A Randomized Phase II Trial of Tamoxifen Versus Z-Endoxifen HCL in Postmenopausal Women With Metastatic Estrogen Receptor Positive, HER2 Negative Breast Cancer
Phase: PHASE2
Conditions: Recurrent Breast Carcinoma, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

 
 
1 
Update #05 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
____________________________________________ 
PROTOCOL UPDATE TO ALLIANCE A011203 
____________________________________________ 
 
A RANDOMIZED PHASE II TRIAL OF TAMOXIFEN VERSUS Z-ENDOXIFEN HCL IN 
POSTMENOPAUSAL WOMEN WITH METASTATIC ESTROGEN RECEPTOR POSITIVE, 
HER2 NEGATIVE BREAST CANCER 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other: 
 
 
Expedited review is allowed. IRB approval (or disapproval) is required within 90 days. Reconsent 
is not required, please follow the policy of your IRB of record regarding notifying patients of new 
information contained in this update. 
The changes included in this update to A011203 have been made in response to the NCI Action 
Letter from Dr. Howard Streicher (streicherh@ctep.nci.nih.gov), dated May 1, 2018. This Action 
Letter is posted on the A011203 study page on the Alliance web site. A revised CAEPR for Z-
Endoxifen HCl with new risk information has been added to the protocol. Therefore, the model 
consent form has been revised to incorporate this new risk information, consistent with the NCI 
Model Consent Template instructions. There are no changes to the risk/benefit ratio.  
UPDATES TO PROTOCOL 
Page 2 (Document History): 
The study document history table has been removed. This table now appears as a separate document on 
the protocol landing page. 
Section 3.2.13 (None of the following co-morbid conditions): 
A note stating “Serious adverse events will be reported on CTEP-AERS using CTCAE v5.0” has been 
added to this section. 
 
 

 
 
2 
Section 8.2.1 (Tamoxifen therapy): 
A note stating “Serious adverse events will be reported on CTEP-AERS using CTCAE v5.0” has been 
added at the end of this section. 
Section 8.2.2 (Z-Endoxifen HCl): 
Note: Serious adverse events will be reported on CTEP-AERS using CTCAE v5.0. 
Section 9.2 (Expedited Adverse event reporting): 
The third sentence has been revised to state that CTCAE Version 5.0 will be utilized for expedited AE 
reporting as of April 1, 2018. 
Section 9.3 (Z-Endoxifen HCl CAEPR): 
The Z-Endoxifen HCL CAEPR has been replaced with the revised CAEPR Version 2.0, September 25, 
2017. 
• 
This CAEPR version includes frequency data. The previous version did not have the categories 
for Likely, Less Likely or Rare but Serious. 
• 
The section below utilizes CTCAE 5.0 language unless otherwise noted. 
 
• 
Added New Risk:  
• 
Less Likely: Hypertension 
• 
Also Reported on Z-Endoxifen HCl Trials But With Insufficient Evidence for 
Attribution: Abdominal distension; Alkaline phosphatase increased; Blood bilirubin 
increased; Cognitive disturbance; Colonic perforation; Cough; Creatinine increased; 
Dehydration; Dyspnea; Ear pain; Edema face; Flashing lights; Hyperkalemia; 
Hypernatremia; Hypokalemia; Hyponatremia; Sinus bradycardia; Sore throat; Stroke; 
Sudden death NOS; Vaginal dryness 
• 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on Z-Endoxifen HCl Trials But With 
Insufficient Evidence for Attribution: Arthralgia; Constipation; Dizziness; 
Hypocalcemia; Hypophosphatemia; Rash acneiform; Vomiting 
• 
Decrease in Risk Attribution:  
• 
Changed to Also Reported on Z-Endoxifen HCl Trials But With Insufficient Evidence 
for Attribution from Possible: Hyperhidrosis; Hypothyroidism; INR increased 
• 
Provided Further Clarification: 
• 
Gastrointestinal disorders - Other (burping) (CTCAE 4.0 language) is now reported as 
Belching. 
• 
Irritability under the GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS SOC (CTCAE 4.0 language) is now reported under the PSYCHIATRIC 
DISORDERS SOC 
Section 13.1.6.1 (Adverse Events): 
A note stating “Serious adverse events will be reported on CTEP-AERS using CTCAE v5.0” has been 
added at the end of this section. 
UPDATES TO MODEL CONSENT: 
In the Section entitled “What possible risks can I expect from taking part in this study?” the following 
changes have been made under “Possible Side Effects of Z-Endoxifen HCl. 
• 
Added New Risk:  
• 
Occasional: High blood pressure, which may cause blurred vision, dizziness, headache 

 
 
3 
• 
Increase in Risk Attribution:  
• 
Changed to Occasional from Also Reported on Z-Endoxifen HCl Trials But With 
Insufficient Evidence for Attribution (i.e., added to the Risk Profile): Constipation; 
Vomiting; Dizziness; Acne 
• 
Decrease in Risk Attribution: 
• 
Changed to Also Reported on Z-Endoxifen HCl Trials But With Insufficient Evidence 
for Attribution from Possible (i.e., removed from the Risk Profile): Increased sweating 
• 
Changed to Rare from Occasional: Kidney damage which may require dialysis 
• 
Provided Further Clarification:  
• 
Pain in muscles (under Occasional) is now reported as Pain (under Occasional). 
PLEASE NOTE:  The potential risks listed in the CAEPR whose relationship to Z-Endoxifen HCl is 
still undetermined are not required by CTEP to be described in the ICD; however, they may be 
communicated to patients according to local IRB requirements. 
Replacement protocol and model consent documents have been issued. 
This study remains closed to accrual. 
____________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 
 

Version Date: 04/24/2018 
Update #05 
1 
ALLIANCE A011203 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A011203 
A RANDOMIZED PHASE II TRIAL OF TAMOXIFEN VERSUS Z-ENDOXIFEN HCL IN 
POSTMENOPAUSAL WOMEN WITH METASTATIC ESTROGEN RECEPTOR POSITIVE, 
HER2 NEGATIVE BREAST CANCER 
Investigational Agent: Z-Endoxifen HCl (NSC #750393)  supplied by CTEP, DCTD, NCI. Commercial 
Agent: Tamoxifen: (NSC #180973) 
Clinical Trials.gov Identifier: NCT02311933 
Study Chair 
Matthew P. Goetz, MD 
Mayo Clinic 
200 First Street, SW 
Rochester, MN 55905 
Tel: 507-284-2511 Fax: 507-284-1803 
goetz.matthe w@mayo.edu 
Community Oncology Co-chair 
John T. Reynolds, MD 
Sanford Health 
222 North 7th Street 
Bismarck, ND 58501 
Tel: 701-323-5741 
john.reynolds@s anfordhealth.org 
Pharmacogenomics Co-chair 
Solid Tumor Correlative Science Co-chairs
Joel Reid, PhD 
W. Fraser Symmans, MD
John R. Hawse, PhD 
Minetta Liu, MD 
Mayo Clinic 
The University of Texas MD 
Anderson Cancer Center 
Mayo Clinic 
Mayo Clinic 
Tel: 507-284-0822 
Tel: 713-792-7962 
Tel: 507-284-4268 
Tel: 507-293-9160 
reid@mayo.edu 
fsymmans@mdanderson.org
hawse.john@mayo.edu
Liu.minetta@mayo.edu 
Pharmacogenomics and Population 
Disease Committee Chair 
Pharmacology Committee Chair 
Lisa A. Carey, MD 
Ann H. Partridge, MD 
Mark J. Ratain, MD 
Tel: 919-966-4431 
Tel: 617-632-3800 
Tel: 773-702-4400 
lisa_carey@med.unc.edu 
ahpartridge@partners.org 
mratain@medicine.bsd.uchicago.edu 
 
Primary Statistician
Secondary Statistician
Biostatistician
Vera J. Suman, PhD
Travis J. Dockter, MS
Ann L. Oberg, PhD
Tel: 507-284-8803
507-266-9803
Tel: 507-538-1556 
suman@mayo.edu
doctor.travis@mayo.edu
oberg.ann@mayo.edu
Protocol Coordinator
Data Manager
Heather P. Becker
Amy Oeltjen
Tel: 773-834-2546
Tel: 507-538-0570
hpbecker@uchicago.edu
oeltjen.amy@mayo.edu
Participating Groups: Alliance/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Medical Research Foundation, Inc. 
NRG/NRG Oncology Foundation, Inc. 
SWOG/SWOG 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
2 
 
Study Resources: 
Expedited Adverse Event Reporting:  
http://eapps-ctep.nci.nih.gov/ctepaers/ 
Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org 
 
 
Protocol Contacts: 
A011203 Nursing Contact 
Cesar Figueras, BSN, RN 
Institution: St. Joseph Mercy Hospital 
Tel: 734-712-5628  
E-mail: Cesar.Figueras@stjoeshealth.org 
A011203 Pharmacy Contact 
Zoe Ngo, PharmD 
Institution: UCSF Helen Diller Family 
Comprehensive Cancer Center 
Tel: 415-353-7052  
Email: Zoe.Ngo@ucsfmedctr.edu 
Alliance Biorepository at Ohio State University 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 Fax: 614-293-7967 
Email: path.calgb@osumc.edu 
Alliance Biorepository at Mayo Clinic (BAP) 
BAP Freezer 
Mayo Clinic 
St SL-16 
150 Third Street SW 
Rochester MN, 55902 
Biospecimen Resource Manager 507-538-0602 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, and 
dose modification: 
Study Chair, Nursing Contact, Protocol Coordinator, 
and (where applicable) Data Manager 
Questions related to data submission, RAVE or patient 
follow-up: 
Data Manager  
Questions regarding the protocol document: 
Protocol Coordinator 
Questions related to IRB issues and model consent 
revisions: 
Alliance Regulatory Inbox 
regulatory@allianceNCTN.org 
Questions regarding AdEERS reporting: 
Regulatory Affairs Manager 
regulatory@allianceNCTN.org 
773-702-9814 
Questions regarding specimens/specimen submissions: 
Appropriate Alliance Biorepository 
 
 
 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
3 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For study data submission: 
Regulatory documentation can 
be submitted to the CTSU via: 
 
ONLINE: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
EMAIL: 
CTSURegulatory@ctsu.coccg.
org (regulatory documentation 
only) 
FAX:  
215-569-0206 
MAIL:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
For regulatory questions call 
the CTSU Regulatory Help 
Desk at 1-866-651-CTSU 
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/OPE
NSYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com. 
Data collection for this study will be 
done exclusively through Medidata 
Rave. Please see the data submission 
section of the protocol for further 
instructions. 
The most current version of the study protocol and all related forms and documents must be 
downloaded from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org. Access to the CTSU members’ website is managed through the Cancer Therapy 
and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and 
requires user log on with CTEP-IAM username and password. Permission to view and download this 
protocol and its supporting documents is restricted and is based on person and site roster assignments 
housed in the CTSU RSS. 
For clinical questions (i.e. eligibility or treatment-related questions) see the Protocol Contacts, 
Page 2. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at https://www.ctsu.org. 
 
 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
4 
A RANDOMIZED PHASE II TRIAL OF TAMOXIFEN VERSUS Z-ENDOXIFEN HCL IN 
POSTMENOPAUSAL WOMEN WITH METASTATIC ESTROGEN RECEPTOR POSITIVE, 
HER2 NEGATIVE BREAST CANCER 
 
Pre-Registration Eligibility Criteria (see Section 3.0) 
Required Initial Laboratory Values 
Women who agree to undergo a standard of care core biopsy of 
recurrent or metastatic breast cancer, to confirm ER + and HER2 
negative breast cancer (see Sections 3.3.5 and 3.3.6,) 
Hemoglobin > 9 g/dL 
Patient previously treated with an AI either in adjuvant or 
metastatic setting and have clinical resistance as defined in 
Section 3.2.2. 
Platelet 
Count 
≥ 75,000/mm3 
 (see Section 3.2.3). 
Patients with a history of measurable disease as defined by 
RECIST criteria or bone only disease are eligible. Note: Those 
patients with non-measureable disease and bone metastases are 
eligible. 
Creatinine < 1.5 x upper limits of 
normal ULN 
No history of tumors involving spinal cord or heart. 
Total 
Bilirubin 
≤ 1.5 x upper limits of 
normal (ULN) 
No current evidence of visceral crisis, lymphangitic spread. 
No known brain metastasis. 
Women must be age > 18 years. 
 
AST 
≤ 2.5 x upper limits of 
normal (ULN). For pts 
with liver mets < 5 x 
ULN 
Women must be postmenopausal (see Section 3.2.8). 
No more than 2 prior chemo regimens in the metastatic setting. 
Prior AI treatment in either adjuvant or metastatic setting is 
required (see Section 3.2.8). 
Prior endocrine regimens in metastatic setting allowed (see 
Section 3.2.9) 
  
Prior tamoxifen therapy is allowed in the adjuvant setting (see 
Section 3.2.9). 
  
No prior tamoxifen in the metastatic setting. 
  
No prior treatment with endoxifen. 
Patients must have fully recovered from acute, reversible effects 
of prior therapy (see Section 3.2.9) 
 
 
Not receiving any medications or substances that are strong 
inhibitors of CYP2D6 (see Appendix II). 
  
Not receiving any other investigational agents. 
  
No uncontrolled intercurrent illness (see Section 3.2.12) 
  
None of the co-morbid conditions described in Section 3.2.13. 
  
No other active secondary malignancy (see Section 3.2.14) 
  
ECOG performance Status 0-2. 
Able to swallow oral formulation of the study agent. 
  
 
 
 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
5 
Schema 
Treatment is to continue until disease progression or unacceptable adverse event. Patients will be 
followed until death, or a maximum of five years after randomization, whichever comes first. 
1 Cycle = 21 days 
  
 
Pre-registration 
Standard of care core needle biopsy of the breast cancer 
tissue, or site of metastatic disease*** for ER and HER2 
testing required for eligibility and if patient consents, 
addition cores will be taken for research purposes. 
 
 
 
 
 
 
 
 
 
 
 
ER negative or Her2 positive or not 
assessable 
Not eligible for further study; End of study 
participation, further treatment at physician 
discretion. 
 
ER positive and Her2 negative 
Eligible for registration/randomization 
 
 
 
 
 
 
 
 
 
 
Registration/Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 1* 
Z-Endoxifen 
HCl 80 mg/day 
orally 
 
 
 
Arm 2 
Tamoxifen 20 
mg/day orally 
 
 
 
 
 
 
 
 
 
 
Progression 
    Progression 
 
 
 
 
 
 
 
 
 
 
Event 
monitoring 
 
Crossover to Z-
Endoxifen HCl      
80 mg/day orally 
 
 
 
 
 
 
 
 
 
 
Progression 
 
 
 
 
 
 
 
 
 
 
Event monitoring** 
 
* 
Note that the cycle length is 3 weeks in order to improve our ability to compare the median 
progression-free survival times in each treatment arm.   
** During the Event Monitoring Phase of the study, all participating NCTN institutions are being asked 
to provide notification as to whether the participant has progressed, developed a new primary, and/or 
died. Participants are not be required to return to their registering site to undergo any study related 
medical examinations or specimen collections, however NCTN institutions are responsible for the 
collection of follow-up data. All treatment decisions are in the hands of the participant and their 
medical team (see Section 12.0). 
*** See Section 6.2.2. 
 
 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
6 
Table of Contents 
1.0 
BACKGROUND ........................................................................................................................... 8 
1.1 OVERVIEW ................................................................................................................................................................... 8 
1.2 FDA APPROVED ENDOCRINE TREATMENTS FOR THE ADJUVANT TREATMENT OF BREAST CANCER 9 
1.3 THE ENDOCRINE TREATMENT OF ER+, METASTATIC BREAST CANCER .................................................. 10 
1.4 PRECLINICAL ENDOXIFEN ANTITUMOR ACTIVITY......................................................................................... 12 
1.5 SUMMARY OF ENDOXIFEN TOXICOLOGY STUDIES (ENDOXIFEN INVESTIGATOR’S BROCHURE) .... 17 
1.6 STATUS OF NCI IND AND MAYO PHASE I PROTOCOL ................................................................................. 17 
1.7 ANTITUMOR ACTIVITY........................................................................................................................................... 18 
1.8 RATIONALE FOR REQUIRED PRE-REGISTRATION CORE BIOPSY ............................................................... 19 
1.9 REGISTRATION QUALITY OF LIFE (QOL) MEASUREMENTS ....................................................................... 19 
2.0 
OBJECTIVES ............................................................................................................................. 20 
2.1 PRIMARY OBJECTIVE .............................................................................................................................................. 20 
2.2 SECONDARY OBJECTIVES ...................................................................................................................................... 20 
2.3 CORRELATIVE SCIENCE OBJECTIVES ................................................................................................................ 20 
2.4 PHARMACOKINETICS AND PHARMACOGENOMICS OBJECTIVES ............................................................... 20 
3.0 
PATIENT SELECTION............................................................................................................. 21 
3.1 ON-STUDY GUIDELINES ......................................................................................................................................... 21 
3.2 PRE-REGISTRATION ELIGIBILITY CRITERIA..................................................................................................... 21 
3.3 REGISTRATION ELIGIBILITY CRITERIA ............................................................................................................. 23 
4.0 
PATIENT PRE-REGISTRATION, REGISTRATION/RANDOMIZATION AND 
STRATIFICATION ................................................................................................................................ 24 
4.1 CTEP INVESTIGATOR REGISTRATION PROCEDURES .................................................................................... 24 
4.2 CTEP ASSOCIATE REGISTRATION PROCEDURES / CTEP-IAM ACCOUNT ............................................ 25 
4.3 CTSU SITE REGISTRATION PROCEDURES........................................................................................................ 25 
4.4 PRE-REGISTRATION REQUIREMENTS ................................................................................................................. 27 
4.5 PATIENT PRE-REGISTRATION PROCEDURES ................................................................................................... 27 
4.6 PATIENT REGISTRATION/RANDOMIZATION PROCEDURE ............................................................................ 28 
4.7 REGISTRATION TO CORRELATIVE AND COMPANION STUDIES .................................................................. 28 
4.8 STRATIFICATION FACTORS AND TREATMENT ASSIGNMENTS ................................................................... 29 
4.9 RE-REGISTRATION AT THE TIME OF PROGRESSION ....................................................................................... 29 
5.0 
STUDY CALENDAR ................................................................................................................. 30 
5.1 STUDY ARM 1 Z-ENDOXIFEN HCL ..................................................................................................................... 30 
5.2 STUDY ARM 2 TAMOXIFEN ................................................................................................................................... 32 
6.0 
DATA AND SPECIMEN SUBMISSION ................................................................................. 34 
6.1 DATA COLLECTION AND SUBMISSION ............................................................................................................... 34 
6.2 SPECIMEN COLLECTION AND SUBMISSION     TABLE 1 ................................................................................. 35 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................. 43 
7.1 ARM I Z-ENDOXIFEN HCL .................................................................................................................................... 43 
7.2 ARM II TAMOXIFEN................................................................................................................................................. 43 
7.3 CROSSOVER TO Z-ENDOXIFEN HCL FOR ARM II PATIENTS AT DISEASE PROGRESSION .................. 43 
7.4 ADHERENCE ............................................................................................................................................................... 44 
8.0 
DOSE AND TREATMENT MODIFICATIONS ..................................................................... 44 
8.1 ANCILLARY THERAPY, CONCOMITANT MEDICATIONS, AND SUPPORTIVE CARE .................................. 44 
8.2 DOSE MODIFICATIONS ........................................................................................................................................... 45 
9.0 
ADVERSE EVENTS .................................................................................................................. 46 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
7 
9.1 ROUTINE ADVERSE EVENT REPORTING ........................................................................................................... 46 
9.2 EXPEDITED ADVERSE EVENT REPORTING (CTEP-AERES) ....................................................................... 47 
9.3 Z-ENDOXIFEN HCL CAEPR ................................................................................................................................. 50 
10.0 
DRUG INFORMATION ............................................................................................................ 53 
10.1 Z-ENDOXIFEN HCL (NSC 750393) ......................................................................................... 53 
10.2 TAMOXIFEN CITRATE (NSC 180973) ................................................................................................................. 55 
11.0 
MEASUREMENT OF EFFECT ............................................................................................... 56 
11.1 SCHEDULE OF EVALUATIONS ............................................................................................................................... 56 
11.2 DEFINITIONS OF MEASURABLE AND NON-MEASURABLE DISEASE ......................................................... 57 
11.3 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ....................................................................... 57 
11.4 MEASUREMENT OF TREATMENT/INTERVENTION EFFECT .......................................................................... 59 
12.0 
TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF PATIENT .................. 62 
12.1 NO DISEASE PROGRESSION OR UNACCEPTABLE ADVERSE EVENTS ........................................................ 62 
12.2 NO DISEASE PROGRESSION, UNACCEPTABLE ADVERSE EVENTS ............................................................. 62 
12.3 DISCONTINUATION OF PROTOCOL THERAPY .................................................................................................. 62 
12.4 REFUSE TO BEGIN PROTOCOL TREATMENT FOLLOWING RANDOMIZATION ........................................... 62 
12.5 INELIGIBLE PRIOR TO THE START OF PROTOCOL TREATMENT ................................................................... 63 
12.6 INELIGIBLE AFTER TO THE START OF PROTOCOL TREATMENT .................................................................. 63 
12.7 EXTRAORDINARY MEDICAL CIRCUMSTANCES .............................................................................................. 63 
13.0 
STATISTICAL CONSIDERATIONS ...................................................................................... 63 
13.1 STUDY DESIGN ......................................................................................................................................................... 63 
13.2  EVALUATION OF ESR1 ALTERATIONS AND MARKERS OF ENDOCRINE RESISTANCE IN PATIENTS 
TREATED WITH EITHER TAMOXIFEN OR Z-ENDOXIFEN HCL (ALLIANCE A011203-ST1) ......................... 66 
13.3 DNA ALTERATIONS IN PATIENTS TREATED WITH EITHER TAMOXIFEN OR Z-ENDOXIFEN HCL 
(ALLIANCE A011203-ST2) ............................................................................................................................................ 67 
13.4 BIOCHEMICAL MARKERS OF BONE TURNOVER (A011203-ST3) ............................................................... 68 
13.5 Z-ENDOXIFEN HCL AND TAMOXIFEN PHARMACOKINETICS AND PHARMACOGENETICS (A011203-
PP)  ........................................................................................................................................................... 
68 
13.6 INCLUSION OF WOMEN AND MINORITIES ........................................................................................................ 69 
14.0 
CORRELATIVE AND COMPANION STUDIES ................................................................... 70 
14.1 EVALUATION OF ESR1 ALTERATIONS AND MARKER OF ENDOCRINE RESISTANCE IN PATIENTS 
TREATED WITH EITHER TAMOXIFEN OR ENDOXIFEN (ALLIANCE A011203-ST1) ........................................ 70 
14.2 DNA ALTERATIONS IN PATIENTS TREATED WITH EITHER TAMOXIFEN OR Z-ENDOXIFEN HCL 
(ALLIANCE A011203-ST2): CIRCULATING TUMOR CELLS AND CIRCULATING CELL FREE DNA ............ 72 
14.3 BIOCHEMICAL MARKERS OF BONE TURNOVER (ALLIANCE A011203-ST3) .......................................... 74 
14.4 Z-ENDOXIFEN HCL AND TAMOXIFEN PHARMACOKINETICS AND PHARMACOGENETICS (ALLIANCE 
A011203-PP1) ................................................................................................................................................................... 75 
15.0 
GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING ................... 77 
16.0 
REFERENCES ............................................................................................................................ 78 
APPENDIX I REGISTRATION FATIGUE/UNISCALE ASSESSMENTS ..................................... 82 
APPENDIX II: LIST OF POTENT CYP450 INDUCERS/INHIBITORS ....................................... 83 
APPENDIX III: PATIENT MEDICATION LOGS ............................................................................ 84 
APPENDIX IV: COLLABORATIVE AGREEMENT........................................................................ 89 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
8 
1.0 
BACKGROUND 
1.1 
Overview 
Over 200,000 women and 2,000 men are diagnosed with breast cancer in the US each 
year[1]. About 70% of breast cancer expresses estrogen receptors (ER) or progesterone 
receptors (PR). In this group of patients, endocrine therapy represents the most important 
treatment modality. Specifically, when administered after surgery, adjuvant hormonal therapy 
(aromatase inhibitor (AI) or sequential tamoxifen followed by AI) results in a greater than 
50% reduction in recurrence and prolongs overall survival compared to no treatment. 
Despite the advantage of aromatase inhibitors over tamoxifen, resistance to hormonal therapy 
remains a public health problem. In the ATAC trial, after a median follow-up of 100 months, 
disease free survival favored anastrozole, with nearly 26% of patients randomized to 
anastrozole experiencing a disease event versus 30% on tamoxifen and difference in overall 
survival [2]. Similar findings were observed with the BIG 1-98 clinical trial [3]. Therefore, 
new strategies are needed for the treatment of AI resistant breast cancer 
Tamoxifen, the selective estrogen receptor modulator (SERM) has been studied and utilized 
in breast cancer for the last forty years. Tamoxifen undergoes extensive hepatic metabolism 
to metabolites (4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen [endoxifen]) 
known to be pharmacologically more active (30-100 fold) than tamoxifen in terms of ER 
binding affinity and ability to suppress estradiol (E2)-stimulated cell proliferation [4]. While 
the concentrations of 4HT are consistently low < 7 nM), endoxifen concentrations are highly 
variable (range undetectable to 80 nM) [5]. Cytochrome P450 2D6 (CYP2D6) is the primary 
hepatic enzyme responsible for the oxidation of N-desmethyl-tamoxifen to endoxifen. While 
CYP2D6 genetic variation is consistently associated with steady state endoxifen 
concentrations, secondary analyses of prospective adjuvant tamoxifen studies administering 5 
years of tamoxifen (NCCTG 89-30-52 [6], ATAC [7], BIG1-98 [8], and ABCSG 8 [9]) have 
reached discrepant conclusions on the importance of CYP2D6 genetic variation and its 
association with disease free survival. 
The largest adjuvant study evaluating the association between the steady state concentrations 
(Css) of tamoxifen and its metabolites and disease recurrence in the adjuvant setting 
demonstrated that endoxifen Css (but not 4HT or tamoxifen) were associated with the risk of 
recurrence [10]. 
In the largest study evaluating the association between CYP2D6 genetic variation and 
progression free survival in tamoxifen treated women in the metastatic setting, Karle et al 
demonstrated that patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a 
significant shorter progression-free survival (PFS) and overall survival (OS) compared to 
patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 
2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 
% for EM-group and 38.5 % for IM + PM-group (p = 0.019) [11]. 
We hypothesized that the direct administration of endoxifen would result in acceptable 
safety, with higher endoxifen concentrations than achievable in tamoxifen treated patients, 
with antitumor activity in patients with ER+ breast cancer refractory to standard therapies. 
The latter hypothesis is based on the following: 
1) Preclinical in vitro and in vivo models demonstrating the superior antitumor activity of Z-
Endoxifen HCl over tamoxifen, in both AI sensitive and AI resistant models 
2) The demonstration of superiority over exemestane + everolimus in a letrozole resistant 
MCF7 in vivo model 

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3) The demonstration of a novel mechanism of action of endoxifen as it relates to inhibition
of Protein Kinase C β1 (PKCβ1).
4) Preclinical data demonstrating that at clinically achievable concentrations (100 nM –
1000 nM), endoxifen may exhibit antitumor activity in tumors with known activating
mutations in ERα, known to confer resistance to tamoxifen and AI’s [12].
Z-Endoxifen HCl (NSC #750393) was synthesized and following the completion of
toxicology studies and demonstration of acceptable pharmacokinetics in rodent models, an
IND was filed and first in humans studies (8821, Mayo) and (8826, NCI) were initiated in
2012. Early data from these trials has demonstrated substantial exposure (300-3000 nM)
to endoxifen over the range of 20-160 mg/day, acceptable safety, and repeated evidence
for antitumor activity in patients refractory to tamoxifen, AI’s, fulvestrant, and
everolimus. Based on these data, we propose a randomized phase II of oral endoxifen with
oral tamoxifen in patients with metastatic or locally advanced breast cancer refractory to
aromatase inhibitors.
1.2 
FDA approved endocrine treatments for the adjuvant treatment of breast cancer 
1.2.1 Tamoxifen 
The SERM, tamoxifen, has been used in the treatment of breast cancer for the last 40 
years. It was first FDA approved for metastatic breast cancer in 1977. It received FDA 
approved for use in post-menopausal women with node positive disease in 1986, pre- and 
post- menopausal women in the adjuvant setting in 1990, in prevention of breast cancer 
in 1998 and for resected ductal carcinoma in situ in 2000.  
Multiple trials have evaluated tamoxifen as adjuvant therapy in breast cancer. These trials 
are well summarized in a meta-analysis from the Early Breast Cancer Trialists Cancer 
Group [13]. 
Analysis of clinical trials where tamoxifen was used for a median of five years showed 
reduction of cancer recurrence risk by 50% in ER + patients during the first five years 
and by 33% during year 5-9 (average risk reduction was 39%, HR 0.61, P<0.00001). 
Breast cancer mortality was also reduced by 30% at year 15 with an absolute difference 
of 9%. During year 5-9, recurrence rates were reduced by 33% despite the fact that 
tamoxifen use at that time was similar between the two arms.  
Studies evaluating 10 versus 5 years of tamoxifen have demonstrated further reductions 
in both recurrence and breast cancer mortality [14]. 
1.2.2 Third generation aromatase inhibitors 
The third-generation aromatase inhibitors anastrozole, exemestane and letrozole have 
become firmly established as important agents for use in adjuvant endocrine therapy and 
result in superior DFS compared to tamoxifen for the postmenopausal adjuvant treatment 
of ER+ breast cancer [2, 3]. An American Society of Clinical Oncology (ASCO) Practice 
Guideline has recommended the use of aromatase inhibitors at some point during 
adjuvant endocrine therapy either as initial therapy or following some period of 
tamoxifen therapy [15].  

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1.3 
The endocrine treatment of ER+, metastatic breast cancer 
1.3.1 Aromatase inhibitors 
In the metastatic setting, aromatase inhibitors are the standard of care for the first line 
therapy of metastatic breast cancer. A series of randomized phase III trials, have 
demonstrated the superiority of AIs (anastrozole, letrozole and exemestane) over TAM as 
first line treatment of metastatic, ER+ breast cancer and a literature based meta-analysis 
confirmed the superiority as it relates to response rate and clinical benefit rate [16]. 
However, nearly all patients receiving an AI for metastatic ER + breast cancer will 
develop progressive disease. Thus, there is a need for new therapeutic and palliative 
agents for metastatic ER + breast cancer refractory to AIs.  
1.3.2 Fulvestrant (Faslodex) 
Fulvestrant is an ER antagonist that down-regulates ER and exhibits anti-tumor activity 
in tumors resistant to TAM. A multicenter, double-blind, randomized trial comparing 
TAM with fulvestrant in previously untreated metastatic/locally advanced breast cancer 
demonstrated that TAM tended to be superior to fulvestrant in terms of time to 
progression (median TTP, 6.8 months and 8.3 months, respectively; P =.088) [17]. 
Because of inadequate pharmacokinetic exposure with the low dose regimen, multiple 
studies have evaluated higher doses of fulvestrant. In the phase III EFECT trial [18], the 
fulvestrant loading dose regimen was compared with the non-steroidal AI, exemestane. 
Median TTP was 3.7 months in both groups (hazard ratio = 0.963; 95% CI, 0.819 to 
1.133; p = 0.6531), with no difference in overall response or clinical benefit rate. 
However, DiLeo et al compared high dose fulvestrant (500 mg day 1 and 14 of cycle 1 
and 500 mg day 1 of subsequent cycles) to fulvestrant (250 mg once monthly) for 
patients with progressive metastatic ER positive breast cancer [19]. In this study, PFS 
was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard 
ratio [HR] = 0.80; 95% CI, 0.68 to 0.94; P = .006). Based on this data, FDA approved the 
use fulvestrant 500 mg as the standard dose in postmenopausal women with metastatic 
HR+ breast cancer progressing following anti-estrogen therapy. 
1.3.3 Combination fulvestrant and aromatase inhibitors 
Three clinical have tested whether the AI fulvestrant combination approach is superior to 
AI alone in postmenopausal women with metastatic breast cancer (FACT, SOFEA and 
SWOG 0226). The FACT trial postmenopausal women with ER+, metastatic breast 
cancer to receive either anastrozole 1 mg PO daily, or anastrozole 1 mg PO daily in 
combination with fulvestrant (loading dose of 500 mg on Day 1, 250 mg on Day 14 and 
250 mg on Day 28, during the first cycle, followed by 250 mg/month). This study 
demonstrated no difference in TTP (10.8 months on combination therapy versus 10.2 
months on anastrozole alone), HR 0.99 (95% CI 0.81 – 1.20), p=0.91), clinical benefit 
rate or OS [20]. 
Similarly, the SOFEA trial (Study of Faslodex with or without concomitant Arimidex vs 
Exemestane following progression on non-steroidal Aromatase inhibitors) randomized 
postmenopausal women with hormone-receptor-positive breast cancer who had either 
relapsed or progressed with locally advanced or metastatic disease on letrozole or 
anastrozole. In this study, participants were randomly assigned (1:1:1) to receive 
fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 
15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus 
anastrozole-matched placebo; or daily oral exemestane (25 mg). Median PFS was 4·4 
months (95% CI 3·4—5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 

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months (3·6—5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0—
4·6) in those assigned to exemestane [21].  
In contrast, the SWOG S0226 trial randomized postmenopausal women with metastatic 
breast cancer to either fulvestrant alone or fulvestrant + anastrozole, using a similar 
eligibility as the FACT trial, but with a greater percentage of treatment naïve patients. In 
this study, the median PFS was 15.0 months (95% CI 13.2 -18.4 months) in the 
combination arm, compared to the 13.5 months (95% CI 12.1 – 15.1 months) in the 
anastrozole arm, p = 0.007, HR 0.8 (95% CI 0.68 - 0.94), favoring the combination 
therapy. Additionally, a significant improvement in OS (combination therapy: 47.7 
months (95% CI 43.4 -55.7) versus the anastrozole arm: 41.3 months (95% CI 37.2 -45.0), 
p = 0.049, HR 0.81 (95% CI 0.65 -1.00) was observed [22].  
One potential difference accounting for the discrepant results of these trials has been 
postulated to be related to a greater number of endocrine naïve cases in the S0226 trial 
than in the FACT or SOFEA trial.  
1.3.4 Tamoxifen 
The activity of TAM in the metastatic setting following AI failure has been evaluated in 
several studies. Osborne et al conducted a randomized phase II trial evaluating the 
activity of tamoxifen +/- gefitinib in either hormonally naïve (stratum I) or patients who 
relapsed on AI (stratum II). In stratum II, for patients randomized to TAM alone, the 
objective response rate was 0% and progression free survival 7.0 month [23]. In the 
TAMRAD study, patients who had failed a non-steroidal AI were randomized to either 
tamoxifen alone or tamoxifen + everolimus. Notably, in this trial, time to progression was 
4.5 months in patients randomized to the tamoxifen arm with a 6 month complete benefit 
rate (complete, partial or stable disease) of 42%. 
1.3.5 PI3K/mTOR pathway in endocrine resistant breast cancer 
Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of 
rapamycin (mTOR) pathway has been extensively linked to the development of 
endocrine resistance in ER positive breast cancer. Specifically, cross-talk between ER 
signaling pathways and the PI3K/AKT/mTOR pathway is associated with the 
development of endocrine resistance when ER positive cells undergo long term estrogen 
deprivation (LTED) mimicking AI resistance [24]. These observations have led to the 
development of clinical studies which have demonstrated that in patients with acquired 
endocrine resistance, the addition of an mTOR inhibitor to hormonal therapy prolonged 
PFS [25, 26]. 
Bachelot et al randomized postmenopausal women with hormone receptor-positive, 
human epidermal growth factor receptor 2-negative, AI-resistant metastatic breast cancer 
to either tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d 
alone (n = 57) (randomized phase II). Randomization was stratified by primary and 
secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined 
as the percentage of all patients with a complete or partial response or stable disease at 6 
months. The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus 
and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased 
from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, 
corresponding to a 46% reduction in risk of progression with the combination (hazard 
ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with 
tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81).  

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The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% 
with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), 
and diarrhea (39% v 11%). 
The BOLERO-2 study was a phase 3, randomized trial which compared everolimus and 
exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 
patients with hormone-receptor–positive advanced breast cancer who had recurrence or 
progression while receiving previous therapy with a nonsteroidal aromatase inhibitor. 
Progression free survival time was significantly increased with the addition of everolimus 
to exemestane. The median progression-free survival was 6.9 months with everolimus 
plus exemestane and 2.8 months with placebo plus exemestane, according to assessments 
by local investigators (hazard ratio for progression or death, 0.43; 95% confidence 
interval [CI], 0.35 to 0.54; P<0.001) [26]. Importantly, while there was no difference in 
quality of life during treatment in the two arms of the study, like the TAMRAD study, 
there was evidence for an increase in toxicity, including Grade 3/4 stomatitis, anemia, 
hyperglycemia, fatigue and pneumonitis. 
In the only study evaluating mTOR inhibitors in patients with enodocrine sensitive 
metastatic breast cancer, the addition of temsirolimus to letrozole did not improve PFS 
[27]. 
1.3.6 Summary of available treatments for ER+ breast cancer that is AI refractory 
In summary, for women with ER+ positive breast cancer, nonsteroidal AI’s are the 
standard of care. However, in patients with disease refractory to non-steroidal AI’s, the 
FDA approved treatments most commonly utilized include fulvestrant, exemestane, or 
exemestane + everoliumus. The time to progression for single agent tamoxifen in patients 
with AI refractory breast cancer is similar to exemestane or fulvestrant (range 4-7 
months). Everolimus containing regimens result in the most impressive PFS rates (8-10 
months); however, the toxicity of everolimus containing regimens (fatigue, stomatitis, 
pneumonitis, diarrhea, anorexia) are substantial for some patients, leading to treatment 
discontinuation in 9% of patients enrolled onto BOLERO-2 [28]. In all cases, these drugs 
simply prolong PFS and resistance develops in all cases. New strategies are therefore 
needed. 
1.4 
Preclinical Endoxifen antitumor activity 
1.4.1 Activity in hormonally sensitive models 
As summarized in Section 1.1, the pharmacology of tamoxifen is complex, and there are 
conflicting retrospective clinical studies regarding the importance of endoxifen Css in 
tamoxifen treated patients. Therefore, we sought to evaluate the antitumor activity of 
endoxifen in multiple different ER+ hormonally sensitive and resistant models to further 
elucidate and compare the activity and mechanism of action of endoxifen compared with 
tamoxifen. 
First, we assessed the growth inhibition properties of TAM and endoxifen in BT474 cells 
(ER+/HER2+) and MCF-7 (parental and HER2-expressing). Compared to TAM, 
endoxifen potently inhibited the growth of estrogen- stimulated BT474 cells and MCF-
7/HER2 cells however TAM activated tumor growth. 
 
 

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Multiple laboratories have demonstrated bi-directional cross-talk between the ER and 
EGFR/HER2 pathways in breast cancer [29-31]. MAPK, which has been activated 
through EGFR or HER2 signaling, can phosphorylate the ER leading to co-activator 
recruitment and increased ER transcriptional activity. Concomitantly, ER can induce 
expression of specific EGFR receptors and ligands, including amphiregulin, leading to 
activation of this signaling pathway [32]. Increased activity of the MAPK pathway has 
been demonstrated in long-term estrogen-deprived and estrogen non-responsive human 
breast cancer cell lines [33] as well as in ER positive cells that express HER2 [29]; and 
activation of this signaling pathway contributes to anti-estrogen resistance in MCF-7 
breast cancer cells [34]. While the role of TAM in regard to the stimulation of the 
EGFR/HER2/MAPK pathway is well documented, there are no data in regard to 
endoxifen’s effect on this pathway.  
In MCF-7 cells (wild type and HER2+) as well as BT474 cells (ER+/HER2+), we 
examined the effect of endoxifen on EGFR/HER2/MAPK signaling. In MCF-7 wild type 
and HER2+, TAM (regardless of concentration) and 4-OH TAM [at concentrations (10 
nM) observed in TAM treated humans], [35] activates p42/p44 MAPK. In contrast, 
endoxifen does not activate MAPK, with significantly lower levels of pMAPK.  
We then compared TAM with endoxifen using an in vivo model previously used by Dr. 
Angela Brodie’s laboratory to demonstrate the superiority of letrozole over TAM (MCF-
7/AC-1) [36]. Tumors were stimulated with androstenedione, and once tumor size 
reached 300 mm3, mice were randomly assigned to receive once daily subcutaneous 
injections of vehicle, tamoxifen or letrozole (10 ug/day), or once daily oral gavage of low 
dose endoxifen (25 mg/kg) or high dose endoxifen (75 mg/kg) for the period indicated 
(Figure 1). At 4 weeks, both doses of endoxifen resulted in greater anti-tumor activity (in 
terms of percent change in tumor volume) than either control or TAM (all p values 
<0.008). 
After 4 weeks, treatment on the TAM arm was discontinued; however, the letrozole and 
endoxifen arms continued. Notably, both doses of endoxifen were substantially superior 
to letrozole (out to 46 weeks). In the letrozole arm, resistance was observed at 24 weeks, 
characterized by increase in tumor volume by at least 300% from the starting volumes. At 
that point, mice were randomly assigned either tamoxifen or endoxifen. The median 
tumor volume (after 4 weeks of treatment and expressed as a % of its size prior to 
randomization) was significantly different comparing mice randomized to endoxifen 
(73.3%; range: 69.3 to 80.75%) versus tamoxifen (148.39%; range: 114.07 to 165.99%) 
(Wilcoxon rank sum test p=0.016). 
 
 

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1.4.2 Antitumor activity of Endoxifen compared with Exemestane and Exemestane + 
Everolimus in a Letrozole resistant breast cancer model 
Because a current standard of care is to utilize exemestane plus everolimus in AI resistant 
breast cancer, we sought to compare the activity of endoxifen with control (letrozole), 
exemestane alone, and exemestane + everolimus in an aromatase expressing MCF7 
letrozole resistant breast cancer. MCF7/AC1 tumors were established were grown in 
setting of letrozole and androstenedione, and once tumor size reached 200 mm3, all mice 
continued androstenedione and were randomly assigned to 1) continue letrozole, or 2) 
exemestane, 3) exemestane + everolimus, or 4) endoxifen (50 mg/kg) (Figure 2). 
After 23 weeks, endoxifen and exemestane + everolimus were superior to exemestane 
alone (endoxifen vs. exemestane p = 0.003; exemestane + everolimus vs. exemestane 
alone 
p 
= 
0.13). 
Additionally, 
endoxifen 
tended 
to 
be 
superior 
to 
exemestane+everoliumus (p = 0.15). 
 
Fig 1. Athymic nude mice bearing established subcutaneous MCF7/AC1 xenografts were treated once daily with subcutaneous 
injections of vehicle, tamoxifen or letrozole (10 ug/day), or once daily oral gavage of low dose endoxifen (25 mg/kg) or high dose 
endoxifen (75 mg/kg) for the period indicated. B ) Initial 4 w eek data co mparing tamoxifen with either low or high dose endoxifen.  

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I
n
In summary, we have generated preclinical evidence to suggest that endoxifen is 1) 
superior to tamoxifen in both an letrozole sensitive and letrozole resistant model; 2) is 
significantly superior to exemestane in letrozole resistant MCF7 breast cancer 3) a trend 
towards greater antitumor activity as compared to exemestane + everolimus in letrozole 
refractory breast cancer. 
1.4.3 Endoxifen inhibits PKCB1 
In order to further understand how endoxifen’s mechanisms of action may differ from 
TAM, conducted shape screening, pharmacophore modeling and ligand-protein docking 
(Anne Bode) comparing tamoxifen with endoxifen in order to identify oncogenic kinases 
Z-Endoxifen HCl may differentially regulate. We demonstrated that protein kinase C 
(PKC) resulted in a docking energy for Endoxifen as E(End-PROT) < ~-8 kcal/mol, but 
showed a remarkable increase for TAM as their energy difference ∆E(End/TAM-PROT) 
> ~2 kcal/mol. Base on this, we performed kinase enzyme assays (Reaction Biology), 
which demonstrated that endoxifen inhibited PKCβ1 (IC50 350 nM) while the IC50 for 
TAM was substantially higher (> 5 micromolar) (Goetz et al. data unpublished).  
Figure 2. MCF7/AC1 Letrozole (L) -resistant xenografts were established in ovariectomized 
athymic nude mice by daily sc. injections of Androstenedione (AND) (100 ug/day) and L 
(10ug/day). Once tumors reached an average volume of ~150 mm3 , all mice (n=12/group) 
continued to receive AND and were then randomized to one of the following: L (10 ug sc), 
Exemestane (E) (250 ug sc), E (250 ug sc) + RAD001 (2.5 mg/kg oral), or Endoxifen (50 
mg/kg oral). Volumes of the xenografts were measured weekly with calipers. Mean tumor 
volumes and their standard error of the mean are shown for the 23 week study.  

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These data suggest that this unique non-genomic effect of endoxifen on PKCβ1 may 
impart and advantage for endoxifen over tamoxifen, especially in hormonally resistant 
breast cancer that exhibits activated growth factor signaling.  
While the overall contribution of PKC to the activity of endoxifen is unknown, it should 
be noted that the endoxifen plasma concentrations achieved in the in vivo mouse studies, 
as well as in breast cancer patients on the Phase I trial, exceed the in vitro IC50 of 
endoxifen for this kinase.  
1.4.4 The potential activity of endoxifen in endocrine resistant breast cancer harboring 
ER mutations 
While protein levels of ER continue to be the most important factor determining response 
to endocrine therapy, an emerging area of research has demonstrated that genetic 
alterations in ESR1, either through mutations in the ligand binding domain, fusions, or 
the presence of ESR1 amplification, are associated with endocrine resistance. 
Additionally, a key oncogenic co-activator, SRC3 (AIB1), known to be associated with 
tamoxifen and AI resistance is more likely to avidly bind ER in these settings, leading to 
potential resistance and/or greater agnostic effects of SERMS. Therefore, new drug 
strategies are needed in patients with ESR1 alterations whose tumors continue to express 
the ER, but are resistant to standard hormonal therapies. 
With regard to ESR1 mutations, recent data suggest that these alterations are rare in 
newly diagnosed breast cancer, but reported in up to 20% of recurrent breast cancers [12, 
37]. These mutations lead to a conformational change in the LBD which mimics the 
conformation of activated ligand-bound receptor and constitutive, ligand-independent 
transcriptional activity resulting in and resistance to hormonal therapy. Preclinical studies 
suggest that cell lines that harbor some of these mutations, while insensitive to estrogen 
deprivation, retain sensitivity to higher doses of fulvestrant or SERMs (endoxifen and 
4HT). However, the concentrations of SERMS used in the study by Robinson et al [12] 
(1 micromolar) are neither observed nor achievable in tamoxifen treated humans [5]. 
However, we have demonstrated that endoxifen concentrations known to be able to 
inhibit the growth of ESR1 mutants in vivo (1 micromolar) were achievable in the 
endoxifen phase I study (range 300 nM-3000 nM). As a proof of principle, in the phase I 
endoxifen study, a patient with evidence for the ESR1 D538G activating mutation 
(obtained from liver biopsy) had evidence for a 50% reduction in target lesions in the 
liver, and was on study for 6 months. Notably, this patient had prior progression on an AI, 
chemotherapy, and Faslodex. 
Additional data suggest that amplification of ESR1, observed more commonly in de novo 
resistant tamoxifen treated breast cancers and additionally observed in AI resistant breast 
cancers, may be an important marker of disease resistance. Finally, ESR1 fusions, as 
described by Li et al, appears additionally to confer resistance to hormonal therapy but 
are rare [38].  
In our MCF7 AC1 letrozole resistant model, we have identified ESR1 amplification in 
the letrozole resistant MCF7/AC1 cells (but not parental). These findings are consistent 
with other groups that have demonstrated ESR1 amplification in MCF7 LTED cells [38]. 
Using the MCF7 letrozole resistant line, we identified that at 1 hour, TAM, 4-hydroxy 
TAM, and estrogen phosphorylated SRC3, with additional downstream activation of 
IGF1R, PDK1, and AKT, as well as ERK and AP1 (c-Jun, c-Fos). Conversely, Z-Endx 
reduced SRC3 phosphorylation as well as IGF1R, PDK1, AKT, c-Jun and c-Fos (data not 
shown).  

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In summary, these preclinical data suggest that Endx may be superior to tamoxifen, 
especially in tumors that contain ER alterations including ESR1 amplification, as well as 
activating mutations associated with resistance to tamoxifen and AI’s.  
1.5 
Summary of endoxifen toxicology studies (Endoxifen Investigator’s Brochure) 
Doses of ≤ 200 mg/kg/day were well-tolerated when given orally for four days to female 
Sprague-Dawley rats. Microscopic lesions in the liver (hepatocellular cytoplasmic 
vacuolization and glycogen depletion) were noted in almost all dose groups (2-
200 mg/kg/day), and did not appear to be dose-related. Z-Endoxifen HCl given to rats via 
gavage once daily for 28 days resulted in lethality at doses ≥80 mg/kg/day (≥480 mg/m2/day). 
The MTD was 20 mg/kg/day. Clinical signs of toxicity (abdominal distention, dyspnea, 
hunched posture, and discharge from the nose/mouth) occurred mainly in rats given ≥ 80 
mg/kg/day. Changes in clinical pathology parameters were noted in ALT, AST, ALP, 
calcium, albumin, and total protein; decreased uterine weight also occurred. Target organs 
were the heart, kidney, liver, lung, GI tract, ovary, skeletal muscle, small and large intestine, 
adrenal gland, prostate, and lymphoid organs. Female reproductive tract (ovarian) toxicity 
was dose-limiting in rats. Skeletal muscle necrosis was also noted at the MTD, but was not 
dose-limiting. Liver, lung, heart, kidney, GI, skeletal muscle, and reproductive tract toxicity 
were dose-limiting at doses exceeding the MTD. With the exception of ovarian cysts and 
histiocytic infiltration of the lung, Z-Endoxifen HCl toxicity appeared to be reversible after a 
28-day recovery period. A NOAEL was not established. 
Z-Endoxifen HCl exhibited dose-limiting emesis in female dogs given daily oral doses of 30
mg/kg/day for four consecutive days for 28 days. Administration of Z-Endoxifen HCl orally
to beagle dogs resulted in reproductive tract toxicity in males (atrophy of the prostate and
testes, depletion of spermatozoa in the epididymides) and females (vaginal epithelium
hyperplasia), and thymic atrophy in both males and females. Reproductive tract lesions were
not reversible after a 28-day recovery period. A NOAEL was not established. The MTD of Z-
Endoxifen HCl in rats and dogs dosed orally once daily for 28 days was 20 mg/kg/day and >
30 mg/kg/day, respectively. With respect to body surface area, the MTD in dogs (> 600
mg/m2/day) was at least 5-fold greater than the rat MTD (120 mg/m2/day). Peak plasma
levels and the AUC were also higher in dogs than in rats (10-fold and 5-fold higher,
respectively). The relative lack of toxicity at greater plasma levels in the dog compared to the
rat may be due to a species difference in the metabolism of Z-Endoxifen HCl.
1.6 
Status of NCI IND and Mayo Phase I protocol 
The progress regarding the NCI program to develop Z-Endoxifen HCl is listed here. The Z-
Endoxifen HCl (NSC #750393) IND was filed by NCI on November 9, 2010 and activated 
on December 9, 2010. The first patient enrolled onto Mayo’s phase I protocol of endoxifen 
hydrochloride (NCI protocol 8821, MC093C) beginning in March 2011. MC093C is a 
phase I study evaluating escalating doses of Z-Endoxifen HCl in AI refractory patients. 
Women with metastatic breast cancer were required to progress on an AI and to 
have received at least one line of chemotherapy in the metastatic setting. Patients were 
enrolled to an accelerated titration schedule (2 pts/dose level) until moderate toxicity or 
DLT, and then to a 3+3 design. Z-Endoxifen HCl was administered orally once daily (28 
day cycle). Dilated eye exams were performed at baseline, end of cycle 2, and after 6 
cycles to evaluate for retinal toxicity. PK was performed on days 1-2, 3, 7, 14, and 28, 
and prior to subsequent cycles.  
Summary of MC093C (NCT01327781) As of 8/28/2013, a total of 25 patients had been 
treated at 7 dose levels, including 3 patients at 20 mg (2 evaluable for toxicity), 2 at 40 mg, 8 
at 60 mg (6 evaluable for toxicity), 3 at 80 mg, 3 at 100 mg, 3 at 120 mg and 3 at 160 mg. 

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Thus far, Cycle 1 dose limiting toxicity (pulmonary embolism) was observed in 1/6 patients 
at the 60 mg dose level, with no additional DLT at the higher dose levels. Dilated 
ophthalmologic examinations were performed at baseline and following completion of cycle 
2 and at the completion of 6 cycles (for patients continuing on study). Thus far, no eye 
toxicity has been observed. 
A similar phase I study is ongoing at NCI (NCT01273168) in patients with hormonally 
positive cancer.  
According to the Z-Endoxifen HCl IB dated June, 2013, a summary of the adverse events in 
both studies are as follows: A total of 32 patients have been treated on the two DCTD-
sponsored trials. Adverse events associated with the administration of Z-Endoxifen HCl in 
the trials have been mostly grades 1-2 hot flashes (50%), anemia (25%), fatigue (25%), 
lymphocyte count decreased (22%), nausea (19%), platelet count decreased (19%), 
hypertriglyceridemia (16%), irritability (16%), anorexia (13%), AST increased (13%), edema 
limbs (13%), and WBCs decreased (13%). Thromboembolic event (grades 3-4) and 
hypertriglyceridemia (grade 4) have also been reported. 
An analysis of pharmacokinetic data from MC093C is listed on Table 1. This demonstrates 
the following: 
a) Z-Endoxifen HCl Cmax and AUC increased in a dose-dependent manner. 
b) Steady-state trough concentrations are reached by Day 7. 
c) There is a 3-fold accumulation of drug over the 28-day cycle. The half-life is 45 hours 
based on accumulation. 
d) A 20 and 100 mg/day dose yields Css of 0.39 and 2.48 uM, respectively. 
Table 1 
Dose (mg) 
20 
40 
60 
80 
100 
120 
160 
Day 
1 
28 
1 
28 
1 
28 
1 
28 
1 
28 
1 
28 
1 
28 
N 
6 
5 
7 
5 
11 
9 
3 
3 
3 
3 
3 
3 
3 
2 
Tmax (h) 
4.0 
1.8 
3.4 
2.6 
5.2 
5.4 
4.0 
3.0 
19.5 
2.2 10.0 2.7 3.7 6.0 
Cmax (ng/ml) 
66.7 
258 
143 
346 
286 
547 
228 
849 
460 
1280 420 1260 635 1950
C24h (ng/ml) 
34.1 
146 
67.3 
248 
119 
379 
138 
602 
194 
926 357 813 333 1360
AUC0-24h (mg/L*h) 
1.09 
4.22 
2.00 
6.42 
3.74 
9.43 
3.73 
15.4 
5.97 
26.9 7.0420.2 9.8138.0 
Accumulation (AUC) 
 
3.7 
 
3.0 
 
3.5 
 
4.1 
 
4.4 
 
3.4 
 
3.8 
Half-life (h) 
 
53.1 
 
41.4 
 
55.0 
 
59.9 
 
65.1 
 
47.3 
 
54.8 
1.7 
Antitumor Activity 
Significant anti-tumor activity has been observed at multiple different dose levels.  
At the 160 mg/day dose level, a patient who progressed on tamoxifen, anastrozole, faslodex, 
and exemestane + everolimus had a partial response (including greater than 50% reduction in 
hepatic metastatic disease). This progressed after 10 months of treatment. 

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19 
At the 100 mg/day dose, a patient who had progressed on multiple different AI’s and faslodex 
had a confirmed PR lasting 225 days  
At the 80 mg/day, a patient who had progressed on both letrozole and fulvestrant had a non-
confirmed PR with a PFS 169 days. A second patient treated at 80 mg/day had stable disease 
lasting > 270 days. 
At 60 mg/day, a patient had stable disease lasting for >270 days. 
At the 40 mg/day, a patient who had progressed on both letrozole and fulvestrant has a 
confirmed partial response and has now been progression free for > 480 days. 
At the 40 mg/day dose level, a patient who had progressed on exemestane, tamoxifen, 
fulvestrant, and exemestane + everolimus who has exhibited stable disease for > 280 days. 
In summary, Z-endoxifen HCl exhibits superior anti-tumor activity both in vitro and in vivo 
compared to TAM and exhibits substantial anti-tumor activity in an in vivo tumor bearing 
model resistant to letrozole. In this same model, we have demonstrated that endoxifen 
regulates substantially different set of genes than TAM, and have identified that endoxifen 
has differential effects on important oncogenic biomarkers already implicated in both 
tamoxifen and AI resistance including our preclinical modeling demonstrates that endoxifen 
exhibits differential effects on these biomarkers compared to tamoxifen, resulting in effects 
on downstream signaling (pAKT) (both in vitro and in vivo), With regard to bone effects, we 
have demonstrated substantial differences in bone remodeling between tamoxifen and Z-
Endoxifen HCl. 
Based on pharmacokinetics of endoxifen observed in the phase I study, and the preclinical 
data regarding the IC50 for endoxifen’s inhibiton of PKCβ1 (350 nM), we will proceed with 
the 80 mg/day dose, which achieves Css concentrations of > 1uM, is associated with maximal 
inhibition of the ER, and associated with robust antitumor activity in the phase I study. 
1.8 
Rationale for the Required Pre-registration Core Biopsy 
As part of A011203, a biopsy of metastatic disease is required prior to enrollment. This 
biopsy is a standard of care procedure to ascertain ER, PR, and HER2 status. The decision to 
make this biopsy a requirement prior to registration was based on several notable recent 
reports that demonstrate that: 1) ER and HER2 status changes over time (not just from 
adjuvant to metastatic, but over time in the metastatic setting); 2) change in ER and/or HER2 
status affects prognosis and 3) patients proven to have either ER negative or HER2 positive 
breast cancer should not be treated with an endocrine agent, since alternative FDA approved 
regimens exist for these patients. For further explanation, please review the report by 
Lindstorm LS et al. in 2012 (http://www.ncbi.nlm.nih.gov/pubmed/?term=22711854). 
1.9 
Registration Quality of Life (QOL) Measurements 
QOL measurements of fatigue and overall perception of QOL are routinely included in 
Alliance studies and will be assessed upon registration in this study. Evidence has arisen 
indicating that baseline single-item assessments of fatigue and overall QOL are strong 
prognostic indicators for survival in cancer patients, independent of performance status. This 
evidence was derived from two separate meta-analyses recently presented at ASCO, the first 
involving 23 NCCTG and Mayo Clinic Cancer Center oncology clinical trials, the second 
involving 43 clinical trials. Routine inclusion of these measures should be considered similar 
to that of including performance status, either as stratification or prognostic covariates [39] 
[40]. It will take approximately a minute to complete this measure. 

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20 
2.0 
OBJECTIVES  
2.1 
Primary Objective 
2.1.1 To assess whether progression-free survival with Z-Endoxifen HCl relative to that with 
tamoxifen is prolonged in postmenopausal women with local advanced or metastatic ER 
positive/Her2 negative breast cancer.  
2.2 
Secondary Objectives 
2.2.1 To assess the safety profile of each of these agents in this patient population. 
2.2.2 To assess whether the tumor response rate (as determined using the RECIST criteria) 
among those randomized to Z-endoxifen HCl differs from that among those randomized 
to tamoxifen. 
2.2.3 To estimate the median progression-free survival time for those who receive Z-Endoxifen 
HCl after disease progression with tamoxifen. 
2.3 
Correlative Science Objectives 
2.3.1 To examine whether ERα alterations (defined as either ER activating mutations or ER 
amplification) are associated with longer PFS or higher response rates in the Z-Endoxifen 
HCl arm compared to the tamoxifen arm. 
2.3.2 To determine changes in lipid profiles comparing tamoxifen and Z-endoxifen HCl. 
2.3.3 For each treatment, to evaluate changes in markers of bone formation and absorption after 
12 weeks (4 cycles) of treatment. 
2.3.4 For all patients and by treatment arm, to determine whether progression-free survival 
differs with respect to the sensitive to endocrine therapy (SET) index.  
2.3.5 To examine whether DNA alterations as measured by Foundation medicine in all coding 
exons of 287 cancer-related genes as well as 78 polymorphisms in 34 ADME-related 
genes are associated with longer PFS or higher response rates in the Z-Endoxifen HCl 
arm compared to the tamoxifen arm.  
2.3.6 To assess whether the molecular characteristics identified in the tumor biopsies are 
detectable in the CTCs and/or cfDNA. 
2.3.7 For each treatment arm: to examine changes in ER expression on CTCs, changes in ESR 
mutations or amplification is CTCs or CfDNA and explore the impact of these changes 
on PFS and response rates. 
2.4 
Pharmacokinetics and Pharmacogenomics Objectives 
2.4.1 To further characterize pharmacokinetics, pharmacogenetics and metabolism of Z-
Endoxifen HCl and tamoxifen. 
2.4.2 To determine the impact of the concentrations of tamoxifen and its metabolites on PFS in 
the tamoxifen arm. 
2.4.3 To determine the impact of the concentrations of Z-Endoxifen HCl and its metabolites on 
PFS in the endoxifen arm. 
2.4.4 To determine the impact of genetic variation in the enzymes responsible for tamoxifen 
and Z-Endoxifen HCl metabolism. 

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3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Contact Information page. Please note that the 
Study Chair cannot grant waivers to eligibility requirements.  
3.1 
On-study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are 
enrolled. All relevant medical and other considerations should be taken into account when 
deciding whether this protocol is appropriate for a particular patient. Physicians should 
consider the risks and benefits of any therapy, and therefore only enroll patients for whom 
this treatment is appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make 
this protocol unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers. Patients are not considered to have a “currently active” malignancy if they have 
completed therapy and are free of disease for ≥ 3 years. 
3.2 
Pre-registration Eligibility Criteria  
___ 
3.2.1 
Women who agree to undergo a standard of care core biopsy of recurrent or metastatic 
breast cancer (see Section 6.2.2 for details of biopsy) to confirm the ER+ (>10% nuclear 
staining) and HER2 negative status (see Sections 3.3.5 and 3.3.6). 
3.2.2 Patient must have been previously treated with an aromatase inhibitor (either letrozole, 
anastrozole or exemestane) either in the adjuvant or metastatic setting, and have one of 
the following types of primary or secondary endocrine resistant disease. 
Primary Clinical Resistance is defined as one of the following: 
___ 
• 
Recurrence within the first 2 years of adjuvant endocrine therapy while on aromatase 
inhibitor therapy  
___ 
• 
Progression within first 6 months of initiating first-line endocrine therapy (either 
aromatase inhibitor or fulvestrant containing regimen) for the treatment of metastatic 
breast cancer.  
Secondary Clinical Resistance is defined as one of the following: 
___ 
• 
Recurrence after year 2 while receiving adjuvant aromatase inhibitor therapy, or 
within 12 months of completing adjuvant aromatase inhibitor therapy.  
• 
Progression occurring 6 or more months after initiating the first endocrine therapy for 
metastatic disease (either fulvestrant or aromatase inhibitor containing regimen). 
___ 
3.2.3 
Patients with a history of measurable disease as defined by RECIST criteria (See Section 
11.0) or bone only disease are eligible. Note: Those patients with non-measurable 
disease and bone metastases are eligible. 
___ 
3.2.4 
No history of tumors involving spinal cord or heart. 

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___ 
3.2.5 
No current evidence of visceral crisis or lymphangitic spread.  
___ 
3.2.6 
No known brain metastases. 
___ 
3.2.7 
Women age ≥ 18 years. 
___ 
3.2.8 
Women must be postmenopausal 
Postmenopausal status is verified by: 
___ 
• 
Prior bilateral surgical oophorectomy, or 
___ 
• 
Age > 60 years, or 
___ 
• 
Age < 60 with no menses for > 1 year with FSH and estradiol levels within post 
menopausal range, according to institutional standard. 
___ 
3.2.9 
Prior treatment 
• 
No more than two prior chemotherapy regimens in the metastatic setting. 
• 
Prior treatment with an aromatase inhibitor (either anastrozole, letrozole or 
exemestane), either in the adjuvant or metastatic setting is required. 
• 
Unlimited prior endocrine regimens in the metastatic setting, which may have 
included everolimus or a CDK4/6 inhibitor (such as a palbociclib, abemaciclib or 
ribociclib) containing regimens. 
• 
Prior tamoxifen treatment is allowed in the adjuvant setting, but patients must not 
have experienced relapse within 1 year of stopping tamoxifen.  
• 
No prior treatment with tamoxifen in the metastatic setting. 
• 
No prior treatment with endoxifen. 
• 
Patients who have not fully recovered from acute, reversible effects of prior therapy 
regardless of interval since last treatment are not eligible to participate in this study. 
EXCEPTION: Neuropathies – if grade 2 neuropathies have been stable for at least 3 
months since completion of prior treatment patient is eligible. 
___ 
3.2.10 Not receiving any medications or substances that are strong inhibitors of CYP2D6 (see 
Appendix II). 
___ 
3.2.11 Not receiving any other investigational agents. 
___ 
3.2.12 No uncontrolled intercurrent illness including, but not limited to: 
• 
Ongoing or active infection 
• 
Symptomatic congestive heart failure 
• 
Unstable angina pectoris 
• 
Uncontrolled symptomatic cardiac arrhythmia 
• 
Uncontrolled hypertension (defined as blood pressure > 160/90) 
 
 

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23 
___ 
3.2.13 None of the following co-morbid conditions: 
• 
Cataracts of grade 2 or greater as per CTCAE Version 4.0 
• 
Retinopathy of grade 2 or greater as per CTCAE Version 4.0 
 
Note: Patients that have cataracts that do not require surgery are eligible. 
 
Note: Serious adverse events will be reported on CTEP-AERS using CTCAE v5.0. 
• 
DVT/PE within the past 6 months  
 
Note: Patients that are on anticoagulant therapy for maintenance are eligible as long 
as the DVT and /or PE occurred > 6 months prior to enrollment, and there is no 
evidence for active thrombosis (either DVT or PE). 
___ 
3.2.14 No other active second malignancy other than non-melanoma skin cancers within 3 
years of pre-registration. A second malignancy is not considered active if all treatment 
for that malignancy is completed and the patient has been disease-free for at least 3 
years prior to pre-registration. 
___ 
3.2.15 ECOG Performance Status: 0-2 
___ 
3.2.16 Able to swallow oral formulation of the study agent. 
___ 
3.2.17 Required Initial Laboratory Values: 
Hemoglobin 
> 9 g/dL 
Platelet Count 
≥ 75,000/mm3 
Creatinine 
< 1.5 x upper limits of normal ULN 
Total Bilirubin 
≤ 1.5 x upper limits of normal (ULN) 
AST 
≤ 2.5 x upper limits of normal (ULN)  
For patients with liver metastasis: < 5 x upper limits of normal (ULN) 
3.3 
Registration Eligibility Criteria 
Registration must be completed within 28 days of Pre-registration 
___ 
3.3.1 
Patients with either measurable disease as defined by RECIST criteria (See Section 
11.0) or bone only disease are eligible. Note: Those patients with both non-measurable 
disease and bone metastases are eligible. 
• 
Non-measurable bone only disease: Non-measurable bone only disease may include 
any of the following: blastic bone lesions, lytic bone lesions without a measurable 
soft-tissue component, or mixed lytic-blastic bone lesions without a measurable soft-
tissue component. 
• 
Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or 
MRI, can be considered as measurable lesions if the soft tissue component otherwise 
meets the definition of measurability previously described.  
___ 
3.3.2 
No tumors involving spinal cord or heart. 
___ 
3.3.3 
No visceral crisis, lymphangitic spread or known brain metastases: Visceral crisis is not 
the mere presence of visceral metastases, but implies severe organ dysfunction as 
assessed by symptoms and signs, laboratory studies, and rapid progression of disease. 

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___ 
3.3.4 
Histologic 
confirmation, 
from 
the 
A011203 
Pre-registration 
biopsy, 
by 
institutional/local pathologist of either locally advanced or metastatic breast cancer that 
is estrogen receptor positive and HER2 negative. 
Those patients with bone only disease with either no tumor or insufficient tumor for 
ER/PR and HER2 staining after the bone biopsy are still eligible to participate in this 
study. 
___ 
3.3.5 
Estrogen receptor positive disease is defined as > 10% nuclear staining. 
3.3.6 
HER2 Negative Disease as per 2013 ASCO/CAP guidelines, one of the following 
must apply: 
___ 
 
1) 0 or 1+ by IHC and not amplified by ISH 
___ 
 
2) 0 or 1+ by IHC and ISH not done 
___ 
 
3) 2+ by IHC and not amplified by ISH or  
___ 
 
4) IHC not done and not amplified by ISH 
___ 
3.3.7 None of the following therapies are allowed prior to registration*:  
• Chemotherapy ≤ 2 weeks  
• Immunotherapy ≤ 2 weeks  
• Biologic therapy ≤ 2 weeks  
• Hormonal therapy ≤ 2weeks  
• Monoclonal antibodies ≤ 2 weeks  
• Radiation therapy ≤ 2 weeks  
• Anti-Her-2 or other “targeted” (e.g. mTOR) therapy ≤ 2 weeks 
*Note: Any toxicities derived from these therapies must be < grade 2 prior to starting 
study therapy. 
4.0 
PATIENT PRE-REGISTRATION, REGISTRATION/RANDOMIZATION AND STRATIFICATION 
4.1 
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>. 

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25 
4.2 
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>. 
4.3 
CTSU Site Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients. Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to: an active 
Federal Wide Assurance (FWA) number, an active roster affiliation with the Lead Network 
or a participating organization, a valid IRB approval, and compliance with all protocol 
specific requirements. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. For 
sites using the CIRB, IRB approval information is received from the CIRB and applied to the 
RSS in an automated process. Signatory Institutions must submit a Study Specific Worksheet 
for Local Context (SSW) to the CIRB via IRBManager to indicate their intent to open the 
study locally. The CIRB’s approval of the SSW is then communicated to the CTSU 
Regulatory Office. In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
 

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4.3.1 Downloading Site Registration Documents 
Site registration forms may be downloaded from the A011203 protocol page located on 
the CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment 
housed in the CTSU RSS.  
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the NCTN - Alliance link to expand, then select trial protocol #A021202 
• 
Click on the Site Registration Documents link 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided 
4.3.2 Requirements for A011203 Site Registration 
• 
CTSU Transmittal Sheet (optional) 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, 
or combination is accepted ) 
4.3.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS. 
ONLINE: www.ctsu.org (members’ section) Regulatory Submission Portal 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
FAX: 215-569-0206 
MAIL: CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
 

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4.3.4 Checking Your Site’s Registration Status 
You can verify your site registration status on the members’ section of the CTSU website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
4.4 
Pre-registration Requirements 
• 
Patient pre-registration can occur only after screening evaluation is complete, pre-
registration eligibility criteria have been met, and the study site is listed as site is listed as 
“approved” in the CTSU RSS. 
• 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease 
and willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and 
discomforts. Current human protection committee approval of this protocol and a consent 
form is required prior to patient consent and pre-registration. 
4.5 
Patient Pre-Registration Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp>) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
in the Rave database. OPEN can be accessed at http://open.ctsu.org or from the OPEN tab on 
the CTSU members’ side of the website at https://www.ctsu.org. A user manual is available 
for OPEN users on the CTSU site. 
Following the Pre-registration, and prior to registration/randomization (days -28 to -1 
see Section 5.1 and 5.2), a standard of care biopsy of metastatic breast tissue must be taken 
for local pathologic review. Of note, if the patient has had a recent biopsy (within 28 days 
prior to pre-registration) of metastatic breast tissue after the most recent progression, this 
sample can substituted for local pathological review for determination of ER, PR and HER2 
status.  
 
 

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28 
For patients who have consented to the correlative tissue studies, additional tissue cores will 
be obtained at the time of the pre-registration biopsy (see Sections 6.2.2 and 6.2.3). 
If the local pathology assessment finds that the patient does not have ER positive, HER2 
negative disease, the CRA will enter the Alliance ID number obtained at pre-registration; 
upload a copy of the local pathology report, de-identified (but including the patient’s Alliance 
ID number) into RAVE for documentation of estrogen receptor and HER2 status; and 
complete the end of pre-registration phase case report form. The patient will not proceed to 
registration or randomization. No further follow-up is required. Research tissue cores need 
not be submitted. Future treatment is at the discretion of the patient’s medical team. 
4.6 
Patient Registration/Randomization procedure 
If the local pathology assessment finds that the patient does have ER positive, HER2 negative 
disease, CRA will enter the Alliance ID number obtained at pre-registration and the 
stratification factors into the OPEN registration system and obtain a treatment assignment. 
The CRA will also enter the Alliance ID number obtained at pre-registration; upload a copy 
of the local pathology report, de-identified (but including the patient’s Alliance ID number), 
into RAVE for documentation of estrogen receptor and HER2 status; complete the end of 
pre-registration phase case report forms as well as the baseline patient status case report 
forms and submit the research tissue cores. 
4.7 
Registration to Correlative and Companion Studies 
4.7.1 Registration to Substudies described in Section 14.0  
There are four substudies within Alliance A011203. These correlative science studies 
must be offered to all patients enrolled on Alliance A011203 (although patients may 
opt to not participate). These substudies do not require separate IRB approval. The 
substudies included within Alliance A011203 are: 
• 
Evaluation of ESR1 alterations and markers of endocrine resistance in patients treated 
with either tamoxifen or Z-Endoxifen HCl Alliance A011203-ST1, (Section 14.1) 
• 
Circulating tumor cells and circulating cell free DNA, A011203-ST2 (Section 14.2) 
• 
Biochemical markers of bone turnover, Alliance A011203-ST3 (Section 14.3) 
• 
Z-Endoxifen HCl and tamoxifen pharmacokinetics and pharmacogenetics, Alliance 
A011203-PP1 (Section 14.4) 
If a patient answers “yes” to “Question #1” in the model consent, they have consented to 
participate in the substudy described in Section 14.1, the patient should be registered to 
Alliance A011203-ST1. If a patient answers “yes” to “Question #2” in the model consent, 
they have consented to participate in the substudy described in Sections 14.2, 14.3 and 
14.4, and the patient should be registered to Alliance A011203-ST2, A011203 ST3 and 
A011203-PP1. Patients should be registered to the correlative studies at the same time 
they are registered to the treatment trial (A011203).  
 
 

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29 
4.8 
Stratification Factors and Treatment Assignments 
Endocrine resistant disease 
1) Primary endocrine resistant disease* 
2) Secondary endocrine resistant disease** 
Prior CDK 4/6 inhibitor and/or everolimus 
1) Prior CDK 4/6 inhibitor or everolimus or both 
2) No prior CDK 4/6 inhibitor and no prior everolimus 
Disease type 
1) Measureable by RECIST criteria 
2) Bone only disease 
*Primary endocrine resistant disease is defined as one of the following:  
• 
Recurrence within the first 2 years of adjuvant endocrine therapy while on aromatase 
inhibitor therapy 
• 
Progression within the first 6 months of initiating first-line endocrine therapy (either 
aromatase inhibitor or fulvestrant containing regimen) for the treatment of metastatic 
breast cancer. 
 
**Secondary Clinical Resistance is defined as one of the following: 
• Recurrence after year 2 while receiving adjuvant aromatase inhibitor therapy, or within 12 
months of completing adjuvant aromatase inhibitor therapy.  
• 
Progression occurring 6 or more months after initiating the first endocrine therapy for 
metastatic disease (either fulvestrant or aromatase inhibitor containing regimens). 
4.9 
Re-registration at the Time of Progression 
Patients who meet the RECIST criteria for disease progression during tamoxifen treatment 
may switch to Z-Endoxifen HCl until disease progression is documented. Please note that 
patients who opt to cross over must be re-registered to the study within 14 days of 
progression documentation.  
Re-registration procedures:  
OPEN may be accessed at https://open.ctsu.org, from the OPEN tab on the CTSU website at 
https://www.ctsu.org.  
To enroll a patient within OPEN, institution staff must have:  
1. A valid and active CTEP-IAM account. This is the same user ID and password used for 
CTSU’s 
website 
(for 
more 
information 
see 
https://www.ctsu.org/public/CTEP-
IAM_Factsheet.pdf).  
2. Enrollment of patients on Alliance A011203 coordinated protocols requires a “Registrar” 
role in the ALLIANCE roster. Assignment of the “Registrar” role is managed through the 
Alliance Central Office.  
The OPEN system will provide the registering site with a printable confirmation of re-
registration. Please print the confirmation for your records. Further instructional information 
is provided on the CTSU members’ website OPEN tab, or within the OPEN URL. For any 
additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923, 
or 
ctsucontact@westat.com. 

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5.0 
STUDY CALENDAR 
Pre-Study Testing Intervals for all patients 
• 
To be completed ≤ 14 DAYS before Pre-registration: All laboratory studies, history and 
physical. 
• 
To be completed ≤ 28 DAYS before registration: Any imaging utilized for tumor measurement 
per protocol. 
5.1 Study Arm 1 Z-Endoxifen HCl 
 
Prior to pre-
registration 
Pre-registration 
Period (any 
time during 
days -28 to -1) 
Days 1 of each 
treatment cycle*  
At PD or 
discontinuation 
of protocol 
therapy** 
Tests & Observations 
 
 
 
 
History and physical, weight, PS 
X 
 
X 
X 
Height 
X 
 
 
 
Pulse, Blood Pressure 
X 
 
X 
X 
Adverse Event Assessment 
 
 
X 
X 
Patient Medication Log 
 
 
X(1) 
X(1) 
Registration Fatigue/Uniscale 
Assessment 
 
A 
 
 
Standard of care biopsy of either 
locally recurrent or metastatic 
breast cancer is required for 
determination of ER, PR and 
HER2  
 
B 
 
 
Laboratory Studies 
 
 
 
 
AST, creatinine, Total Bilirubin 
X 
X 
X 
X 
Complete Blood Count, 
Differential, Platelets 
X 
X 
X 
X 
Albumin, Alk Phos, ALT, 
calcium, glucose, phosphorous, 
sodium, potassium,  
 
X 
X 
X 
Fasting lipid profile (total 
Cholesterol, LDL, HDL, 
triglycerides) 
 
C 
C 
 
Imaging Tumor 
Measurements/Evaluation of 
Indicator Lesions 
 
 
 
 
CT/MRI 
 
D, E, F 
D,  
D, E 
Bone Scan/PET-CT scan 
 
D, E, F 
E 
E 
Correlative Studies: For Patients who consent to participate 
 
Tissue and Blood samples 
See Sections 6.0 and 14.0. 
* Cycle length is 21 days. Labs completed prior to registration may be used for day 1 of cycle one tests if obtained < 
21 days prior to treatment. For subsequent cycles, labs, scans, tests and observations may be obtained no more 
than +/- 3 days prior to day 1 of treatment. 
** After treatment discontinuation, patients will be followed yearly for a maximum of 5 years from study 
registration/randomization (see Section 12.3).  
1. Medication Log must begin on the day the patient begins study medication and must be completed per protocol 
until treatment discontinuation (see Section 7.4). 

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31 
A. To be completed after Pre-registration and prior to treatment, and will take approximately a minute to complete 
(see Section 1.8 and Appendix I). 
B.  A standard of care biopsy of locally recurrent or metastatic breast cancer during the pre-registration period is 
required to confirm ER, PR and HER2 status by an institutional/local pathologist and for submission of a research 
block for optional correlative studies. However, if a prior biopsy was performed on a locally recurrent/metastatic 
site within 90 days of pre-registration, and no anti-cancer therapy was administered during that time period, that 
specimen can be used for confirmation of ER/PR/HER2 and for submission of tissue for optional correlative 
studies.   
C. Lipid profile is required at Pre-registration (baseline), cycles 2, 4 and 8 and thereafter at the discretion of the 
treating physician. 
D. Acceptable imaging modalities for measurable disease include: a CT, spiral CT, MRI, and chest x-ray. A FDG-
PET scanning is allowed to complement CT scanning in assessment of progressive disease. 
E. Tumor measurements are required during the pre-registration period (days -28 to -1), at completion of cycles 2, 4, 
and 6 (approximately, every 6 weeks) then every 4 cycles (approximately every 3 months) thereafter until disease 
progression, as determined in Section 11.0. The same imaging method utilized at baseline must be used at all 
disease assessments and must include all target and non-target lesions recorded at baseline. 
For patients without bone metastases, bone scans after the baseline bone scan are at the discretion of the treating 
physician. See Section 11.0 for acceptable modalities for tumor imaging. 
For patients with non-measurable bone only disease, follow-up imaging either with PET/CT or bone scan should 
be performed at the time of tumor assessment. The same imaging method utilized at baseline must be used at all 
tumor assessments. 
F. Need not be repeated if performed before pre-registration period, but not more than 28 days prior to registration. 
 
 

ALLIANCE A011203 
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32 
5.2 Study Arm 2 Tamoxifen 
 
 
Prior to 
pre-
registration 
 
Pre-
registrati
on Period 
(any time 
during 
days -28 
to -1) 
Tamoxifen treatment 
phase 
Z-Endoxifen HCl Crossover 
phase 
Days 1 of 
each 
treatment 
cycle  
At PD or 
or 
discontin-
uation of 
tamoxifen 
** 
Day 1 of 
each 
treatment 
cycle  
At PD, or 
discontinuation 
of Z-Endoxifen 
HCl 
** 
Tests & Observations 
 
 
 
 
 
 
History and physical, weight, 
PS 
X 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Pulse, Blood Pressure 
X 
 
X 
X 
X 
X 
Adverse Event Assessment 
 
 
X 
X 
X 
X 
Patient Medication Log 
 
 
X(1) 
X(1) 
X(1) 
X(1) 
Registration 
Fatigue/Uniscale Assessment 
 
A 
 
 
 
 
Standard of care biopsy of 
either locally recurrent or 
metastatic breast cancer for 
determination of ER, PR and 
HER2 in metastatic disease 
specimen 
 
B 
 
 
 
 
Laboratory Studies 
 
 
 
 
 
 
AST, creatinine, Total 
Bilirubin 
X 
X 
X 
X 
X(2) 
X, G 
Complete Blood Count, 
Differential, Platelets 
X 
X 
X 
X 
X(2) 
X, G 
Albumin, Alk Phos, ALT, 
calcium, glucose, 
phosphorous, sodium, 
potassium 
 
X 
X 
X 
X(2) 
X, G 
Fasting lipid profile (total 
Cholesterol, LDL, HDL, 
triglycerides) 
 
C 
C 
 
C 
 
Imaging Tumor 
Measurements/Evaluation 
of Indicator Lesions 
 
 
 
 
 
 
CT/MRI  
 
D, E, F 
D, E 
 
D, E(3) 
D, E, G 
Bone Scan/PET-CT scan 
 
D, E, F 
E 
 
E(3) 
E, G  
Correlative Studies: For Patients who consent to participate 
 
 
 
Tissue and Blood samples 
See Sections 6.0 and 14.0. 
* Cycle length is 21 days. Labs completed prior to registration may be used for day 1 of cycle one tests if obtained < 
21 days prior to treatment. For subsequent cycles, labs, scans, tests and observations may be obtained no more 
than +/- 3 days prior to day 1 of treatment. 
 
 

ALLIANCE A011203 
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33 
** Patients who progress on tamoxifen may crossover to Z-Endoxifen HCl treatment. Patients will be followed 
for disease outcome during Z-Endoxifen HCl treatment phase where the baseline tumor measurement is 
considered to be the tumor size at disease progression on tamoxifen. Following the discontinuation of Z-
Endoxifen HCl, patients will be followed yearly for a maximum of 5 years from randomization. Future 
treatment is at the discretion of patient’s physician. 
Patients who choose not to crossover to Z-Endoxifen HCl will be followed yearly for a maximum of 5 years 
from randomization. Future treatment is at the discretion of patient’s physician (see Section 12.3). 
1. Medication Log must begin on the day the patient begins study medication and must be completed per protocol 
(see Section 7.4). 
2. Labs completed prior to crossover may be used for day 1 of cycle one tests if obtained < 21 days prior to start of 
treatment. 
3. Scans are not required day 1 of cycle 1 of Z-Endoxifen HCl. The scans taken at the time of progression on 
tamoxifen will serve as the baseline scan for the cross-over phase of the study. 
A. To be completed after Pre-registration and prior to treatment, and will take approximately a minute to complete 
(see Section 1.8 and Appendix I). 
B.  A standard of care biopsy of locally recurrent or metastatic breast cancer site during the pre-registration period is 
required to confirm ER, PR and HER2 status by an institutional/local pathologist and for submission of a research 
block for optional correlative studies. However, if a prior biopsy was performed on a locally recurrent/metastatic 
site within 90 days of pre-registration, and no anti-cancer therapy was administered during that time period, that 
specimen can be used for confirmation of ER/PR/HER2 and for submission of tissue for optional correlative 
studies. 
C.  Lipid profile is required at Pre-registration (baseline), cycles 2, 4 and 8 and thereafter at the discretion of the 
treating physician. 
D. Acceptable imaging modalities for measurable disease include: a CT, spiral CT, MRI, and chest x-ray. A FDG-
PET scanning is allowed to complement CT scanning in assessment of progressive disease. 
E. Tumor measurements are required during the pre-registration period (days -28 to -1), at completion of cycles 2, 4, 
and 6 (approximately, every 6 weeks) then every 4 cycles (approximately every 3 months) thereafter until disease 
progression, as determined in Section 11.0. The same imaging method utilized at baseline must be used at all 
disease assessments and must include all target and non-target lesions recorded at baseline. 
For patients without bone metastases, bone scans after the baseline bone scan are at the discretion of the treating 
physician. See Section 11.0 for acceptable modalities for tumor imaging. 
For patients with non-measurable bone only disease, follow-up imaging either with PET/CT or bone scan should 
be performed at the time of tumor assessment. The same imaging method utilized at baseline must be used at all 
tumor assessments. 
F. Need not be repeated if performed before pre-registration period, but not more than 28 days prior to registration. 
G. Baseline imaging tumor measurements and laboratory studies for patients crossing over to the Z-Endoxifen HCl 
phase, are those taken at the time of disease progression on the Tamoxifen treatment arm. Z-Endoxifen HCl 
treatment should start no more than 28 days after documentation of disease progression.  
 
 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
34 
6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data collection and submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support System 
(RSS). To access Rave via iMedidata, the site user must have an active CTEP-IAM account 
(check at https://eapps-ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating organization roster at 
the enrolling site. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To 
accept 
the 
invitation, 
site 
users 
must 
log 
into 
the 
Select 
Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, 
and click on the “accept” link in the upper right-corner of the iMedidata page. Please note, 
site users will not be able to access the study in Rave until all required Medidata and study 
specific trainings are completed. Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
Users who have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
A Schedule of Forms is available on the Alliance study webpage, within the Case Report 
Forms section. The Schedule of Forms is also available on the CTSU site within the study-
specific Education and Promotion folder, and is named Time & Events. 
 
 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
35 
6.2 
Specimen collection and submission 
 
 
 
 
Table 1 
 
Post pre-
registration 
and < 14 
prior to 
registration 
Cycle 1, Day 1 
prior to start of 
treatment 
(Baseline) 
At the end 
of Cycle 2 
(prior to 
start of 
Cycle 3) 
At the end of 
Cycle 8 (prior to 
start of Cycle 9) 
At 
time 
of 
disease 
progression 
Submit to: 
 
 
Standard of care from local, regional or distant site: core biopsies of breast cancer 
tissue or lymph nodes, or punch biopsy of skin/chest wall, liver , lung or bone for ER, 
PR and HER2 status  
Mandatory for all patients at Pre-registered to A011203:  
Core biopsies 
of breast 
cancer tissue 
(See Section 
6.2.2) 
Formalin 
fixed paraffin 
embedded 
block  
A 
 
 
 
 
Local/ 
institutional 
pathology 
laboratory. 
upload report 
into RAVE 
with 1st data 
submission. 
 
 
A011203-ST1 
Core biopsies 
of breast 
cancer tissue 
(See Section 
6.2.3 
Formalin 
fixed paraffin 
embedded 
block  
X(1) 
 
 
 
 
OSU 
 
 
A011203-ST2 
CTC 
 (See Section 
6.2.4 
 
Kit 1  
 
Two 10 mL 
whole blood 
samples in K2-
EDTA tubes 
(provided in ST-2 
kit) 
Two 10 mL 
whole blood 
samples in 
K2-EDTA 
tubes 
(provided in 
CTC kit) 
Two 10 mL 
whole blood 
samples in K2-
EDTA tubes 
(provided in ST-
2 kit) 
Two 10 mL 
whole blood 
samples in K2-
EDTA tubes 
(provided in 
ST-2 kit) 
BAP freezer 
Mayo Clinic 
cfDNA 
(See Section 
6.2.4) 
 
Kit 1  
 
Two 10 mL 
whole blood 
samples in Streck 
Cell Free DNA 
BCT tubes 
(provided in ST-
2kit) 
Two 10 mL 
whole blood 
samples in 
Streck Cell 
Free DNA 
BCT tubes 
(provided in 
ST-2 kit) 
Two 10 mL 
whole blood 
samples in Streck 
Cell Free DNA 
BCT tubes 
(provided in ST-
2 kit) 
Two 10 mL 
whole blood 
samples in 
Streck Cell 
Free DNA 
BCT tubes 
(provided in 
ST2 kit) 
BAP freezer 
Mayo Clinic  
 
 
A011203-ST3 
Bone 
turnover 
(FASTING) 
(See Section 
6.2.5) 
 
One 10 mL whole 
blood sample in 
Non-additive red 
top tube  
One 10 mL 
whole blood 
sample in 
Non-additive 
red top tube 
One 10 mL 
whole blood 
sample in Non-
additive red top 
tube 
One 10 mL 
whole blood 
sample in Non-
additive red 
top tube 
OSU 
 
 
A011203-PP1 
PG 
(See Section 
6.2.6) 
 
One 10 mL whole 
blood sample in 
EDTA (purple top*) 
 
 
 
OSU 
A 
Core biopsy (1-2 cores) to be used for local clinical assessment of ER, PR and HER2 status, as 
described in Section 6.2.2. 
1) Research Cores (2-3 cores) to be used for biomarker analyses described in Section 6.2.2. These cores 
will be collected at the same time as the clinical cores. For those patients who consented to the 
correlative studies, research biospecimens are not to be submitted until the patient eligibility has been 
confirmed and they have been registered and randomized. 
* 
The pharmacogenetic sample may be drawn at any after Pre-registration. 
 
 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
36 
Table 2 
 
Cycle 1, Day 1 
prior to start of 
treatment 
(Baseline) 
Cycle 1, Day 1: 2-4 
hours post drug 
administration 
Cycle 1, Day 1: 4-6 
hours post drug 
administration* 
Cycle 1, Day 2 
Prior 
to 
drug 
administration 
Submit to: 
PK 
(see 
Section 
6.2.7) 
 
Kit 2  
One 6 mL whole 
blood sample in 
EDTA (purple top) 
tube 
One 6 mL whole 
blood sample in 
EDTA (purple top) 
tube 
One 6 mL whole blood 
sample in EDTA 
(purple top) tube 
One 6 mL whole blood 
sample in EDTA 
(purple top) tube 
BAP Freezer 
at Mayo 
Clinic 
 
PK (see Section 6.2.7 
 
Kit 2  
End of Cycle 2, (prior to 
the start of Cycle 3) 
End of Cycle 8, 
(prior 
to 
the 
start of Cycle 9) 
At 
the 
time 
of 
disease progression 
Submit to: 
One 6 mL whole blood 
sample in EDTA (purple 
top) tube 
One 6 mL whole 
blood sample in 
EDTA 
(purple 
top) tube 
One 6 mL whole 
blood 
sample 
in 
EDTA (purple top) 
tube 
BAP Freezer 
at 
Mayo 
Clinic 
* Do not draw samples within two hours of each other. 
** 1) Patient must record the time of day that the dose was taken on the previous day and bring their A011203 Study 
Medication Log to this visit. 2) Patient should be reminded not to take the dose of study treatment on this day 
until after the blood sample has been drawn. 
For those patients with crossover from tamoxifen to Z-Endoxifen HCl, the following 
samples will be collected as follows for patients who have consented:  
 
End of Cycle 2, (prior to 
the start of Cycle 3) 
End of Cycle 8, 
(prior to the start 
of Cycle 9) 
At the time of disease 
progression 
Submit to: 
A011203-ST2 
CTC 
 (See Section 
6.2.4 
Kit 1 
Two 10 mL whole blood 
samples in K3-EDTA tubes 
(provided in CTC kit) 
Two 10 mL whole 
blood samples in 
K2-EDTA tubes 
(provided in CTC 
kit) 
Two 10 mL whole blood 
samples in K2-EDTA 
tubes (provided in CTC 
kit) 
BAP Freezer  
Mayo Clinic 
cfDNA 
(See Section 
6.2.4) 
Kit 1  
Two 10 mL whole blood 
samples in Streck Cell Free 
DNA BCT tubes 
Two 10 mL whole 
blood samples in 
Streck Cell Free 
DNA BCT tubes 
Two 10 mL whole blood 
samples in Streck Cell 
Free DNA BCT tubes 
BAP freezer 
Mayo Clinic 
 
 
A011203-ST3 
Bone 
turnover (See 
Section 6.2.5 
One 10 mL whole blood 
sample in Non-additive red 
top tube 
One 10 mL whole 
blood 
sample 
in 
Non-additive 
red 
top tube  
One 10 mL whole blood 
sample in Non-additive 
red top tube 
OSU 
 
 
A011203-PP1 
PK 
(See Section 
6.2.7)  
Kit 2  
One 6 mL whole blood 
sample in EDTA (purple top) 
tube  
One 6 mL whole 
blood sample in 
EDTA (purple top) 
tube 
One 6 mL whole blood 
sample in EDTA (purple 
top) tube 
BAP freezer 
Mayo Clinic 
 
 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
37 
Blood Specimen Collection Kits 
Specialized blood specimen collection kits will be provided by the Alliance Biorepository at 
Mayo Clinic (BAP), for A011203 ST-2 CTC and cfDNA specimens (Kit 1) and A011203 
PP1 PK specimens only (Kit 2). Kits should be ordered using the Biospecimen Accessioning 
Processing Fax Supply Order Form, which is available on the A011203 study page of the 
Alliance and CTSU web sites. Kit 1 and Kit 2 should be ordered at the time of Pre-
registration, for patients who have consented to the correlative blood studies. The kits will 
contain the tubes for blood specimen collection for a single visit, a container for shipping 
samples to the Alliance Biorepository at Mayo Clinic (BAP) with an affixed return shipping 
label. For questions regarding kit ordering, contact the Biospecimen Resource Manager at 
507-538-0602. 
6.2.1 Specimen Submission using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA 
THIS SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL: 
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS web page to access the on-line user manual, 
FAQs, and training videos. To report technical problems, such as login issues or 
application errors, please contact: 1-855-55-BIOMS or Bioms@alliancenctn.org. For 
assistance in using the application or questions or problems related to specific specimen 
logging, please contact: 1-855-55-BIOMS or Bioms@alliancenctn.org. 
After logging collected specimens in BioMS, the system will create a shipping manifest. 
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A011203), 
Alliance patient ID number, date and type of specimen collected (e.g., serum, whole 
blood). 
A copy of the shipping manifest produced by BioMS must be printed and placed in 
the shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a 
method of shipping that is secure and traceable. Extreme heat precautions should be 
taken when necessary.  
6.2.2 Pre-registration period standard of care core biopsy of breast cancer tissue derived 
from a local, regional or distant site for mandatory confirmation of ER, PR and 
HER2 status and for optional translational sub-study A011203-ST1 
Core needle biopsies will be collected using a core needle that is 18 gauge or wider that is 
designed for standard clinical testing. The initial 1-2 cores should be collected for clinical 
diagnostic purposes, including standard testing of ER, PR and HER2 from all patients. 
The preferred ER antibody is SP-1 and the preferred PR antibody is SP-2. During the 
same procedure (for those patients who have consented to A011203-ST1), an additional 
2-3 research cores will be collected, immediately formalin-fixed for at least 6 hours and 
then processed into one paraffin block that is separate from the clinical tissue block. 
Close proximity to the passes will be attempted. Image guided biopsies are to be 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
38 
performed per usual standard clinical care. The amount of tissue collected will follow the 
guidelines listed below.  
Patients who undergo a research biopsy procedure, for the purpose of this protocol, and 
in whom inadequate tissue is obtained for optional correlative studies, are still eligible for 
the treatment study and are not required to undergo a repeat biopsy for the correlative 
tissue studies. 
Breast: Total goal of 3-5 core biopsy specimens will be obtained using standard 
institutional guidelines for a diagnostic core biopsy of a breast mass 
Skin/chest wall: A goal of 3-5 punch biopsies 
Lymph node: A goal of 3-5 core biopsy specimens  
Liver: A goal of 3-5 core biopsy specimens will be obtained using standard institutional 
guidelines 
Lung: Because of the risk of pneumothorax associated with core needle biopsies of lung, 
if a patient has another accessible site of disease (i.e. skin, lymph node, liver), the non-
lung site should be biopsied preferentially.  If no other sites are available, a standard of 
care biopsy to confirm ER/PR, and HER2 should be done, and collection of additional 1-
2 research cores will be left to the clinical judgment of the physician performing the 
procedure. 
Bone: Because the yield of malignant tissue from bone biopsies tends to be low, if a 
patient has another accessible site of disease (i.e. skin, lymph node, liver), that site should 
be biopsied preferentially. If bone is the only biopsy-accessible site, then a goal of 3-5 
core biopsy specimens will be obtained institutional guidelines. Note: Patients in which a 
bone biopsy was performed and no tumor or inadequate tissue was obtained for 
ER/PR/HER2 are not required to undergo a repeat biopsy and these patients are eligible 
to participate in this study. 
If a patient has more than one site of disease, only one site needs to be biopsied. For 
patients who have NOT consented to sub-study A011203-ST1, tissue will be fixed in 
formalin and the local site will perform an H&E, ER, PR and HER2 analysis using 
standard procedures (IHC/ISH) to confirm the presence or ER+, HER2 negative breast 
cancer. 
For patients who have consented to sub-study A011203-ST1, 2-3 research cores will 
be collected (at the same time as the clinical cores) and all cores will be fixed in formalin, 
paraffin embedded and labeled as a research block. This research block will be sent to the 
Alliance Biorepository at Ohio State for evaluation of 1) ESR1 alterations 2) markers of 
endocrine resistance and additional IHC markers (PKCB1 and SRC3)( A011203-ST1) 
(see Section 6.2.3) . Note, tissue samples will not be sent to the Alliance Biorepository at 
Ohio State for those patients that have not consented to the translational tissue component 
A011203-ST1. For those patients who consented to the correlative studies, research 
biospecimens are not to be submitted until the patient eligibility has been confirmed and 
they have been registered and randomized. 
6.2.3 Breast tissue collection and processing for Evaluation of ESR1 alterations and 
markers of endocrine resistance in patients treated with either tamoxifen or Z-
Endoxifen HCl for patients who have consented (Alliance A011203-ST1) 
The FFPE research block, as described in Section 6.2.2, will be sent to the Alliance 
Biorepository at Ohio State University. At the completion of the study, the tumor 
block(s) will be sectioned and used for nucleic acid extraction for the following 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
39 
translational objectives: DNA (Foundation medicine) and RNA (SET index). Additional 
sections will be cut for IHC analyses of SRC3 and PKCβ1, to be performed at the Mayo 
Clinic. 
Formalin fixed paraffin embedded specimens for A011203 ST1 should be sent at ambient 
temperature to: 
Alliance Biorepository at Ohio State University 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 Fax: 614-293-7967 
Shipment on Monday through Thursday by overnight service to assure receipt is 
encouraged.  
6.2.4 Circulating tumor cells (CTC) and circulating cell free DNA (cfDNA) for patients 
who have consented A011203-ST2 
For patients who consent to participate in A011203-ST2, the following specimens will be 
collected. 
Circulating Tumor Cell Capture and Analysis (CTC) 
The specimens will be collected at the following time points:  
1) Cycle 1, Day 1 prior to the start of treatment 
2) End of Cycle 2, (prior to the start of Cycle 3) 
3) End of Cycle 8, (prior to the start of Cycle 9) 
4) At the time of disease progression 
For those patients with crossover from tamoxifen to Z-Endoxifen HCl, CTC samples 
will be collected as follows: 
1) End of Cycle 2, (prior to the start of Cycle 3) 
2) End of Cycle 8, (prior to the start of Cycle 9) 
3) At the time of disease progression 
Two 10 mL blood samples will be collected in K2-EDTA tubes CTC specific kits will be 
used for this study. Once a patient has been Pre-registered one ST-2 kit should be 
ordered for per patients, using the A011203 Biospecimen Accessioning Processing 
Fax Order Form, which may be downloaded from the A011203 study page of the 
Alliance and the CTSU web sites. Instructions for processing these blood samples are 
provided in the blood specimen collection kits and must be followed in order for the 
samples to be viable. 
Samples should be kept at ambient temperature after collection and during shipping. Ship 
CTC sample and cfDNA samples together to: 
BAP Freezer 
Mayo Clinic 
St SL-16 
150 Third Street SW 
Rochester MN, 55902 
507-538-0602 

ALLIANCE A011203 
Version Date: 04/24/2018 
Update #05 
40 
Samples for the CTC studies should be collected and shipped Monday – Thursday. 
However, if the subject can only be seen on Fridays, please contact the Biospecimen 
Resource Manager Roxanne Neumann for additional instructions 507-528-0602, 
Email: Neumann.roxann@mayo.edu. 
Circulating Cell Free DNA Isolation and Analysis (cfDNA) 
The specimens will be collected at the following time points:  
1) Cycle 1, Day 1 prior to the start of treatment 
2) End of Cycle 2, (prior to the start of Cycle 3) 
3) End of Cycle 8, (prior to the start of Cycle 9 
4) At the time of disease progression 
For those patients with crossover from tamoxifen to Z-endoxifen HCl, cfDNA 
samples will be collected as follows: 
1) End of Cycle 2, (prior to the start of Cycle 3) 
2) End of Cycle 8, (prior to the start of Cycle 9) 
3) At the time of disease progression 
Two 10 mL blood samples will be collected in Streck Cell Free DNA BCT tubes. These 
samples will be processed within 7 days of collection for cfDNA extraction and 
subsequent analyses. All of these samples must be labeled for immediate processing. The 
Streck Cell Free DNA BCT tubes will be provided for this study TBD… 
The Streck tubes for cfDNA should be kept at 6°C (42.8°F) to an ambient temperature of 
37°C (98°F) during shipping. Ship cfDNA sample and CTC samples together to: 
BAP Freezer 
Mayo Clinic 
St SL-16 
150 Third Street SW 
Rochester, MN 55902 
507-538-0602 
Samples for the cfDNA studies should be collected and shipped Monday – Thursday. 
However, if the study participant can only be seen on Fridays, please contact the 
Biospecimen Resource Manager Roxann Neumann for additional instructions Tel: 
507-538-0602 Email: Neumann.roxann@mayo.edu.  
6.2.5 Biochemical markers of bone turnover for patients who have consented (Alliance 
A011203-ST3) 
The FASTING specimens will be collected at the following time points:  
1) Cycle 1, Day 1 prior to the start of treatment 
2) End of Cycle 2, (prior to the start of Cycle 3) 
3) End of Cycle 8, (prior to the start of Cycle 9) 
4) At the time of disease progression 
For those patients with crossover from tamoxifen to Z-Endoxifen HCl, bone 
turnover samples will be collected as follows: 
1) End of Cycle 2, (prior to the start of Cycle 3) 
2) End of Cycle 8, (prior to the start of Cycle 9) 
3) At the time of disease progression 

ALLIANCE A011203 
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For each time point, 10mL of whole blood will be collected in a Non-additive red top 
tube. Gently invert approximately 5 times to mix clot activator with blood. Let blood clot 
for 30 minutes. Observe a dense clot. Centrifuge at approximately 1300g (or in 
accordance with centrifuge manufacturer’s instructions) for 10 minutes at room 
temperature. After centrifugation, place approximately 1.0 mL aliquots of serum into 
2.0mL cryovials. Immediately label and freeze cryovials at –70°C or colder. If –70°C or 
colder freezer is not available, temporary storage on dry ice or at –20°C prior to shipment 
is acceptable for up to approximately 48 hours. Samples should be placed in a biohazard 
bag and shipped on dry ice by overnight express courier to:  
Alliance Biorepository at Ohio State University 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 Fax: 614-293-7967 
Shipment on Monday through Thursday by overnight service to assure receipt is 
encouraged.  
6.2.6 Blood submission for pharmacogenetics (A011203-PP) 
All patients treated with Z-Endoxifen HCl or tamoxifen, who have consented, to 
A010203-PP will provide a single blood sample for pharmacogenetic analysis as 
follows: 
Day 1, Cycle 1 prior to treatment or at any time after Pre-registration, collect a 10-mL 
sample of blood in an EDTA (Purple top) tube. The tube should be inverted 
approximately 8-10 times to mix the EDTA. Refrigerate sample until shipping. The 
sample should be placed in a biohazard bag and shipped the same day on a cold pack by 
overnight to: 
Alliance Biorepository at Ohio State University 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 Fax: 614-293-7967 
Shipment on Monday through Thursday by overnight service to assure receipt is 
encouraged.  
 
 

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6.2.7 Blood submission for pharmacokinetics for patients who have consented (A011203-
PP1) 
For all patients who have consented to A011203-PP, blood samples for 
pharmacokinetics will be collected in all patients treated with Z-Endoxifen HCl or 
tamoxifen, according to the following schedule: 
• 
Cycle 1 Day 1: Prior to drug administration 
• 
Cycle 1 Day 1: 2-4 hours after drug administration 
• 
Cycle 1 Day 1: 4-6 hours after drug administration Note: Do not draw samples within 
2 hours of each other.) 
• 
Cycle 1 Day 2: Prior to drug administration 
• 
End of Cycle 2, (prior to the start of Cycle 3) prior to drug administration  
• 
End of Cycle 8, (prior to the start of Cycle 9) prior to drug administration 
• 
At the time of disease progression 
For those patients with crossover from tamoxifen to Z-Endoxifen HCl, 
pharmacokinetic samples will be collected as follows: 
• 
End of Cycle 2, (prior to the start of Cycle 3) prior to drug administration  
• 
End of Cycle 8, (prior to the start of Cycle 9) prior to drug administration 
• 
At the time of disease progression 
Notes: 1) The patient must record the time of day that the dose was taken on the previous 
day. 2) The patient should be reminded not to take the dose on this day until after the 
blood sample is drawn.) 
NOTE: Samples are light sensitive. Use amber tubes or cover tubes with aluminum foil 
to prevent exposure to light. 
For each time point, 6mL blood sample will be collected in 6mL EDTA (purple top) tube, 
wrapped in aluminum foil and immediately cooled in an ice water bath. Blood must be 
processed for plasma isolation within 20 minutes of collection. 
Blood will be subjected to centrifugation (2,000 rpm for 10 minutes) in a refrigerated 
centrifuge kept at 4°C. Following centrifugation, the plasma will be transferred to a 
polypropylene tube, capped, wrapped in aluminum foil and immediately frozen at -70°C.  
Tube labels must contain the following data: 
• 
Alliance protocol number (A011203), Alliance patient ID number, patient’s initials 
and date and type of specimen collected (plasma). 
• 
Date, cycle number and time of collection (i.e. pretreatment, 1, 2, and 4 hours after 
the oral dose) 
These same data should be recorded in nurse’s notes, on the Alliance A011203 
Phamacokinetics Study Form that will be uploaded into RAVE. A copy of the form 
should be sent with the samples. 
Send frozen plasma samples on dry ice via overnight courier to the Alliance Pathology 
Coordinating Office. 
Send frozen plasma samples on dry ice, Monday-Wednesday via overnight courier to: 
BAP Freezer 
Mayo Clinic 
St SL-16 
150 Third Street SW 
Rochester MN, 55902 
507-538-0602 

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7.0 
TREATMENT PLAN/INTERVENTION 
Patients will be randomized with equal probability to receive daily treatment with Z-Endoxifen 
HCl or tamoxifen. Treatment on Arms I and II will continue until disease progression or 
unacceptable adverse event.  
Protocol treatment is to begin ≤ 14 days of registration/randomization in order to allow for Z-
Endoxifen HCl to arrive for patients assigned to Arm I. 
7.1 
Arm I Z-Endoxifen HCl 
Agent 
Dose 
Route 
Day 
Retreatment Cycle 
Z-Endoxifen HCl 
80 mg 
Oral 
(2 
x 
40mg 
capsule) 
Days 1-21 
Every 21 days (+/- 3 
days) 
1. Patients will take Z-Endoxifen HCl on an empty stomach (1 hour before or 2 hours after 
meals).  
2. Patients should be instructed that the Z-Endoxifen HCl should be refrigerated. The Z-
Endoxifen HCl should be dispensed with a cooler pack that the patient can use to 
transport this study medication. 
7.2 
Arm II Tamoxifen 
Agent 
Dose 
Route 
Day 
Retreatment Cycle 
Tamoxifen 20 mg Oral (1 x 20 mg tablet) Days 1-21 Every 21 days (+/- 3 days) 
1. Patients will take tamoxifen without regard to meals. 
7.3 
Crossover to Z-Endoxifen HCl for Arm II Patients at Disease Progression 
Please note that patients who opt to cross over should be re-registered to the study within 14 
days of progression documentation.  
Patients with measureable disease who meet the RECIST criteria for disease progression and 
patients with bone only disease who progress during tamoxifen treatment may switch to Z-
Endoxifen HCl. 
Those patients with both non-measureable disease and bone metastases are also eligible to 
cross over to Z-Endoxifen HCl. 
Palliative radiation, if administered, should be completed prior to re-registration. Note that 
imaging studies obtained at the time of disease progression on Tamoxifen treatment Arm 
should be used to obtain the baseline tumor measurements for the Z-Endoxifen HCl crossover 
phase. These images must have been taken no more than 28 days prior to re-registration. Also, 
lesions that have been irradiated must not be used to evaluate tumor response to Z-Endoxifen 
HCl. 
Z-Endoxifen HCl treatment should start no later than 28 days after documentation of 
progression. 
 
 

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Agent 
Dose Route 
Day 
Retreatment Cycle 
Z-Endoxifen HCl 
80 
mg 
Oral (2 x 40mg 
capsule) 
Days 1-21 
Every 21 days (+/- 3 days) 
7.4 
Adherence 
Patients will be taking oral medication at home, without direct supervision. Drug compliance 
will be monitored until the discontinuation of Z-Endoxifen HCl or tamoxifen using A011203 
Study Medication Logs found in Appendix III. Patients should bring the Medication Log to 
each clinic visit. A study team member will review the Medication Log, discuss any missed 
dose or discrepancy and document it. The Medication Log should be returned to the treating 
institution and compliance must be documented in the medical record by any member of the 
care team. 
8.0 
DOSE AND TREATMENT MODIFICATIONS  
8.1 
Ancillary therapy, concomitant medications, and supportive care 
8.1.1 Colony stimulating factors 
Routine use of colony-stimulating factors (G-CSF or GM-CSF) are not allowed.  
8.1.2 Concurrent therapy 
Use of other concurrent chemotherapy or anti HER2 therapy, immunotherapy, 
radiotherapy, or any ancillary therapy considered investigational (utilized for a non-FDA-
approved indication and in the context of a research investigation) is not allowed. 
Patient who are receiving tamoxifen (Arm II), should not be treated with strong CYP2D6 
inhibitors while receiving study treatment (see Section 10.1.5 and Appendix II). 
8.1.3 Expected prominent symptoms 
Vasomotor symptoms such as hot flashes, sweating, as well as other estrogen withdrawal 
symptoms including insomnia, depression, and weight gain may be prominent in patients 
receiving Z-Endoxifen HCl and/or tamoxifen. These symptoms should not be treated 
with dose reduction, rather, intervention with either an SSRI or SNRI that is not known to 
be a potent CYP2D6 inhibitor (see Appendix II for a list of acceptable drugs). CYP2D6 
catalyzes the formation of endoxifen from tamoxifen. Among SSRIs studied, venlafaxine 
had the least effect on endoxifen levels. Paroxetine was the most potent inhibitor of 
CYP2D6, resulting in the lowest endoxifen concentrations. 
If the patient continues to have symptoms that are bothersome, a 2nd line intervention 
such as gabapentin should be initiated. A dose reduction should be considered if these 
symptoms persist despite 2 lines of intervention. 
 
 

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8.1.4 Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment and treatment of other newly diagnosed or 
concurrent medical conditions and concomitant medications such as anti-diarrheals, 
analgesics and anti-emetics. All blood products and concomitant medications received 
from Cycle 1 Day 1 of study drug until 30 days after the final dose are to be recorded in 
the medical record. 
8.1.5 Not to be considered for any other studies involving pharmacologic agents 
Patients participating in this trial are not to be considered for enrollment in any other 
study involving a pharmacologic agent (drugs, biologics, immunotherapy approaches, 
gene therapy) whether for symptom control or therapeutic intent. 
8.1.6 Non-protocol hormones or other chemotherapeutic agents may not be administered. 
Patients who initiate such treatment will be removed from protocol therapy due to either 
concurrent medical condition or desire for alternative therapy, depending upon reasons 
these non-protocol medications were given. 
8.1.7 Antiemetics may be used at the discretion of the attending physician. 
8.1.8 Diarrhea: Diarrhea is not anticipated as a side effect from either drug. However, this 
could be managed conservatively with loperamide. The recommended dose of loperamide 
is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free (maximum 16 
mg/day). 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
8.1.9 Palliative radiation therapy may not be administered during protocol treatment. Patients 
who require radiation therapy during protocol treatment will be removed from protocol 
therapy due to disease progression. 
8.2 
Dose Modifications 
CTEP-AERS reporting may be required for some adverse events (see Section 9.0). 
8.2.1 Tamoxifen therapy 
There will be no dose reductions for Tamoxifen therapy. Tamoxifen therapy may be 
permanently discontinued at the discretion of the treating physician for other tamoxifen 
related toxicity. 
Tamoxifen will be held for grade 3 or 4 hepatic function impairment. Resume tamoxifen 
therapy at the previous dose when hepatic toxicity resolves to < grade 1 or baseline. 
If tamoxifen therapy is held for > 3 weeks (1 cycle), permanently discontinue protocol 
therapy. 
Note: Vasomotor symptoms defined as flushing, hot flashes and sweating will be graded 
using the CTCAE Version 4.0. Please see Section 8.1.3 regarding instructions for 
treatment of these symptoms.  

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Note: Serious adverse events will be reported on CTEP-AERS using CTCAE v5.0. 
8.2.2 Z-Endoxifen HCl 
If a grade 3 or 4 lymphopenia, thrombocytopenia, or hypertryglyceridemia, hold Z-
Endoxifen HCl therapy until toxicity resolves to < grade 2. Reduce dose to 40mg daily. If 
the toxicities do not resolve to ≤ grade 1 or baseline severity within 21 days (1 cycle), 
treatment is to be discontinued and the patient will go to event monitoring. If toxicity 
recurs, treatment is to be discontinued. 
If a grade 3 or 4 non-hematologic event that is attributed to Z-Endoxifen HCl occurs, 
hold therapy until toxicity resolves to < grade 1 or back to baseline (if baseline is grade 2) 
and reduce dose to 40mg daily. If the toxicities do not resolve to ≤ grade 1 or baseline 
severity within 21 days (1 cycle), treatment is to be discontinued and the patient will go 
to event monitoring.  
The prompt reporting of adverse events is the responsibility of each investigator engaged 
in clinical research, as required by Federal Regulations. Adverse events must be 
described and graded using the terminology and grading categories defined in the NCI’s 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The CTCAE 
is available at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Attribution 
to protocol treatment for each adverse event must be determined by the investigator and 
reported on the required forms, using the codes provided. 
Note: Serious adverse events will be reported on CTEP-AERS using CTCAE v5.0. 
9.0 
ADVERSE EVENTS 
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial 
are done to ensure the safety of patients enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Adverse events are reported in a routine manner 
at scheduled times according to the study calendars in Section 5.0. For this trial, Adverse 
Events: Baseline, Adverse Events: Solicited and Adverse Events: Other forms are used for 
routine AE reporting in Rave. 
Category 
(CTCAE SOC) 
Adverse 
Event/ 
Symptoms 
Baseline Each 
evaluation 
Grading scale (if not 
CTCAE) 
Vascular 
disorders 
Hot flashes 
X 
X 
 
Thromboembolic 
events 
 
 
 
Metabolism and 
Nutrition 
disorders 
Hypertriglyceridemia 
X 
X 
 
Investigations 
Aspartate 
aminotransferase 
(AST) increased 
X 
X 
 

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1. Patients who report visual symptoms in between their baseline and follow-up visits should be 
evaluated by ophthalmology.  
9.2 
Expedited Adverse event reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined 
in the table below. Alliance investigators are required to notify the Investigational Drug 
Branch (IDB), the Alliance Central Office, the Study Chair, and their Institutional Review 
Board if a patient has a reportable serious adverse event. The descriptions and grading scales 
found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 
will be utilized for AE reporting as of April 1, 2018. The CTCAE is identified and located on 
the 
CTEP 
website 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE. Expedited AE reporting for this 
study must only use CTEP-AERS (CTEP Adverse Event Reporting System), accessed via the 
CTEP home page, http://ctep.cancer.gov. In the rare occurrence when Internet connectivity is 
lost, a 24-hour notification is to be made to CTEP by telephone at 301-897-7497. Once 
Internet connectivity is restored, the 24-hour notification phoned in must be entered 
electronically into CTEP-AERS by the original submitter at the site. 
Note: All deaths on study require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause should be provided. 
 
 

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9.2.1 Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE ≤ 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death
2)
A life-threatening adverse event
3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization
for ≥ 24 hours
4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life
functions
5)
A congenital anomaly/birth defect.
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize
the patient or subject and may require medical or surgical intervention to prevent one of the
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10
calendar days of learning of the AE.
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
•
All Grade 4, and Grade 5 AEs
Expedited 10 calendar day reports for: 
•
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
•
Grade 3 adverse events
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. 
Footnote “1” above applies after this reporting period. 
•
Expedited AE reporting timelines defined:

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
“24 hours; 5 calendar days” – The investigator must initially report the AE via AdEERS ≤ 24
hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 calendar days of the initial
24-hour report.

“10 calendar days” - A complete CTEP-
AERS report on the AE must be submitted ≤ 10 calendar days of the investigator learning of the event.
•
Use the NCI protocol number and the protocol-specific patient ID provided during trial
registration on all reports.
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
•
All adverse events reported via AdEERS (i.e., serious adverse events) should also be forwarded
to your local IRB.
•
Alliance A011203 uses a drug under a CTEP IND. The reporting requirements for
investigational agents under a CTEP IND should be followed for all agents (any arm) in this trial.
•
Reporting of cases of secondary AML/MDS is to be done using the NCI/CTEP Secondary
AML/MDS Report Form. New primary malignancies should be reported using the study form Notice of
New Primary.
Secondary Malignancy: 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI 
IND/IDE be reported via AdEERS. Three options are available to describe the event:  
•
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])
•
Myelodysplastic syndrome (MDS)
•
Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via 
the routine reporting mechanisms outlined in each protocol.  
•
Treatment expected adverse events include those listed in Section 10.0 and in the package insert.
•
CTEP-AERS reports should be submitted electronically.
•
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”,
the Pregnancy Information Form should be completed and submitted, along with any additional medical
information (form is available on the CTEP web site at http://ctep.cancer.gov/). The potential risk of
exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) should be documented in
the “Description of Event” section of the AdEERS report.

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9.3 
Z-Endoxifen HCl CAEPR 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Z-Endoxifen HCl (NSC 750393) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 125 patients. Below is the CAEPR for Z-
Endoxifen HCI.  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 Version 2.0, September 25, 20171 
 
 Adverse Events with Possible  
 Relationship to Z-Endoxifen HCl 
 (CTCAE 5.0 Term) 
[n= 125] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Constipation 
 
  
 
Diarrhea 
 
  
 
Dry mouth 
 
  
 
Dyspepsia 
 
  
 
Gastroesophageal reflux disease  
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Cholesterol high 
 
  
Lymphocyte count decreased  
 
 Lymphocyte count decreased (Gr 2) 
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hyperglycemia 
 
  

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 Adverse Events with Possible  
 Relationship to Z-Endoxifen HCl 
 (CTCAE 5.0 Term) 
[n= 125] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Hypertriglyceridemia 
 
 Hypertriglyceridemia (Gr 2) 
 
Hypoalbuminemia 
 
  
 
Hypocalcemia 
 
  
 
Hypophosphatemia 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Myalgia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Dysgeusia 
 
  
 
Headache 
 
  
 
Hypersomnia 
 
  
 
Peripheral sensory neuropathy 
 
  
PSYCHIATRIC DISORDERS 
  
 
Agitation 
 
  
 
Anxiety 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Irritability 
 
 Irritability (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Rash acneiform 
 
  
 
Rash maculo-papular 
 
  
VASCULAR DISORDERS 
  
Hot flashes 
 
 
 Hot flashes (Gr 2)  
 
 Hypertension 
 
  
 
Thromboembolic event 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIG.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
Adverse events reported on Z-Endoxifen HCl trials but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Z-Endoxifen HCl caused the adverse event: 
 
CARDIAC DISORDERS - Sinus bradycardia 
EAR AND LABYRINTH DISORDERS - Ear pain; Vestibular disorder 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Dry eye; Flashing lights; Floaters 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Belching; Colonic 
perforation; Flatulence; Lip pain; Mucositis oral; Oral dysesthesia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Fever; 
Sudden death NOS 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (infected hair follicle) 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Creatinine increased; 
INR increased; Investigations - Other (low HDL); Weight loss 

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METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Buttock pain; 
Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Paresthesia; Seizure; Stroke 
PSYCHIATRIC DISORDERS - Depression; Libido decreased 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Vaginal discharge; Vaginal 
dryness; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus 
VASCULAR DISORDERS - Peripheral ischemia 
 
Note: Z-Endoxifen HCl in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 

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10.0 DRUG INFORMATION 
10.1 
Z-Endoxifen HCl (NSC 750393) 
10.1.1 Procurement 
Z-Endoxifen is an investigational agent in this study and open label supplies will be
provided for treatment Arm I and for patients on Arm II who crossover to Z-Endoxifen
HCl therapy after disease progression, by the Pharmaceutical Management Branch
(PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer treatment and
Diagnosis (DCTD), National Cancer Institute (NCI). Using the PMB Online Ordering
Process (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).
Access to OAOP requires the establishment of a CTEP Identity and Access Management
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active”
account status and a “current” password.” See Section 10.1.8 for further instructions.
Procurement of Z-Endoxifen HCl for Crossover patients 
For patients randomized to tamoxifen and who progressed on treatment, open label 
supplies of Z-Endoxifen HCl may be ordered using the PMB OAOP as described above.  
10.1.2 Formulation 
Z-Endoxifen HCl as 40 mg (Swedish orange-colored size 2) capsules.
The capsules contain the inactive ingredients microcrystalline cellulose, ascorbic acid, 
sodium croscarmellose, colloidal silicon dioxide, and magnesium stearate. The capsules are 
packaged in high-density polyethylene (HDPE) bottles containing 30 capsules each. 
10.1.3 Storage and stability 
Capsules should be stored in the refrigerator at 2-8ºC. Shelf-life surveillance of the intact 
bottles is on-going. Capsules are not to be re-packaged for dispensing purposes. Capsules 
are to be dispensed to study participants in the original manufacturer’s container. 
Z-Endoxifen HCl should be dispensed with a cooler pack that the patient can use to
transport this study medication.
10.1.4 Administration 
Capsules should be taken by mouth at approximately the same time each day on an empty 
stomach, either 1 hour before or 2 hours after meals, in accordance with Section 7.1 of 
the protocol. 
10.1.5 Potential drug interactions 
No significant drug interactions with Z-Endoxifen HCl are known at this time. Because 
the potential of Z-Endoxifen HCl to inhibit and/or induce any CYP450 enzyme is not 
known, every effort should be made to switch patients taking drugs that are known to be 
potent inducers/inhibitors of CYP450 enzymes to other medications prior to starting 
therapy. A list of drugs that are potent CYP450 inhibitors/inducers are included in 
Appendix II. 

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10.1.6 Pharmacokinetic information 
a) Absorption  
In rats, absorption occurs within 15 minutes following oral administration. Mean peak 
plasma concentrations were observed at 2 hours post dosing. Oral absorption was linear 
with bioavailability greater than 67% over the range 20 mg/kg to 140 mg/kg in rats. 
Absorption in dogs was also linear with a bioavailability greater than 50% over the range 
15 mg/kg to 100 mg/kg. 
b) Distribution  
There is no information available at this time.  
c) Metabolism  
Z-Endoxifen HCl, along with 4-hydroxy-TAM, is the most metabolically active form of 
the selective estrogen receptor modulator, tamoxifen. Z-Endoxifen HCl concentrations 
are 20-fold higher than 4HT levels, and display considerable variability between patients, 
depending on the activity of CYP2D6. Other phase II metabolizing enzymes such as 
glucuronide (UGT) and sulfate (SULT), may affect endoxifen exposure, since preclinical 
studies have implicated these enzymes in the conjugation of Z-Endoxifen HCl. Z-
Endoxifen HCl is the key metabolite necessary to fully inhibit ERα transcription and 
proliferation.  
d) Excretion 
In mice, peak plasma concentrations were maintained for 8 to 24 hours with plasma 
concentrations of 0.1μM to 2μM respectively. Terminal elimination half-life was 6.5 h.  
Using a different formulation of endoxifen (endoxifen sulfate), Jina Pharmaceuticals has 
presented data regarding single dose endoxifen pharmacokinetics studies in humans. 
Ahmad et al (2010) reported results of an open label, single oral dose, randomized, dose 
escalating parallel study in 40 healthy male and female fasting subjects. Eight subjects 
received a single dose of 0.5, 1, 2, or 4 mg endoxifen tablets. Tamoxifen (Nolvadex) 20 
mg tablets were administered to eight subjects as reference. Blood samples were 
collected at predose and up to 528 hours post dose for PK. Single oral dose of endoxifen 
at 0.5, 1, 2, or 4 mg was safe and well tolerated. Adverse events were not found and no 
clinically significant changes in laboratory or other safety variables were noted. 
Endoxifen displayed near dose-proportional pharmacokinetics, and small deviations from 
dose. The drug at all doses was rapidly absorbed with Tmax 6±2.9 h and half-life (t1/2) 
of 54.9±8.6. Increase in Cmax and AUC appeared proportional to dose when consecutive 
dose increments were compared. Endoxifen administered at 0.5, 1, 2, or 4 mg resulted in 
1.36, 3.8, 5.5, and 14.5 ng/mL Cmax and 99.1, 231, 330, 763 ng.h/mL AUC0-inf, 
respectively. When compared with endoxifen levels in 20 mg tamoxifen administered 
subjects, 0.5, 1, 2, and 4 mg endoxifen showed 228%, 804%, and 1,216%, 3,385% higher 
Cmax, respectively, while Tmax was significantly lower in endoxifen treated subjects 
(Ahmand et al., 2010). 
10.1.7 Adverse events 
The most common adverse effects of Z-Endoxifen HCl have been mostly grades 1-2 hot 
flashes (50%), anemia (25%), fatigue (25%), lymphocyte count decreased (22%), nausea 
(19%), platelet count decreased (19%), hypertriglyceridemia (16%), irritability (16%), 
anorexia (13%), AST increased (13%), edema limbs (13%), and WBCs decreased (13%). 

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Thromboembolic event (grades 3-4) and hypertriglyceridemia (grade 4) have also been 
reported. 
10.1.8 Agent ordering and agent accountability 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated. PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained). The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form for Oral Agents 
(DARF). 
10.2 
Tamoxifen citrate (NSC 180973) 
Please refer to the FDA-approved package insert for tamoxifen citrate for product 
information, extensive preparation instructions, and a comprehensive list of adverse events. 
10.2.1 Procurement 
Tamoxifen is commercially available and will not be supplied by the Pharmaceutical 
Management Branch (PMB) for this study. 
10.2.2 Formulation 
Tamoxifen is available in 10 mg and 20 mg tablets for oral administration. 
10.2.3 Storage and Stability 
Tamoxifen tablets should be stored at room temperature. The product label will contain 
the expiration date. 
10.2.4 Administration 
Tamoxifen will be administered orally, at a dose of 20 mg daily without regard to meals. 
 
 

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10.2.5 Potential Drug Interactions 
Tamoxifen is extensively metabolized by CYP isoforms. In particular CYP2D6 catalyzes 
the formation of endoxifen and 4-hydroxytamoxifen, both of which are significantly 
more potent than tamoxifen. Inhibition of CYP2D6 activity, as a result of variant 
polymorphisms or concomitant administration of CYP2D6 inhibitors, is associated with 
decreased endoxifen levels. SSRIs are increasingly used to manage hot flashes, including 
hot flashes secondary to tamoxifen. Improvement in symptoms may result from 
decreased generation of endoxifen, and the potential exists for decreased effectiveness of 
tamoxifen. Among SSRIs studied, venlafaxine had the least effect on endoxifen levels. 
Paroxetine was the most potent inhibitor of CYP2D6, resulting in the lowest endoxifen 
concentrations. 
10.2.6 Pharmacokinetic information 
Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration 
of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The 
decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination 
half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl 
tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg 
tamoxifen given twice daily for 3 months to patients results in average steady-state 
plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL 
(range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma 
concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg 
tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL 
(range 152-706 ng/mL), respectively. After initiation of therapy, steady state 
concentrations for tamoxifen are achieved in about 4 weeks and steady-state 
concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a 
half-life of approximately 14 days for this metabolite. In a steady-state, crossover study 
of 10 mg NOLVADEX (tamoxifen citrate) tablets given twice a day vs. a 20 mg 
NOLVADEX (tamoxifen citrate) tablet given once daily, the 20 mg NOLVADEX 
(tamoxifen citrate) tablet was bioequivalent to the 10 mg NOLVADEX (tamoxifen 
citrate) tablets. 
10.2.7 Adverse events  
The most common adverse events reported in recent trials with tamoxifen include hot 
flashes, nausea and vaginal discharge. Tamoxifen is also associated venous thrombosis 
and pulmonary embolism. As a result of tamoxifen’s estrogenic effect on the 
endometrium, endometrial hyperplasia and endometrial cancer have been observed. In 
contrast, the estrogenic effect of tamoxifen is protective in bone (less osteoporosis and 
fewer fractures compared to aromatase inhibitors), and tamoxifen also reduces 
cholesterol. 
11.0 MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) 
Changes in the largest diameter of the tumor lesions and the short axis measurements in the case of 
lymph nodes are used in the RECIST guideline. 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be re-evaluated every 6 weeks (every 2 cycles) 
for the first 8 cycles of treatment and then every 12 weeks (every 4 cycles) until progression.  

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For patients randomized to Arm 2 who crossover to Z-Endoxifen HCl, disease evaluations 
should occur every 6 weeks after starting Z-Endoxifen HCl for the first 8 cycles of treatment 
and then every 12 weeks until progression 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.2.1 Measurable Disease 
A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as 2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).  
Tumor lesions in a previously irradiated area are not considered measurable disease. 
Lytic bone lesions, with an identifiable soft tissue component, evaluated by X-ray, CT 
(with bone windows) or MRI, can be considered as measurable lesions if the soft tissue 
component otherwise meets the definition of measurability described above 
11.2.2 Non-Measurable Disease 
All other lesions (or sites of disease) are considered non-measurable disease, including 
pathological nodes (those with a short axis ≥ 1.0 to < 1.5 cm). Bone lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable as well. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. In addition, lymph nodes that have a short axis < 1.0 cm are 
considered non-pathological (i.e., normal) and should not be recorded or followed. 
For patients enrolled onto A011023 who are determined to have non-measurable bone 
only disease, follow-up imaging (either with PET/CT or bone scan) should be performed 
at the time of tumor assessment. The method of assessment used at baseline must be used 
consistently. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods:  
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. For patients 
having only lesions measuring at least 1 cm to less than 2 cm must use CT imaging 
for both pre- and post-treatment tumor assessments.  
11.3.2 Acceptable Modalities for Measurable Disease: 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
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As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. 
The lesions should be measured on the same pulse sequence. Ideally, the same type 
of scanner should be used and the image 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: 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.  
• 
Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT scans are 
preferable. 
• 
FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease. A 
‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid with an 
update greater than twice that of the surrounding tissue on the attenuation corrected 
image; otherwise, an FDG-PET scanned lesion is considered ‘negative.’ New lesions 
on the basis of FDG-PET imaging can be identified according to the following 
algorithm: 
a. 
Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a sign 
of PD based on a new lesion. 
b. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  
1) 
If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  
2) 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT at the same evaluation, additional follow-up CT scans (i.e., additional 
follow-up scans at least 4 weeks later) are needed to determine if there is truly 
progression occurring at that site. In this situation, the date of PD will be the 
date of the initial abnormal PDG-PET scan.  
3) 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, it is 
not classified as PD. 
11.3.3 Measurement at Follow-up Evaluation:  
• 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
• 
Cytologic and histologic techniques can be used to differentiate between PR and CR 
in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain.) 
 
 

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11.4 
Measurement of Treatment/Intervention Effect 
11.4.1 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 lesions 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline. These lesions can be non-nodal or nodal (as 
defined in 11.2.1), where no more than 2 lesions are from the same organ and no 
more than 2 malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions.  
• 
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion (or malignant lymph node) does not lend itself to 
reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected.  
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the baseline sum of dimensions (BSD). The BSD will be used as 
reference to further characterize any objective tumor response in the measurable 
dimension of the disease.  
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD). If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm. If the target lesion (or 
target lymph node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned. If it is the opinion of the 
radiologist that the target lesion or target lymph node has likely disappeared, the 
measurement should be recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
11.4.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.2.2) are classified as non- target lesions or 
non-target lymph nodes and should also be recorded at baseline. These lesions and lymph 
nodes should be followed in accord with Section 11.4.3.3. 
11.4.3 Response Criteria 
11.4.3.1 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X-
ray must be measured on re-evaluation. Specifically, a change in objective status to 
either a PR or CR cannot be done without re-measuring target lesions and target 
lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. In 
selected circumstances, certain non-target organs may be evaluated less frequently. 
For example, bone scans may need to be repeated only when complete response is 
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11.4.3.2 
Evaluation of Target Lesions 
• Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to < 1.0 cm. 
• Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target 
lymph nodes at current evaluation) taking as reference the BSD (see Section 
11.4.1). 
• Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node that was 
normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short axis 
during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes at current 
evaluation) taking as reference the MSD (Section 11.4.1). In addition, the PBSD 
must also demonstrate an absolute increase of at least 0.5 cm from the MSD.  
c. See Section 11.3.2 for details in regards to the requirements for PD via FDG-PET 
imaging. 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
11.4.3.3 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
• Complete Response (CR): All of the following must be true: 
a. Disappearance of all non-target lesions.  
b. Each non-target lymph node must have a reduction in short axis to <1.0 cm. 
• Non-CR/Non-PD: Persistence of one or more non-target lesions or non-
target lymph nodes. 
• Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node that was 
normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short axis 
during follow-up.  
b. Unequivocal progression of existing non-target lesions and non-target lymph 
nodes. (NOTE: Unequivocal progression should not normally trump target lesion 
and target lymph node status. It must be representative of overall disease status 
change.)  
c. See Section 11.3.2 for details in regards to the requirements for PD via FDG-PET 
imaging. 
 
 

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11.4.4 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, 
and new disease as defined in the following tables: 
For Patients with Measurable Disease 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
* 
See Section 11.4.3.1 
11.4.5 For those patients with non-measurable, bone-only disease, objective progression 
will be established if at least 1 of the following criteria is met: 
- the appearance of 1 or more new lesions (in bone or outside of bone), or 
- unequivocal progression of existing bone lesions. 
The finding of a new lesion should be unequivocal and no attributable to findings thought 
to represent something other than tumor (for example, some ‘new ributab lesions may be 
simply healing or flare of preexisting lesions). Pathologic fracture, new compression 
fracture, or complications of bone metastases will not be considered as evidence of 
disease progression, unless at least 1 of the above criteria is met. 
11.4.6 Symptomatic Deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that 
time, and not either related to study treatment or other medical conditions, should be 
reported as PD due to “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration. 

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12.0 TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF PATIENT 
12.1 
No disease progression or Unacceptable Adverse Events 
Patients who have not had disease progression and have not developed unacceptable toxicity 
will be eligible for re-treatment at their current dose level until disease progression, 
unacceptable toxicity, or refusal.  
12.2 
No disease Progression, Unacceptable Adverse Events  
Those patients who have not had disease progression, but have experienced unacceptable 
toxicity may be eligible for retreatment at a lower dose (see Section 8.0). 
12.3 
Discontinuation of Protocol Therapy  
Reasons why the protocol therapy may be discontinued: 
• 
Tumor progression 
• 
Request by the patient to withdraw 
• 
Unacceptable toxicity 
• 
Inter-current illness  
• 
Administration of alternative treatment  
Arm 1 patients: 
Patients who discontinue treatment for any of the above reasons will proceed to event 
monitoring. Patients will be followed yearly for a maximum of 5 years from study 
registration. Once a patient has discontinued study treatment, future therapy is at the 
discretion of the treating physician.  
Arm 2 patients: 
Patients randomized to tamoxifen who progress during tamoxifen treatment may choose to 
switch to Z-Endoxifen HCl and continue on Z-Endoxifen HCl until disease progression is 
noted. After disease progression during Z-Endoxifen HCl treatment patient will proceed to 
event monitoring. Patients will be followed yearly for a maximum of 5 years from study 
registration. Once a patient has discontinued study treatment, future therapy is at the 
discretion of the treating physician. 
Patients who discontinue treatment for any of the above reasons other than progression or 
patients who refuse to crossover to Z-Endoxifen HCl will proceed to event monitoring. 
Patients 
will be 
followed 
yearly 
for 
a 
maximum 
of 
5 
years 
from 
study 
registration/randomization. Once a patient has discontinued study treatment, future therapy is 
at the discretion of the treating physician. 
12.4 
Refuse to begin protocol treatment following randomization 
If an eligible patient refuses to begin treatment following randomization (and is classified as a 
cancel by the Research Base), all on-study materials and the End of Active Treatment/Cancel 
Notification Form must be submitted. For those patients who also consent to the correlative 
studies, research biospecimens are not to be submitted. No further data submission is 
necessary. Future therapy is at the discretion of the treating physician. 
 
 

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12.5 
Ineligible prior to the start of protocol treatment 
If a patient is determined not to have satisfied each and every eligibility criteria for study 
entry after randomization but prior to the start of protocol treatment, on-study materials must 
be submitted. For those patients who also consent to the correlative studies, research 
biospecimens are not to be submitted. Bio-specimens should not be submitted. No further 
data submission is necessary. Future therapy is at the discretion of the treating physician. 
12.6 
Ineligible after to the start of protocol treatment 
If a patient is determined not to have satisfied each and every eligibility criteria but has 
received some study treatment and is having some clinical benefit, the patient may be able to 
continue study treatment per protocol after consultation with the study chair. If the patient 
does continue on study treatment, study forms and bio-specimens should be submitted using 
the same schedule as eligible patients. If the patient does not continue study treatment, the 
patient will go into event monitoring phase for a maximum of 5 years post randomization. 
Future therapy is at the discretion of the treating physician. 
12.7 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. 
In this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
A randomized phase II clinical trial design was chosen to assess whether Z-Endoxifen HCl 
shows promise in providing greater in antitumor activity (in terms of increasing progression-
free survival) than tamoxifen in postmenopausal women with metastatic ER positive breast 
cancer that is endocrine resistant. 
This study will use a dynamic allocation procedure to allocate an equal number of patients to 
each of the treatment arm. This procedure will balance the marginal distributions of the 
stratification factors between these treatment arms. The stratification factors that will be used 
are: prior palbociclib and/or everolimus, type of disease and degree of endocrine resistance 
(see Section 4.8). 
All patients meeting the eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for assessment of all of the clinical endpoints. Patients will be 
included in the treatment group they were randomized to regardless of their actual treatment 
or duration of treatment. Summary statistics for patient and tumor characteristics, eligibility 
rates, length of follow‑ up, and treatment acceptance rates will be calculated by assigned 
treatment arm. 
13.1.2 Definition and documentation of primary endpoint. 
The primary endpoint is progression-free survival (PFS) defined as the time from 
randomization to documentation of local, regional or distant disease progression or death 
without progression of disease.  
 
 

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13.1.3 Sample Size, Accrual Time and Study Duration 
This trial was designed under the assumption that the median progression-free survival 
time among patients receiving tamoxifen is 3.0 months. Disease assessments in this trial 
are made at a frequency that is half the hypothesized median of the tamoxifen arm. Stone 
et al [41, 42] (2, 3) found that when disease assessments are made at a frequency that is 
half the control median, the difference in power between the log-rank test (with 
documented progression times) and generalized log-test with interval censored data was 
< 3%. As such we will determine the sample size assuming a log-rank test will be used 
with one-sided alpha=0.10 and power=95% so that the interval censored approach with 
the generalized log-rank test will have a power of > 90%.  
With a sample size of 80 eligible patients (40 per treatment arm randomized in equal 
numbers) over a 15 month period and followed at least another 9 months after the close 
of enrollment before analysis is undertaken, a one-sided alpha=0.10 generalized log-rank 
test will have at least a 90% chance of detecting a 50% decrease in hazard of disease 
progression with Z-Endoxifen HCl relative to tamoxifen.  
That corresponds to being able to detect an increase in the median PFS time from 3.0 
months with tamoxifen to 6.0 months with Z-Endoxifen HCl.  
An additional 14 patients will be screened to account for ineligible patients (tumors that 
are ER negative on biopsy) and those who cancel participation prior to starting treatment. 
As of November 1, 2016, 24 (30%) of the 81patients enrolled on this trial were found to 
have ER negative and/or HER2 positive breast cancer, a second primary cancer, or 
benign disease, making them ineligible. Therefore, the number of patients needed to be 
screened to obtain 80 eligible patients will be increased from 94 to 115 patients. 
The efficacy analysis will be conducted when at least 72 patients have provided 
documentation of local, regional or distant disease progression or death without 
progression of disease. 
13.1.3.1 Study duration 
It is anticipated that the enrollment period will be 15 months and the minimum follow-up 
period after the close of enrollment will 9 months, and an additional 3 months will be 
required to complete data submissions and curate the study data. Thus, it is anticipated 
that primary efficacy analysis will begin approximately 27 months after the trial is 
activated. 
13.1.4 Interim efficacy/futility analysis plan 
No formal interim efficacy/futility analysis is planned as the enrollment would be 
compete when 50% of the events will have occurred. 
13.1.5 Analysis plan for primary efficacy endpoint 
Progression-free survival estimates will be determined using nonparametric maximum 
likelihood estimation for interval censored data. The generalized log-rank test for interval 
censored data will be used to assess whether PFS differs between the treatment arms (1,2). 
A secondary analysis of the primary clinical endpoint will follow the approach proposed 
by Freidlin et al. using scan times of 3 and 6 months [43]. 
 
 

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13.1.6 Secondary Clinical Endpoints 
13.1.6.1 Adverse Events 
Per CTEP Version 4.0 of the NCI CTCAE, an adverse event (AE) is any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medical treatment or procedure that may or 
may not be considered related to the medical treatment or procedure. All grade 2, 3, 4 
or 5 adverse events will be documented and assigned an attribute by treating clinician 
as to its relationship to treatment. 
Note: Serious adverse events will be reported on CTEP-AERS using CTCAE v5.0. 
For a given AE, the proportion of patients on each treatment arm who report 
developing a grade 2-5 of this AE will be determined. 
13.1.6.2 Tumor Response Rate by study arm 
The tumor response rate is defined as the 100% time the number of patients with a 
CR or PR (as defined by the RECIST criteria) on 2 consecutive evaluations at least 6 
weeks apart divided by the total number of eligible patients who began study 
treatment. A 90% binomial confidence interval will be constructed for the true 
response rate. 
13.1.6.3 Overall survival distribution by study arm 
Overall survival time is defined as the time from randomization to death due to any 
cause. The distribution of survival times will be estimated using the method of 
Kaplan-Meier. 
13.1.7 Monitoring  
The study chair, the faculty statistician and the executive officer will review the trial data 
every 3 months to identify accrual, toxicity, and endpoint problems that might be 
developing. The faculty and secondary statistician will prepare a report containing 
accrual, adverse events, and efficacy data which will be submitted to the ALLIANCE 
Data and Safety Monitoring Board on a semi-annual basis. 
Safety stopping rules will be applied to each treatment arm separately. If 3 or more of the 
first 10 patients randomized to a given treatment arm or 30% of more of patients 
randomized to that treatment arm thereafter develops a grade 4 hematologic or non-
hematologic toxicity possibly, probably or definitely related to treatment, the enrollment 
to the trial will be temporarily suspended so that all AE data can be examined. The study 
chair and the faculty statistician will formulate a trial recommendation to present to the 
ALLIANCE DSMB and CTEP for approval. 
The study chair and the faculty statistician will formulate a trial recommendation to 
present to the ALLIANCE DSMB and CTEP for approval.  
13.1.8 Other Considerations 
Toxicity, patterns of treatment failure observed in this study and scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate these 
trials earlier than anticipated. 
 
 

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13.2 
 Evaluation of ESR1 alterations and markers of endocrine resistance in patients treated 
with either tamoxifen or Z-Endoxifen HCl (Alliance A011203-ST1)  
13.2.1 Objectives 
13.2.1.1 To examine whether DNA alterations as measured by Foundation medicine in all 
coding exons of 287 cancer-related genes as well as 78 polymorphisms in 34 
ADME-related genes (assessed using a biopsy of metastatic disease obtained after 
progression on AI) are associated with longer PFS or higher response rates in the Z-
Endoxifen HCl arm compared to the tamoxifen arm.  
13.2.1.2 To examine whether SRC3 (AIB1) IHC expression levels (assessed using a biopsy 
of metastatic disease obtained after progression on AI) is associated with longer PFS 
or higher response rates in the Z-Endoxifen HCl compared to tamoxifen arm. 
13.2.2 Analysis methods – DNA alterations 
Data will be returned from Foundation Medicine as presence or absence of various DNA 
alterations, along with description of type and location of the alteration. The nature of 
alterations found in each pathway and gene will be described in tabular format. 
Association of presence or absence of DNA alterations with PFS will be assessed overall 
(presence/absence of any alteration), by pathway (presence/absence of alterations within 
a given pathway), and by gene (presence/absence of alterations within a given gene) via 
Cox regression with the goal of evaluating hazard ratio estimates and confidence 
intervals. Similarly, associations with response rates will be evaluated via logistic 
regression overall, by pathway, and by gene with the goal of evaluating odds ratio 
estimates and confidence intervals. Alterations will be considered together 
(polymorphisms, mutations, amplifications, indels, and fusions combined) as well as by 
type of alteration, e.g., for polymorphisms alone, mutations alone, etc. Model fit and 
stability will be evaluated, and exact methods used if needed. Due to sample size and 
expected prevalence rates, we expect the ability to adjust for covariates to be limited. 
These analyses will be performed in data from both treatment arms combined, as well as 
within treatment arm. This allows us to assess both prognostic and predictive ability in an 
exploratory fashion. The ER and PI3K pathways are of primary interest; other pathways 
will be examined as well. In addition, raw data will be received, and state-of-the-art 
bioinformatics algorithms utilized to assess the potential for genetic alterations not yet 
discovered. 
13.2.3 Power – DNA alterations 
The total trial sample size is 80 patients, with 40 for each treatment. Previous experience 
demonstrates successful assay rates range from 73% in ER+ Her2- patients [44] to 95% 
successful assay rate in a diverse set of cancers [45]. Based on these rates, the expected 
sample size per treatment arm is from 29 to 38. A previous study in this patient 
population found 96% of subjects to have at least one known somatic alteration, and 104 
genes to have at least one known somatic alteration [44]. The same study found 56% of 
patients to have genetic alterations in the PI3K pathway and 44% to be wild type. Given 
the sample size and expected prevalence rates, these analyses are considered to be 
exploratory and hypothesis generating. 
 
 

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13.2.4 Analysis methods – SRC3 (AIB1) and PKCβ1 IHC expression levels 
Approximately 25% of patients are anticipated to have metastatic SRC3-positive disease. 
Within each treatment arm, a point and interval estimate of the difference in tumor 
response rate between those with metastatic SRC3-positive disease and those with 
metastatic SRC3-negative disease will be constructed using the properties of the binomial 
distribution. Also, a point and interval estimate of the odds of disease progression among 
those with metastatic SRC3-positive disease relative to those with metastatic SRC3-
negative disease will be ascertained from the parameter estimates of fitting a proportional 
hazard model to the progression data. The proportion of patients with metastatic PKCβ1 
expressing breast cancer is unknown. Within each treatment arm, a point and interval 
estimate of the difference in tumor response rate between those with metastatic 
PKCβ1positive disease and those with metastatic PKCβ1-negative disease will be 
constructed using the properties of the binomial distribution. Also, a point and interval 
estimate of the odds of disease progression among those with metastatic PKCβ1-positive 
disease relative to those with metastatic PKCβ1negative disease will be ascertained from 
the parameter estimates of fitting a proportional hazard model to the progression data. 
13.3 
DNA alterations in patients treated with either tamoxifen or Z-Endoxifen HCl (Alliance 
A011203-ST2) 
13.3.1. Objectives 
13.3.1.1 To assess whether the molecular characteristics identified in the tumor biopsies are 
detectable in CTCs and/or cfDNA. 
13.3.1.2 For each treatment arm, to examine ESR1 mutations or amplifications identified in 
CTCs or cfDNA change over time and explore the impact of these changes on PFS 
and response rates.  
13.3.2 Analysis methods 
For each patient, the genetic alterations seen in their tumor biopsy and their circulating 
tumor cells will be compared to ascertain which genetic alteration was seen in both tumor 
biopsy materials and CTCs, seen in only their tumor biopsy material, or seen in only their 
CTCs. For each alternation observed, we will tabulate the proportion of patients who had 
the genetic alternation seen in both tumor biopsy materials and CTCs, the proportion of 
patients who had the genetic alternation seen in only their tumor biopsy material, the 
proportion of patients who had the genetic alternation seen in only their CTCs, and the 
proportion of patients who did not have the genetic alternation in tumor biopsy materials 
or CTCs. 
Toy et al. conducted a genetic analysis of tumors taken from individuals with metastatic 
ER-positive breast cancer whose tumors had grown or spread to new sites after at least 3 
months with hormonal therapy. They found in 14 (17.5%) of 80 cases there were 
mutations in ESR1 affecting the ligand-binding domain. The prevalence of mutations in 
this gene among the tumors from the patients who relapsed on hormonal treatment was 
were higher than that seen in The Cancer Genome Atlas (TCGA) invasive primary 
(untreated) breast cancer and luminal A and luminal B primary breast cancer cases, 
suggesting that these mutations may have a role in the development of acquired 
resistance to hormonal treatment. 
 
 

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For each treatment arm:  
- a point and interval estimate of the proportion of patients with ESR1mutated 
CTCs prior to the start of treatment or is found to have ESR1mutated CTCs 
during treatment at or prior to progression will be determined using the 
properties of the binomial distribution 
- a point and interval estimate of the proportion of patients with ESR1mutated 
CTCs prior to the start of treatment who progress within the first 4 months of 
treatment will be determined using the properties of the binomial distribution 
- a point and interval estimate of the hazard of disease progression among the 
patients with ESR1mutated CTCs prior to the start of treatment or at end of the 
second cycle of treatment relative to patients who do not have ESR1mutated 
CTCs either prior to the start of treatment or at end of the second cycle of 
treatment will be constructed using the results of fitting a Cox model to time to 
progression data. 
13.4 
Biochemical markers of bone turnover (A011203-ST3) 
For each of the biomarkers of bone formation (namely, bone-specific alkaline phosphatase, 
osteocalcin, P1NP) and bone resorption (namely, CTX-1, Trap5b and bone sialoprotein) the 
percent change after 2 cycles of treatment from pre-treatment levels will be determined. 
A two sided alpha=0.01 z-test will be used to assess whether the percent change in a given 
bone absorption biomarker differs with respect to treatment. 
Assuming the variability in percent change in a given bone absorption biomarker is similar 
between the treatment arms and at least 32 or more patients on each treatment arm have both 
a pre and Week 8 biomarker determination, then a two sided alpha=0.01 z-test will have a 
90% chance of detecting whether the mean difference between the percent change in the 
biomarker of those treated with Z-Endoxifen HCl and that of those treated with tamoxifen is 
at least 1 standard deviation or more. 
13.5 
Z-Endoxifen HCl and Tamoxifen Pharmacokinetics and Pharmacogenetics (A011203-
PP) 
The pharmacokinetic, pharmacogenetic and pharmacodynamic data will be examined in an 
exploratory and hypothesis-generating fashion. A population PK will be developed using the 
software program NONMEM®, Version 7 (ICON Development Solutions, Ellicott City, MD, 
USA). The model will be parameterized in terms of AUC (the primary endpoint), as well as 
clearance and volume of distribution. Criteria for model selection will include the likelihood 
ratio test, shrinkage estimates, reasonableness of parameter estimates, as well as goodness-of-
fit plots. Attempts will be made to identify the covariates that affect drug behavior or those 
that explain variability in this patient population. 
The primary pharmacokinetic endpoint for exploring relationships with efficacy/adverse 
effects will be endoxifen AUC. Pharmacokinetic-Pharmacodynamic relationships will be 
explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters 
of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations 
and may be followed by model-based analyses. The data may be pooled with data from 
other/future studies for additional population PK/PD analyses. 
 
 

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13.6 
Inclusion of Women and Minorities 
This study will be available to all eligible women regardless of race or ethnic group. 
Men are excluded from this study the eligibility criteria requires all participants to have failed 
an aromatase inhibitor and aromatase inhibitors are not FDA approved for men. 
 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
3 
0 
3 
Native Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
0 
0 
17 
0 
17 
White 
15 
0 
80 
0 
95 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
15 
0 
100 
0 
115 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, or other Spanish culture or 
origin, regardless of race. The term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original peoples of North, Central, or South 
America, and who maintains tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent 
including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific Islanders in previous data collection 
strategies.)  
Black or African American – a person having origins in any of the black racial groups of Africa. Terms such as “Haitian” or 
“Negro” can be used in addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original peoples of Hawaii, Guam, 
Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or North Africa.  
 
 
 

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14.0 CORRELATIVE AND COMPANION STUDIES  
There are 4 substudies within this protocol and all patients are encouraged to participate.  
14.1 
Evaluation of ESR1 alterations and marker of endocrine resistance in patients treated 
with either tamoxifen or endoxifen (Alliance A011203-ST1) 
14.1.1 Background 
While protein levels of ER continue to be the most important factor determining response 
to endocrine therapy, an emerging area of research has demonstrated that genetic 
alterations in ESR1, either through mutations in the ligand binding domain, fusions, or 
the presence of ESR1 amplification, are associated with endocrine resistance. 
Additionally, a key oncogenic co-activator, SRC3 (AIB1), known to be associated with 
tamoxifen and AI resistance is more likely to avidly bind ER in these settings, leading to 
potential resistance and/or greater agnostic effects of SERM. Therefore, new drug 
strategies are needed in patients with ESR1 alterations whose tumors continue to express 
the ER, but are resistant to standard hormonal therapies. 
With regard to ESR1 mutations, recent data suggest that these alterations are rare in 
newly diagnosed breast cancer, but reported in up to 20% of recurrent breast cancers [37]. 
These mutations lead to a conformational change in the LBD which mimics the 
conformation of activated ligand-bound receptor and constitutive, ligand-independent 
transcriptional activity resulting in and resistance to some forms of hormonal therapy. 
More specifically, preclinical studies suggest that cell lines that harbor some of these 
mutations, while insensitive to estrogen deprivation, retain sensitivity to higher doses of 
fulvestrant or potent SERMs such as endoxifen and 4HT. However, the concentrations of 
SERMS used in the study by Robinson et al [12] (1 micromolar) are neither observed nor 
achievable in tamoxifen treated humans [26]. Conversely, substantial endoxifen 
concentration can be achieved in humans (1-2 µM) and it is reasonable to hypothesize 
that these levels of endoxifen may be effective in patients with ESR1 mutations or 
amplification. 
Additional data suggest that amplification of ESR1, observed more commonly in de novo 
resistant tamoxifen treated breast cancers and additionally observed in AI resistant breast 
cancers, may be an important marker of disease resistance. Finally, ESR1 fusions, as 
described by Li et al, appears additionally to confer resistance to hormonal therapy but 
are rare [38].  
To compare the activity of endoxifen with tamoxifen, we performed an in vivo study 
comparing Z-Endx with letrozole and tamoxifen in an MCF7 aromatase expressing 
(MCF7/AC1) cell line. In that model, endoxifen was superior to both tamoxifen and 
letrozole, and importantly demonstrated substantially greater activity compared to 
tamoxifen in letrozole resistant MCF7/AC1. In this latter model, we have identified ESR1 
amplification in the letrozole resistant MCF7/AC1 cells (but not parental) consistent with 
other groups that have demonstrated ESR1 amplification in MCF7 LTED cells [38]. 
Additionally, in the letrozole resistant MCF7/AC1 model, we identified substantial 
alterations in SRC3 after 4 weeks of either tamoxifen or endoxifen treatment (increase in 
SRC3 phosphorylation with tamoxifen while a decrease in SRC3 phosphorylation with 
endoxifen. Using the MCF7 letrozole resistant line, we identified that at 1 hour, TAM, 4-
HT and estrogen activated SRC3, with additional downstream activation of IGF1R, 
PDK1, and AKT, as well as ERK and AP1 (c-Jun, c-Fos). Conversely, Z-Endox reduced 
SRC3 phosphorylation as well as IGF1R, PDK1, AKT, c-Jun and c-Fos (data not shown). 
 
 

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As noted previously, we have demonstrated that endoxifen inhibited PKCβ1 (IC50 350 
nM) while the IC50 for TAM was substantially higher (>5 micromolar) and that 
inhibition of PKCβ1 led to reductions in SRC3 phosphorylation at 1 hour (Goetz et al 
data unpublished).These data suggest that this unique non-genomic effects of endoxifen 
on PKCβ1 may impart an advantage for endoxifen over tamoxifen, especially in 
hormonally resistant breast cancer that exhibits activated growth factor signaling. 
To be eligible for enrollment in A011023, a biopsy of metastatic disease will be required, 
and those patients with ER levels > 10% (obtained in the local laboratory using ASCO 
CAP guidelines) will be eligible. Two additional research cores will be obtained on all 
patients, and a representative core will be sent to Foundation medicine to analyze all 
coding exons of 287 cancer-related genes including ESR1 alterations (mutations, 
amplification and fusions) as well as 78 polymorphisms in 34 ADME-related genes. 
Fraser Symmans, MD leads a collaborative effort at M.D. Anderson Cancer Center that is 
focused on the development of predictive and treatment-prognostic gene expression 
signatures in breast cancer. The sensitivity to endocrine therapy (SET) index represents 
the genes with strongest correlation to expression of endocrine receptor gene expression. 
The SET index has been demonstrated to be prognostic for tamoxifen treatment of node-
negative ER+ breast cancer and chemo-endocrine treatment of Stage II-III ER+ breast 
cancer [46], and also progression-free and overall survival for endocrine treatment of 
relapsed Stage IV ER+ breast cancer [47]. However, SET index was not prognostic for 
the natural history of node-negative ER+ breast cancer that did not receive any adjuvant 
systemic therapy [46]. The SET index is undergoing translation for use with formalin-
fixed paraffin-embedded tumor samples and that assay will be applied to this study as a 
correlative science project.  
14.1.2 Objectives 
14.1.2.1 
To examine whether ESR1 alterations (defined as either ER activating mutations or 
ER amplification) (assessed using a biopsy of metastatic disease obtained after 
progression on AI) is associated with longer PFS or higher response rates in the Z-
Endoxifen HCl arm compared to the tamoxifen arm. 
14.1.2.2 
To examine whether SRC3 (AIB1) or PKCβ1 IHC expression levels (assessed 
using a biopsy of metastatic disease obtained after progression on AI) is associated 
with longer PFS or higher response rates in the Z-Endoxifen HCl compared to 
tamoxifen arm. 
14.1.2.3 
To examine whether ERα alterations (defined as either ER activating mutations or 
ER amplification) are associated with longer PFS or higher response rates in the Z-
Endoxifen HCl arm compared to the tamoxifen arm. 
14.1.3 Methods 
Patients are eligible for A011203 if their tumor is determined to be ERα positive. An 
additional 2-3 research cores will be obtained for the tissue translational studies for 
consenting patients. A biopsy of metastatic disease for patients that have progressed on 
prior hormonal therapy may be considered a standard of care, since multiple studies have 
demonstrated that ER and HER2 expression can change, and this change is associated 
with differences in DFS and OS [48]. Specifically, tamoxifen is not indicated for ER 
negative breast cancer. Furthermore, if the tumor is determined to be HER2+, patients 
would be eligible for anti-HER2 based therapy off study. Therefore, a biopsy at the time 
of pre-registration is required for all patients for confirmation of ER status. See Section 

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6.2.3 for details of specimen collection. 
A portion of the tissue, corresponding to approximately 75% of the total from the biopsy 
as described in Section 6.2.3 will be fixed in formalin and sent to the Alliance 
Biorepository at Ohio State University for these analyses. There, the tumor block (s) will 
be used for nucleic acid extraction for the following translational objectives: DNA 
(Foundation medicine) and RNA (SET index) as well as sections cut for IHC analyses of 
PKCβ1and SRC3. 
There, either one or two cores (depending on total volume) will be cut for an H&E (to 
confirm tumor) followed by 10 unstained sections (10 micron) for DNA (Foundation 
Medicine) and RNA extraction (SET index). Three 5 micron sections will additionally be 
cut for assessment of PKCβ1 [49] as well as total and phosphorylated SRC3 using the 
method previously described [50]. The Foundation Medicine DNA sequencing assay will 
be performed as previously described [37]. For the SET index, random primer reverse 
transcription will be performed using the Sensation Plus kit (Affymetrix) and labeled 
cDNA will be hybridized to Affymetrix U133 gene expression arrays. The SET index 
will be calculated from the normalized gene expression values using pre-defined methods. 
SET index will be compared to PFS between and across treatments as a continuous 
variable and as pre-defined categories of low and high SET index.  
The remaining tissue any residual DNA/RNA will be stored in the Alliance Biorepository 
at Ohio State University. See Section 6.2.3 for shipping instructions.  
14.2 
DNA alterations in patients treated with either tamoxifen or Z-Endoxifen HCl (Alliance 
A011203-ST2): Circulating tumor cells and circulating cell free DNA  
14.2.1 Background 
Comprehensive noninvasive monitoring of genetic alterations over time should help 
guide use of molecularly targeted drug therapies, including endocrine therapy for breast 
cancer. If the driving genetic alterations of an individual patient’s tumor are known, 
monitoring those alterations globally through serial blood sampling as opposed to 
repeated tumor biopsies of a single site would allow clinicians to respond directly to 
changes in genetic alterations and allow for truly tailored drug selection. This “liquid 
biopsy” approach is clearly favorable from the perspective of patient comfort, health 
economics, and maximizing therapeutic efficacy, although controversy remains as to 
whether circulating tumor cells or circulating cell free DNA is more representative of 
underlying tumor biology. We propose to evaluate the peripheral blood for specific ESR1 
alterations identified in tumor biopsies and determine whether or not serial changes in 
those alterations correlate with patient outcomes relative to treatment with either 
tamoxifen or endoxifen. 
Circulating Tumor Cells (CTCs) 
That CTCs have biologic relevance in breast cancer is clear, as their relative abundance 
in the peripheral blood has strong correlations with disease related outcomes in both early 
stage and advanced disease [51-54]. The development of CTCs as a “liquid biopsy” by 
which to perform ongoing tumor assessments in relation to treatment exposure is possible 
with recent technologic advances that allow for the capture of CTCs with epithelial, 
EMT-like, and/or stem cell like phenotypes, and for molecular characterization by 
immunocytochemistry, fluorescence in situ hybridization, RT-PCR, and next generation 
sequencing. Mayo Clinic Rochester has access to several platforms for CTC capture and 
analysis with the goal of studying the most clinically relevant population of CTCs for a 
given translational research question.  

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Circulating Cell Free DNA (cfDNA) 
Several studies indicate that circulating cell free DNA (cfDNA) includes representation 
of key genetic alterations related to cancer progression or resistance to systemic therapy; 
these alterations include mutations of tumor suppressor genes (e.g., TP53) and oncogenes 
(e.g., PIK3CA, KRAS and BRAF). Commercially available platforms exist with a 
predefined set of genes and point mutations of interest for use across multiple 
malignancies. A more flexible system for individualized monitoring is needed. Mayo 
Clinic Rochester has developed an internal assay for this purpose. 
14.2.2 Objectives 
14.2.2.1 
To assess whether the molecular characteristics identified in the tumor biopsies are 
detectable in CTCs and/or cfDNA. 
14.2.2.2 
For each treatment arm, to examine whether ESR1 mutations or amplifications 
identified in CTCs or cfDNA change over time and explore the impact of these 
changes on PFS and response rates.  
14.2.3 Methods 
Minetta Liu, MD leads a collaborative effort at Mayo Clinic Rochester that is focused on 
the optimization, validation, and implementation of CTC and cfDNA analyses in clinical 
practice. The platforms, technology, and expertise required to complete the proposed 
work are validated and available. To reduce patient discomfort and inconvenience, every 
effort will be made to collect the blood samples in conjunction with venous access for 
routine blood draws or chemotherapy administration. 
Circulating Tumor Cell Capture and Analysis 
Two 10 mL whole blood samples will be collected in a K3-EDTA tube at baseline (Cycle 
1, Day 1 prior to the start of treatment), end of Cycle 2, (prior to the start of Cycle 3), end 
of Cycle 8, (prior to the start of Cycle 9) and at the time of disease progression. These 
samples will be processed within 96 hours of collection using the Cynvenio platform [55] 
[56] to isolate CTCs. ER expression will be assessed by immunofluorescence. Expression 
of other genes may also be assessed using RNA based assays. DNA will be extracted 
from the CTCs for the evaluation of prespecified gene mutations using the same 
techniques applied to cfDNA (below). See Sections 6.2.4 for shipping instructions. 
For those patients with crossover from tamoxifen to Z-Endoxifen HCl, CTC samples 
will be collected as follows: 
1) End of Cycle 2, (prior to the start of Cycle 3) on Z-Endoxifen HCl 
2) End of Cycle 8, (prior to the start of Cycle 9) on Z-Endoxifen HCl 
3) At the time of disease progression on Z-Endoxifen HCl 
Circulating Cell Free DNA Isolation and Analysis 
Two 10 mL whole blood samples will be collected in Streck Cell Free DNA BCT tubes 
at baseline (Cycle 1, Day 1 prior to the start of treatment), end of Cycle 2, (prior to the 
start of Cycle 3), end of Cycle 8, (prior to the start of Cycle 8) and at the time of disease 
progression. These samples will be processed within 7 days of collection for cfDNA 
extraction using the Qiagen QIAmp Circulating Nucleic Acid kit according to 
manufacturer’s specifications. Evaluation for prespecified gene mutations will be 
performed using digital droplet PCR with the RainDrop platform (raindancetech.com). 
Circulating free RNA may also be measured. See Sections 6.2.4 for shipping instructions. 

A L LI A N C E A 0 1 1 2 0 3  
Versi o n Date: 0 4/ 2 4 / 2 0 1 8 
U p date # 0 5 
7 4  
F or  t h ose  p atie nts  wit h  cr oss o ver  fr o m  t a m o xife n  t o  Z - En d o xife n  H Cl , cf D N A 
sa m ples will be c ollecte d as f oll o ws: 
1)  E n d of C ycle 2, ( pri or t o t he start of C ycle 3) o n Z- E n d o xife n H Cl  
2)  E n d of C ycle 8, ( pri or t o t he start of C ycle 9) o n  Z- E n d o xife n H Cl  
3) At t he ti me of disease pr o gressi o n o n Z- E n d o xife n H Cl  
1 4. 3 
Bi oc he mic al m ar kers of b o ne t ur n o ver ( Alli a nce A 0 1 1 2 0 3-S T 3) 
1 4. 3. 1 B ac k gr o u n d 
I n  p ost me n o pa usal  w o me n,  ta m o xife n  is  k n o w n  t o  i ncrease  b o ne  mi neral  de nsit y  a n d 
re d uce t he ris k of fract ure. Data fr o m o ur gr o u p ha ve n o w de m o nstrate d t hat treat me nt of 
o variect o mize d  mice  wit h  a n  a nti -ca ncer  d ose  of  e n d o xife n  ( 5 0  m g/ k g/ da y)  res ults  i n 
s u bsta ntial  i ncreases  i n  b o ne  mi neral  de nsit y  a n d  b o ne  mi neral  c o nte nt  t hr o u g h o ut  t he 
s kelet o n [5 7 ]. A d diti o nall y, we ha ve de m o nstrate d t hat a m o derate d ose of e n d o xife n ( 1 0 
m g/ k g/ da y)  has  si mila r  effects  i n  a  pre-cli nical  o variect o mize d  rat  m o del.  I nteresti n gl y, 
t his sa me d ose of e n d o xife n res ulte d i n i ncrease d b o ne mass i n i ntact rats ( u n p u blis he d 
data), a n effect o p p osite of t hat re p orte d f or ot her selecti ve estr o ge n rece pt or m o d ulat ors 
i ncl u din g ta m o xife n a n d ral o xife ne.  I n or der t o o btai n data wit h re gar d t o t he effects of 
e n d o xife n o n b o ne, a n d t o directl y c o m pare t his t o t he k n o w n effects of ta m o xife n, we 
will assess ser u m pr oc olla ge n t y pe 1 a mi n o -ter mi nal pr o pe pti de ( P 1 N P, a b o ne f or mati o n 
mar ker)  a n d  C -T el o pe pti de  of  T y pe  I  C olla ge n  ( C T X -1,  a  b o ne  res or pti o n  mar ker)  at 
baseli ne, f oll o wi n g 6 wee ks of treat me nt a n d f oll o wi n g 6 m o nt hs of treat me nt. Sa m ples 
will be dra w n fasti n g i n t he A M a n d t he assa ys will be c o n d ucte d usi n g vali date d E LI S As 
i n Dr. Ha wse’s la b orat or y. 
1 4. 3. 2 O bjecti ve  
F or  eac h  treat me nt,  t o  e val uate  c ha n ges  i n  mar kers  of  b o ne  f or mati o n  a n d  re bs or pti o n 
after 2 c ycles of treat me nt. 
1 4. 3. 3 Met h o ds  
1 0 ml  of  w h ole  bl o o d  will  be  c ollecte d  i n  a  N o n-a d diti ve  re d  t o p  t u be. S er u m will  be  
pr ocesse d a n d ali q u o te d acc or di n g t o i nstit uti o nal pr oce d ure s a n d s u bse q ue ntl y fr oze n at 
- 2 0C or c ol der u ntil rea d y t o s hi p t o t he Allia nce Bi ore p osit or y at O hi o State U ni versit y . 
See Secti o n 6. 2. 5  f or details of s peci me n c ollecti o n a n d pr ocessi n g. 
T he s peci me ns will be c ollecte d at t he f oll o wi n g ti me  p oi nts: 
1)  C ycle 1, Da y 1 pri or t o t he start of treat me nt 
2)  E n d of C ycle 2, ( pri or t o t he start of C ycle 3) 
3)  E n d of C ycle 8, ( pri or t o t he start of C ycle 9) 
4) At t he ti me of disease pr o gressi o n  
F or t h ose p atie nts wit h  cr oss o ver fr o m t a m o xife n t o Z - En d o xif e n  H Cl , P K sa m ples 
will be c ollecte d as f oll o ws:  
1)  E n d of C ycle 2, ( pri or t o t he start of C ycle 3) o n Z - E n d o xife n H Cl  
2)  E n d of C ycle 8, ( pri or t o t he start of C ycle 9) o n Z - E n d o xife n H Cl  
3) At t he ti me of disease pr o gressi o n  o n Z- E n d o xife n H Cl  
Alterati o ns  i n  t he  le vels  of  b o ne  f or mati o n  ( b o ne -s pecific  al kali ne  p h os p hatase, 
oste ocalci n  a n d  P 1 N P)  a n d  res or pti o n  ( C T X -1,  Tra p 5 b  a n d  b o ne  sial o pr otei n)  m ar kers 
will be deter mi ne d t  i n d u plicate usi n g a p pr o xi matel y 5 0 µ L of ser u m  thr o u g h t he use of 

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commercially available ELISA kits from Immunodiagnostic Systems following the 
manufacturers protocol. 
14.4 
Z-Endoxifen HCl and Tamoxifen Pharmacokinetics and Pharmacogenetics (Alliance 
A011203-PP1)  
14.4.1 Background 
Population variability of Z-Endoxifen HCl plasma concentrations will be lower following 
administration of Z-Endoxifen HCl than following administration of tamoxifen. In the 
ongoing Mayo Phase I trial, a daily dose of 40 mg/day has achieved sustained 
concentrations of >140 ng/ml Z-Endoxifen HCl after the first dose and >300 ng/ml at 
steady-state which is achieved 7 days after beginning treatment. In contrast, a daily dose 
of 100 mg/day has achieved sustained concentrations of > 450 ng/ml Z-Endoxifen HCl 
after the first dose and >1250 ng/ml at steady-state. However, the variability of steady-
state Z-Endoxifen HCl levels has not been ascertained due to the small number of 
patients treated to date. 
Population variability of Z-Endoxifen HCl and tamoxifen plasma concentrations are 
associated with genetic differences in drug metabolism and transport enzymes. 
Pharmacogenetic studies will focus on genotyping enzymes involved in the transport and 
metabolism of Z-Endoxifen HCl and tamoxifen. 
The role of CYP2D6 in the metabolism of tamoxifen to Z-Endoxifen HCL and 4-OH-
Tam has been evaluated previously. CYP2D6 genotyping will be performed to assess the 
presence/absence of the following variants: 
CYP2D6 Allele 
Nucleotide Change 
Enzyme Metabolism 
*1 
None (wild type) 
(Normal) 
*3  
2549A>del 
No activity 
*4 
1846G>A 
No activity 
*5 
Gene deletion 
No activity 
*6 
1707T->del 
No activity 
*10 
100C->T 
Decreased activity 
*17 
1023C->T 
Decreased activity 
*41 
-1584C, 2850T, and 988A 
Decreased activity 
Gene duplication 
 
Depends on the allele duplicated 
(increased/decreased) 
The glucuronidation of tamoxifen and its metabolites has previously been evaluated. The 
active metabolite, 4-OH-Tam, (but not Z-Endoxifen HCl) appears to undergo both N-
glucuronidation and O-glucuronidation. For N-glucuronidation, only UGT1A4 appears to 
glucuronidate 4-OH-Tam. In contrast, all UGT isoforms were able to O-glucuronidate 4-
OH-Tam. The most important enzyme responsible for the O-glucuronidation of the trans 
isomers of 4-OH-Tam and Z-Endoxifen HCl is UGT2B7. Notably, the rate of O-
glucuronidation is significantly lower in human liver microsomal specimens appears 
known to carry functional UGT2B7 polymorphisms, suggesting that genetic variability in 
UGT2B7 may affect endoxifen pharmacokinetics. 

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Additionally, several transporters expressed in cancer cells play important roles in 
resistance to TAM, and therefore, possibly Z-Endoxifen HCl. Adenosine triphosphate–
binding cassette (ABC) transporter B1 (ABCB1; also known as multidrug resistance 1 
[MDR1]), ABCC2 (also known as multidrug resistance-associated protein 2 [MRP2]), 
and ABCG2 (also known as breast cancer resistance protein [BCRP]), may be involved 
in the transport of Z-Endoxifen HCl, and genetic variation may influence the individual 
difference in Z-Endoxifen HCl pharmacokinetics and efficacy. In one recently published 
study of patients receiving TAM in the adjuvant setting, a significant association was 
found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in 
patients with AA v GG genotypes).31 Therefore, we will assess whether polymorphisms 
in ABCB1, ABCC2 and ABCG2 are associated with Z-Endoxifen HCl steady state 
concentrations and response. 
Based on these data, we will develop assays to determine whether functional 
polymorphisms in UGT [e.g., UGT2B7(268Tyr)] are associated with steady state 
concentrations of Z-Endoxifen HCl as well as response. Genomic DNA extracted from 
peripheral blood will be used to assess for key polymorphisms in genes involved in the 
transport of Z-Endoxifen HCl including but not limited to rs2032582 (2677G>T/A) and 
rs3213619 (–129T>C) in ABCB1 and rs2273697 (1249G>A) in ABCC2. In addition, we 
may use the germ line DNA collected to consider other candidate SNPs involved in drug 
metabolism and transport. 
Pharmacodynamic relationships with endoxifen pharmacogenetics and pharmacogenetics 
will be investigated in an exploratory analysis. 
14.4.2 Objectives 
To further characterize pharmacokinetics, pharmacogenetics and metabolism of Z-
Endoxifen HCl and tamoxifen. 
14.4.3 Methods 
14.4.3.1 
Blood samples for pharmacokinetics will be collected in all patients treated 
with Z-Endoxifen HCl or tamoxifen, who have consented, according to the 
following schedule: 
• Cycle 1 Day 1: Prior to drug administration 
• Cycle 1 Day 1: 2-4 hours after drug administration 
• Cycle 1 Day 1: 4-6 hours after drug administration Note: Do not draw samples 
within 2 hours of each other.) 
• Cycle 1 Day 2: Prior to drug administration 
• End of Cycle 2, (prior to the start of Cycle 3) 
• End of Cycle 8, (prior to the start of Cycle 9) 
• At the time of disease progression 
For those patients with crossover from tamoxifen to Z-Endoxifen HCl, PK 
samples will be collected as follows: 
• End of Cycle 2, (prior to the start of Cycle 3) on Z-Endoxifen HCl 
• End of Cycle 8, (prior to the start of Cycle 9) on Z-Endoxifen HCl 
• At the time of disease progression on Z-Endoxifen HCl 

A L LI A N C E A 0 1 1 2 0 3  
Versi o n Date: 0 4/ 2 4 / 2 0 1 8 
U p date # 0 5 
7 7  
N O T E:  Sa m ples  are  li g ht  se nsiti ve.  Use  a m ber  t u bes  or  c o ver  t u bes  wit h 
al u mi n u m f oil t o pre ve nt e x p os ure t o li g ht. 
P har mac o ki netics bl o o d sa m ples will be c ollecte d i n 6 ml E D T A ( p ur ple t o p) t u bes, 
wra p pe d i n al u mi n u m f oil a n d i m me diatel y c o ole d i n a n ice water bat h. Bl o o d m ust 
be pr ocesse d f or plas ma is olati o n wit hi n 2 0 mi n utes of c ollecti o n. 
Bl o o d will be s u bj ecte d t o ce ntrif u gati o n ( 2, 0 0 0 r p m f or 1 0 mi n utes) i n a 
refri gerate d ce ntrif u ge ke pt at 4° C. F oll o wi n g ce ntrif u gati o n, t he plas ma will be 
tra nsferre d t o pol y pr o p yle ne t u bes, ca p pe d, wra p pe d i n al u mi n u m f oil a n d 
i m me diatel y fr oze n at - 7 0° C. T u be la bels m ust c o ntai n t he f oll o wi n g data: 
• Patie nt i de ntificati o n n u m ber  
•  Date a n d ti me ( 2 4- h o ur cl oc k)) of c ollecti o n 
T he P har mac o ki netic sa m ples will be se nt t o B A P Freezer at t he Ma y o Cli nic  (see 
Secti o n 6. 2. 7 ). 
T he plas ma c o nce ntrati o n -ti me data will be will be a nal yze d b y n o n-li near mi xe d 
effects  m o deli n g  usi n g  t he  pr o gra m  N O N M E M  ( P harsi g ht  C or p.,  M o u ntai n vie w, 
C A) t o deter mi ne cleara n ce, v ol u me of distri b uti o n a n d c o ntri b uti o ns of i nter - a n d 
i ntra-s u bj ect varia bilit y. 
1 4. 4. 3. 2 
All p atie nts tre ate d wit h Z - En d o xif e n  H Cl  or t a m o xife n , w h o h a ve c o nse nte d, 
will pr o vi de a si n gle bl o o d s a m ple f or p h ar m ac o ge netic a n al ysis.  
Ge n o mic  D N A  will  be  e xtracte d b y  t he  Allia nce  Bi ore p osit or y  at  C T S U fr o m 
peri p heral bl o o d c ollecte d pri or t o treat me nt. Ge n ot y pi n g f or ke y p ol y m or p his ms i n 
ge nes i n v ol ve d i n c o nj u gati o n a n d tra ns p ort of Z- E n d o xife n H Cl  will be a nal yze d.  
Ge n o t y pi n g  assa ys  pri maril y  i nc or p orate  p ol y merase  c hai n  reacti o ns  ( P C R)  t o 
a m plif y  D N A  re gi o ns  of  i nterest  usi n g  se q ue nce -s pecific  pri mers.  P ol y m or p hic 
variati o ns  are  detecte d  b y  se veral  met h o ds, i ncl u di n g  D N A  se q ue nci n g,  fra g me nt 
size  a nal ysis  ( wit h  Ge ne Sca n)  an d/ or  fl u or esce nt  pr o be  detecti o n  met h o ds. 
Allelic  varia nt  assa ys  are  esta blis he d  wit h  a p pr o priate  vali dati o n  ( usi n g  C orriel 
et h nic  D N A  pa nels,  Har d y -Wei n b ur g  e q uili bri u m  a n d  et h nic  fre q ue ncies),  a n d 
a p plie d t o D N A sa m ples fr o m pr ot oc ol patie nts.  
T he P har mac o ge netic  sa m ples will be se nt t o Allia nce Bi ore p osit or y at O hi o State 
U ni versit y.  
1 5. 0  G E N E R A L R E G U L A T O R Y C O N SI D E R A TI O N S A N D C R E D E N TI A LI N G  
T here a re n o cre de ntiali n g re q uire me nts f or t his st u d y. 
 
 

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mouse skeleton. PLoS One, 2014. 9(5): p. e98219. 
 
 

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APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and recorded on the Registration Fatigue/Uniscale Assessments Form (see Forms Packet). 
 
If needed, this appendix can be adapted to use as a source document. A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
How would you describe: 
 
Your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
Your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 
 
 
 

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APPENDIX II: LIST OF POTENT CYP450 INDUCERS/INHIBITORS 
 
Inhibitors 
1A2 
2C8 
2C9 
2D6 
2A4,5,7 
Fluvoxamine 
Ciprofloxacin 
Gemfibozil 
Fluconazole 
Buproion 
Fluoxetine 
Paroxetine 
Quindine 
HIV Antivirals: 
Indinavir 
Nelfinavir 
Ritonavir 
 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
Saquinavir 
Telithromycin 
 
Inducers 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E 
3A4,5,7 
Broccoli 
Brussel sprouts 
Insulin 
Methylcholanthrene 
Modafinil 
Nafcillin 
Beta-
naphthoflavone 
Omeprazole 
Tabacco 
Phenobarbital 
Rifampin 
Rifampin 
Rifanpin 
Secobarbital 
Carbamazine 
Norethindrone 
Predisone 
Rifampin 
Dexamethaxone
Rifampin 
Ethanol 
Isoniazid 
HIV Anti-
virals: 
Efavirenz 
Barbiturates 
Carbamzepine 
Glucocorticoids 
Modafinil 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
St. John’s wort 
Troglitazone 
 
The tables above do not contain comprehensive lists of potent CYP450 inducers and inhibitors. Refer to 
other credible information sources for up-to-date information 
 
 

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APPENDIX III: PATIENT MEDICATION LOGS 
 
 
 

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Z-Endoxifen HCL Medication Log (Arms 1 and Crossover Group) 
 
Number of Capsules Given:____________ 
Capsule Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of Capsules returned:_____________ 
 
(To be completed by RN)  
    
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS  
1. Take ________, 40 mg Z-Endoxifen HCl capsules by mouth daily, at approximately the same 
time each day on an empty stomach, either 1 hour before or 2 hours after meals. The capsules 
should be swallowed whole and must not be crushed or broken. 
2. If a dose is missed, please take the dose as soon as possible, but only if there are 12 or more 
hours remaining before the next dose. 
a. If the dose is due in less than 12 hours, skip the missed dose and take the next dose as 
scheduled. 
b. Remember to record missed doses. 
3. If vomiting occurs after taking Z-Endoxifen HCl, do not take a replacement dose on that day. 
Resume at the next scheduled dose. 
4. Z-Endoxifen capsules should be stored in the refrigerator. 
 
 
 

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CYCLE #: _______    # of WEEKS___________ 
 
DAY 
Medication 
DATE 
TIME 
Number of 40 
mg capsules 
taken 
Comments 
Example 
Z-Endoxifen HCl 
07/01/2012 
9:00 
AM/PM 
2 
 
1 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
2 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
3 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
4 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
5 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
6 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
7 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
8 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
9 
Z-Endoxifen HCl 
 
 
AM/PM/ 
 
 
10 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
11 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
12 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
13 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
14 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
15 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
16 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
17 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
18 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
19 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
20 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
21 
Z-Endoxifen HCl 
 
 
AM/PM 
 
 
 
 
Patient Signature: _________________________________________Date:__________ 
Consenting Professional/Research RN Signature: ______________Date:__________  
Comments:_____________________________________________________________ 
 
 
 

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Tamoxifen Medication Log (Arm 2) 
 
Number of Pills Given:____________  
Pill Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
Number of Pills returned:_____________ 
 
(To be completed by RN)  
    
PLEASE FILL OUT AND BRING THIS SHEET TO ALL VISITS. 
 
SPECIAL INSTRUCTIONS  
1. Take one (1) 20 mg tablet of Tamoxifen by mouth each day without regard to meals. The 
tablets should be swallowed whole and must not be crushed or broken. 
2. If a dose is missed, please take the dose as soon as possible, but only if there are 12 or more 
hours remaining before the next dose 
a. If the dose is due in less than 12 hours, skip the missed dose and take the next dose as 
scheduled 
3. If vomiting occurs after taking Tamoxifen, do not take a replacement dose on that day. 
Resume at the next scheduled dose. 
4. Tamoxifen tablets should be stored at room temperature. 
 
 

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CYCLE #: _______    # of WEEKS___________ 
 
DAY 
Medication 
DATE 
TIME 
Number of 20 
mg tablets taken 
Comments 
Example 
Tamoxifen 
07/01/2012 
9:00 
AM/PM 
1 
 
1 
Tamoxifen 
 
 
AM/PM 
 
 
2 
Tamoxifen 
 
 
AM/PM 
 
 
3 
Tamoxifen 
 
 
AM/PM 
 
 
4 
Tamoxifen 
 
 
AM/PM 
 
 
5 
Tamoxifen 
 
 
AM/PM 
 
 
6 
Tamoxifen 
 
 
AM/PM 
 
 
7 
Tamoxifen 
 
 
AM/PM 
 
 
8 
Tamoxifen 
 
 
AM/PM 
 
 
9 
Tamoxifen 
 
 
AM/PM 
 
 
10 
Tamoxifen 
 
 
AM/PM 
 
 
11 
Tamoxifen 
 
 
AM/PM 
 
 
12 
Tamoxifen 
 
 
AM/PM 
 
 
13 
Tamoxifen 
 
 
AM/PM 
 
 
14 
Tamoxifen 
 
 
AM/PM 
 
 
15 
Tamoxifen 
 
 
AM/PM 
 
 
16 
Tamoxifen 
 
 
AM/PM 
 
 
17 
Tamoxifen 
 
 
AM/PM 
 
 
18 
Tamoxifen 
 
 
AM/PM 
 
 
19 
Tamoxifen 
 
 
AM/PM 
 
 
20 
Tamoxifen 
 
 
AM/PM 
 
 
21 
Tamoxifen 
 
 
AM/PM 
 
 
 
Patient Signature: _________________________________________Date:__________ 
Consenting Professional/Research RN Signature: ______________Date:__________  
Comments:_____________________________________________________________ 
 
 
 

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APPENDIX IV: COLLABORATIVE AGREEMENT 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design of 
the proposed combination protocol, and the existence of any obligations that would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for 

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Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 30 
days from the date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to CTEP 
for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information.