.1 
Sample Preparation Guidelines 
Blood tubes should be labeled with the ECOG-ACRIN protocol 
number “E3108", patient initials, ECOG-ACRIN patient sequence 
number, institution name, date and time drawn and time point.  
Plasma, Sodium Heparin green top tube  
• 
Draw 6mL of blood into one (1) sodium heparin (green top) 
vacutainer tube. Cover blood immediately after collection. 
• 
Centrifuge tube at 4°C for 15 minutes at 3500 RPM.   
NOTE: 
Tamoxifen metabolites are extremely sensitive. Work in 
low-light areas during processing (tin foil may be 
removed briefly while in centrifuge). 
• 
Pipette plasma into three (3) cryotubes of 1mL each; place any 
remaining plasma into a fourth cryotube.   
NOTE: 
Wrap each cryotube entirely with foil; a sample label 
must be placed on the cryotube itself and an additional 
label placed on the foil. 
• 
Freeze and store samples at -70°C or lower until time of shipment. 
11.2.2 
Shipping Procedures 
Log the samples into the ECOG-ACRIN Sample Tracking System 
(STS) the day of shipment. If the STS is unavailable, a Generic 
Specimen Submission Form (#2981) must be submitted with the 
samples. Once STS is available, retroactively log the shipment into 
STS, using the actual collection and shipping dates.   
Samples should be shipped Sunday through Thursday, to arrive 
Monday through Friday.  The laboratory is closed weekends and 
holidays.  
Frozen blood samples must be shipped overnight on dry ice.  It is 
recommended that multiple patient samples be batched and shipped 
together on a quarterly basis.  
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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 Boulevard 
Houston, TX 77030 
Toll Free Phone: 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
An STS shipping manifest form must be generated and shipped with 
all sample submissions. 
11.3 
Methods 
Genotyping of tamoxifen disposition genes: DNA will be extracted from whole 
blood as we have previously described (3). Tamoxifen disposition appears to be 
associated with genetic variants in at least 4 genes. We will genotype 14 genetic 
variants in these genes, including variants in the CYP2D6 and UGT2B7 genes, 
using predesigned Taqman assays.  
A 10 ml sample of blood will be collected in a heparinized (green-top) tube and 
transported over ice, wrapped in aluminum foil. Plasma from this sample will be 
used to analyze levels of tamoxifen, 4-hydroxy tamoxifen and 4-hydroxy-N-
desmethyl-tamoxifen using an HPLC assay with UV detection as described 
below.  
Tamoxifen and its metabolite concentrations in plasma were determined by using 
high-performance liquid chromatography with online photocyclization as 
previously described by Fried and Wainer (19), with minor modifications (20). In 
brief, this method allows for the rapid extraction and specific detection of 
tamoxifen and its metabolites on the basis of a technique originally described by 
Kikuta and Schmid (21)  that used a mobile phase of 65% acetonitrile, 35% 
potassium phosphate (pH 3.0) and eluted the metabolites on a 4.6 x 250 mm 0.5-
µm cyanonitrile column (21). This method has been modified to use a novel 
column-switching technique (19) that allows for high recovery and precise 
separation of the drug and metabolites. Consistent separation of tamoxifen, N-
desmethyl-tamoxifen, 4-hydroxy-tamoxifen, endoxifen, and N-didesmethyl-
tamoxifen was achieved using this method. We found that the limits of 
quantification were 0.5 ng/mL and 0.25 ng/mL for endoxifen and 4-hydroxy-
tamoxifen, respectively. The inter- and intra-day coefficients of variation were 
less than 10% at the midpoint of the standard curves for each metabolite tested. 
11.4 
Banking 
The residuals and/or derivatives of blood samples collected for this study will be 
retained at the ECOG-ACRIN Central Repository for possible use in ECOG-
ACRIN approved future studies. If future use is denied or withdrawn by the 
patient, the samples will be removed from consideration for use in any future 
study. 
11.5 
Sample Inventory Submission Guidelines  
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Inventories of all samples collected, aliquoted, and used on the above mentioned 
laboratory studies will be submitted electronically by secure web application to 
the ECOG-ACRIN Operations Office - Boston on a monthly basis or upon 
request by any laboratory holding and/or using specimens associated with this 
study.  
11.6 
Lab Data Transfer Guidelines  
The data collected or generated on the above mentioned laboratory studies will 
be submitted electronically via secure data portal to the ECOG-ACRIN 
Operations Office - Boston  on a quarterly basis. The quarterly cut-off dates are 
March 31, June 30, September 30, and December 31. 
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12. 
Records to Be Kept 
Please refer to the E3108 Forms Packet for the forms submission schedule and copies 
of all forms. The E3108 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
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. 
Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying any 
source documents. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma 
concentrations after coadministration of tamoxifen and the selective serotonin 
reuptake inhibitor paroxetine. Journal of the National Cancer Institute 
2003;95(23):1758-64. 
2. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and 
tamoxifen metabolism during adjuvant breast cancer treatment. Journal of the 
National Cancer Institute 2005;97(1):30-9. 
3. Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors 
on tamoxifen metabolism: implication for optimization of breast cancer treatment. 
Clin Pharmacol Ther 2006;80(1):61-74. 
4. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen 
biotransformation is associated with clinical outcomes of efficacy and hot flashes. J 
Clin Oncol 2005;23(36):9312-8. 
5. Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6 
metabolism in women receiving adjuvant tamoxifen. Breast cancer research and 
treatment 2007;101(1):113-21. 
6. Nowell S, Sweeney C, Winters M, et al. Association between sulfotransferase 1A1 
genotype and survival of breast cancer patients receiving tamoxifen therapy. Journal 
of the National Cancer Institute 2002;94(21):1635-40. 
7. Nowell SA, Ahn J, Rae JM, et al. Association of genetic variation in tamoxifen-
metabolizing enzymes with overall survival and recurrence of disease in breast 
cancer patients. Breast cancer research and treatment 2005;91(3):249-58. 
8. Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B, Wingren S. Genetic 
variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in 
postmenopausal patients with breast cancer. Breast Cancer Res 2007;9(1):R7. 
9. Wegman PP, Wingren S. CYP2D6 variants and the prediction of tamoxifen response 
in randomized patients: author response. Breast Cancer Res 2005;7(6):E7. 


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10. Higgins M, Rae JM, Flockhart D, Hayes DF, Stearns V. Pharmacogenetics of 
Tamoxifen: Who should undergo CYP2D6 genetic testing? . J Natl Compr Canc 
Netw 2009;In Press. 
11. Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with 
adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin 
Oncol 2007;25(33):5187-93. 
12. Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J. Clinical implications of 
CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast 
cancer. J Clin Oncol 2007;25(25):3837-45. 
13. Kiyotani K, Mushiroda T, Sasa M, et al. Impact of CYP2D6*10 on recurrence-free 
survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer 
science 2008;99(5):995-9. 
14. Bonanni B, Macis D, Maisonneuve P, et al. Polymorphism in the CYP2D6 tamoxifen-
metabolizing gene influences clinical effect but not hot flashes: data from the Italian 
Tamoxifen Trial. J Clin Oncol 2006;24(22):3708-9; author reply 9. 
15. Wegman P, Vainikka L, Stal O, et al. Genotype of metabolic enzymes and the benefit 
of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 
2005;7(3):R284-90. 
16. Xu Y, Sun Y, Yao L, et al. Association between CYP2D6 *10 genotype and survival 
of breast cancer patients receiving tamoxifen treatment. Ann Oncol 2008;19(8):1423-
9. 
17. Newman WG, Hadfield, K.D., Latif, A.,Roberts, S.A., Shenton, A., McHague, C., 
Lalloo, F., Howell, S., Evans, G. Impaired tamoxifen metabolism reduces survival in 
familial breast cancer patients. Clin Cancer Res 2008;14(18):5913-8. 
18. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The 
CYP2D6 activity score: translating genotype information into a qualitative measure of 
phenotype. Clin Pharmacol Ther 2008;83(2):234-42. 
19. Fried KM, Wainer IW. Direct determination of tamoxifen and its four major 
metabolites in plasma using coupled column high-performance liquid 
chromatography. J Chromatogr B Biomed Appl 1994; 655: 261-8. 
20. Lee KH, Ward BA, Desta Z, Flockhart DA, Jones DR. Quantification of tamoxifen and 
three metabolites in plasma by high-performance liquid chromatography with 
fluorescence detection: application to a clinical trial. J Chromatogr B Analyt Technol 
Biomed Life Sci 2003; 791: 245-53. 
21. Kikuta C, Schmid R. Specific high-performance liquid chromatographic analysis of 
tamoxifen and its major metabolites by "on-line" extraction and post-column 
photochemical reaction. J Pharm Biomed Anal 1989; 7: 329-37. 


ECOG-ACRIN 
E3108 
Cancer Research Group 
Version Date: May 1, 2014 
 
NCI Update Date: March 25, 2015 
55 
A Phase II Prospective Trial Correlating Progression Free Survival with CYP2D6 Activity 
in Patients with Metastatic Breast Cancer Treated with Single Agent Tamoxifen 
 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) - 
[Deleted in Addendum #4] 
 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
 
 


ECOG-ACRIN 
E3108 
Cancer Research Group 
Version Date: May 1, 2014 
 
NCI Update Date: March 25, 2015 
56 
A Phase II Prospective Trial Correlating Progression Free Survival with CYP2D6 Activity 
in Patients with Metastatic Breast Cancer Treated with Single Agent Tamoxifen 
 
Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
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 E3108 
4. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 


ECOG-ACRIN 
E3108 
Cancer Research Group 
Version Date: May 1, 2014 
 
NCI Update Date: March 25, 2015 
57 
Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
• 
Generic Specimen Submission Form (#2981) 
Instructions: 
1. Complete blank areas of the pathologist's instructional memo and forward it, along with the 
List of Required Material to the appropriate pathologist.  
2. The pathologist should return the required pathology samples and surgical pathology 
reports, along with the completed Generic Specimen Submission Form (#2981) (Part B 
completed). If any other reports are required, they should be obtained from the appropriate 
department at this time. 
3. Keep a copy of the Generic Specimen Submission Form (#2981)for your records. (The 
original should be sent to the CBPF.) 
4. Double-check that ALL required forms, reports and pathology samples are included in the 
package to the ECOG-ACRIN Central Biorepository and Pathology. (See appropriate List of 
Required Material.) 
Pathology specimens submitted WILL NOT be processed by the Pathology Coordinating 
Office until all necessary items are received. 
5. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology FacilityMD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
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 CBPF by telephone 1-844-744-2420, by fax (713) 563-6506, 
or by email eacbpf@mdanderson.org. 


ECOG-ACRIN 
E3108 
Cancer Research Group 
Version Date: May 1, 2014 
 
NCI Update Date: March 25, 2015 
58 
List of Required Material 
E3108: 
A Phase II Prospective Trial Correlating Progression Free Survival with CYP2D6 Activity in 
Patients with Metastatic Breast Cancer Treated with Single Agent Tamoxifen 
Pre-Treatment 
1. 
Generic Specimen Submission Form (#2981) 
2. 
Institutional pathology report (must be included with EVERY pathology submission). 
3. 
Pathology materials. 
• 
Original diagnostic paraffin embedded primary tumor block and block from metastatic 
site (when available) 
NOTE: 
If unable to submit blocks, submit fifteen (15) 5-micron sections on uncharged 
slides or contact the CBPF for alternatives at 1-844-744-2420 or 
eacbpf@mdanderson.org. 
NOTE: 
Submit only from patients who have consented to banking. 
 
 


 
59 
MEMORANDUM 
TO:  
__________________________________________________ 
 (Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: Submission of Pathology Materials for E3108:  A Phase II Prospective Trial 
Correlating Progression Free Survival with CYP2D6 Activity in Patients with 
Metastatic Breast Cancer Treated with Single Agent Tamoxifen 
 
The patient named on the attached requesthas been entered onto an ECOG-ACRIN protocol 
by ______________________________ (ECOG-ACRIN Investigator). This protocol requests 
the submission of pathology materials for banking. 
Keep a copy of the submission for your records and return, the surgical pathology report(s), 
the slides and/or blocks and any other required material (see List of Required Material) to the 
Clinical Research Associate (CRA).  The CRA will forward all required pathology material to 
the ECOG-ACRIN Central Biorepository and Pathology Facility (CBPF). 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN CBPF for 
future studies.  Blocks will be returned for purposes of patient management care upon 
request. 
If you have any questions regarding this request, please contact the ECOG-ACRIN CBPF at 
1-844-744-2420, or by fax (713) 563-6506. 
The ECOG-ACRIN CRA at your institution is: 
Name: 
____________________________________________ 
Address: ___________________________________________ 
Phone: 
____________________________________________ 
 
 
Thank you. 
 
 
Rev. 8/12 


ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
60 
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 
E3108 
Cancer Research Group 
Version Date: May 1, 2014 
 
NCI Update Date: March 25, 2015 
61 
A Phase II Prospective Trial Correlating Progression Free Survival with CYP2D6 Activity 
in Patients with Metastatic Breast Cancer Treated with Single Agent Tamoxifen 
 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 


ECOG-ACRIN 
E3108 
Cancer Research Group 
Version Date: May 1, 2014 
 
NCI Update Date: March 25, 2015 
62 
A Phase II Prospective Trial Correlating Progression Free Survival with CYP2D6 Activity 
in Patients with Metastatic Breast Cancer Treated with Single Agent Tamoxifen 
 
Appendix IV 
 
Medication Diary for Tamoxifen 
 
Please complete this diary on a daily basis. Write in the amount of the dose of tamoxifen 
that you took in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take 
your daily dose, please write in “0”, but remember to take your prescribed dose at the 
next regularly scheduled time. 
If you experience any health/medical complaints or take any medication other than those 
in this study, please record this information. 
You should take tamoxifen (one 20 mg pill) every day until your health care team tells 
you to stop. 
 
Cycle # (Month): 
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Tamoxifen 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Tamoxifen 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Tamoxifen 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Tamoxifen 
 
 
 
 
 
 
 
 


ECOG-ACRIN 
E3108 
Cancer Research Group 
Version Date: May 1, 2014 
 
NCI Update Date: March 25, 2015 
63 
HEALTH/MEDICAL COMPLAINTS 
Please record all health/medical complaints you may have experienced below. 
Please describe what you experienced 
Date started 
Date stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER MEDICATION 
Record only medication (prescription and/or over-the-counter, including herbal medications and 
vitamins) taken other than tamoxifen. 
 
Name of Medication 
Why did you take the 
medication? 
Date medication 
started? 
Date medication 
stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature 
_________________________________________________________