Clinical trial NCT01275677
Conditions: HER2/Neu Positive Progesterone Receptor Positive Recurrent Breast Carcinoma Stage IA Breast Cancer AJCC v7 Stage IB Breast Cancer AJCC v7 Stage IIA Breast Cancer AJCC v6 and v7 Stage IIB Breast Cancer AJCC v6 and v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIC Breast Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2011-02-08; Completion date: 2025-06-02
Enrollment: 3270 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III clinical trial studies chemotherapy with or without trastuzumab after surgery to see how well they work in treating women with invasive breast cancer. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) and giving chemotherapy after surgery may kill more tumor cells. Monoclonal antibodies, such as trastuzumab, can block cancer growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether combination chemotherapy is more effective with trastuzumab in treating breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves invasive disease-free survival (IDFS) in women with resected node-positive or high-risk node-negative breast cancer which is reported as human epidermal growth factor receptor (HER)2-low by all HER2 testing performed.

SECONDARY OBJECTIVES:

I. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves disease-free survival (DFS)-ductal carcinoma in situ (DCIS) in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

II. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves breast cancer-free survival (BCFS) in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

III. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves recurrence-free interval (RFI) in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

IV. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves distant recurrence-free interval (DRFI) in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

V. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves overall survival (OS) in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

VI. To evaluate the associations between amenorrhea and circulating reproductive hormone levels, and the associations between chemotherapy regimen, amenorrhea, and IDFS benefit in premenopausal women eligible at baseline for the menstrual history assessments.

VII. To evaluate the toxicity associated with each of the regimens. VIII. To test the hypothesis that the HER2 messenger ribonucleic acid (mRNA) level is the predictor of the degree of benefit from trastuzumab and the threshold for benefit in the adjuvant setting is lower than defined by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines for HER2 assays (immunohistochemistry \[IHC\] and fluorescent in situ hybridization \[FISH\]).

IX. To identify and/or validate molecular predictors of the degree of benefit from the addition of trastuzumab to chemotherapy (TC or AC→WP).

X. To test the alternative hypothesis that the main determinant of trastuzumab response in the adjuvant setting of HER2-low breast cancer is through antibody-dependent cellular cytotoxicity (ADCC) by demonstrating that the polymorphism of the Fcgamma receptor gene is predictive of the degree of benefit from the addition of trastuzumab to chemotherapy (TC or AC→WP).

XI. To examine the relationship between behavioral host factors (obesity, tobacco, alcohol) and comorbid conditions that may influence systemic inflammation and breast cancer outcomes, controlling for tumor/stage characteristics and treatment assignment.

XII. To examine the relationship between medication exposures that may influence systemic inflammation and breast cancer outcomes, controlling for tumor/stage characteristics and treatment assignment.

XIII. To examine the relationship between comorbid conditions, medication exposures, and behavioral host factors together and breast cancer outcomes, controlling for tumor/stage characteristics and treatment assignment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

NOTE: \*Chemotherapy regimen is based on the investigator's preference.

ARM I:

GROUP IA: Patients receive docetaxel intravenously (IV) over 60 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.

GROUP IB: Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning 2-3 weeks after last dose of doxorubicin hydrochloride and cyclophosphamide, patients also receive paclitaxel IV over 60 minutes once weekly for 12 doses in the absence of disease progression or unacceptable toxicity.

ARM II:

GROUP IIA: Patients receive docetaxel and cyclophosphamide as in Group IA. Patients also receive trastuzumab IV over 30-90 minutes on day 1. Courses repeat every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity.

GROUP IIB: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in Group IB. Patients also receive trastuzumab IV over 30-90 minutes weekly for 12 doses and then every 3 weeks for subsequent doses. Treatment repeats every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 5 years and then every 12 months for 5 years.

Arms: arm 1: GROUP IA: Patients receive docetaxel IV over 60 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.

GROUP IB: Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning 2-3 weeks after last dose of doxorubicin hydrochloride and cyclophosphamide, patients also receive paclitaxel IV over 60 minutes once weekly for 12 doses in the absence of disease progression or unacceptable toxicity. arm 2: GROUP IIA: Patients receive docetaxel and cyclophosphamide as in Group IA. Patients also receive trastuzumab IV over 30-90 minutes on day 1. Courses repeat every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity.

GROUP IIB: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in Group IB. Patients also receive trastuzumab IV over 30-90 minutes weekly for 12 doses and then every 3 weeks for subsequent doses. Treatment repeats every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cyclophosphamide intervention 2: Docetaxel intervention 3: Doxorubicin intervention 4: Doxorubicin Hydrochloride intervention 5: Laboratory Biomarker Analysis intervention 6: Paclitaxel intervention 7: Quality-of-Life Assessment intervention 8: Trastuzumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Correlative studies intervention 6: Given IV intervention 7: Ancillary studies intervention 8: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
NSABP B-47 
Page 1 
NRG ONCOLOGY 
NSABP PROTOCOL B-47 
ClinicalTrials.gov NCT01275677 
 
A Randomized Phase III Trial of Adjuvant Therapy Comparing 
Chemotherapy Alone (Six Cycles of Docetaxel Plus Cyclophosphamide or 
Four Cycles of Doxorubicin Plus Cyclophosphamide Followed by 
Weekly Paclitaxel) to Chemotherapy Plus Trastuzumab in  
Women with Node-Positive or High-Risk Node-Negative 
HER2-Low Invasive Breast Cancer 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is  
sponsored by the National Cancer Institute (NCI).  The trial will be led by NRG Oncology  
with the participation of the network of NCTN organizations (U.S. Institutions): the Alliance for Clinical 
Trials in Oncology, ECOG-ACRIN Cancer Research Group, NRG Oncology, and SWOG 
NRG Oncology 
Nova Tower 2 
Two Allegheny Center – Suite 1200 
Pittsburgh, PA  15212 
TELEPHONE: 412-339-5300 
 
NRG Oncology Statistics and Data 
Management Center 
One Sterling Plaza 
201 North Craig Street, Suite 500 
Pittsburgh, PA  15213 
TELEPHONE: 412-624-2666 
 
FAX: 412-624-1082 
Clinical Coordinating Department: 1-800-477-7227 
(For Clinical Questions Only) 
 
KEY STUDY PERSONNEL 
NRG Oncology Chairman: Norman Wolmark, MD 
NRG Oncology Breast Committee Chair: Eleftherios Mamounas, MD, MPH 
Protocol Chair: Louis Fehrenbacher, MD 
Protocol Officer: Priya Rastogi, MD 
Behavioral and Health Outcomes Officer: Patricia Ganz, MD 
Protocol Statistician: Reena Cecchini, PhD 
Protocol Pathologist: Soonmyung Paik, MD 
 
Protocol B-47 IND #113988 (trastuzumab), sponsored by the NCI 
STUDY DRUG 
NSC# 
DRUG SUPPLY 
Trastuzumab 
688097 
Genentech, a Member of the Roche Group, through the NCI 
and through F. Hoffmann-La Roche, Ltd. for ICORG 
 
NCI Version Date: February 8, 2018 (Replaces all other versions) 


 
NCI Version Date: 02/08/18 
NSABP B-47 
Page 2 
NRG ONCOLOGY 
NSABP PROTOCOL B-47 
A Randomized Phase III Trial of Adjuvant Therapy Comparing 
Chemotherapy Alone (Six Cycles of Docetaxel Plus Cyclophosphamide or Four Cycles of 
Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel) to Chemotherapy 
Plus Trastuzumab in Women with Node-Positive or High-Risk Node-Negative 
HER2-Low Invasive Breast Cancer 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 8 
February 8, 2018 
- 
Amendment 7 
May 26, 2016 
June 30, 2016 
Amendment 6 
November 28, 2014 
June 15, 2015 
Amendment 5 
April 16, 2014 
July 2, 2014 
Amendment 4 
April 2, 2013 
May 20, 2013 
Amendment 3 
March 12, 2013 
May 20, 2013 
Update 1 
January 3, 2012 
January 26, 2012 
Amendment 2 
December 12, 2011 
January 26, 2012 
Amendment 1 
September 15, 2011 
January 26, 2012 
Activation 
November 5, 2010 
January 6, 2011 
 


 
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NSABP B-47 
Page 3 
PROTOCOL REVISION RECORD 
Original Version: 
 
November 5, 2010 
 
Amendment #1: 
 
September 15, 2011 
Sections Changed/Added: 
 
Cover Page 
Information Resources 
 
CTSU Information Resources 
 
Glossary of Selected Abbreviations and Acronyms 
 
Section 1.0: 
Schema 
 
Section 4.0: 
4.2.6, 4.2.7, 4.3.1, 4.3.13 
 
Section 5.0: 
5.1 (Table 6) 
Section 6.0: 
6.0 (Tables 8, 9, 10) 
Section 7.0: 
7.1 (Table 11) 
Section 8.0: 
8.2.1 
 
Section 9.0: 
9.3 (Table 15), 9.4 (Table 16) 
 
Section 12: 
12.2 
 
Section 13.0: 
13.3.4 (Table 31), 13.3.5 (Table 32), 13.3.6, 13.6 
 
Appendix E: 
1.0, 4.0, 5.1, 6.1 
 
Appendix F: 
Inserted new appendix; subsequent appendix has been relettered 
 
Appendix G: 
Pages 13, 15, 17 
 
Amendment #2: 
 
December 13, 2011 
 
Sections Changed: 
 
Information Resources 
 
Section 6.0: 
6.0 (Table 8 and Table 9) 
 
Section 13.0: 
13.1.1, 13.2 (Table 30), 13.4.2, 13.5 
 
Appendix F: 
Paragraph 1, 2.0, 3.0 
 
Appendix G: 
Pages 10, 11 
 
Update #1: 
 
 
January 3, 2012 
 
Sections Changed: 
 
Cover Page 
 
Section 12.0: 
12.2 
 
Appendix G: 
Cover Page, Page 1 
 


 
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Page 4 
Amendment #3: 
 
March 12, 2013 
Sections Changed: 
 
Cover Page 
 
Information resources 
 
Section 4.0: 
4.2.6 
 
Section 6.0: 
(Table 9) 
 
Section 8.0: 
8.2.6.1, 8.3.5.1 
 
Section 9.0: 
9.3 (Table 16) 
 
Section 11.0: 
11.1 
 
Section 12.0: 
12.2, 12.2.2, 12.2.6, 12.2.7, 12.2.8 
 
Section 13.0: 
13.3 
 
Section 18.0: 
18.0 
 
Appendix E 
1.0 
Amendment #4: 
 
April 2, 2013 
Sections Changed: 
 
Cover Page 
 
Information resources 
 
Section 12.0: 
12.2, 12.2.2, 12.2.6, 12.2.7, 12.2.8 
 
Section 18.0: 
18.0 
 
Appendix E 
1.0 
Amendment #5: 
 
April 16, 2014 
Sections Changed: 
Throughout the protocol, the following have been changed: 
• 
The NSABP and the NSABP Operations Center were changed to NRG Oncology where 
appropriate. 
• 
All references to NSABP Biostatistical Center have been changed to NRG Oncology 
Statistics and Data Management Center (SDMC). 
• 
Division has been changed to Department throughout the protocol where appropriate. 
• 
References to the "Adverse Event Expedited Reporting System (AdEERS)" have been 
changed to "CTEP Adverse Event Reporting System (CTEP-AERS)." 
 
Cover Page 
 
Information Resources 
 
CTSU Information Resources 
 
Glossary of Selected Abbreviations and Acronyms 
 
Section 13.0: 
13.1.1, 13.2 (Table 30), 13.3, new 13.3.7 added and subsequent sections   
 
 
 
renumbered, 13.3.8 
 
Section 15.0: 
New Sections 15.1, 15.2, and 15.3 added and subsequent sections renumbered, 
15.5, 15.8 
 
Section 16.0: 
16.2, 16.3 
 
Appendix E: 
Deleted and subsequent appendix relettered 
 
Sample Consent Form 


 
NCI Version Date: 02/08/18 
NSABP B-47 
Page 5 
Amendment #6: 
November 28, 2014 
Sections Changed: 
 
Cover Page 
 
Section 4.0: 
4.1 
 
Section 13.0: 
13.3.8 
 
Sample Consent Form 
Amendment #7: 
May 26, 2016 
Sections Changed: 
 
Cover Page 
 
Information Resources 
 
CTSU Information Resources 
 
Glossary of Selected Abbreviations and Acronyms 
 
Section 1.0: 
1.0 
 
Section 2.0: 
2.9 
 
Section 3.0: 
3.2.6 
 
Section 4.0: 
4.0 
 
Section 6.0: 
6.0 
 
Section 7.0: 
7.3.1, 7.3.2, 7.4.3 
 
Section 8.0: 
8.1 (Table 12), 8.2.6.3, 8.2.6.4, 8.2.6.5, 8.2.7, 8.3.5.3, 8.3.5.4 
 
Section 12.0: 
12.2 
 
Section 13.0: 
13.2 (Table 30), 13.3.1, 13.3.4 (Table 31) 
 
Section 15.0: 
15.0 
 
Section 16.0: 
16.2 
 
Section 17.0: 
17.9.1, 17.9.5 
 
Section 19.0: 
References #70 and #109 
Amendment #8: 
February 8, 2018 
Sections Changed: 
 
Cover Page 
 
Information Resources 
 
CTSU Information Resources 
 
Section 2.0: 
2.9 
 
Section 8.0: 
8.1 (Table 12), 8.2.6.5, 8.2.7 
 
Section 15.0: 
15.3.4 


 
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TABLE OF CONTENTS 
INFORMATION RESOURCES ............................................................................................................ 11 
CANCER TRIALS SUPPORT UNIT (CTSU) INFORMATION RESOURCES ............................................... 13 
GLOSSARY OF SELECTED ABBREVIATIONS AND ACRONYMS ................................................ 14 
 
1.0 
OVERVIEW OF THE STUDY DESIGN .................................................................................. 18 
2.0 
BACKGROUND ...................................................................................................................... 21 
2.1 
Introduction .................................................................................................................. 21 
2.2 
Current definition of HER2 positivity as an indication for trastuzumab ......................... 21 
2.3 
NSABP B-31/NCCTG 9831 study results ..................................................................... 22 
2.4 
Benefit from trastuzumab observed in HER2-negative subset in NSABP B-31 .............. 22 
2.5 
Central review from other adjuvant trials for trastuzumab ............................................. 23 
2.6 
Technical validation of the B-31 HER2-negative results ............................................... 24 
2.7 
Biological bases of the efficacy of adjuvant trastuzumab in HER2-low breast cancer .... 27 
2.8 
Choice of chemotherapy ............................................................................................... 42 
2.9 
Rationale for the Menstrual History Study and examination of the biology of  
amenorrhea in women treated for breast cancer ............................................................. 45 
2.10 
Rationale for examining the host environment factors and the possible role of  beta-
adrenergic receptors and inflammatory processes on the progression of cancer .............. 48 
3.0 
STUDY AIMS AND ENDPOINTS........................................................................................... 50 
3.1 
Primary aim and endpoint ............................................................................................. 50 
3.2 
Secondary aims and endpoints ...................................................................................... 50 
4.0 
PATIENT ELIGIBILITY AND INELIGIBILITY ..................................................................... 53 
4.1 
Patient selection guidelines ........................................................................................... 53 
4.2 
Conditions for patient eligibility ................................................................................... 53 
4.3 
Conditions for patient ineligibility ................................................................................ 56 
5.0 
CARDIAC SAFETY MONITORING ....................................................................................... 58 
5.1 
Timing of LVEF assessments ....................................................................................... 58 
5.2 
Important LVEF assessment guidelines......................................................................... 58 
5.3 
Reporting LVEF assessments........................................................................................ 58 
5.4 
Reporting cardiac events ............................................................................................... 59 
5.5 
Reporting selected late cardiac events ........................................................................... 59 
5.6 
Required cardiac event follow-up reporting................................................................... 60 
6.0 
REQUIREMENTS FOR ENTRY, TREATMENT AND FOLLOW-UP .................................... 61 
7.0 
PATHOLOGY AND CORRELATIVE SCIENCE STUDIES .................................................... 68 
7.1 
Overview of requirements ............................................................................................. 68 
7.2 
Use of specimens .......................................................................................................... 68 
7.3 
Specimen submission and identification procedures ...................................................... 69 
7.4 
Planned studies ............................................................................................................. 69 
8.0 
BEHAVIORAL AND HEALTH OUTCOMES CORRELATIVE SCIENCE STUDIES ............ 71 
8.1 
Overview ...................................................................................................................... 71 
8.2 
Menstrual History (MH) study ...................................................................................... 72 
8.3 
Host factors study ......................................................................................................... 76 
8.4 
Menstrual History and Host Factors requirements following cancer events .................... 78 
9.0 
TREATMENT REGIMEN ........................................................................................................ 79 
9.1 
Chemotherapy regimen for Group 1A (TC [docetaxel and cyclophosphamide]) ............ 79 


 
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9.2 
Chemotherapy and trastuzumab regimen for Group 2A (TC+H®H [docetaxel plus 
cyclophosphamide plus trastuzumab followed by trastuzumab]) .................................... 79 
9.3 
Treatment regimen for Group 1B (AC®WP [doxorubicin plus cyclophosphamide 
followed by weekly paclitaxel]) .................................................................................... 81 
9.4 
Treatment regimen for Group 2B (AC®WP+H®H [doxorubicin plus  
cyclophosphamide followed by weekly paclitaxel plus trastuzumab followed by 
trastuzumab])................................................................................................................ 81 
9.5 
Dose determination ....................................................................................................... 83 
9.6 
Cardiac safety criteria for initiation of trastuzumab therapy following AC (for  
Group 2B patients only) ................................................................................................ 83 
9.7 
Supportive therapy........................................................................................................ 84 
9.8 
Adjuvant radiation therapy............................................................................................ 85 
9.9 
Adjuvant endocrine therapy .......................................................................................... 85 
9.10 
Prohibited therapies ...................................................................................................... 86 
9.11 
Participation in other clinical trials ................................................................................ 86 
10.0 
CHEMOTHERAPY TREATMENT MANAGEMENT ............................................................. 87 
10.1 
General instructions ...................................................................................................... 87 
10.2 
Management of anemia ................................................................................................. 87 
10.3 
Treatment management for TC (Groups 1A and 2A) ..................................................... 87 
10.4 
Treatment management for AC (Groups 1B and 2B) ..................................................... 90 
10.5 
Treatment management for WP and WP+H (Groups 1B and 2B) .................................. 92 
11.0 
TRASTUZUMAB TREATMENT MANAGEMENT (GROUPS 2A AND 2B) ......................... 97 
11.1 
General instructions ...................................................................................................... 97 
11.2 
Trastuzumab instructions when chemotherapy is held or discontinued........................... 97 
11.3 
Heart failure and left ventricular systolic dysfunction .................................................... 97 
11.4 
Other trastuzumab-specific instructions ........................................................................ 98 
12.0 
DRUG INFORMATION ......................................................................................................... 101 
12.1 
Chemotherapy ............................................................................................................ 101 
12.2 
Trastuzumab (IND #113988; NSC #688097) .............................................................. 101 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS ........................................................... 106 
13.1 
B-47 definitions for AE reporting ............................................................................... 106 
13.2 
Adverse events reported for trastuzumab..................................................................... 106 
13.3 
Expedited reporting of adverse events ......................................................................... 111 
13.4 
Routine reporting of adverse events ............................................................................ 117 
13.5 
Reporting selected late cardiac adverse events on the B-47 Follow-up Form (Form F)  
and Form CR .............................................................................................................. 117 
13.6 
Reporting breast cancer recurrence, secondary malignancies, and second  
primary cancer ............................................................................................................ 118 
14.0 
DOCUMENTATION OF BREAST CANCER RECURRENCE AND SECOND 
MALIGNANCIES .................................................................................................................. 119 
14.1 
General instructions .................................................................................................... 119 
14.2 
Local recurrence ......................................................................................................... 119 
14.3 
Regional recurrence .................................................................................................... 119 
14.4 
Distant recurrence ....................................................................................................... 120 
14.5 
Contralateral breast cancer .......................................................................................... 121 
14.6 
Second primary cancer................................................................................................ 121 
14.7 
Documentation requested following death................................................................... 121 
 


 
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15.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ....................... 122 
15.1 
CTEP investigator registration procedures .................................................................. 122 
15.2 
CTEP associate registration procedures / CTEP-IAM account ..................................... 122 
15.3 
CTSU registration procedures ..................................................................................... 122 
15.4 
Patient consent form ................................................................................................... 124 
15.5 
Patient enrollment ....................................................................................................... 124 
15.6 
Required submission of tumor samples ....................................................................... 124 
15.7 
Regulatory requirement for Canadian institutions ........................................................ 124 
15.8 
Oncology Patient Enrollment Network (OPEN) .......................................................... 124 
15.9 
Patient study number .................................................................................................. 125 
15.10 Patient-initiated discontinuation of study therapy ........................................................ 125 
15.11 Withdrawal from the study ......................................................................................... 125 
15.12 Investigator-initiated discontinuation of study therapy ................................................ 125 
16.0 
REQUIRED DATA COLLECTION ....................................................................................... 126 
16.1 
Data collection ........................................................................................................... 126 
16.2 
Instructions for completion and submission of B-47 forms and materials .................... 126 
16.3 
Data monitoring for CTEP .......................................................................................... 126 
17.0 
STATISTICAL CONSIDERATIONS ..................................................................................... 127 
17.1 
Primary endpoint ........................................................................................................ 127 
17.2 
Secondary endpoints ................................................................................................... 127 
17.3 
Stratification and randomization ................................................................................. 127 
17.4 
Patient cohorts ............................................................................................................ 127 
17.5 
Sample size calculation ............................................................................................... 127 
17.6 
Statistical analysis ...................................................................................................... 128 
17.7 
Monitoring of adverse events ...................................................................................... 129 
17.8 
Sample size considerations and analysis plan for correlative studies dealing with  
HER2 mRNA and Fcγ receptor polymorphism............................................................ 129 
17.9 
Statistical considerations for Menstrual History and Host Factors sub-studies ............. 130 
17.10 Issues relating to racial and ethnic differences ............................................................. 135 
18.0 
PUBLICATION INFORMATION AND ADMINISTRATIVE AGREEMENTS..................... 137 
19.0 
REFERENCES ....................................................................................................................... 139 
 
 
Figure 1 
NSABP B-47 Schema ................................................................................................... 20 
Figure 2 
Benefit from adjuvant trastuzumab is not associated with the HER2 gene copy  
numbers measured by FISH (data from HERA trial)12 ................................................. 23 
Figure 3 
Benefit from adjuvant trastuzumab is not associated with the HER2 gene copy  
numbers measured by FISH13 ...................................................................................... 24 
Figure 4 
HER2 mRNA levels in central HER2 assay positive and negative tumors in B-31 ......... 25 
Figure 5 
Chromosomal mapping of the differentially expressed genes between central HER2  
assay positive versus negative tumors from B-31 .......................................................... 26 
Figure 6 
Benefit from lapatinib in the metastatic setting is not observed in HER2-FISH-negative 
patients. ........................................................................................................................ 27 
Figure 7 
No benefit from trastuzumab added to paclitaxel in the treatment of HER2-negative 
metastatic breast cancer ................................................................................................ 28 
Figure 8 
ER mRNA level is a linear prognosticator for patients treated with tamoxifen ............... 29 
Figure 9 
ER measurement by IHC is a non-linear prognosticator for patients treated with 
tamoxifen ..................................................................................................................... 29 
Figure 10 
Interaction between HER2 mRNA level and trastuzumab benefit .................................. 31 


 
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Figure 11 
Full nCounter assay (NanoString) data set (n=1568) ..................................................... 32 
Figure 12 
HER mRNA expression levels according to clinical HER2 assay results ....................... 33 
Figure 13 
DFS of patients with tumors that have gain of function mutations in PI3 kinase gene  
or loss of PTEN expression ........................................................................................... 34 
Figure 14 
Kaplan-Meier estimates of PFS according to FcRIIIa polymorphism ............................. 35 
Figure 15 
Trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) of breast  
cancer targets ................................................................................................................ 36 
Figure 16 
HER2 mRNA expression levels measured by Quantigene Plex assay (Panomics) .......... 37 
Figure 17 
Pre- and post-trastuzumab CK-19 mRNA detection by real-time RT-PCR in peripheral 
blood or bone marrow of 16 patients with breast cancer  
(Wilcoxon  paired t test, p<0.001) ................................................................................. 39 
Figure 18 
Representative patterns of overexpression of HER2/neu in human  breast cancer .......... 40 
Figure 19 
Duration of amenorrhea in months according to age group ............................................ 46 
Figure 20 
Rate of prolonged amenorrhea at each time point for chemotherapy and tamoxifen 
intention-to-treat groups ............................................................................................... 46 
 
Table 1 
Relative risks of DFS and OS among patients in the ACTH group as compared with  
the ACT group* ............................................................................................................ 23 
Table 2 
Compilation of HER2 mRNA assays in B-31 discovery set ........................................... 31 
Table 3 
Levels of HER2 expression in three commonly used breast cancer cell lines measured  
by IHC and flow cytometry .......................................................................................... 37 
Table 4 
Taxane-trastuzumab interaction analysis ....................................................................... 38 
Table 5 
HER2 re-evaluation by serum HER2, CTC, and metastatic tissue .................................. 41 
Table 6 
Timing of LVEF assessments ....................................................................................... 58 
Table 7 
Tests, exams, and other requirements prior to randomization......................................... 61 
Table 8 
Tests, exams, and other requirements during therapy and through Year 1 for  
Groups 1A and 1B ........................................................................................................ 63 
Table 9 
Tests, exams, and other requirements during therapy and through Year 1 for  
Groups 2A and 2B ........................................................................................................ 65 
Table 10 
Tests, exams, and other requirements during year 2 through year 10 for patients in all 
treatment groups ........................................................................................................... 67 
Table 11 
Summary of B-47 tumor and blood sample submission requirements ............................ 68 
Table 12 
Overview of requirements for BAHO studies ................................................................ 71 
Table 13 
Treatment regimen for Group 1A (TC) ......................................................................... 79 
Table 14 
Treatment regimen for Group 2A (TC+H®H) .............................................................. 80 
Table 15 
Treatment regimen for Group 1B (AC®WP) ................................................................ 81 
Table 16 
Treatment regimen for Group 2B (AC®WP+H®H) .................................................... 82 
Table 17 
LVEF requirements for initiation of trastuzumab therapy after AC (Group 2B only) ..... 84 
Table 18 
Dose levels for TC (Groups 1A and 2A) ....................................................................... 87 
Table 19 
Treatment management for TC (Groups 1A and 2A) ..................................................... 88 
Table 20 
Treatment management for docetaxel-related neuropathy .............................................. 89 
Table 21 
Treatment management for docetaxel-related musculoskeletal pain ............................... 90 
Table 22 
Dose levels for AC (Groups 1B and 2B) ....................................................................... 90 
Table 23 
Treatment management for AC (Groups 1B and 2B) ..................................................... 91 
Table 24 
Dose levels for paclitaxel (Groups 1B and 2B) .............................................................. 93 
Table 25 
Treatment management for weekly paclitaxel (Groups 1B and 2B) ............................... 94 
Table 26 
Treatment management for paclitaxel-related neuropathy.............................................. 95 
Table 27 
Treatment management for paclitaxel-related musculoskeletal pain ............................... 96 
Table 28 
Trastuzumab management based on LVEF assessments (Groups 2A and 2B) ................ 98 
Table 29 
Treatment management for trastuzumab-related adverse events (Groups 2A and 2B) .... 99 
Table 30 
Comprehensive adverse events and potential risks list (CAEPR) for trastuzumab ........ 106 


 
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Table 31 
CTEP-AERS expedited reporting requirements for adverse events that occur under a 
CTEP IND within 30 days of the last dose of the investigational agent  
(trastuzumab)1 ............................................................................................................ 112 
Table 32 
CTEP-AERS expedited reporting requirements for adverse events that occur within  
30 days of the last dose of chemotherapy .................................................................... 114 
Table 33 
Interim monitoring schedule ....................................................................................... 128 
Table 34 
Expected racial and ethnic composition of NSABP B-47 ............................................ 136 
 
Appendix A 
Assessment of performance status and activities of daily living ................................... 148 
Appendix B 
Hypertension management recommendations.............................................................. 149 
Appendix C 
Determination of menopausal status ............................................................................ 150 
Appendix D 
CTCAE grade 2 cardiac disorder adverse events that prohibit trastuzumab therapy ..... 151 
Appendix E 
Trastuzumab information and instructions for all Ireland Co-operative Oncology 
Research Group (ICORG) ........................................................................................... 152 
 


 
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INFORMATION RESOURCES 
NRG Oncology 
http://www.nsabp.pitt.edu 
NRG Oncology 
Nova Tower 2 
Two Allegheny Center – Suite 1200 
Pittsburgh, PA  15212 
Phone: 412-339-5300 
NRG Oncology Statistics and 
Data Management Center 
(SDMC) 
One Sterling Plaza 
201 North Craig Street, Suite 500 
Pittsburgh, PA  15213 
Phone: 412-624-2666 
Fax: 412-624-1082 
(General office fax) 
Questions/problems regarding 
IRB review & informed consent 
NRG Oncology 
Department of Regulatory Affairs 
Phone: 412-339-5300 
E-mail: regulatory@nsabp.org 
Submission of IRB approval 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA  19103 
Regulatory Submission Portal:  (Sign 
in at www.ctsu.org) 
Questions concerning eligibility 
and clinical aspects of the trial 
NRG Oncology 
Clinical Coordinating Department 
Phone: 1-800-477-7227 
E-mail: ccdpgh@nrgoncology.org 
Questions concerning drug 
orders, shipments, transfers, and 
returns (see Section 12.0) 
NRG Oncology SDMC 
Phone: 412-624-2666 
Fax: 412-624-1082 
For mail (USPS): 
Pharmaceutical Management Branch, 
CTEP, DCTD 
NCI Shady Grove 
Room 5W228, MSC 9725 
9609 Medical Center Drive 
Bethesda, MD 20892-9725 
For express courier: 
Pharmaceutical Management Branch, 
CTEP, DCTD 
NCI Shady Grove 
Room 5W228, MSC 9725 
9609 Medical Center Drive 
Rockville, MD 20850 
Phone: 240-276-6575 
Fax: 240-276-7893 
E-mail: 
PMBAfterHours@mail.nih.gov 
Submission of tumor blocks (see 
Section 7.0) 
NRG Oncology SDMC 
One Sterling Plaza 
201 North Craig Street, Suite 500 
Pittsburgh, PA  15213 
Note: when sending blocks, or other 
materials, please indicate on the 
package “Pathology Specimens 
Enclosed.” 
Questions regarding receipt of 
specimens: 
Phone: 412-624-2666 
For all other questions: 
Phone: 412-697-6611 
Refer to the B-47 Pathology and 
Correlative Science Instructions in the 
Members' Area of the NSABP Web site 
or the CTSU Member Web site. 
Arrangement for return of 
blocks that are not to be stored 
or to request kits for 2 mm core 
sampling of existing 
tumor/lymph node block(s) 
NRG Oncology Biospecimen 
Bank-Pittsburgh 
E-mail: 
nrgbiobankpgh@nrgoncology.org 
Phone: 412-697-6611 
Submission of all blood samples 
Baylor College of Medicine  
NRG Oncology Serum Bank 
Room N1220 
One Baylor Plaza 
Houston, TX  77030 
Phone: 713-798-1647 
Fax: 713-798-1642 
Refer to the B-47 Pathology and 
Correlative Science Instructions in the 
Members' Area of the NSABP Web site 
or the CTSU Member Web site. 


 
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INFORMATION RESOURCES (continued) 
 
Questions concerning expedited 
adverse event reporting  
(see Section 13.3) 
NRG Oncology SDMC 
B-47 AE Reporting Nurse 
Phone: 412-383-2557 
Fax: 412-622-2113 
SAEReportingpgh@nrgoncology.org 
Submission of patient-completed 
questionnaires (see Section 8.3) 
NRG Oncology SDMC 
B-47 Data Manager 
Phone: 412-624-2666 
Fax: 412-622-2115 
Refer to the B-47 Data Forms page in 
the Members' Area of the NSABP Web 
site or the CTSU Member Web site. 
Submission of data forms/questions  
concerning data management 
NRG Oncology SDMC 
B-47 Data Manager 
Phone: 412-624-2666 
Refer to the B-47 Data Forms page in 
the Members’ Area of the NSABP Web 
site or the CTSU Member Web site. 


 
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CANCER TRIALS SUPPORT UNIT (CTSU) INFORMATION RESOURCES 
For regulatory requirements: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal:  
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
For patient enrollments: 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_ 
SYSTEM/ or 
https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
Submit study data directly to 
the NRG Oncology SDMC 
through the Online Data Entry 
function unless otherwise 
specified in the protocol. 
Submit study data online through 
the Online Data Entry function 
located in the Study Management 
Area of Coordinator Online in the 
Members’ Area of the NSABP 
Web site.  Contact the Support 
Desk at 
support@nrgoncology.org for an 
account. 
NRG Oncology Statistics and 
Data Management Center 
One Sterling Plaza 
201 North Craig Street, Suite 500 
Pittsburgh, PA 15213 
Do not submit study data or forms 
to CTSU Data Operations.  Do 
not copy the CTSU on data 
submissions. 
• For clinical questions (i.e. patient eligibility or treatment-related), contact the Clinical 
Coordinating Department at NRG Oncology at 1-800-477-7227. 
• For data submission questions, contact the B-47 Data Manager at NRG Oncology SDMC by 
calling 412-624-2666. 
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 Member Web site is located at https://www.ctsu.org 
The most current version of the study protocol and all supporting documents must be downloaded from 
the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access to 
the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and 
Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username 
and password. 


 
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GLOSSARY OF SELECTED ABBREVIATIONS AND ACRONYMS 
AC 
doxorubicin (Adriamycin) and cyclophosphamide 
ACE inhibitor 
angiotensin converting enzyme inhibitor 
ACT 
doxorubicin (Adriamycin) and cyclophosphamide followed by paclitaxel (Taxol) 
ACTH 
doxorubicin (Adriamycin) and cyclophosphamide followed by paclitaxel (Taxol) 
 
and trastuzumab (Herceptin) 
AC®WP 
doxorubicin (Adriamycin) and cyclophosphamide followed by weekly paclitaxel 
 
(Taxol) 
AC®WP+H®H 
doxorubicin (Adriamycin) and cyclophosphamide followed by weekly paclitaxel 
(Taxol) and trastuzumab (Herceptin) followed by trastuzumab (Herceptin) 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADL 
activities of daily living 
AE 
adverse event 
AMH 
anti-Müllerian hormone 
ANC 
absolute neutrophil count 
ARB 
angiotensin II receptor blocker 
ARDS 
acute respiratory distress syndrome 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
aspartate aminotransferase 
AT 
doxorubicin (Adriamycin) and docetaxel (Taxotere) 
BAHO 
Behavioral and Health Outcomes 
BCFS 
breast cancer-free survival 
BCIRG 
Breast Cancer International Research Group 
BMI 
body mass index 
BP 
blood pressure 
BSA 
body surface area 
BWFI 
bacteriostatic water for injection 
CAEPR 
Comprehensive Adverse Event and Potential Risks 
CAF 
cyclophosphamide, doxorubicin (Adriamycin), fluorouracil 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CDC 
complement-dependent cytotoxicity 
CEF 
cyclophosphamide, epirubicin, fluorouracil 
CHF 
congestive heart failure 
CI 
confidence interval 
CISH 
chromagen in situ hybridization 
CMF 
cyclophosphamide, methotrexate, fluorouracil 
CRA 
chemotherapy-related amenorrhea 
CRP 
C-reactive protein 
CT 
computed tomography 
CTC 
circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTEP-AERS 
CTEP-Adverse Event Reporting System 
CTEP-IAM 
CTEP-Identity and Access Management 
CTSU 
Cancer Trials Support Unit 
DBCG 
Danish Breast Cancer Group 
D/C 
discontinue 


 
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GLOSSARY OF SELECTED ABBREVIATIONS AND ACRONYMS (continued) 
DCIS 
ductal carcinoma in situ 
DCTD 
Division of Cancer Treatment and Diagnosis 
DFS 
disease-free survival 
DMC 
Data Monitoring Committee 
DRFI 
distant recurrence-free interval 
DTC 
disseminated tumor cells 
EBCTCG 
Early Breast Cancer Trialists' Collaborative Group 
ECG 
electrocardiogram 
EpCAM 
epithelial cell adhesion molecule 
ER 
estrogen receptor 
ErbB2 
epidermal growth factor receptor 2 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
G-CSF 
granulocyte colony stimulating factor 
GI 
gastrointestinal 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GnRH 
gonadotropin-releasing hormone 
GWAS 
genome-wide association study 
H 
trastuzumab (Herceptin) 
H&E 
hematoxylin and eosin 
HER2 
human epidermal growth factor receptor 2 
HERA 
Herceptin Adjuvant Trial 
HR 
hazard ratio 
IB 
Investigator's Brochure 
IBTR 
ipsilateral breast tumor recurrence 
ICORG 
All Ireland Co-operative Oncology Research Group 
IDB 
Investigational Drug Branch 
IDFS 
invasive disease-free survival 
IHC 
immunohistochemistry 
IND 
investigational new drug 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram 
LBA 
ligand-binding assay 
LCIS 
lobular carcinoma in situ 
LHRH 
luteinizing hormone-releasing hormone 
LLN 
lower limit of normal 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
MAF 
minor allele frequency 
mg 
milligram 
mg/m2 
milligrams per meter squared 
MH 
menstrual history 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 


 
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GLOSSARY OF SELECTED ABBREVIATIONS AND ACRONYMS (continued) 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
MUGA 
multigated acquisition (scan) 
n 
sample size 
N/A 
not applicable 
NCCN 
National Comprehensive Cancer Network 
NCCTG 
North Central Cancer Treatment Group 
NCI 
National Cancer Institute 
NCIC 
National Cancer Institute of Canada 
NCTN 
National Clinical Trials Network 
NK 
natural killer 
NOS 
not otherwise specified 
NSABP 
National Surgical Adjuvant Breast and Bowel Project 
NSAID 
non-steroidal anti-inflammatory drug 
NSC 
National Service Center 
OPEN 
Oncology Patient Enrollment Network 
OR 
overall response 
OS 
overall survival 
P 
paclitaxel 
p 
probability 
PAF 
L-phenylalanine mustard, doxorubicin, fluorouracil 
PASS 
Power Analysis and Sample Size 
PET 
positron emission tomography 
PF 
L-phenylalanine mustard, fluorouracil 
PFS 
progression-free survival 
PgR 
progesterone receptor 
pHER2 
phosphorylated HER2 
PMB 
Pharmaceutical Management Branch 
PTEN 
phosphatidylinositol phosphate 3'-phosphatase 
QRT-PCR 
quantitative real-time reverse transcription-polymerase chain reaction 
RFI 
recurrence-free interval 
RNA 
ribonucleic acid 
RR 
relative risk 
RT 
radiation therapy 
RTOG 
Radiation Therapy Oncology Group 
RT-PCR 
reverse transcription-polymerase chain reaction 
SABCS 
San Antonio Breast Cancer Symposium 
SDMC 
Statistics and Data Management Center 
SERM 
selective estrogen receptor modulator 
SN 
sentinel node 
SNP 
single nucleotide polymorphism 
SQ, SC 
subcutaneous 
SWFI 
sterile water for injection 
TAC 
docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide 
TC 
docetaxel (Taxotere) and cyclophosphamide 
TCH 
docetaxel (Taxotere), carboplatin, and trastuzumab (Herceptin) 
TC+H®H 
docetaxel (Taxotere), cyclophosphamide, and trastuzumab (Herceptin) followed 
 
by trastuzumab (Herceptin) 
Topo IIA 
topoisomerase II alpha 
ULN 
upper limit of normal 


 
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GLOSSARY OF SELECTED ABBREVIATIONS AND ACRONYMS (continued) 
uPAR 
urokinase receptor, plasminogen activator 
USON 
US Oncology, Inc. 
WP 
weekly paclitaxel 
WP+H 
weekly paclitaxel and trastuzumab 


 
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1.0 
OVERVIEW OF THE STUDY DESIGN 
Note: Accrual closed on February 10, 2015, following achievement of the sample size goal. 
NSABP B-47, a Phase III, multicenter, open-label, randomized adjuvant therapy trial, will 
compare the value of adding trastuzumab to chemotherapy relative to chemotherapy without 
trastuzumab in women with resected node-positive or high-risk node-negative HER2-low 
invasive breast cancer.  For the B-47 trial, HER2-low is defined as either an IHC score of 1+ or 
an IHC score of 2+ with negative in situ hybridization. 
This trial will determine whether the addition of trastuzumab to standard chemotherapy regimens 
improves invasive disease-free survival relative to chemotherapy alone.  Secondary aims include 
determining whether the addition of trastuzumab to chemotherapy improves disease-free survival, 
breast cancer-free survival, recurrence-free interval, distant recurrence-free interval, and overall 
survival relative to chemotherapy alone.  Additionally, the toxicities of the regimens will be 
compared. 
The investigator must indicate at the time of study entry which of the two B-47 chemotherapy 
regimens the patient will receive.  The non-anthracycline regimen (for patients in Groups 1A and 
2A) is TC (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2) administered IV every 3 weeks 
for 6 cycles.  The anthracycline regimen (for patients in Groups 1B and 2B) is AC®WP 
(doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 administered IV either every 3 weeks 
or every 2 weeks [per investigator discretion] for 4 cycles followed by paclitaxel 80 mg/m2 IV 
administered weekly for 12 doses). 
Patients will be randomized to receive chemotherapy with or without trastuzumab therapy.  For 
patients receiving the TC chemotherapy regimen, trastuzumab will be given every 3 weeks during 
and following chemotherapy until 1 year after the first trastuzumab dose (8 mg/kg loading dose;  
6 mg/kg for the remaining doses).  For patients receiving the AC®WP chemotherapy regimen, 
trastuzumab will begin with the first dose of weekly paclitaxel and will be given weekly for  
12 doses (4 mg/kg loading dose; 2 mg/kg for the remaining weekly doses).  Following completion 
of WP, trastuzumab will continue with 6 mg/kg doses given every 3 weeks for a total of 1 year of 
trastuzumab therapy.  Patients will also receive adjuvant radiation therapy and endocrine therapy, 
as clinically indicated. 
Menopausal status will be determined at baseline for all patients.  Women who have had a 
menstrual period within 12 months before randomization (and have not had a hysterectomy) will 
have menstrual history information collected at 3 and 6 months and then every 6 months until  
3 years after randomization.  Additionally, women in this menstrual history cohort will also be 
asked to consent to blood sample collection at baseline and follow-up time points until 2 years 
after randomization.  Samples will be assayed for estradiol, FSH, and anti-Müllerian hormone to 
provide biological correlates of amenorrhea and to examine the interaction of chemotherapy 
regimens, trastuzumab, and endocrine therapies with menstrual status as determined by biological 
evaluation and menstrual history data.  In addition, blood samples will be prepared and isolated 
into DNA, RNA, plasma, and serum for future research studies on those women who became 
amenorrheic with therapy versus those who did not to better inform potential biological and 
hormonal factors that may be responsible for the beneficial effects of amenorrhea.  DNA from 
blood samples will be used for comprehensive genotyping to assess for genetic predictors of 
chemotherapy-related amenorrhea. 
In addition, other host factors that may influence the risk for cancer recurrence will be examined 
in the entire B-47 study population, including comorbid conditions, medications that may have 
systemic effects on inflammatory processes (e.g., metformin, beta blockers, ARBs, ACE 
inhibitors, and aspirin), weight and weight gain, and tobacco and alcohol use.  For all B-47 


 
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patients (who consented to submission of optional blood samples), plasma C-reactive protein will 
be assessed at baseline (pre-treatment) and at one year after randomization. 
Tumor blocks must be submitted for correlative science studies, which will include the evaluation 
of molecular and other predictors of the benefit of adding trastuzumab to chemotherapy for 
patients with HER2-low breast cancer.  Submission of a tumor sample is a study requirement for 
all patients.  Tumor samples will be used to test hypotheses related to the use of trastuzumab for 
HER2-low breast cancer.  These hypotheses address the predictive effect of tumor cell gene 
expressions and putative therapeutic immunologic mechanisms.  Also, additional blood samples 
from all B-47 patients who have consented to optional blood sample submission will be collected 
before therapy begins and at 1 year following randomization.  These samples will be used to 
identify predictors of trastuzumab benefit. 
The B-47 study will enroll 3,260 patients over a period of approximately 3 years and 2 months.  It 
is anticipated that the definitive analysis will be carried out approximately 6 years after study 
initiation. 


 
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Women with Resected Node-Positive or High-Risk Node-Negative 
Invasive Breast Cancer Determined to be HER2-Low 
STRATIFICATION 
•
IHC score (1+, 2+) 
•
Number of positive nodes (0-3, 4-9, 10+) 
•
Hormone receptor status (ER-positive and/or PgR-positive, ER- and PgR-negative) 
•
Intended chemotherapy regimen (TC [docetaxel + cyclophosphamide], 
AC®WP [doxorubicin + cyclophosphamide followed by weekly paclitaxel])* 
RANDOMIZATION 
Arm 2 
(Groups 2A and 2B)* 
Chemotherapy* 
+ 
Trastuzumab x 1 year** 
(TC + trastuzumab or 
AC®WP + trastuzumab®trastuzumab) 
Arm 1 
(Groups 1A and 1B)* 
Chemotherapy* 
(TC or AC®WP) 
* 
At the time of study entry, the investigator must designate which of the following two chemotherapy regimens 
 
will be administered: 
- Chemotherapy regimen A for Groups 1A and 2A 
 
TC: Docetaxel 75 mg/m2 IV + cyclophosphamide 600 mg/m2 IV every 3 weeks for 6 cycles. 
- Chemotherapy regimen B for Groups 1B and 2B 
 
AC®WP: Doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV every 3 weeks for 4 cycles 
 
followed by paclitaxel 80 mg/m2 IV weekly for 12 doses; at the investigator's discretion, 
 
doxorubicin/cyclophosphamide may be administered every 2 weeks for 4 cycles (dose-dense schedule). 
** Trastuzumab:  
- 
Given with TC (Group 2A): 8 mg/kg loading dose on Day 1 of Cycle 1 of TC; then 6 mg/kg IV cycles 2–6.  
After completion of TC, trastuzumab will continue with 6 mg/kg IV every 3 weeks for 11 doses. 
- 
Given with AC ® WP (Group 2B): 4 mg/kg loading dose beginning with the first dose of weekly paclitaxel; 
then 2 mg/kg weekly for a total of 12 weekly doses; after completion of WP, trastuzumab will continue with  
6 mg/kg doses IV every 3 weeks for a maximum of 13 doses. 
Figure 1.  
NSABP B-47 SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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2.0 
BACKGROUND 
2.1 
Introduction 
The joint analysis of NSABP B-31/NCCTG 9831 demonstrated major reductions in disease 
recurrence and death from HER2-gene-amplified or protein-overexpressing breast cancer with the 
incorporation of a year of trastuzumab into a standard AC®paclitaxel adjuvant chemotherapy 
regimen.  These findings, confirmed by BCIRG 006 and HERA, changed the standard of adjuvant 
therapy for women with the HER2-positive breast cancer.1-3  Central testing of specimens from 
patients enrolled in NSABP B-31 demonstrated that 174 of 1787 (9.7%) cases had neither gene 
amplification nor overexpression of HER2.  Surprisingly, these patients appeared to derive 
similar benefit from the addition of trastuzumab to patients with tumors that were centrally 
confirmed as HER2-positive (RR for DFS=0.34 95% CI: 0.14-0.80; p=0.014).  A study to 
validate the central testing findings by three independent pathologists confirmed the apparent 
benefit from trastuzumab in a subset of patients from this cohort for whom specimens were 
available (RR for DFS=0.34; 95% CI: 0.14-0.80; p=0.039).4 
Comprehensive correlative science studies utilizing archived tumor tissue blocks from B-31 have 
demonstrated provocative results: 1) HER2 mRNA expression level but not HER2 gene copy 
number (by FISH) showed a significant statistical interaction with trastuzumab, confirming HER2 
as a treatment target.  A lower expression level of HER2 mRNA was associated with lesser 
degree of benefit from trastuzumab.  However, when the mRNA cut-off for trastuzumab benefit 
was applied to expression in HER2-negative breast cancers, a significant proportion of  
HER2-negative tumors expressed HER2 mRNA levels above the cut-off.  2) Candidate markers 
identified from the metastatic disease setting such as PI-3-Kinase gene mutation or loss of PTEN 
were not associated with resistance to trastuzumab. 
Together, these data suggest that there may be important differences in the mechanism of action 
of trastuzumab in the adjuvant setting compared to the metastatic disease setting and that the 
threshold of HER2 expression for benefit from adjuvant trastuzumab added to standard 
chemotherapy may be much lower than that observed in the metastatic disease setting. 
NSABP Protocol B-47 will determine if these provocative, unexpected findings can be confirmed 
in a prospective, Phase III trial supported by extensive correlative science studies to understand 
how trastuzumab might improve invasive disease-free survival (IDFS) and overall survival (OS) 
in women diagnosed with breast cancer regarded as HER2-negative by the ASCO/CAP HER2 
Testing Guidelines.5 
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
  
 
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2.8 
Choice of chemotherapy 
The information summarized earlier suggests that the potential benefit of trastuzumab in the 
adjuvant therapy of early HER2-low breast cancer would be achieved when administered in 
combination with chemotherapy.  Results of four large Phase III trials evaluating the role of 
trastuzumab incorporated into standard anthracycline-based adjuvant chemotherapy regimens in 
women with HER2-positive breast cancer defined by standard criteria have demonstrated a 
consistent 30–50% reduction in hazard for DFS events 3-4 years following randomization along 
with a 35–40% reduction in risk for mortality.1-3  These remarkable benefits were achieved 
without an increase in toxicity, with the important exception of low rates of congestive heart 
failure ranging from 1.9–3.8%.1-3,41  Predictive factors for increased risk of severe cardiac 
toxicity were evaluated in NSABP B-31 and NCCTG N9831.  In the B-31 population, age  
> 50 years (p=0.03), the need for hypertension medication at entry (p=0.02), and baseline LVEF 
below 55% (p=0.0003) were predictors for a cardiac event.  Women < 50 years had a risk of 
2.3%, women aged 50 to 59 had a risk of 5.1%, and women ³ 60 years had a risk of 5.4%.  The 
need for hypertension medication is also a predictor for a cardiac event and increased the risk to 
6.8%.  The major increase in risk occurred in women with baseline LVEF within the normal 
range but with a value < 55%.  Their 5-year cumulative risk was 12.9%.43  The analysis of risk 
factors for a cardiac event from N9831 supported the findings of B-31.  Women ³ 60 years had a 
risk of 6.6%, women aged 50 to 59 years had a 2.8% risk, and women < 50 years had a 2.1% risk 
(p=0.003).  Previous or current use of antihypertensive agents increased the risk to 6.0% 
(p=0.005).  Baseline LVEF above the LLN but < 55% increased the risk to 5.6% (p=0.033).44 
BCIRG 006 evaluated a non-anthracycline arm consisting of docetaxel, carboplatin, and 
trastuzumab (TCH) and reported an HR for DFS of 0.67 (CI: 0.54–0.83; p=0.0003) relative to a 
control regimen of AC followed by docetaxel.1  The DFS HR for the investigational 
anthracycline-based chemotherapy regimen adding trastuzumab to AC followed by docetaxel 
relative to the chemotherapy alone was 0.61 (CI: 0.48–0.76; p<0.0001).  At this time, the results 
achieved with the two trastuzumab arms are indistinguishable in terms of efficacy.  However, the 
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rate of CHF reported with the TCH regimen was only 0.4%.  Thus, omission of the anthracycline 
markedly reduced the rate of the major toxicity of trastuzumab, without reducing the apparent 
benefit. 
Since the B-47 study will evaluate the role of trastuzumab in the adjuvant therapy of a patient 
population with HER2-low breast cancer, it will be important to employ chemotherapy regimens 
with very low rates of cardiac toxicity when combined with trastuzumab and which are 
considered as standards of care when used without trastuzumab in patient populations with 
HER2-negative disease.  We propose to allow investigators the choice of employing docetaxel  
75 mg/m2 plus cyclophosphamide 600 mg/m2 (TC) every 3 weeks for 6 cycles or an 
anthracycline regimen of AC®WP (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 
administered IV every 14 days or every 21 days for 4 cycles followed by paclitaxel 80 mg/m2 IV 
administered weekly for 12 doses).  Patients will be randomized to receive chemotherapy with or 
without trastuzumab therapy. 
2.8.1 
Rationale for non-anthracycline chemotherapy option of TC 
We propose to use a non-anthracycline chemotherapy regimen as one of the 
chemotherapy treatment options based upon two considerations: 1) It does not appear that 
the distinct subtype of HER2 non-amplified breast cancer benefits substantially from 
anthracyclines, and 2) cardiotoxicity considerations are of major importance in this study. 
Anthracyclines have been used in most standard adjuvant chemotherapy regimens for 
decades.  Early clinical trials of unselected higher risk breast cancer cohorts of all 
subtypes showed improved outcomes when an anthracycline regimen was compared to a 
similar regimen without an anthracycline (CEF vs. CMF, CAF vs. CMF, PAF vs. PF).45  
The modest outcome advantage was previously thought to be shared by the entire cohort.  
The EBCTCG overview of 16,000+ participants confirmed the benefit of adjuvant 
anthracyclines in breast cancer patients unselected for gene expression subtype.46  The 
recent recognition that the main target of anthracyclines is the topoisomerase II alpha 
(topo IIA) protein now allows anthracycline chemotherapy to be considered a targeted 
therapy.47-49  The majority (88–98%) of topo IIA alterations (mostly amplifications but 
some deletions) occur in the HER2-positive gene-amplified subset of breast cancers.50  
The topo IIA gene is in very close proximity to the HER2 gene on chromosome 17, and 
they are commonly in the same amplicon. 
O’Malley et al studied the benefit of epirubicin in the NCIC MA.5 trial and demonstrated 
that the previously shown modest benefit in DFS and OS of CEF over CMF can be 
explained by a large benefit confined to the subset of patients with topo IIA alterations.50  
No benefit was seen in patients with the non-altered topo IIA.  HER2-positive gene 
amplification and topo IIA amplifications/alterations were highly associated in this 
population, as expected. 
While the updated overview analyses conducted in 2005/2006 by the EBCTCG continue 
to show benefits of anthracycline-based chemotherapy regimens relative to 
non-anthracycline, non-taxane-based regimens (absolute reduction in risk for recurrence 
at 10 years of 2.9% and an absolute reduction in mortality of 3.2%),51 results of 
retrospective analyses such as above, of tumor specimens from patients treated in 
prospective, randomized trials (NSABP B-11, NSABP B-15, NCIC MA.5, DBCG 89-D 
studies, and others) evaluating the benefits of adding an anthracycline to 
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appears to be largely limited to the subset of patients with HER2-overexpressing breast 
cancers.52-59  Prospective randomized trials to address these retrospective findings have 
not been completed.  A trial to compare TC to TAC in patients with HER2-negative 
tumors is underway. 
The US Oncology (USON) trial 9735 compared TC to standard AC in 1016 women with 
node-positive or high-risk, node-negative operable breast cancer.  Patients were randomly 
assigned to 4 cycles of either standard-dose AC x 4 cycles (60/600 mg/m2) [n=510] or 
TC x 4 cycles (75/600 mg/m2) [n=506], administered every 3 weeks.  After a median 
follow-up of 7 years, DFS was statistically superior for TC relative to AC, 81% vs. 75% 
(HR=0.74; p=0.033), and the survival difference between TC and AC was significant, 
87% and 82% (HR=0.69; p=0.032).60  The TC arm was associated with more myalgias, 
arthralgias, edema, and febrile neutropenia, while patients on the AC arm experienced 
more nausea and vomiting.  In the AC group, one patient died from CHF and four 
patients from MI.  In the TC group, no cases of CHF were observed though two patients 
had an MI.61,62  An exploratory analysis of DFS according to age, hormone-receptor 
status, and nodal status demonstrated that the benefit was present in all subsets.61  Jones 
et al also presented data at the 2009 SABCS evaluating toxicity of the TC regimen 
combined with trastuzumab in 260 patients with the HER2+ breast cancer subtype.  Nine 
patients (3.4%) discontinued trastuzumab due to decreases in ejection fraction.  Sixteen 
patients (6.1%) had declines of LVEF below 50% during treatment.  No patients 
experienced CHF.63 
The average age at presentation of HER2 non-amplified breast cancer is older than the 
average age for HER2 amplified breast cancer (average age of a B-31 patient at entry was 
49 years old).  Since age over 60 is a risk factor of trastuzumab cardiotoxicity, there are 
many women over this age with HER2 non-amplified breast cancer who might 
potentially benefit from trastuzumab but would face increased cardiotoxicity risk.  Since 
this trial will specifically target patients with tumors that do not overexpress HER2, the 
non-anthracycline TC regimen (which has demonstrated superiority to AC in patients not 
selected for HER2 status) represents an appropriate adjuvant chemotherapy regimen 
option for the patients in B-47. 
2.8.2 
Rationale for duration of TC chemotherapy to be 6 cycles 
NSABP B-30 enrolled 5351 women with node-positive breast cancer and was enrolling 
patients during the same time period as B-31.  The study compared AC x 4 followed by 
docetaxel x 4 vs. TAC x 4 vs. AT x 4.  The primary aim of the study was to determine if 
there was a significant difference in OS in the AC®T vs. TAC x 4 arms.  There was a 
trend toward superiority of AC®T vs. TAC with a HR of 0.86 (p=0.086) for OS.  AC®T 
was superior to TAC x 4 for reduction in DFS events with a HR of 0.83 (p=0.006).  
Toxicities were similar in AC®T and TAC with the notable exception that febrile 
neutropenia was more frequent in the AC®T arm (22% vs. 16%; p=0.0001).  However, 
primary prophylaxis with G-CSF was required in the TAC arm, but not in the AC®T 
arm.64  The difference in treatment cycles delivered (8 vs. 4) may be a likely explanation 
for the difference in DFS seen. 
In BCIRG 005, TAC x 6 was compared with sequential AC x 4 followed by docetaxel x 4 
(similar to the B-30 arm with AC followed by docetaxel) in 3298 women with  
node-positive, HER2-normal breast cancer.  The primary endpoint of DFS showed no 
difference between the arms (HR=1.002 95% CI 0.86–1.16).  The TAC arm administered 


 
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without primary G-CSF prophylaxis had a significantly higher rate of febrile neutropenia 
(17.9% vs. 8.3%; p< 0.0001) and thrombocytopenia (2.5% vs. 1.3%; p=0.01) than 
AC®T, while the AC®T arm had a greater incidence of neuropathy, nail changes, and 
myalgias.26  The equivalency seen in the BCIRG 005 study may have been a result of a 
higher number of chemotherapy cycles in TAC x 6.65 
The successful adjuvant trastuzumab trials utilized 6–8 cycles of chemotherapy including 
B-31 (8 cycles).  Although USON 9735 used only 4 cycles of chemotherapy, we have 
chosen to use 6 cycles of TC in order to more closely emulate the B-31 study and the TC 
component of TAC in BCIRG 005. 
2.8.3 
Rationale for anthracycline chemotherapy option of AC®WP 
The results of USON 9735,66 the evolving long-term anthracycline cardiotoxicity data, 
and the emerging evidence of the targeted nature of anthracycline therapy have initiated 
an ongoing question regarding the continued role of anthracyclines in the adjuvant 
chemotherapy of HER2-negative breast cancer.  While topo IIA represents a critical 
target of anthracyclines, the activity cannot be explained solely by inhibition of topo IIA.  
Additionally, topo IIA is expressed by tumors with high proliferation rates, so the 
possibility of benefit in the subset of patients with tumors that are HER2-negative, but 
have a high proliferation rate, remains unclear.67  Data from B-31 and N9831 indicate 
that younger patients without hypertension and with baseline LVEFs above 55% have a 
low risk for cardiac toxicity even with the sequential AC®PH regimens.43,44  A trial 
conducted by the MSKCC demonstrated that the administration of dose-dense AC 
followed by WPH does not appear to increase the risk of cardiac toxicity over the non-
dose-dense schedule of AC, and dose-dense administration of AC®P appears to offer 
advantages in patients with triple-negative breast cancer.68  Thus, investigators and 
younger women with high risk breast cancer may prefer AC®WP as a regimen relative 
to TC. 
The primary aim of B-47 is to determine the benefit of adding trastuzumab to 
chemotherapy in this patient population.  It is not expected that there will be differential 
trastuzumab benefits based on the choice of TC or AC®WP.  However, to avoid 
imbalance between the chemotherapy options, chemotherapy choice will be a 
stratification factor.  Provision for investigator choice of chemotherapy will support 
optimal enrollment rates and minimize risk for selective exclusion of high-risk patients 
due to concerns about lack of an anthracycline option. 
 
 
 
 
 
 
 
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3.0 
STUDY AIMS AND ENDPOINTS 
3.1 
Primary aim and endpoint 
Aim: To determine whether the addition of trastuzumab to chemotherapy (TC or AC®WP) 
improves invasive disease-free survival (IDFS) in women with resected node-positive or  
high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing 
performed. 
Endpoint: IDFS, defined as time to local invasive recurrence following mastectomy, local 
invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant 
recurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding 
squamous or basal cell carcinoma of the skin), or death from any cause prior to recurrence or 
second primary cancer.97 
3.2 
Secondary aims and endpoints 
3.2.1 
Disease-free survival (DFS-DCIS) 
Aim: To determine whether the addition of trastuzumab to chemotherapy  
(TC or AC®WP) improves DFS-DCIS in women with resected node-positive or  
high-risk node-negative breast cancer which is reported as HER2-low by all HER2 
testing performed. 
Endpoint: DFS-DCIS, defined as time to local recurrence following mastectomy, local 
recurrence (invasive or DCIS) in the ipsilateral breast following lumpectomy, regional 
recurrence, distant recurrence, contralateral breast cancer (invasive or DCIS), invasive 
second primary cancer (excluding squamous and basal cell carcinoma of the skin), or 
death from any cause prior to recurrence or second primary cancer.97 
3.2.2 
Breast cancer-free survival (BCFS) 
Aim: To determine whether the addition of trastuzumab to chemotherapy  
(TC or AC®WP) improves BCFS in women with resected node-positive or high-risk 
node-negative breast cancer which is reported as HER2-low by all HER2 testing 
performed. 
Endpoint: BCFS, defined as time from randomization until local recurrence (invasive or 
DCIS), regional recurrence, or distant recurrence, contralateral breast cancer (invasive or 
DCIS), or death from any cause. 
3.2.3 
Recurrence-free interval (RFI) 
Aim: To determine whether the addition of trastuzumab to chemotherapy  
(TC or AC®WP) improves RFI in women with resected node-positive or high-risk  
node-negative breast cancer which is reported as HER2-low by all HER2 testing 
performed. 
Endpoint: RFI, defined as time from randomization until invasive local, regional, or 
distant recurrence, or death from breast cancer (censored for deaths from other causes).97 


 
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3.2.4 
Distant recurrence-free interval (DRFI) 
Aim: To determine whether the addition of trastuzumab to chemotherapy  
(TC or AC®WP) improves DRFI in women with resected node-positive or high-risk 
node-negative breast cancer which is reported as HER2-low by all HER2 testing 
performed. 
Endpoint: DRFI, defined as time from randomization until the first diagnosis of distant 
metastasis or death from breast cancer, regardless of occurrence of any intervening local 
or regional recurrences, contralateral breast cancers, or non-breast second primary 
cancers.  This endpoint is censored at the time of death from causes other than breast 
cancer.97 
3.2.5 
Overall survival (OS) 
Aim: To determine whether the addition of trastuzumab to chemotherapy  
(TC or AC®WP) improves OS in women with resected node-positive or high-risk  
node-negative breast cancer which is reported as HER2-low by all HER2 testing 
performed. 
Endpoint: OS, defined as time from randomization to death from any cause. 
3.2.6 
Menstrual history 
Aim: To evaluate the associations between amenorrhea and circulating reproductive 
hormone levels, and the associations between chemotherapy regimen, amenorrhea, and 
IDFS benefit in premenopausal women eligible at baseline for the menstrual history 
assessments. 
Endpoint: Amenorrhea, circulating reproductive hormone suppression, and IDFS as 
defined in Section 17.9. 
3.2.7 
Toxicity 
Aim: To evaluate the toxicity associated with each of the regimens. 
Endpoint: Frequencies of adverse events categorized using the NCI Common 
Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). 
3.2.8 
Molecular predictors of efficacy 
Aim: To test the hypothesis that the HER2 mRNA level is the predictor of the degree of 
benefit from trastuzumab and the threshold for benefit in the adjuvant setting is lower 
than defined by current ASCO/CAP Guidelines for HER2 assays (IHC and FISH). 
Aim: To identify and/or validate molecular predictors of the degree of benefit from the 
addition of trastuzumab to chemotherapy (TC or AC®WP). 
Aim: To test the alternative hypothesis that the main determinant of trastuzumab response 
in the adjuvant setting of HER2-low breast cancer is through ADCC by demonstrating 
that the polymorphism of the Fcγ receptor gene is predictive of the degree of benefit from 
the addition of trastuzumab to chemotherapy (TC or AC®WP). 


 
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3.2.9 
Inflammatory correlates of outcome 
Aim: To examine the relationship between behavioral host factors (obesity, tobacco, 
alcohol) and comorbid conditions that may influence systemic inflammation and breast 
cancer outcomes, controlling for tumor/stage characteristics and treatment assignment. 
Aim: To examine the relationship between medication exposures that may influence 
systemic inflammation and breast cancer outcomes, controlling for tumor/stage 
characteristics and treatment assignment. 
Aim: To examine the relationship between comorbid conditions, medication exposures 
and behavioral host factors together and breast cancer outcomes, controlling for 
tumor/stage characteristics and treatment assignment. 


 
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4.0 
PATIENT ELIGIBILITY AND INELIGIBILITY 
Note: Accrual closed on February 10, 2015, following achievement of the sample size goal. 
4.1 
Patient selection guidelines 
Although the guidelines in Section 4.1 are not inclusion/exclusion criteria, investigators should 
consider each of these factors when selecting patients for the trial.  Investigators should also 
consider all other relevant factors (medical and non-medical), as well as the risks and benefits of 
the study therapy, when deciding if a patient is an appropriate candidate for this trial. 
• 
Patients should have a life expectancy of at least 10 years, excluding their diagnosis of breast 
cancer.  (Comorbid conditions should be taken into consideration, but not the diagnosis of 
breast cancer.) 
• 
Women of reproductive potential must agree to use an effective non-hormonal method of 
contraception (for example condoms, some intrauterine devices, diaphragms, tubal ligation, 
vasectomized partner, or abstinence) during therapy and for at least 6 months (Arm 1 
patients) and for at least 7 months (Arm 2 patients) after the last dose of study therapy 
(chemotherapy or trastuzumab). 
• 
Submission of tumor samples from the breast surgery is required for all patients (see 
Section 7.1).  Therefore, the local pathology department policy regarding release of tumor 
samples must be considered in the screening process.  Patients whose tumor samples are 
located in a pathology department that by policy will not submit any samples for research 
purposes should not be approached for participation in the B-47 trial. 
4.2 
Conditions for patient eligibility 
A patient cannot be considered eligible for this study unless all of the following conditions are met. 
4.2.1 
The patient must have signed and dated an IRB-approved consent form that conforms to 
federal and institutional guidelines. 
4.2.2 
The patient must be female. 
4.2.3 
The patient must be ³ 18 years old. 
4.2.4 
The patient must have an ECOG performance status of 0 or 1 (see Appendix A). 
4.2.5 
The tumor must be unilateral invasive adenocarcinoma of the breast on histologic 
examination. 
4.2.6 
All of the following staging criteria (according to the 7th edition of the AJCC Cancer 
Staging Manual) must be met: 
• 
By pathologic evaluation, primary tumor must be pT1-3; 
• 
By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, 
pN1c), pN2a, pN2b, pN3a, or pN3b  
If pN0, one of the following criteria must be met: 
- 
pT2 and ER negative and PgR negative; or 
- 
pT2 and ER positive (PgR status may be positive or negative) and either grade 3 
histology or Oncotype DX® Recurrence Score of ³ 25; or 
- 
pT3 regardless of hormone receptor status, histologic grade, and Oncotype DX® 
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4.2.7 
HER2 status of the primary tumor must be evaluated prior to randomization; all testing 
performed must indicate that the tumor is HER2-low as defined below. 
• 
IHC must be performed and the IHC staining results must indicate a score of 1+  
(in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be 
performed and must indicate that the tumor is HER2-low as described below). 
• 
If ISH testing is performed, test results must be as follows and IHC must be 1+ or 
2+: The ratio of HER2 to CEP17 must be < 2.0 or, if a ratio was not performed, the 
HER2 gene copy number must be < 4 per nucleus. 
Note: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+ to 2+, the 
higher intensity score in the range should be used to determine eligibility. 
4.2.8 
The patient must have undergone either a total mastectomy or breast-conserving surgery 
(lumpectomy).  (Patients who have had a nipple-sparing mastectomy are eligible.) 
4.2.9 
For patients who undergo lumpectomy, the margins of the resected specimen must be 
histologically free of invasive tumor and DCIS as determined by the local pathologist.  If 
pathologic examination demonstrates tumor at the line of resection, additional operative 
procedures may be performed to obtain clear margins.  If tumor is still present at the 
resected margin after re-excision(s), the patient must undergo total mastectomy to be 
eligible.  (Patients with margins positive for LCIS are eligible without additional 
resection.) 
4.2.10 For patients who undergo mastectomy, margins must be free of gross residual tumor.  
(Patients with microscopic positive margins are eligible as long as post-mastectomy RT 
of the chest wall will be administered.) 
The patient must have completed one of the procedures for evaluation of pathologic 
nodal status listed below. 
• 
Sentinel lymphadenectomy alone: 
- 
If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b; 
- 
If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or 
pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the nodal 
involvement must be limited to 1 or 2 positive nodes. 
• 
Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph 
nodes if the sentinel node (SN) is positive; or 
• 
Axillary lymphadenectomy with or without SN isolation procedure. 
4.2.11 The interval between the last surgery for breast cancer (treatment or staging) and 
randomization must be no more than 84 days. 
4.2.12 The patient must have ER analysis performed on the primary tumor prior to 
randomization.  If ER analysis is negative, then PgR analysis must also be performed.  
(Either the core biopsy or surgical resection specimen can be used for ER/PgR testing.)  
Patients with a primary tumor that is hormone receptor-positive or receptor-negative are 
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4.2.13 The most recent postoperative blood counts, performed within 6 weeks prior to 
randomization, must meet the following criteria: 
• 
ANC must be ³ 1200/mm3; 
• 
Platelet count must be ³ 100,000/mm3; and 
• 
Hemoglobin must be ³ 10 g/dL. 
4.2.14 The following criteria for evidence of adequate hepatic function must be met based on the 
results of the most recent postoperative tests performed within 6 weeks prior to 
randomization: 
• 
total bilirubin must be £ ULN for the lab unless the patient has a bilirubin elevation  
> ULN to 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow 
conjugation of bilirubin; and  
• 
alkaline phosphatase must be £ 2.5 x ULN for the lab; and 
• 
AST must be £ 1.5 x ULN for the lab. 
• 
Alkaline phosphatase and AST may not both be > the ULN.  For example, if the 
alkaline phosphatase is > the ULN but £ 2.5 x ULN, the AST must be £ the ULN.  If 
the AST is > the ULN but £ 1.5 x ULN, the alkaline phosphatase must be £ ULN. 
Note: If ALT is performed instead of AST (per institution's standard practice), the ALT 
value must be £ 1.5 x ULN; if both were performed, the AST must be £ 1.5 x ULN. 
4.2.15 Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if 
liver imaging (CT, MRI, PET-CT, or PET scan) performed within 90 days prior to 
randomization does not demonstrate metastatic disease and the requirements in criterion 
4.2.15 are met. 
4.2.16 Patients with alkaline phosphatase that is > ULN but £ 2.5 x ULN or unexplained bone 
pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan 
performed within 90 days prior to randomization does not demonstrate metastatic disease. 
4.2.17 The most recent postoperative serum creatinine performed within 6 weeks prior to 
randomization must be £ ULN for the lab. 
4.2.18 LVEF assessment must be performed within 90 days prior to randomization.  LVEF 
assessment performed by 2-D echocardiogram is preferred; however, MUGA scan may 
be substituted based on institutional preferences. 
• 
For patients who will receive the TC chemotherapy regimen, the LVEF must be  
³ 50% regardless of the cardiac imaging facility's lower limit of normal. 
• 
For patients who will receive the AC®WP chemotherapy regimen, the LVEF 
must be ³ 55% regardless of the cardiac imaging facility's lower limit of normal. 
Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF 
assessments, it is critical that this baseline study be an accurate assessment.  If the 
baseline LVEF is > 70%, the investigator is encouraged to have the accuracy of the initial 
LVEF result confirmed and repeat the test if the accuracy is uncertain.  (See Sections 5.2 
and 5.3 for LVEF instructions.) 


 
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4.3 
Conditions for patient ineligibility 
Patients with one or more of the following conditions are NOT eligible for this study. 
4.3.1 
Primary tumor with any of the following HER2 testing results: 
• 
IHC staining intensity: 
• 
0 on all evaluations of specimens 
• 
3+ on evaluation of any specimen 
• 
ISH with a ratio of HER2 to CEP17 ³ 2.0  on evaluation of any specimen 
• 
ISH result indicating HER2 gene copy number ³ 4 per nucleus on evaluation of any 
specimen. 
4.3.2 
T4 tumors including inflammatory breast cancer. 
4.3.3 
Definitive clinical or radiologic evidence of metastatic disease.  (Note: Chest imaging 
[mandatory for all patients] and other imaging [if required] must have been performed 
within 90 days prior to randomization.) 
4.3.4 
Synchronous or previous contralateral invasive breast cancer.  (Patients with synchronous 
and/or previous contralateral DCIS or LCIS are eligible.) 
4.3.5 
Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS.   
(Patients with synchronous or previous ipsilateral LCIS are eligible.) 
4.3.6 
History of non-breast malignancies (except for in situ cancers treated only by local 
excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to 
randomization. 
4.3.7 
Previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy. 
4.3.8 
Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast 
cancer prior to randomization.  
4.3.9 
Whole breast RT prior to randomization or partial breast RT that cannot be completed on 
or before the date of randomization (see Section 9.8 and 9.10.3). 
4.3.10 Continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an 
aromatase inhibitor.  Patients are eligible if these medications are discontinued prior to 
randomization (see Section 9.9). 
4.3.11 Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone 
replacement therapy.  Patients are eligible if these medications are discontinued prior to 
randomization (see Section 4.1). 
4.3.12 Cardiac disease (history of and/or active disease) that would preclude the use of the drugs 
included in the treatment regimens.  This includes but is not confined to: 
Active cardiac disease 
• 
angina pectoris that requires the current use of anti-anginal medication; 
• 
ventricular arrhythmias except for benign premature ventricular contractions; 
• 
supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication; 
• 
conduction abnormality requiring a pacemaker; 
• 
valvular disease with documented compromise in cardiac function; and 
• 
symptomatic pericarditis. 


 
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History of cardiac disease 
• 
myocardial infarction documented by elevated cardiac enzymes or persistent regional 
wall abnormalities on assessment of LV function; 
• 
history of documented CHF; and 
• 
documented cardiomyopathy. 
4.3.13 Hypertension defined according to the following ineligibility criteria: 
• 
For patients who will receive TC (regardless of the patient's age): Uncontrolled 
hypertension defined as sustained systolic BP > 150 mmHg or diastolic BP  
> 90 mmHg.  (Patients with initial BP elevations are eligible if initiation or 
adjustment of BP medication lowers pressure to meet entry criteria.) 
• 
For patients < 50 years old who will receive AC®WP: Uncontrolled hypertension 
defined as sustained systolic BP > 150 mmHg or diastolic BP > 90 mmHg.  Patients 
with initial BP elevations are eligible if initiation or adjustment of BP medication 
lowers pressure to meet entry criteria. 
• 
For patients ³ 50 years old who will receive AC®WP: 
- 
Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or 
diastolic BP > 90 mmHg. 
- 
Controlled hypertension (systolic BP £ 150 mmHg and diastolic BP  
£ 90 mmHg), if anti-hypertensive medication(s) are needed. 
Note: Patients who are not eligible based on the AC®WP regimen BP criteria but who 
meet the TC regimen BP criteria are eligible for B-47, if the intended chemotherapy 
regimen is changed to TC. 
4.3.14 Active hepatitis B or hepatitis C with abnormal liver function tests. 
4.3.15 Intrinsic lung disease resulting in dyspnea. 
4.3.16 Poorly controlled diabetes mellitus. 
4.3.17 Active infection or chronic infection requiring chronic suppressive antibiotics. 
4.3.18 Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory 
neuropathy) ³ grade 2, per the CTCAE v4.0. 
4.3.19 Conditions that would prohibit administration of corticosteroids. 
4.3.20 Chronic daily treatment with corticosteroids with a dose of ³ 10 mg/day 
methylprednisolone equivalent (excluding inhaled steroids). 
4.3.21 Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and 
Cremophor® EL. 
4.3.22 Pregnancy or lactation at the time of study entry.  (Note: Pregnancy testing must be 
performed within 2 weeks prior to randomization according to institutional standards 
for women of childbearing potential.) 
4.3.23 Other non-malignant systemic disease that would preclude the patient from receiving 
study treatment or would prevent required follow-up. 
4.3.24 Psychiatric or addictive disorders or other conditions that, in the opinion of the 
investigator, would preclude the patient from meeting the study requirements. 
4.3.25 Use of any investigational product within 30 days prior to randomization. 


 
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5.0 
CARDIAC SAFETY MONITORING 
5.1 
Timing of LVEF assessments 
LVEF assessments are required at the timepoints listed on Table 6. 
TABLE 6.  Timing of LVEF assessments 
For patients in Groups 1A and 
1B 
(TC; AC®WP) 
For patients in Group 2A 
(TC+H) 
For patients in Group 2B 
(AC®WP+H®H) 
• 
Baseline – within 90 days  
prior to randomization 
• 
At 12 months following 
randomization for the first 800 
patients randomized to  
Arm 1 (chemotherapy 
regimens A and B) 
• 
Baseline – within 90 days 
prior to randomization 
• 
At 3 months following 
randomization (after 
cycle 4) 
• 
At 6 months following 
randomization 
• 
At 9 months following 
randomization 
• 
At 12 months following 
randomization 
• 
Baseline – within 90 days  
prior to randomization 
• 
At 3 months following 
randomization (10–21 days 
after the last dose of AC 
[before WP+H begins]) 
• 
At 6 months following 
randomization 
• 
At 9 months following 
randomization 
• 
At 12 months following 
randomization 
5.2 
Important LVEF assessment guidelines 
• 
2-D echocardiogram is the preferred method for assessment of LVEF.  However, LVEF 
assessment by MUGA scan is permitted. 
• 
All LVEF assessments should be performed by the same method (either 2-D 
echocardiogram or MUGA scan) that was performed at baseline. 
• 
Investigators are strongly urged to schedule the LVEF assessment at the same cardiac 
imaging facility that performed the patient's baseline LVEF assessment. 
• 
If trastuzumab is discontinued for any reason, protocol-mandated LVEF assessments should 
continue to be obtained.  (Exception: LVEF assessments are not required following a 
documented invasive breast cancer recurrence, invasive contralateral breast cancer, or second 
nonbreast primary cancer excluding squamous or basal cell skin cancers or new in situ 
carcinomas of any site.) 
5.3 
Reporting LVEF assessments 
• 
The LVEF value must be reported on the LVEF Assessment report form (Form LVA) as a 
numerical value that is a whole number. 
- 
If the facility performing the assessment has not reported the LVEF as a whole number, 
decimals reported as ³ 5 should be rounded up and decimals reported as < 5 should be 
rounded down.  For example, an LVEF of 54.5% will be rounded up and reported as 
55%; an LVEF of 54.4% will be rounded down and reported as 54%. 
- 
If the facility performing the assessment will only report the LVEF as a range, the mean 
(average) of the values used for the range should be calculated so that a single numerical 
value can be reported. 


 
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• 
During therapy and until 30 days after the last dose of study therapy (either as part of required 
CTEP-AERS reports or as part of routine AE reporting), ³ grade 2 decreases in LVEF must 
also be reported as an AE (see "Ejection Fraction Decreased" in the Investigations section of 
the CTCAE v4.0). 
• 
Submission of Form LVA with the echocardiogram scan or MUGA scan report to the NRG 
Oncology SDMC (see Information Resources on page 11) is required within 21 days after 
all LVEF assessments.  For all patients, regardless of treatment assignment, Form LVA must 
be submitted as follows: 
- 
Following required LVEF assessments at the protocol-specified time points  
(see Section 5.1) 
- 
If an LVEF assessment is performed because the patient has signs or symptoms of CHF, 
i.e., ³ grade 3 left ventricular systolic dysfunction or ³ grade 2 heart failure per the 
CTCAE v4.0, at any time through 10 years following randomization (see Section 5.5) 
5.4 
Reporting cardiac events 
The cardiac events listed in Sections 5.4.1 and 5.4.2, as defined in the CTCAE v4.0, must be 
reported in an expedited manner via CTEP-AERS from the time of the first dose of study 
therapy (chemotherapy with or without trastuzumab) until 2 years following 
randomization.  The Cardiac Report form (Form CR) must be submitted to the NRG Oncology 
SDMC within 21 days of learning of the cardiac events listed.  Also submit Form LVA and the 
echocardiogram or MUGA scan report, if applicable.  (Refer to Section 13.3 for instructions 
regarding expedited reporting.) 
5.4.1 
Protocol-defined cardiac events 
• 
³ grade 2 heart failure 
• 
³ grade 3 left ventricular systolic dysfunction 
• 
Definite cardiac death defined as any grade 5 AE included in the Cardiac Disorders 
section of the CTCAE v4.0 
• 
Sudden death NOS as defined in the General Disorders section of the CTCAE v4.0 
5.4.2 
Other cardiac events 
• 
³ grade 3 acute coronary syndrome 
• 
³ grade 3 myocardial infarction 
5.5 
Reporting selected late cardiac events 
For the first 2 years following randomization, selected cardiac events will be reported via  
CTEP-AERS and on Form CR as described in Section 5.4.  Beginning at Year 3 and continuing 
through Year 10, the following selected late cardiac events, as defined in the Cardiac Disorders 
section of the CTCAE v4.0, will be reported on the B-47 follow-up form and Form CR: 
• 
³ grade 3 acute coronary syndrome 
• 
³ grade 2 heart failure 
• 
³ grade 3 left ventricular systolic dysfunction 
• 
³ grade 3 myocardial infarction 


 
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5.6 
Required cardiac event follow-up reporting 
A cardiac event follow-up form will be used to collect information regarding the resolution of 
heart failure and left ventricular systolic dysfunction, as well as the need for therapy to 
manage symptoms of CHF.  After NRG Oncology reviews documentation related to the initial 
report of heart failure or left ventricular systolic dysfunction (reported via CTEP-AERS or on the 
B-47 follow-up form), the Program Coordinator will be notified whether or not submission of a 
cardiac event follow-up form will be required.  When required, a cardiac event follow-up form 
will be submitted every 6 months for 2 years. 


 
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6.0 
REQUIREMENTS FOR ENTRY, TREATMENT AND FOLLOW-UP 
Note: Accrual closed on February 10, 2015, following achievement of the sample size goal. 
Tests, exams, and other assessments required prior to randomization are listed on Table 7.  
Requirements during Year 1 are outlined on Table 8 for patients in Groups 1A and 1B and on 
Table 9 for patients in Groups 2A and 2B.  Requirements for Years 2 through 10 are listed on 
Table 10 for patients in all treatment groups. 
TABLE 7.  Tests, exams, and other requirements prior to randomization 
Required Assessments 
Prior to Randomization 
Determination of local pathology department's policy 
re: submission of tumor samples (see Section 4.1) 
X 
Consent form signed by the patient 
X 
Determination of hormone receptor status (see Section 4.2.13) 
X 
HER2 analysis (see Sections 4.2.7 and 4.3.1) 
X 
History & physical exam 
  Xa 
Within 4 weeks 
(must be 
postoperative) 
Height & weight 
X 
Performance status (see Appendix A) 
X 
Menstrual history 
  Xb 
Menopausal status (see Appendix C) 
  Xc 
Assessment of BP and BP medications 
X 
Assessment of concomitant medications 
X 
Assessment of alcohol and tobacco use and comorbid conditions 
(questionnaire completed by the patient) 
  Xd 
CBC/differential/platelet count 
X 
Within 6 weeks 
(must be most recent 
postoperative test 
results) 
Total bilirubin/alkaline phosphatase/ASTe 
X 
Serum creatinine 
X 
Pregnancy test 
  Xf 
Within 2 weeks 
2-D echocardiogram (or MUGA scan) 
  Xg 
Within 90 days 
ECG 
X 
Chest imaging (chest CT scan or chest x-ray) 
    Xh,i 
Liver imaging 
    Xi,j 
Within 90 days 
(if required) 
Bone nuclear imaging 
    Xi,k 
Bilateral breast imaging 
  Xl 
Within 180 days 
(Table 7 is continued on the next page.) 


 
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TABLE 7.  Tests, exams, and other requirements prior to randomization (continued) 
a 
The exam can be performed by a physician or other healthcare professional. 
b 
The baseline menstrual history assessment will identify women who will be included in the 
menstrual history study after randomization. 
c 
An estradiol level may be required.  Refer to the criteria in Appendix C. 
d 
Questionnaire must be completed after signing the B-47 consent form. 
e 
ALT may be substituted for AST if required by the institution's standard practice. 
f 
For women of childbearing potential: Pregnancy testing should be performed according to 
institutional standards. 
g 
2-D echocardiogram is the preferred method for assessment of LVEF.  However, LVEF 
assessment by MUGA scan is permitted. 
h 
PET scans and PET-CT scans are permitted as an alternative to CT scans of the chest and chest x-
ray. 
i 
Canadian investigators: Refer to Section 15.7 for regulatory requirements related to PET scans. 
j 
Liver imaging is required if alkaline phosphatase or AST is > ULN.  Acceptable methods of liver 
imaging include CT, MRI, PET-CT, and PET scans to rule out metastatic disease. 
k 
Bone nuclear imaging is required if alkaline phosphatase is > ULN or if the patient has unexplained 
bone pain.  PET scan or PET-CT scan is permitted as a substitute for a bone scan. 
l 
MRI is permitted before entry as a substitute for a mammogram (ultrasound is not).  Imaging will 
be unilateral for patients who have had mastectomy with or without reconstruction. 
 


 
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TABLE 8.  Tests, exams, and other requirements during therapy and through Year 1 for Groups 1A and 1B 
Required assessments 
(see footnote a) 
After 
randomization 
Within 3 days before 
each cycle 
(beginning with Cycle 2) 
4 weeks after last 
chemotherapy dose 
From end of chemotherapy 
through Year 1 
History & physical examb 
 
X 
X 
X 
(every 6 months) 
Adverse event assessment 
 
  Xc 
  Xc 
  Xc 
Weight 
 
X 
 
  X 
(12 months from randomization) 
Height 
 
 
 
Assessment of concomitant 
medications 
 
 
 
Assessment of alcohol/tobacco 
use and comorbid conditions 
(questionnaire completed by the 
patient) 
 
 
 
CBC/differential/platelets 
 
X 
(For WP, prior to doses 
1, 4, 7, and 10) 
 
 
Serum creatinine 
 
 
 
Total bilirubin/alk phos/ASTd 
 
 
 
2-D echocardiogram (or MUGA 
scan)e 
 
 
 
X 
(12 months from randomization) 
Bilateral mammogram 
 
 
X 
(every 12 months)f 
Submission of tumor sample(s) 
Xg 
 
 
 
Menstrual history assessment 
 
  Xh 
(about 3 months from 
randomization)i 
Xh 
(6 months from 
randomization) 
Xh 
(12 months from randomization) 
Submission of blood samples for 
patients in the MH study 
population 
Xj 
(before therapy begins) 
Xj 
(about 3 months from 
randomization)i 
Xj 
(6 months from 
randomization) 
Xj 
(12 months from randomization) 
Submission of blood samples for 
all consenting B-47 patients 
Xk 
(before therapy begins) 
 
 
Xk 
(12 months from randomization) 
(Table 8 is continued on the next page.) 


 
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TABLE 8.  Tests, exams, and other requirements during therapy and through Year 1 for Groups 1A and 1B (continued) 
a 
H&P, bloodwork, x-rays, scans, and other testing may be performed more frequently at the discretion of the investigator. 
b 
Updated H&P with exams (by physician or other healthcare professional) appropriate for therapy-related assessments and follow-up evaluations. 
c 
See instructions in Sections 5.4, 5.6, and Table 32 in Section 13.3 for reporting cardiac events; also see Section 13.4.2 for instructions regarding 
submission of Form TRTAE. 
d 
ALT may be substituted for AST if required by the institution's standard practice. 
e 
Only required for the first 800 patients randomized to Arm 1.  2-D echo is the preferred method of LVEF assessment, but MUGA scan is permitted.  If 
possible, all LVEF assessments should be performed by the same method at the same facility. 
f 
Mammogram is required; unilateral for patients who have had mastectomy with or without reconstruction.  First mammogram will be 1 year from the 
most recent mammogram (or MRI) performed prior to randomization and then every 12 months. 
g 
Submission of tumor sample(s) is required for all patients within 90 days following randomization; see Information Resources, Section 7.1, B-47 
Pathology and Correlative Science Instructions. 
h 
Only for patients who, at time of randomization, were determined to be in the MH study population (see Section 8.2).  Assessments are required even if 
the patient has not agreed to blood sample submission. 
i 
Before Cycle 5 for patients receiving TC; before WP for patients receiving AC®WP. 
j 
These blood samples are only required for patients who, at time of randomization, were determined to be in the MH study population and who have 
agreed to optional blood sample collections when signing the consent form (see Information Resources, Sections 7.1 and 8.2.6, and the B-47 Pathology 
and Correlative Science Instructions). 
k 
These blood samples are only required for patients who have agreed to optional sample collections when signing the consent form (see Information 
Resources, Sections 7.1, 8.3.5, and the B-47 Pathology and Correlative Science Instructions). 
NOTE: Tests, exams, assessments, and blood sample submissions are not required following a documented invasive breast cancer recurrence, invasive 
contralateral breast cancer, or second nonbreast primary cancer excluding squamous or basal cell skin cancers or new in situ carcinomas of any site.  
Follow-up for subsequent cancer events and for survival continues to be required every 6 months until year 6 and then every 12 months through Year 10.  (See 
Section 13.0 for adverse event reporting requirements.) 


 
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TABLE 9.  Tests, exams, and other requirements during therapy and through Year 1 for Groups 2A and 2B 
Required assessments 
(see footnote a) 
After 
randomization 
Within 3 days before 
each 
chemotherapy cycle 
(beginning with  
Cycle 2) 
2-4 weeks after last  
chemotherapy dose 
Every 9 weeks 
during trastuzumab  
(after completion of 
chemotherapy) 
At 12 months 
from randomization 
History & physical examb 
 
X 
X 
  Xc 
X 
Adverse event assessment 
 
  Xd 
  Xd 
  Xd 
  Xe 
Weight 
 
X 
 
X 
X 
Height 
 
 
 
 
Assessment of concomitant 
meds 
 
 
 
 
Assessment of alcohol/tobacco 
use and comorbid conditions 
(questionnaire completed by 
patient)  
 
 
 
 
CBC/differential/platelets 
 
X 
(For WP, prior to 
doses 1, 4, 7, and 10) 
 
 
 
Serum creatinine 
 
 
 
 
Total bilirubin/alk phos/ASTf 
 
 
 
 
2-D echocardiogram 
(or MUGA scan)g 
 
  Xh 
(3 months from 
randomization) 
X 
(6 months from 
randomization) 
X 
(9 months from 
randomization) 
X 
Bilateral mammogram 
 
 
X (every 12 months)i 
Submission of tumor sample(s) 
  Xj 
 
 
 
 
Menstrual history assessment 
 
  Xk 
(about 3 months from 
randomization)l 
  Xk 
(6 months from 
randomization) 
 
  Xk 
Submission of blood samples 
for patients in the MH study 
population 
  Xm 
(before therapy 
begins) 
  Xm 
(about 3 months from 
randomization)l 
  Xm 
(6 months from 
randomization) 
 
  Xm 
Submission of blood samples 
for all consenting B-47 
patients 
  Xn 
(before therapy 
begins) 
 
 
 
  Xn 
(Table 9 is continued on the next page.) 


 
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TABLE 9.  Tests, exams, and other requirements during therapy and through Year 1 for Groups 2A and 2B (continued) 
a 
H&P, bloodwork, x-rays, scans, and other testing may be performed more frequently at the discretion of the investigator. 
b 
Updated H&P with exams (by physician or other healthcare professional) appropriate for therapy-related assessments and follow-up evaluations. 
c 
Assessment sufficient for identification of AEs is required every 9 weeks; more comprehensive assessment should be performed every 12 weeks. 
d 
See instructions for reporting cardiac events in Sections 5.4, 5.6, and Table 32 in Section 13.3; also see Section 13.4.2 for instructions regarding 
submission of Form TRTAE. 
e 
AE assessment must be performed 30 days after the last dose of trastuzumab; this assessment may be based on patient exam or phone assessment. 
f 
ALT may be substituted for AST if required by the institution's standard practice. 
g 
Required for all patients randomized to Arm 2.  2-D echo is the preferred method of LVEF assessment, but MUGA scan is permitted.  If possible, all 
LVEF assessments should be performed by the same method at the same facility. 
h 
This LVEF assessment must be 10–21 days after the last AC dose (before beginning WP+H) for patients in Groups 2B and after Cycle 4 for patients in 
Group 2A (TC+H).  See Table 6. 
i 
Mammogram is required; unilateral for patients who have had mastectomy with or without reconstruction.  First mammogram will be 1 year from the 
most recent mammogram (or MRI) performed prior to randomization and then every 12 months. 
j 
Submission of tumor sample(s) is required for all patients within 90 days following randomization; see Information Resources, Section 7.1, and B-47 
Pathology and Correlative Science Instructions. 
k 
Only for patients who, at time of randomization, were determined to be in the MH study population (see Section 8.2).  Assessments are required even if 
the patient has not agreed to blood sample submission. 
l 
Before Cycle 5 for patients receiving TC; before WP for patients receiving AC®WP. 
m Blood samples are only required for patients who, at time of randomization, were determined to be in the MH study population and who have agreed to 
optional blood sample collections when signing the consent form (see Information Resources, Sections 7.1 and 8.2.6, and the B-47 Pathology and 
Correlative Science Instructions). 
n 
Blood samples are only required for patients who have agreed to optional sample collections when signing the consent form (see Information Resources, 
Sections 7.1, 8.3.5, and the B-47 Pathology and Correlative Science Instructions). 
NOTE: Tests, exams, assessments, and blood sample submissions are not required following a documented invasive breast cancer recurrence, invasive 
contralateral breast cancer, or second nonbreast primary cancer excluding squamous or basal cell skin cancers or new in situ carcinomas of any site.  
Follow-up for subsequent cancer events and for survival continues to be required every 6 months until year 6 and then every 12 months through Year 10.  (See 
Section 13.0 for adverse event reporting requirements.) 


 
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TABLE 10.  Tests, exams, and other requirements during year 2 through year 10 for patients in all treatment groups 
Required assessments 
(see footnote a) 
Years 2 through 5 
(from randomization) 
Years 6 through 10 
(from randomization) 
History & physical examb 
X 
(every 6 months) 
X 
(every 12 months) 
Adverse event assessment 
  Xc  
(every 6 months for selected late cardiac AEs) 
  Xc 
(every 12 months for selected late cardiac AEs) 
Weight 
  X 
(24, 36, 48, and 60 months from randomization) 
 
Height 
 
Assessment of concomitant medications 
 
Assessment of alcohol/tobacco use and comorbid 
medical conditions 
(questionnaire completed by patient) 
 
Menstrual history assessment 
Xd 
(18, 24, 30, and 36 months from randomization) 
 
Submission of blood samples for patients in the 
MH study populatione 
Xe 
(18 and 24 months from randomization) 
 
Bilateral mammogram 
Xf 
(every 12 months) 
Xf 
(every 12 months) 
a 
H&P, bloodwork, x-rays, scans, and other testing may be performed more frequently at the discretion of the investigator. 
b 
Updated H&P with exams (by physician or other healthcare professional) appropriate for follow-up evaluations. 
c 
See instructions in Sections 5.4, 5.5, 5.6, Table 31 or Table 32 in Section 13.3, and 13.5 for reporting cardiac events including selected late cardiac events. 
d 
Only for patients who, at time of randomization, were determined to be in the MH study population (see Section 8.2).  Assessments are required even if 
the patient has not agreed to blood sample submission. 
e 
Blood samples are only required for patients who, at time of randomization, were determined to be in the MH study population and who have agreed to 
optional blood sample collections when signing the consent form (see Information Resources, Sections 7.1 and 8.2.6, and the B-47 Pathology and 
Correlative Science Instructions). 
f 
Mammogram is required; unilateral for patients who have had mastectomy with or without reconstruction. 
NOTE: Tests, exams, assessments, and blood sample submissions are not required following a documented invasive breast cancer recurrence, invasive 
contralateral breast cancer, or second nonbreast primary cancer excluding squamous or basal cell skin cancers or new in situ carcinomas of any site.   
Follow-up for subsequent cancer events and for survival continues to be required every 6 months until year 6 and then every 12 months through Year 10.   
(See Section 13.0 for adverse event reporting requirements and Sections 8.2.6 and 8.3.5 for blood sample submission requirements.) 


 
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7.0 
PATHOLOGY AND CORRELATIVE SCIENCE STUDIES 
7.1 
Overview of requirements 
Tumor sample submission is a protocol requirement and therefore mandatory for participation in 
the study (see Table 11 for specific requirements).  By signing the B-47 consent form, the 
patient has agreed to tumor sample submission.  Submission of the blood samples is only 
required for patients who agreed to optional blood sample collections in the B-47 consent form. 
TABLE 11.  Summary of B-47 tumor and blood sample submission requirements 
Specimen requirements 
After 
randomization 
before therapy 
begins 
Within 90 days 
after 
randomization 
At 3, 6, 12, 18, 
and 24 months 
after randomization 
Tumor blocks required for all 
patients: 
- At least one paraffin block from the 
primary tumor (preferably more 
than one block) 
- one block from at least one positive 
lymph node (if applicable) 
 
Yesa,b 
 
Diagnostic H&E slides 
No 
No 
No 
Blood samples for all B-47 consenting 
patientsc 
Yesc 
No 
Yesc 
(at 12 months only) 
Blood samples for patients in the MH 
study populationd 
Yesd 
No 
Yesd 
a 
If possible, the submitted block should be the one used for original HER2 testing and should 
contain the largest tumor volume. 
b 
If the pathology department refuses to provide a block for research purposes, refer to the B-47 
Pathology and Correlative Science Instructions for alternative sample submission instructions. 
c 
Blood samples are only required for patients who have agreed to optional blood sample 
collections when signing the B-47 consent form (see Information Resources and Sections 7.1and 
8.3.5). 
d 
Blood samples are only required for patients who, at time of randomization, were determined to 
be in the menstrual history study population and who have agreed to optional blood sample 
collections when signing the B-47 consent form (see Information Resources and Sections 7.1 and 
8.2.6). 
Note: Refer to the Members’ Area of the NSABP Web site for the B-47 Pathology and Correlative 
Science Instructions. 
7.2 
Use of specimens 
The tumor and blood samples collected in this study will be used for studies specified in the B-47 
protocol and for studies to be conducted in the future related to the purposes of the B-47 study 
and not currently described in the protocol document. 
Specific aims include the following: developing predictive tests for degree of benefit from 
trastuzumab; developing prognostic tests for patients treated with chemotherapy alone or 
chemotherapy plus trastuzumab; and testing the role of ADCC as a mechanism of action of 
trastuzumab.  The procured specimens, including DNA samples derived from them, will not be 


 
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used for hereditary genetic studies involving genes conferring susceptibility to cancer or other 
diseases unless additional consent is obtained from the patient or an anonymization process is 
used.  Results of the correlative science studies will not be reported to the patient or her physician 
and will not have any bearing on her treatment. 
7.3 
Specimen submission and identification procedures 
Refer to Information Resources on page 11 and to the B-47 Pathology Instructions in the 
Members' Area of the NSABP Web site for details regarding submission of specimens. 
7.3.1 
Blocks 
Submitted blocks are initially shipped to and logged into the database at the NRG 
Oncology SDMC.  These samples are then stripped of patient identifiers except the  
B-47 Patient ID number and forwarded to the NRG Oncology Biospecimen Bank-
Pittsburgh where they are assigned a code number for further processing and study. 
7.3.2 
Blood samples for B-47 correlative science studies 
The blood specimens are to be submitted to the NRG Oncology Serum Bank at the 
Baylor College of Medicine where they are logged into the database and assigned a 
specimen number.  The samples are stripped of patient identifiers, except the B-47 
Patient ID number, and are processed and stored until assays are performed to examine 
the role of a polymorphism of the Fcγ Receptor as a predictor of trastuzumab benefit.  
The samples collected at the 12-month time point will be used to identify immunological 
parameters that may correlate with treatment outcomes resulting from the addition of 
trastuzumab therapy.  Additionally, these blood samples will also be used for the B-47 
Host Factors sub-study (see Section 8.3.5). 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
Re
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e
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9.0 
TREATMENT REGIMEN 
9.1 
Chemotherapy regimen for Group 1A (TC [docetaxel and cyclophosphamide]) 
• 
Chemotherapy should begin within 2 weeks following randomization. 
• 
Central venous access is at the investigator's discretion.  If prophylactic coumadin  
(or equivalent) is used, the dose should not exceed 1 mg/day. 
• 
Infusion times and the order of drug administration may be altered at the investigator's 
discretion or per practice standards. 
TABLE 13.  Treatment regimen for Group 1A (TC) 
Drug 
Dose 
Dosing Interval 
Planned 
Duration 
Docetaxel (T) 
75 mg/m2 IV over 60 minutes 
(See footnote below for 
premedication instructions) 
Day 1 
every 3 weeks 
Cycles 1-6 
Cyclophosphamide (C) 
600 mg/m2 IV over 30 minutes 
All patients should receive premedications as follows before each docetaxel dose: 
• 
Dexamethasone 8 mg by mouth twice daily the day before and the day of chemotherapy is 
recommended.  At the physician’s discretion, dexamethasone may be continued on the day 
after chemotherapy.  An equivalent dose of other corticosteroids may be substituted 
(dexamethasone 8 mg = methylprednisolone 40 mg = prednisone 50 mg = prednisolone  
50 mg). 
• 
Administration of IV dexamethasone (dose at the investigator's discretion) as a substitute for 
oral dexamethasone prior to chemotherapy is at the investigator's discretion. 
• 
At the investigator's discretion, other non-steroidal premedications, e.g., diphenhydramine 
hydrochloride 50 mg IV and H-2 blocker IV (cimetidine 300 mg, ranitidine 50 mg, or 
famotidine 20 mg) may be given in addition to dexamethasone. 
9.2 
Chemotherapy and trastuzumab regimen for Group 2A (TC+H®H [docetaxel plus 
cyclophosphamide plus trastuzumab followed by trastuzumab]) 
• 
Chemotherapy and trastuzumab should begin within 2 weeks following randomization. 
• 
Central venous access is recommended.  If prophylactic coumadin (or equivalent) is used, 
the dose should not exceed 1 mg/day. 
• 
Infusion times and the order of drug administration may be altered at the treating physician's 
discretion or per practice standards. 


 
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TABLE 14.  Treatment regimen for Group 2A (TC+H®H) 
Drug 
Dose 
Dosing Interval 
Planned Duration 
Docetaxel (T) 
75 mg/m2 IV over 60 minutes 
(See footnote a for premedication 
instructions) 
Day 1 
every 3 weeks 
Cycles 1-6 
Cyclophosphamide (C) 
600 mg/m2 IV over 30 minutes 
Trastuzumab (H) 
See footnote b re: LVEF 
requirements 
First dose: 
8 mg/kg IV over 90 minutesc 
Day 1 of Cycle 1 only 
Subsequent doses during TC: 
6 mg/kg IV over 30-60 minutesc 
Day 1  
every 3 weeks 
Cycles 2-6 
Continue trastuzumab 3 weeks after the last dose of chemotherapy/trastuzumab 
Trastuzumab (H) 
See footnote b re: LVEF 
requirements 
6 mg/kg IV over 30-90 minutesc 
(Use of premedications is at the 
investigator's discretion) 
Every 3 weeks 
Until 1 year 
following first 
trastuzumab dose 
regardless of any 
missed dosesd 
a 
All patients should receive premedications as follows before each docetaxel dose: 
• 
Dexamethasone 8 mg by mouth twice daily the day before and the day of chemotherapy is 
recommended.  At the physician’s discretion, dexamethasone may be continued on the  
day after chemotherapy.  An equivalent dose of other corticosteroids may be substituted  
(dexamethasone 8 mg = methylprednisolone 40 mg = prednisone 50 mg = prednisolone  
50 mg). 
• 
Administration of IV dexamethasone (dose at the investigator's discretion) as a substitute for 
oral dexamethasone prior to chemotherapy is at the investigator's discretion. 
• 
At the physician's discretion, other non-steroidal premedications, e.g., diphenhydramine 
hydrochloride 50 mg IV and H-2 blocker IV (cimetidine 300 mg, ranitidine 50 mg, or 
famotidine 20 mg) may be given in addition to dexamethasone. 
b 
See Section 11.3 (including Table 28) for LVEF requirements for the continuation of trastuzumab. 
c 
See Table 29 for instructions regarding trastuzumab infusion-related reactions, allergic reactions, 
and anaphylaxis. 
d 
One year of therapy is defined as 51 weeks and includes the period of time trastuzumab is given 
with chemotherapy (18 weeks) + the time during which trastuzumab is given alone (33 weeks).  
For patients who have received all of the planned therapy on schedule, 17 doses of trastuzumab 
will be administered. 
 


 
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9.3 
Treatment regimen for Group 1B (AC®WP [doxorubicin plus cyclophosphamide followed 
by weekly paclitaxel]) 
• 
Chemotherapy should begin within 2 weeks following randomization. 
• 
Central venous access is at the investigator's discretion.  If prophylactic coumadin (or 
equivalent) is used, the dose should not exceed 1 mg/day. 
• 
Infusion times and the order of drug administration may be altered at the treating physician's 
discretion or per practice standards. 
TABLE 15.  Treatment regimen for Group 1B (AC®WP) 
Drug 
Dose 
Dosing Interval 
Planned 
Duration 
Doxorubicin (A) 
60 mg/m2 IV over 15 minutes 
Day 1  
every 3 weeks 
OR 
Day 1 
every 2 weeks 
(dose-dense)a 
Cycles 1-4 
Cyclophosphamide (C) 
600 mg/m2 IV over 30 minutes 
Initiate 3 weeks after the last dose of AC (see footnote b) 
Paclitaxel (WP) 
80 mg/m2 IV over 60 minutes 
See footnote c for 
premedications 
Weekly 
12 dosesd 
a 
Choice of AC schedule (every 3 weeks or every 2 weeks [dose-dense]) is at the investigator’s 
discretion.  If the dose-dense schedule is used, primary prophylaxis with G-CSF is required 
during AC (see Section 9.7.1 for instructions). 
b 
If the dose-dense schedule is used for AC, paclitaxel will be initiated 2-3 weeks after the last dose  
of AC. 
c 
All patients should receive premedications as follows before each paclitaxel dose: 
• 
Dexamethasone 10 mg IV, completed 30 minutes before each paclitaxel administration.  (At 
the investigator's discretion, dexamethasone may be tapered during the paclitaxel cycles.) 
• 
Diphenhydramine hydrochloride 50 mg IV and an H-2 blocker IV (cimetidine 300 mg,  
ranitidine 50 mg, or famotidine 20 mg) before each paclitaxel administration. 
d 
Paclitaxel therapy must stop 16 weeks after the first dose of paclitaxel.  If medical or non-medical 
treatment delays occur during paclitaxel therapy, administer as many of the remaining doses as 
possible by 16 weeks. 
 
9.4 
Treatment regimen for Group 2B (AC®WP+H®H [doxorubicin plus cyclophosphamide 
followed by weekly paclitaxel plus trastuzumab followed by trastuzumab]) 
• 
Chemotherapy should begin within 2 weeks following randomization. 
• 
Central venous access is recommended.  If prophylactic coumadin (or equivalent) is used, 
the dose should not exceed 1 mg/day. 
• 
Infusion times and order of drug administration may be altered at the treating physician's 
discretion or per practice standards. 


 
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TABLE 16.  Treatment regimen for Group 2B (AC®WP+H®H) 
Drug 
Dose 
Dosing Interval 
Planned Duration 
Doxorubicin (A) 
60 mg/m2 IV over 15 minutes 
Day 1 every 3 weeks 
OR 
Day 1 every 2 weeks 
(dose-dense)a 
Cycles 1-4 
Cyclophosphamide (C) 
600 mg/m2 IV over 30 minutes 
Initiate 3 weeks after the last dose of AC (see footnote b) 
Paclitaxel (WP) 
80 mg/m2 IV over 60 minutes 
See footnote c for 
premedications 
Weekly 
12 dosesd 
Trastuzumab (H) 
See footnote e re: LVEF 
requirements 
First dose: 
4 mg/kg IV over 90 minutesf 
Day 1 only 
Subsequent doses during WP: 
2 mg/kg IV over 30 minutesf 
Weekly 
11 dosesg 
Continue trastuzumab 1 week after the last dose of WP/trastuzumab 
Trastuzumab (H) 
See footnote h re: 
LVEF requirements 
6 mg/kg IV over 30–90 
minutesf 
(Use of premedications is at the 
investigator's discretion) 
Every 3 weeks 
Until 1 year 
following first 
trastuzumab dose 
regardless of any 
missed dosesi 
a 
Choice of AC schedule (every 3 weeks or every 2 weeks [dose-dense]) is at the investigator’s 
discretion.  If the dose-dense schedule is used, primary prophylaxis with G-CSF is required 
during AC (see Section 9.7.1 for instructions). 
b 
If the dose-dense schedule is used for AC, paclitaxel will be initiated 2–3 weeks after the last dose  
of AC. 
c 
All patients should receive premedications as follows before each paclitaxel dose: 
• 
Dexamethasone 10 mg IV, completed 30 minutes before each paclitaxel administration.  (At 
the investigator's discretion, dexamethasone may be tapered during the paclitaxel cycles.) 
• 
Diphenhydramine hydrochloride 50 mg IV and an H-2 blocker IV (cimetidine 300 mg, 
ranitidine 50 mg, or famotidine 20 mg) before each paclitaxel administration. 
d 
Paclitaxel therapy must stop 16 weeks after the first dose of paclitaxel.  If medical or non-medical 
treatment delays occur during paclitaxel therapy, administer as many of the remaining doses as 
possible by 16 weeks. 
e 
The post-AC LVEF must meet Section 9.6 (Table 17) criteria before trastuzumab therapy begins. 
f 
See Table 29 for instructions regarding trastuzumab infusion-related reactions, allergic reactions, 
and anaphylaxis. 
g 
If paclitaxel is held, trastuzumab should be continued (see Section 11.2). 
h 
See Section 11.3 (including Table 28) for LVEF requirements for the continuation of trastuzumab. 
i 
One year of therapy is defined as 51-52 weeks and includes the period of time trastuzumab is given 
with weekly paclitaxel (12–16 weeks) + the time during which trastuzumab is given alone  
(36–40 weeks depending on the duration of the weekly paclitaxel therapy).  For patients who have 
received all of the planned therapy (without delays), 12 doses of trastuzumab will be 
administered weekly followed by a maximum of 13 doses administered every 3 weeks. 
 


 
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9.5 
Dose determination 
9.5.1 
Calculation of BSA, chemotherapy doses, and trastuzumab dose 
• 
Recommended chemotherapy and trastuzumab doses will be provided by NRG 
Oncology at the time of study entry. 
• 
Recalculation of BSA and drug doses is required if the patient has a 10% or greater 
change in weight from baseline or, if the dose has already been adjusted due to 
weight change, from the weight at the time of the most recent dose adjustment.  At 
the physician's discretion, the BSA and drug doses may be recalculated before each 
treatment. 
9.5.2 
Rounding doses 
Rounding of drug doses is optional.  If the treating physician decides to round the 
dose(s), follow these guidelines.  (These also apply to dose modifications.) 
• 
Cyclophosphamide (600 mg/m2 IV) 
Doses should be rounded to the nearest 20 mg. 
• 
Docetaxel (75 mg/m2 IV) 
Doses should be rounded to the nearest 5 mg. 
• 
Doxorubicin (60 mg/m2 IV) 
Doxorubicin should be rounded to the nearest 1 mg. 
• 
Paclitaxel (80 mg/m2 IV) 
Paclitaxel should be rounded to the nearest 5 mg. 
• 
Trastuzumab (see Table 14 and Table 16 for dosing) 
Trastuzumab should be rounded to the nearest 20 mg. 
9.6 
Cardiac safety criteria for initiation of trastuzumab therapy following AC (for Group 2B 
patients only) 
See Section 9.6.2 for asymptomatic decrease in LVEF. 
9.6.1 
Patients with cardiac AEs during AC 
If the patient develops any of the following cardiac AEs during AC, protocol therapy 
should be discontinued and further therapy is at the investigator's discretion.  Initiation of 
trastuzumab is prohibited. 
• 
Any ³ grade 2 cardiac AE listed in Appendix D. 
• 
Any ³ grade 3 AE listed in the Cardiac Disorders section of the CTEP Active 
Version of the CTCAE. 


 
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9.6.2 
Patients with asymptomatic decrease in LVEF 
For patients who do not develop symptoms related to LV dysfunction or other cardiac 
AEs as described in Section 9.6.1, initiation of trastuzumab therapy for Group 2B patients 
will depend on the absolute LVEF value and absolute change in percentage points 
between the baseline LVEF and the LVEF assessed 10-21 days after the last AC dose 
as outlined on Table 17. 
TABLE 17.  LVEF requirements for initiation of trastuzumab therapy after AC (Group 2B only) 
LVEF 
assessed 
10-21 days after 
last AC dose 
Change in LVEF percentage points from baseline 
(see footnote a) 
Increase or no 
change 
Decrease of < 10 
percentage points 
Decrease of ³ 10 
percentage points 
³ 55% 
Initiate trastuzumab therapy 
50-54% 
N/A 
Initiate trastuzumab therapy 
Initiate trastuzumab 
therapy and repeat 
echo/MUGA 
in 6 weeksb 
£ 49% 
N/A 
Do NOT initiate trastuzumab therapy; 
Initiate paclitaxel per protocolc 
a 
The baseline LVEF is the LVEF measured prior to randomization. 
b 
If repeat echo/MUGA was required, the LVEF value for the 2nd assessment must meet Table 17 
criteria for trastuzumab to be initiated. 
c 
Patient follow-up (including LVEF assessments) should continue as per protocol instructions on 
Table 9. 
 
9.7 
Supportive therapy 
9.7.1 
G-CSF 
• 
If the dose-dense schedule is followed for AC, primary prophylaxis with G-CSF is 
required.  For all other chemotherapy regimens, use of G-CSF as primary prophylaxis 
is at the investigator’s discretion.  If utilized, it should be administered according to 
the package insert for the agent used. 
• 
If G-CSF support is required during TC therapy (see Table 19) or AC therapy for the  
every-3-week schedule (see Table 23), either pegfilgrastim or filgrastim may be used 
at the investigator's discretion.  If G-CSF support is required during weekly paclitaxel 
therapy (see Table 25), filgrastim must be used. 
• 
Do not administer G-CSF within 24 hours of chemotherapy. 
• 
If required by institutional standards, GM-CSF may be administered as an alternative  
to G-CSF. 


 
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9.7.2 
Erythropoietin 
Use of an erythropoiesis-stimulating agent is not permitted.  (See Section 10.2 for 
instructions regarding ³ grade 3 anemia.) 
9.7.3 
Antiemetic therapy 
Antiemetic therapy should be administered according to National Comprehensive Cancer 
Network (NCCN) or American Society of Clinical Oncology (ASCO) clinical practice 
guidelines. 
9.7.4 
Management of docetaxel-related edema 
Suggested interventions include: 
• 
Hydrochlorothiazide/triamterene (Dyazide®) 1 capsule by mouth daily; dose can be 
increased to twice daily. 
• 
Furosemide (Lasix®) 40 mg by mouth daily if edema progresses despite Dyazide (or 
equivalent) therapy.  Potassium supplementation should be given as needed. 
9.8 
Adjuvant radiation therapy 
Choice of RT, treatment fields, and treatment schedule will be at the discretion of the radiation 
oncologist. 
9.8.1 
Whole breast irradiation (WBI) following breast conserving surgery 
WBI should begin within 6 weeks following the last dose of chemotherapy and will 
overlap with the administration of trastuzumab.  Regional nodal irradiation is at the 
radiation oncologist's discretion. 
9.8.2 
Partial breast irradiation (PBI) following breast conserving surgery 
PBI utilizing 3-D conformal RT or brachytherapy is permitted only if RT is completed 
on or before the date of randomization. 
9.8.3 
Post-mastectomy RT 
RT is at the radiation oncologist's discretion. 
9.9 
Adjuvant endocrine therapy 
Patients with ER-positive and/or PgR-positive tumors should receive a minimum of  
5 years of endocrine therapy. 
• 
Adjuvant endocrine therapy should be initiated 3–6 weeks following the completion of 
chemotherapy and will overlap with the administration of trastuzumab.  At the physician's 
discretion, initiation may be delayed until after completion of RT but should be initiated by 
12 weeks following completion of chemotherapy. 
• 
LHRH agonist/antagonists (e.g., Lupron® and Zoladex®) or ovarian ablation by surgery or 
RT are permitted for premenopausal patients. 
• 
Adjuvant endocrine therapy should be administered according to the current ASCO 
guidelines.  However, selection of endocrine therapy will be at the physician’s discretion.  
The dose and schedule of endocrine therapy should be consistent with the drug package 
insert. 


 
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9.10 
Prohibited therapies 
The following types of treatment, in addition to any cancer therapy other than the therapy 
specified in this protocol, are prohibited until the time of diagnosis of the first breast cancer 
recurrence or diagnosis of a second primary malignancy. 
9.10.1 Chemotherapy 
Administration of chemotherapy other than the chemotherapy specified in this protocol is 
prohibited. 
9.10.2 Targeted therapy 
Administration of targeted therapy for malignancy (other than trastuzumab for  
Groups 2A and 2B patients) is prohibited. 
9.10.3 Radiation therapy 
Partial breast irradiation following randomization is prohibited (see Section 9.8.2). 
9.11 
Participation in other clinical trials 
• 
Patients may participate in the NSABP B-39/RTOG 0413 Trial. 
• 
If a B-47 patient is considering participation in another clinical trial (including supportive 
therapy trials), contact the NRG Oncology Clinical Coordinating Department (see 
Information Resources on page 11). 
 


 
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10.0 
CHEMOTHERAPY TREATMENT MANAGEMENT 
10.1 
General instructions 
• 
The CTCAE v4.0 must be used to grade the severity of AEs.  Refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
• 
All doses must be based on the AE requiring the greatest modification. 
• 
Chemotherapy doses that have been reduced may not be escalated. 
• 
Unless specified otherwise in the treatment management sections/tables, chemotherapy 
should be held for at least 1 week until clinically significant AEs return to £ grade 1. 
10.2 
Management of anemia 
Chemotherapy should not proceed with ³ grade 3 anemia.  Transfusion is acceptable for 
improving the hemoglobin value to allow therapy to continue without delay.  The patient should 
be assessed to rule out other causes of anemia.  Use of erythropoiesis-stimulating agents is 
prohibited. 
10.3 
Treatment management for TC (Groups 1A and 2A) 
• 
If a docetaxel-related hypersensitivity reaction occurs despite premedication, treatment as 
medically indicated will be instituted.  For £ grade 3 allergic reaction or grade 3 anaphylaxis, 
continuation of docetaxel is at the investigator's discretion.  Following a grade 4 allergic 
reaction or grade 4 anaphylaxis, docetaxel must be permanently discontinued. 
• 
Docetaxel-related fluid retention will be treated as per the investigator's discretion.  See 
Section 9.7.4 for management suggestions. 
• 
If trastuzumab must be discontinued before completion of the scheduled TC cycles, the 
remaining TC doses should be administered. 
• 
All dose modifications for TC are based on the dose level changes outlined in Table 18. 
• 
See Table 20 for management of docetaxel-related neuropathy and Table 21 for docetaxel-
related musculoskeletal pain.  Instructions for management of all other TC toxicities are listed 
on Table 19. 
TABLE 18.  Dose levels for TC (Groups 1A and 2A) 
 
Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level -1 
(mg/m2) 
Dose Level -2 
(mg/m2) 
Docetaxel (T) 
75 
60 
Discontinue 
Cyclophosphamide (C) 
600 
500 
Discontinue 
 


 
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TABLE 19.  Treatment management for TC (Groups 1A and 2A) 
Important table instructions: 
• Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs present on the 
scheduled Day 1 for Cycles 2-6 (column 3).  Refer to all sections/tables within Section 10.1–10.3 for additional 
instructions. 
• Modifications for toxicities on this table apply to both docetaxel and cyclophosphamide (TC). 
• Dose modifications must be based on the AE requiring the greatest modification. 
• NOTE: If the docetaxel dose has been previously reduced for docetaxel-specific toxicities (see Table 20 and 
Table 21) and a subsequent toxicity requiring dose reduction of TC occurs, maintain docetaxel at the reduced 
dose level (-1) and decrease cyclophosphamide to dose level -1; or, at the investigator's discretion, discontinue 
all study therapy.  Further therapy is then at the investigator's discretion.  (See Sections 11.1 and 11.2 for 
trastuzumab instructions for Group 2A patients.) 
CTCAE v4.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a)  
Modifications for AEs that 
REQUIRE A DELAY IN 
ADMINISTRATION OF THE 
TREATMENT CYCLE 
(See footnote b) 
Neutrophil count decreased: 
Grade 2 (1000-1199/mm3), 
Grades 3, 4 
 
Maintain dose 
ANC: Hold until ³  1200/mm3.  If recovery 
takes: 
 
1-3 wks – maintain dose and add G-CSF 
 
If receiving G-CSF and recovery takes: 
 
1 wk – maintain dose; 2-3 wks - ¯ one 
 
dose level 
Platelet count decreased: 
Grades 2, 3 
 
Maintain dose 
Platelets: Hold until ³  75,000/mm3.  If 
recovery takes: 
1 wk – maintain dose; 2 to 3 wks - ↓ one 
dose level 
Grade 4 
↓ one dose level 
Hold until ³  75,000/mm3. 
↓ one dose level 
GI (if related to 
chemotherapy): 
Diarrhea 
Grade 2 
 
 
Maintain dose 
 
 
Maintain dose or ↓ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level or D/C 
D/C 
Mucositis - oral 
Grade 2 
 
Maintain dose 
 
Maintain dose or ↓ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level  or D/C 
D/C 
Vomiting (despite 
antiemetics) 
Grade 2 
 
Maintain dose or ¯ one dose 
level 
 
Maintain dose or ↓ one dose level 
Grades 3, 4 
↓ one dose level or D/C 
D/C 
Investigations (hepatic): 
Bilirubin, AST, alk phos 
Grade 2 
 
 
↓ one dose level 
Hold until bilirubin returns to the baseline 
grade 
and AST and alk phos have returned to £ 
grade 1;↓ one dose level 
Grade 3 
↓ one dose level or D/C 
Hold until bilirubin returns to the baseline 
grade 
and AST and alk phos have returned to £ 
grade 1; ↓ one dose level or D/C 
Grade 4 
D/C 
D/C 
(Table 19 is continued on the next page.) 


 
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TABLE 19.  Treatment management for TC (Groups 1A and 2A) (continued) 
Infection or febrile 
neutropenia: 
Grade 2 
(N/A for febrile neutropenia) 
 
Maintain dose and add G-CSF prophylaxis for subsequent chemotherapy cycles 
if neutropenia was present.c 
Grade 3 
Maintain dose and add G-CSF prophylaxis for subsequent chemotherapy 
cycles.  If receiving prophylactic G-CSF, ¯ one dose level. 
Grade 4 
Maintain dose and add G-CSF prophylaxis for subsequent chemotherapy cycles 
or D/C.  If receiving prophylactic G-CSF, ¯ one dose level or D/C. 
Other clinically significant 
AEs:d 
Grade 2 
 
Maintain dose or ¯ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level or D/C 
D/C 
a 
Resolved means that all clinically significant AEs are £ grade 1 (except neutrophils, which must be ³ 
1200/mm3, and bilirubin, which must be £ the baseline grade) on Day 1 of the next scheduled cycle, i.e., 
treatment can be given without delay. 
b 
Hold and check weekly.  With exception of neutrophils and bilirubin, resume treatment when toxicity is £ 
grade 1.  If toxicity has not resolved to £ grade 1 after 3 weeks of delay, discontinue TC (see Section 11.2 for 
trastuzumab instructions for Group 2A). 
c 
If grade 2 criteria for infection include topical antibiotics or other local treatment, use of G-CSF is at the 
investigator's discretion. 
d 
Determination of "clinically significant" AEs is at the discretion of the investigator. 
 
TABLE 20.  Treatment management for docetaxel-related neuropathy 
Nervous System Disorders 
• 
Paresthesias 
• 
Peripheral sensory 
neuropathy 
1 – 7 Days Duration 
Persistent for > 7 Days or 
Caused the Next Cycle  
to be Delayed 
Grade 1 
Maintain docetaxel dose 
Grade 2 
Maintain docetaxel dosea 
Decrease docetaxel 
one dose levelb 
Grade 3 
First episode: 
Decrease docetaxel one dose 
levela 
Second episode: 
Discontinue docetaxel 
Discontinue docetaxel 
Grade 4 
Discontinue docetaxel 
a 
Must be resolved to £ grade 1 on Day 1 of the next cycle. 
b 
Hold chemotherapy for persistent grade 2 neuropathy.  When £ grade 1, resume treatment with 
dose modification for docetaxel (no dose reduction for cyclophosphamide).  If grade 2 toxicity 
persists after 3 weeks of delay, discontinue docetaxel.  (For patients in Group 2A, see Section 11.2 
for instructions regarding trastuzumab.) 


 
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TABLE 21.  Treatment management for docetaxel-related musculoskeletal pain 
Note: The treatment management instructions in Table 21 apply to patients with musculoskeletal pain not 
controlled by analgesics.  Use of narcotics and NSAIDs is encouraged to maintain the docetaxel dose if 
possible. 
Musculoskeletal and 
Connective Tissue Disorders 
• 
Arthralgia 
• 
Myalgia 
1 – 7 Days Duration 
Persistent for > 7 Days or  
Caused the Next Cycle 
to be Delayed 
Grade 1 
(despite analgesics) 
Maintain docetaxel dose 
Grade 2 
(despite analgesics) 
Maintain docetaxel dose 
Maintain docetaxel dose 
or 
Decrease docetaxel one dose level* 
Grade 3 
(despite analgesics) 
First episode: 
Decrease docetaxel one dose level 
Second episode:  
Discontinue docetaxel 
First episode: 
Decrease docetaxel one dose level* 
or 
Discontinue docetaxel 
Second episode:  
Discontinue docetaxel 
* 
Hold docetaxel for persistent grade 2 or 3 musculoskeletal pain.  (Cyclophosphamide and trastuzumab 
should be continued while docetaxel is held.)  When £ grade 1, resume treatment with dose modification.  If 
grade 2 or grade 3 toxicity persists after 3 weeks of delay, discontinue docetaxel.  (For patients in Group 2A, 
see Section 11.2 for instructions regarding trastuzumab.) 
10.4 
Treatment management for AC (Groups 1B and 2B) 
10.4.1 Cardiac AEs during AC 
If the patient develops any of the following cardiac AEs during AC, study therapy should 
be discontinued and further therapy is at the investigator's discretion. 
• 
Any ³ grade 2 cardiac AE listed in Appendix D. 
• 
Any ³ grade 3 AE listed in the Cardiac Disorders section of the CTCAE v.4.0. 
10.4.2 Non-cardiac toxicity 
• 
If AC is discontinued due to non-cardiac toxicity, paclitaxel and, for Group 2B 
patients, trastuzumab should be initiated. 
• 
If AEs occurring during dose-dense AC have resulted in treatment delays, the AC 
therapy should be converted to the every-3-week treatment schedule. 
• 
All dose modifications for AC are based on Table 22 dose level changes.  
Instructions for management of non-cardiac AC toxicities are listed on Table 23.  The 
dose levels on Table 22 and the instructions on Table 23 apply to both AC treatment 
schedules (every-3-weeks and every-2-weeks [dose-dense]). 
TABLE 22.  Dose levels for AC (Groups 1B and 2B) 
 
Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level -1 
(mg/m2) 
Dose Level -2 
(mg/m2) 
Dose Level -3 
Doxorubicin (A) 
60 
50 
40 
Discontinue 
Cyclophosphamide (C) 
600 
500 
400 
Discontinue 


 
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TABLE 23.  Treatment management for AC (Groups 1B and 2B) 
Important table instructions: 
• Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs 
present on the scheduled Day 1 of Cycles 2-4 (column 3).  Refer to other applicable instructions in 
Section 10.1, 10.2, and 10.4. 
• All modifications in dose levels apply to both doxorubicin and cyclophosphamide (AC). 
• Dose modifications must be based on the AE requiring the greatest modification. 
• If the dose-dense schedule for AC is used, primary prophylaxis with G-CSF is required. 
CTCAE v4.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY IN 
ADMINISTRATION OF THE 
TREATMENT CYCLE 
(See footnote b) 
Neutrophil count decreased: 
Grade 2 (1000-1199/mm3), 
Grades 3, 4 
 
Maintain dose 
ANC: Hold until ³  1200/mm3.  If recovery 
takes: 1-3 wks – maintain dose and add  
G-CSFc 
 
If receiving G-CSF and recovery takes:  
1 wk – maintain dose; 2-3 wks – ¯ one 
dose level 
Platelet count decreased: 
Grades 2, 3 
 
Maintain dose 
Platelets: Hold until ³  75,000/mm3.  If 
recovery takes: 
1 wk – maintain dose; 2-3 wks – ¯ one 
dose level 
Grade 4 
↓ one dose level 
Hold until ³  75,000/mm3. 
↓ one dose level 
GI (if related to 
chemotherapy): 
Diarrhea 
Grade 2 
 
 
 
Maintain dose 
 
 
 
Maintain dose or ↓ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level or D/C 
D/C 
Mucositis - oral 
Grade 2 
 
Maintain dose 
 
Maintain dose or ↓ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level or D/C 
D/C 
Vomiting (despite 
antiemetics) 
Grade 2 
 
Maintain dose or ¯ one dose 
level 
 
Maintain dose or ↓ one dose level 
Grades 3, 4 
↓ one dose level or D/C 
D/C 
Investigations (hepatic): 
Bilirubin, AST, alk phos 
Grade 2 
 
 
↓ one dose level 
Hold until bilirubin returns to the baseline 
grade 
and AST and alk phos have returned to £ 
grade 1;↓ one dose level 
Grade 3 
↓ one dose level or D/C 
Hold until bilirubin returns to the baseline 
grade 
and AST and alk phos have returned to £ 
grade 1;↓ one dose level or D/C 
Grade 4 
D/C 
D/C 
(Table 23 is continued on the next page.) 


 
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TABLE 23.  Treatment management for AC (Groups 1B and 2B) (continued) 
CTCAE v4.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT 
CYCLE 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY IN 
ADMINISTRATION OF THE 
TREATMENT CYCLE 
(See footnote b) 
Infection or febrile 
neutropenia: 
Grade 2 
(N/A for febrile 
neutropenia) 
 
 
 
Maintain dose and add G-CSFc prophylaxis for subsequent 
chemotherapy cycles if neutropenia was present.d 
Grade 3 
Maintain dose and add G-CSFc prophylaxis for subsequent 
chemotherapy cycles.  If receiving prophylactic G-CSF, ¯ one dose 
level. 
Grade 4 
Maintain dose and add G-CSFc prophylaxis for subsequent 
chemotherapy cycles or D/C.  If receiving prophylactic G-CSF, ¯ one 
dose level or D/C. 
Other clinically 
significant AEs:e 
Grade 2 
 
Maintain dose or ¯ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level or D/C 
D/C 
a Resolved means that all clinically significant AEs are £ grade 1 (except neutrophils, which must be 
³ 1200/mm3, and bilirubin, which must be £ the baseline grade) on Day 1 of the next scheduled 
cycle (i.e., treatment can be given without delay). 
b Hold and check weekly.  With exception of neutrophils and bilirubin, resume treatment when 
toxicity is ≤ grade 1.  (See Section 10.4.2 regarding dose-dense AC).  If toxicity has not resolved 
after 3 weeks of delay, discontinue AC and proceed to paclitaxel (and trastuzumab for Group 2B). 
c 
Pegfilgrastim, at a fixed dose of 6 mg SQ on Day 2, is preferred.  Filgrastim, if used, should be 
administered according to the drug package insert. 
d If grade 2 criteria for infection include topical antibiotics or other local treatment, use of G-CSF is 
at the investigator's discretion. 
e 
Determination of "clinically significant" AEs is at the discretion of the investigator. 
 
10.5 
Treatment management for WP and WP+H (Groups 1B and 2B) 
See Section 11.0 for trastuzumab (H) management (Group 2B). 
10.5.1 Treatment decisions when paclitaxel must be held or discontinued 
• 
Unless otherwise specified, paclitaxel that is held due to toxicity will not resume until 
the toxicity has resolved to £ grade 1. 
• 
Weekly paclitaxel (WP) must be completed within 16 weeks.  Any of the 12 doses 
remaining after 16 weeks following the first paclitaxel dose should not be 
administered. 


 
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10.5.2 Instructions for dose modifications and treatment delays during paclitaxel 
• 
Dose modifications for paclitaxel are based on the dose level changes outlined on 
Table 24. 
• 
Dose modifications and instructions for management of neuropathy related to 
paclitaxel are outlined on Table 26. 
• 
Dose modifications and instructions for management of musculoskeletal pain related 
to paclitaxel are outlined on Table 27. 
• 
Dose modifications for other toxicities are outlined on Table 25. 
TABLE 24.  Dose levels for paclitaxel (Groups 1B and 2B) 
 
Dose Level 0 
Starting Dose 
(mg/m2) 
Dose Level -1 
(mg/m2) 
Dose Level -2 
(mg/m2) 
Dose Level -3 
Weekly paclitaxel (WP) 
80 
60 
45 
Discontinue 
 


 
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TABLE 25.  Treatment management for weekly paclitaxel (Groups 1B and 2B) 
Important table instructions: 
• Dose modifications must be based on AEs that occurred between treatments (column 2) and AEs present on the 
scheduled treatment day (column 3).  Refer to all sections/tables within Sections 10.1, 10.2, and 10.5 for 
additional instructions. 
• Dose modifications must be based on the AE requiring the greatest modification. 
CTCAE v4.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred between treatments 
but 
DID NOT REQUIRE A 
DELAY 
IN TREATMENT 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY IN THE 
NEXT TREATMENT 
(See footnote b) 
Neutrophil count 
decreased: 
Grades 3, 4 
 
Maintain dose 
ANC: Hold until ³  1000/mm3; maintain dose 
and add G-CSFc 
 
If receiving G-CSF, ¯ one dose level 
Platelet count decreased: 
Grades 2, 3 
 
Maintain dose 
Platelets: Hold until ³  75,000/mm3.  If 
recovery takes: 
1 wk – maintain dose; 2-3 wks – ¯ one dose 
level 
Grade 4 
↓ one dose level 
Hold until ³  75,000/mm3 
↓ one dose level 
GI (if related to 
chemotherapy): 
Diarrhea 
Grade 2 
 
 
Maintain dose 
 
 
Maintain dose or ¯ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level or D/C 
¯ one dose level or D/C 
Mucositis - oral 
Grade 2 
 
Maintain dose 
 
Maintain dose or ↓ one dose level  
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
D/C 
D/C 
Vomiting (despite 
antiemetics) 
Grade 2 
 
Maintain dose or ¯ one dose 
level 
 
Maintain dose or ↓ one dose level 
Grades 3, 4 
↓ one dose level or D/C 
D/C 
Investigations (hepatic): 
Bilirubin, AST, alk phos 
Grade 2 
 
 
↓ one dose level 
Hold until bilirubin returns to the baseline 
grade 
and AST and alk phos have returned to £ grade 
1; ↓ one dose level 
Grade 3 
↓ one dose level or D/C 
Hold until bilirubin returns to the baseline 
grade 
and AST and alk phos have returned to £ grade 
1; ↓ one dose level or D/C 
Grade 4 
D/C 
D/C 
Infection or febrile 
neutropenia: 
Grade 2 
(N/A for febrile neutropenia) 
 
Maintain dose and add G-CSFc prophylaxis for subsequent chemotherapy cycles 
if neutropenia was present.d 
Grade 3 
Maintain dose and add G-CSFc prophylaxis for subsequent chemotherapy 
treatments.  If receiving prophylactic G-CSF, ¯ one dose level. 
Grade 4 
Maintain dose and add G-CSFc prophylaxis for subsequent chemotherapy 
treatments or D/C.  If receiving prophylactic G-CSF, ¯ one dose level or D/C. 
(Table 25 is continued on the next page.) 


 
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TABLE 25.  Treatment management for weekly paclitaxel (Groups 1B and 2B) (continued) 
CTCAE v4.0 
Adverse Event/Grade 
Modifications for AEs that 
occurred between 
treatments but 
DID NOT REQUIRE A 
DELAY 
IN TREATMENT 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY IN THE 
NEXT TREATMENT 
(See footnote b) 
Other clinically 
significant AEs:e 
Grade 2 
 
Maintain dose or ¯ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ one dose level or D/C 
D/C 
a Treatment may not proceed until clinically significant AEs are £ grade 1 (except neutrophils, 
which must be ³ 1000/mm3, and bilirubin, which must be £ the baseline grade). 
b Hold and check weekly.  With exception of neutrophils and bilirubin, resume treatment when 
toxicity is ≤ grade 1.  If toxicity has not resolved to £ grade 1 after 3 weeks of delay, discontinue 
paclitaxel (see Section 11.2 for trastuzumab instructions for Group 2B). 
c 
Only filgrastim on Days 2-6 may be used; pegfilgrastim is prohibited during paclitaxel. 
d If grade 2 criteria for infection include topical antibiotics or other local treatment, use of G-CSF is 
at the investigator's discretion. 
e 
Determination of "clinically significant" AEs is at the discretion of the investigator. 
 
TABLE 26.  Treatment management for paclitaxel-related neuropathy 
Nervous System Disorders 
• 
Paresthesias 
• 
Peripheral sensory 
neuropathy 
1 – 7 Days Duration 
Persistent for > 7 Days or 
Caused the Next Treatment 
to be Delayed 
Grade 1 
Maintain paclitaxel dose 
Grade 2 
Maintain paclitaxel dosea 
Decrease paclitaxel 
one dose levelb 
Grade 3 
First episode: 
Decrease paclitaxel one dose 
levela 
Second episode: 
Discontinue paclitaxel 
Discontinue paclitaxel 
Grade 4 
Discontinue paclitaxel 
a 
Must be resolved to £ grade 1 on the next treatment day. 
b 
Hold paclitaxel for persistent grade 2 neuropathy.  When £ grade 1, resume treatment with dose 
modification for paclitaxel.  If grade 2 toxicity persists after 3 weeks of delay, discontinue 
paclitaxel.  (For patients in Group 2B, see Section 11.2 for instructions regarding trastuzumab.) 
 


 
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TABLE 27.  Treatment management for paclitaxel-related musculoskeletal pain 
Note: The treatment management instructions in Table 27 apply to patients with musculoskeletal pain not 
controlled by analgesics.  Use of narcotics and NSAIDs is encouraged to maintain the paclitaxel dose if 
possible. 
Musculoskeletal and 
Connective Tissue Disorders 
• 
Arthralgia 
• 
Myalgia 
1 – 7 Days Duration 
Persistent for > 7 Days or  
Caused the Next Treatment 
to be Delayed 
Grade 1 
(despite analgesics) 
Maintain paclitaxel dose 
Grade 2 
(despite analgesics) 
Maintain paclitaxel dose 
Maintain paclitaxel dose 
or 
Decrease paclitaxel one dose 
level* 
Grade 3 
(despite analgesics) 
First episode: 
Decrease paclitaxel one dose 
level 
 
Second episode:  
Discontinue paclitaxel 
First episode: 
Decrease paclitaxel one dose 
level* 
or 
Discontinue paclitaxel 
 
Second episode:  
Discontinue paclitaxel 
* 
Hold paclitaxel for persistent grade 2 or 3 musculoskeletal pain.  (Trastuzumab should be 
continued while paclitaxel is held.)  When £ grade 1, resume treatment with dose modification.  If 
grade 2 or grade 3 toxicity persists after 3 weeks of delay, discontinue paclitaxel.  (For patients in 
Group 2B, see Section 11.2 for instructions regarding trastuzumab.) 
 


 
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11.0 
TRASTUZUMAB TREATMENT MANAGEMENT (GROUPS 2A AND 2B) 
11.1 
General instructions 
• 
The CTCAE v4.0 must be used to grade the severity of AEs.  Refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
• 
Treatment decisions should be based on the AE requiring the greatest modification. 
• 
There are no reductions in the trastuzumab dose.  If trastuzumab is held, the loading dose 
followed by the maintenance dose for the remaining doses may be administered, at the 
investigator's discretion, when resuming therapy. 
• 
Trastuzumab must end 1 year (51–52 weeks) following the first trastuzumab dose regardless 
of any missed doses. 
• 
During weekly trastuzumab therapy for Group 2B patients: The trastuzumab treatment 
schedule should be maintained.  If necessary, the timing of a trastuzumab treatment may be 
adjusted to 3 days earlier or 3 days later than the scheduled date of treatment.  However, no 
more than 2 trastuzumab doses may be given in a 2-week period. 
• 
If trastuzumab must be discontinued before completion of the scheduled TC cycles (Group 
2A) or WP cycles (Group 2B), the remaining TC or WP doses should be administered. 
• 
If alternative (non-protocol) therapy is given at any time, study trastuzumab must be 
discontinued. 
• 
In the event of tumor recurrence or diagnosis of a second invasive primary cancer, study 
trastuzumab must be discontinued.  Further therapy is at the investigator's discretion. 
11.2 
Trastuzumab instructions when chemotherapy is held or discontinued 
• 
When weekly paclitaxel is delayed for reasons not requiring a delay in trastuzumab, 
investigators are encouraged to continue trastuzumab.  However, at the discretion of the 
investigator, trastuzumab may also be held.  When docetaxel + cyclophosphamide is delayed, 
trastuzumab should also be held. 
• 
With the exception of cardiac toxicity, pulmonary toxicity, or severe allergic or anaphylactic 
reaction (related to trastuzumab), trastuzumab therapy should continue even if chemotherapy 
has been discontinued before completion of all chemotherapy cycles. 
• 
Refer to related instructions in Section 11.1. 
11.3 
Heart failure and left ventricular systolic dysfunction 
11.3.1 Symptomatic decrease in LVEF 
• 
Grade 2, 3, or 4 heart failure 
Discontinue trastuzumab. 
• 
Grade 3 or 4 left ventricular systolic dysfunction 
Discontinue trastuzumab. 
Note: The protocol-specified schedule for obtaining LVEF assessments should continue 
to be followed even after the discontinuation of study therapy or occurrence of a cardiac 
event. 


 
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11.3.2 Asymptomatic decrease in LVEF 
• 
LVEF requirements for initiation of trastuzumab are addressed in Section 9.6  
(Table 17). 
• 
Patients in Group 2A and Group 2B will undergo scheduled 2-D echocardiograms (or 
MUGA scans) to assess the LVEF at 3, 6, 9, and 12 months following randomization 
(see Table 6). 
• 
The results of the LVEF assessments during trastuzumab therapy will be used to 
determine if trastuzumab can be continued (see Table 28). 
• 
Refer to Section 5.3 for LVEF reporting instructions. 
TABLE 28.  Trastuzumab management based on LVEF assessments (Groups 2A and 2B) 
Table 28 provides instructions for patients who have an asymptomatic decrease in LVEF from 
baseline following any discretionary LVEF assessment during study therapy and at the scheduled 
assessment time points during therapy. 
LVEF 
Asymptomatic decrease in LVEF percentage points from baseline 
Decrease of < 10 
percentage points 
Decrease of ≥ 10  
percentage points 
³ 50% 
Continue trastuzumab 
Continue trastuzumab 
45-
49% 
Continue trastuzumab and repeat 
echo/MUGA in 3 weeks 
Hold trastuzumab and repeat echo/MUGA in  
3 weeks 
£ 44% 
Hold trastuzumab and repeat echo/MUGA in  
3 weeks 
Hold trastuzumab and repeat echo/MUGA in  
3 weeks 
Treatment rules based on "repeat" LVEF results: 
• Trastuzumab must be discontinued when two consecutive "hold" categories occur. 
• Trastuzumab must be discontinued when three intermittent "hold" categories occur. 
• 
If LVEF is maintained at "continue trastuzumab and repeat LVEF" category or improves from 
"hold" to a "continue and repeat LVEF" category, additional LVEF assessments before the next 
scheduled LVEF will be at the investigator's discretion. 
 
11.4 
Other trastuzumab-specific instructions 
Trastuzumab management for other adverse events is outlined on Table 29. 


 
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TABLE 29.  Treatment management for trastuzumab-related adverse events (Groups 2A and 2B) 
CTCAE v4.0 
Adverse Event 
CTCAE 
Grade  
Action to be Taken 
Cardiac Disorders 
Cardiac AEs listed in the 
Cardiac Disorders Section 
of the CTCAE v4.0. 
(Note: For heart failure 
and left ventricular 
systolic dysfunction, refer 
to Section 11.3) 
1 
Continue trastuzumab at the discretion of the investigator. 
2 
Hold trastuzumab and conduct cardiac evaluation.  Based on 
results of this evaluation, refer to Appendix D for grade 2 AEs 
that require discontinuation of trastuzumab.  For other grade 
2 cardiac AEs, trastuzumab should be held during evaluation of 
the AE and until £ grade 1; continue or discontinue at 
investigator's discretion. 
3, 4 
Discontinue trastuzumab. 
Gastrointestinal Disorders 
Diarrhea 
2 
Maintain dose without delay or hold trastuzumab until resolved 
to £ grade 1, then resume. 
3 
Hold trastuzumab until resolved to £ grade 1, then resume. 
4 
Discontinue trastuzumab. 
General Disorders 
Infusion-related reaction 
1, 2, 3, 4 
See instructions for allergic reaction. 
Immune System Disorders 
Allergic reaction 
1 
Slow the infusion and assess the patient; management is at the 
investigator's discretion. 
2 
Stop infusion and administer support medications per 
investigator's discretion.  When symptoms resolve to £ grade 1, 
infusion may be resumed later that day at a slower rate or on the 
next day at a slower rate with pre-meds.  Pre-meds should be 
used for all subsequent treatments. 
3 
Follow instructions for grade 2; trastuzumab may be 
discontinued at the investigator's discretion. 
4 
Discontinue trastuzumab. 
Anaphylaxis 
3 
Follow instructions for grade 3 allergic reactions or, at 
investigator's discretion, discontinue trastuzumab. 
4 
Discontinue trastuzumab. 
Respiratory, Thoracic, and Mediastinal Disorders 
ARDS 
3, 4 
Discontinue trastuzumab. 
Cough 
2, 3 
Follow instructions in footnote a. 
Dyspnea 
1, 2, 3 
Hold trastuzumab; rule out heart failure and non-infectious lung 
disease;  
follow instructions in footnote a. 
4 
Discontinue trastuzumab. 
Hypoxia 
2, 3 
Follow instructions in footnote a. 
4 
Discontinue trastuzumab. 
Pneumonitis 
2 
Follow instructions in footnote a. 
3, 4 
Discontinue trastuzumab. 
Pulmonary edema 
2, 3 
Follow instructions in footnote a. 
4 
Discontinue trastuzumab. 
(Table 29 is continued on the next page.) 


 
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TABLE 29.  Treatment management for trastuzumab-related adverse events (Groups 2A and 2B) 
 
(continued) 
CTCAE v4.0 
Adverse Event 
CTCAE 
Grade  
Action to be Taken 
Respiratory, Thoracic, and Mediastinal Disorders (continued) 
Pulmonary fibrosis 
1 
If fibrosis was present at baseline, trastuzumab may be continued 
at the investigator's discretion.  If new or worsening fibrosis, 
discontinue trastuzumab. 
2, 3, 4 
Discontinue trastuzumab. 
Pulmonary hypertension 
2, 3, 4 
Discontinue trastuzumab. 
Other 
Other clinically  
significant AEsb 
2 
Hold trastuzumab until £ grade 1 or discontinue trastuzumab. 
3, 4 
Discontinue trastuzumab. 
a Hold trastuzumab and determine etiology.  Unless prohibited based on instructions for other clinical diagnoses 
(i.e. other AEs), resume trastuzumab when grade 0 (if the AE requiring trastuzumab to be held was dyspnea) 
or when £ grade 1 (if the AE requiring trastuzumab to be held was ³ grade 2). 
b Determination of "clinically significant" is at the investigator's discretion and applies to those adverse events 
that can be attributed to trastuzumab and are not related to chemotherapy. 
 


 
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12.0 
DRUG INFORMATION 
12.1 
Chemotherapy 
Cyclophosphamide, docetaxel, doxorubicin, and paclitaxel will not be provided and must be 
obtained by the investigator from commercial sources.  Please refer to current FDA-approved 
package insert provided with each drug for toxicity information and instructions for drug 
preparation, handling, and storage. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
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13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
Please refer to Coordinator Online in the Members' Area of the NSABP Web site for general 
information regarding adverse event (AE) reporting. 
13.1 
B-47 definitions for AE reporting 
13.1.1 Investigational agent 
The investigational agent administered in NSABP B-47 is trastuzumab, which is being 
made available under an IND sponsored by the National Cancer Institute (NCI).  For 
patients who receive trastuzumab, expectedness of adverse events is based on the current 
NCI Specific Protocol Exceptions to Expedited Reporting (SPEER) for trastuzumab. 
13.1.2 Commercial agents 
The commercial agents in B-47 are cyclophosphamide, docetaxel, doxorubicin, and 
paclitaxel. 
13.1.3 Investigational combination therapy 
This study includes both investigational and commercial agents.  When an 
investigational agent (trastuzumab) is administered concurrently or sequentially with a 
commercial agent (cyclophosphamide, docetaxel, doxorubicin, or paclitaxel) and an AE 
occurs that is expected for the commercial agent(s), but is not listed for trastuzumab, the 
AE should be considered expected for the combination.  However, if based on clinical 
judgment, the investigator believes the adverse event is possibly, probably, or definitely 
related to the trastuzumab rather than the commercial agent(s), the AE should then be 
considered unexpected for the combination. 
13.1.4 Adverse event characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13.3 
Expedited reporting of adverse events 
NRG Oncology follows procedures for centralized reporting of adverse events.  Centralized 
reporting requires that adverse events be reported to the NRG Oncology SDMC.  The NRG 
Oncology SDMC forwards reports to the appropriate regulatory agencies and the pharmaceutical 
company involved in the trial.  Expedited reporting for B-47 utilizes the CTEP Adverse Event 
Reporting System (CTEP-AERS). 
NRG Oncology is identified in CTEP-AERS as the Lead Group for NRG Oncology protocols that 
require CTEP-AERS reporting.  Expedited AE reporting for this study must be submitted to 
the NRG Oncology Lead Group using CTEP-AERS, accessed via the CTEP home page  
https://eapps-ctep.nci.nih.gov/ctepaers.  In the rare event when Internet connectivity is disrupted, 
a 24-hour notification is to be made to CTEP by telephone at 301-897-7497.  An electronic report 
must be submitted immediately upon re-establishment of the Internet connection. 
13.3.1 Expedited reporting methods 
• 
CTEP-AERS 24 Hour Notification requires that a CTEP-AERS 24-hour 
notification is electronically submitted to the NCI within 24 hours of learning of the 
adverse event.  Each CTEP-AERS 24-hour notification must be followed by either a 
CTEP-AERS 3 Calendar Day Report (see Table 31) or a CTEP-AERS 5 Calendar 
Day Report (see Table 32). 
• 
CTEP-AERS 3 Calendar Day Report requires that a complete report is 
electronically submitted to the NRG Oncology Lead Group within 3 calendar days 
of submission of the CTEP-AERS 24-hour notification. 
• 
CTEP-AERS 5 Calendar Day Report requires that a complete CTEP-AERS report 
is electronically submitted to the NRG Oncology Lead Group within 5 calendar 
days of the investigator learning of the adverse event. 
• 
Supporting documentation is required for all CTEP-AERS reports.  Include the 
protocol number, patient's ID number, and CTEP-AERS ticket number on each page, 
and fax supporting documentation to the NRG Oncology SDMC (412-622-2113). 
13.3.2 Expedited reporting requirements – CTEP-AERS -24, CTEP-AERS, and other protocol 
requirements/exceptions 
• 
Expedited reporting requirements begin with the administration of the first 
chemotherapy dose.  Expedited reporting requirements for all Groups 2A and 2B 
patients who receive trastuzumab are provided in Table 31.  Expedited reporting 
requirements for Groups 1A and 1B patients are provided on Table 32. 
• 
There are protocol-specific requirements and exceptions for expedited reporting.  
Refer to Table 31 and Table 32 for instructions. 
13.3.3 Other recipients of adverse event reports 
Adverse events determined to be reportable must also be reported by the investigator to 
the Institutional Review Board responsible for oversight of the patient according to the 
local IRB's policies and procedures. 


 
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13.3.4 Expedited reporting requirements for patients receiving trastuzumab 
Expedited AE reporting requirements for Groups 2A and 2B patients receiving the 
investigational agent (trastuzumab) are listed in Table 31. 
TABLE 31.  CTEP-AERS expedited reporting requirements for adverse events that occur under a CTEP 
IND within 30 days of the last dose of the investigational agent (trastuzumab)1 
Expected 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 52 
Unexpected 
and 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected Expected 
with 
Hospital- 
ization 
without 
Hospital- 
ization 
Unrelated 
Unlikely 
Not 
Required 
Not Required 
Not Required 
5 Calendar 
Days 
Not 
Required 
5 Calendar 
Days 
5  
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 Calendar 
Days 
Not 
Required 
24-Hour; 
3 Calendar 
Days 
5 Calendar 
Days 
24-Hour; 
3 Calendar 
Days 
5  
Calendar 
Days 
1 Adverse events that occur more than 30 days after the last dose of investigational agent and have an 
attribution of possible, probable, or definite require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 3 calendar days for: 
• 
Grade 4 and grade 5 unexpected events  
CTEP-AERS 5 calendar day report: 
• 
Grade 3 unexpected events with hospitalization 
• 
Grade 5 expected events 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive 
disease, a full report is required as outlined in the table. 
 
Note: All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to agent administration or other cause should be provided. 
 
• Expedited AE reporting timelines defined: 
“24 hours; 3 calendar days” – The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the event followed by a complete CTEP-AERS report to the NRG Oncology Lead Group 
within 3 calendar days of the initial 24-hour report. 
“5 calendar days” - A complete CTEP-AERS report on the AE must be submitted to the NRG Oncology 
Lead Group within 5 calendar days of the investigator learning of the event.  
• Any event that results in a persistent or significant disability/incapacity or a congenital anomaly/birth defect, 
or is an important medical event which based upon medical judgment may jeopardize the patient and require 
intervention to prevent a serious adverse event, must be reported via CTEP-AERS if the event occurs 
following investigational agent administration. 
• Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all 
reports. 
 
(Table 31 is continued on the next page.) 


 
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TABLE 31.  CTEP-AERS expedited reporting requirements for adverse events that occur under a CTEP 
IND within 30 days of the last dose of the investigational agent (trastuzumab)1 
(continued) 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Adverse 
Events that Occur Under a CTEP-IND: 
 
a) Reports submitted via CTEP-AERS 24-hour notification are available for review by both the NCI and NRG 
Oncology after submission.  All other CTEP-AERS reports are first sent to the NRG Oncology Lead Group 
and then are forwarded to the NCI.  The timelines in the table above have been set so that the information can 
be forwarded to the NCI in a timely manner per the NCI/CTEP’s guidelines. 
b) On all reports, use the NCI protocol number, CTEP-AERS ticket number, and the protocol-specific patient ID 
provided during the trial registration.  Fax supporting documentation to the NRG Oncology SDMC. 
c) Hospitalization: AE requires inpatient hospitalization for ³ 24 hours, or prolongation of existing 
hospitalization. 
d) Refer to Section 13.1.3 for instructions regarding assignment of attribution and expectedness for 
investigational combination therapy. 
e) CTEP-AERS reporting is required for grade 2 unexpected adverse events requiring hospitalization and grade 3 
unexpected adverse events with or without hospitalization only if the adverse event is possibly, probably or 
definitely related to the investigational agent. 
f) Protocol-specific expedited reporting requirements: For this study, the adverse events listed below require 
expedited reporting via CTEP-AERS to the NRG Oncology Lead Group within 5 calendar days (or sooner if 
required based on other Table 31 instructions) of learning of the event: 
• 
Respiratory, Thoracic, and Mediastinal Disorders: ³ grade 3 pneumonitis (NOTE: Requires expedited 
reporting via CTEP-AERS from the first dose of study therapy until 30 days after the last dose of the 
investigational agent [trastuzumab]). 
• 
Cardiac disorders regardless of attribution: ³ grade 3 acute coronary syndrome; ³ grade 2 heart failure;  
³ grade 3 left ventricular systolic dysfunction; ³ grade 3 myocardial infarction  (NOTE: These cardiac-
related AEs require expedited reporting via CTEP-AERS from the first dose of study therapy until 2 
years from randomization.  Also, refer to Section 5.4 for additional instructions.) 
• 
Secondary malignancies as defined in Section 13.3.6 (NOTE: Secondary malignancies require expedited 
reporting via CTEP-AERS from the first dose of study therapy until the end of the patient's follow-up): 
- 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
- 
Myelodysplastic syndrome (MDS) 
- 
Treatment-related secondary malignancy 
g) Protocol-specific expedited reporting exceptions:  For this study, the adverse events listed below, including 
hospitalizations for these events, do not require expedited reporting via CTEP-AERS: 
• 
Blood and lymphatic systems disorders: During chemotherapy, grade 3 and grade 4 febrile neutropenia.  
(Note: Beginning 30 days following the last dose of chemotherapy and when a patient is receiving 
trastuzumab alone, grade 4 febrile neutropenia requires expedited reporting and grade 3 febrile 
neutropenia possibly, probably, or definitely related to trastuzumab requires expedited reporting. 
• 
Investigations: During chemotherapy, grade 4 decreased neutrophil count, platelet count, and white blood 
cell count.  (Note: Beginning 30 days following the last dose of chemotherapy and when a patient is 
receiving trastuzumab alone, these grade 4 events require expedited reporting.) 
• 
Neoplasms-malignant (i.e., a second primary malignancy) determined by the investigator to NOT be most 
probably related or definitely related to treatment for malignancy.  (See footnote f and Section 13.6.) 


 
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13.3.5 Expedited reporting requirements for patients receiving only chemotherapy 
Expedited AE reporting requirements for Groups 1A and 1B patients are listed in  
Table 32. 
TABLE 32.  CTEP-AERS expedited reporting requirements for adverse events that occur within 30 days 
of the last dose of chemotherapy 
Attribution 
Grade 2 
Grade 3 
Grade 4b 
Grade 5a,b 
Protocol-
Specific 
Requirements/ 
Exceptions 
Un-
expected 
Un-
expected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
-See footnote 
(c) for other 
requirements  
-See footnote 
(d) for special 
requirements 
-See footnote 
(e) for special 
exceptions 
Unrelated  
or Unlikely 
 
 
 
CTEP-
AERS 
 
CTEP-
AERS 
CTEP-
AERS 
Possible, 
Probable, 
Definite 
 
CTEP-
AERS if 
hospital-
ized 
 
CTEP-
AERS 
24 and 
CTEP-
AERS 
CTEP-
AERS  
24 
and 
CTEP-
AERS 
CTEP-AERS-24: Indicates a CTEP-AERS 24-hour notification must be electronically submitted to the NCI and to the NRG 
Oncology Lead Group within 24 hours of learning of the event. 
CTEP-AERS: 
Indicates a complete expedited report must be electronically submitted to the NRG Oncology Lead Group 
within 5 calendar days of learning of the event. 
Hospitalization: 
AE requires inpatient hospitalization for ³ 24 hours, or prolongation of existing hospitalization. 
All Reports:  
On all reports, use the NCI protocol number, CTEP-AERS ticket number, and the protocol-specific patient 
ID provided during trial registration.  Fax supporting documentation to the NRG Oncology SDMC. 
(Table 32 is continued on the next page.) 


 
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Table 32.  CTEP-AERS expedited reporting requirements for adverse events that occur within 30 days of 
the last dose of chemotherapy (continued) 
a) All deaths within 30 days of the last dose of study therapy require both routine and expedited reporting regardless 
of causality. Attribution to treatment or other cause should be provided. Although a CTEP-AERS expedited 
reporting requirements for adverse events that occur within 30 days of the last dose of chemotherapy 24-hour 
notification is not required for death clearly related to progressive disease, a complete CTEP-AERS report 
is required as outlined in the table. 
b) Adverse events that occur greater than 30 days after the last dose of study therapy with attribution of possible, 
probable or definite to study therapy require reporting as follows: 
• 
CTEP-AERS 24-hour notification followed by a complete CTEP-AERS report within 5 calendar days of 
learning of the event for:   
- 
grade 4 unexpected events  
- 
grade 5 unexpected events 
• 
CTEP-AERS 5-calendar day report for: 
 -  grade 5 expected events 
c) Any event that results in a persistent or significant disability/incapacity or a congenital anomaly/birth defect, or is 
an important medical event which based upon medical judgment may jeopardize the patient and require 
intervention to prevent a serious adverse event, must be reported via CTEP-AERS if the event occurs following 
chemotherapy administration. 
d) Protocol-specific expedited reporting requirements: For this study, the adverse events listed below require 
expedited reporting via CTEP-AERS to the NRG Oncology Lead Group within 5 calendar days (or sooner if 
required based on other Table 32 instructions) of learning of the event: 
• 
Respiratory, Thoracic, and Mediastinal Disorders: ³ grade 3 pneumonitis (NOTE: Requires expedited 
reporting via CTEP-AERS from the first dose of study therapy until 30 days after the last dose of 
chemotherapy.) 
• 
Cardiac disorders regardless of attribution: ³ grade 3 acute coronary syndrome; ³ grade 2 heart failure;  
³ grade 3 left ventricular systolic dysfunction; ³ grade 3 myocardial infarction  (NOTE: These cardiac-related 
AEs require expedited reporting via CTEP-AERS from the first dose of study therapy until  
2 years from randomization.  Also, refer to Section 5.4 for additional instructions.) 
• 
Secondary malignancies as defined in Section 13.3.6 (NOTE: Secondary malignancies require expedited 
reporting via CTEP-AERS from the first dose of study therapy until the end of the patients follow-up): 
- 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
- 
Myelodysplastic syndrome (MDS) 
- 
Treatment-related secondary malignancy 
e) Protocol-specific expedited reporting exceptions: For this study, the adverse events listed below which occur 
including hospitalization for these events, do not require expedited reporting via CTEP-AERS: 
• 
Neoplasms-malignant (i.e., a second primary malignancy) determined by the investigator to NOT be most 
probably related or definitely related to treatment for malignancy.  (See footnote d and Section 13.6.) 
13.3.6 Reporting a secondary malignancy 
A secondary malignancy is a cancer caused by a treatment for previous malignancy  
(e.g., treatment with investigational agent/intervention, radiation, or chemotherapy).  A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
All secondary malignancies that occur on NCI-sponsored trials either during or following 
treatment must be reported via CTEP-AERS within 5 days of learning of the secondary 
malignancy (see either Table 31 or Table 32).  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 


 
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Supporting documentation, including pathology and cytogenetics reports which confirm 
the secondary malignancy, must be faxed to the NRG Oncology SDMC expedited fax at 
412-622-2113.  Each page of supporting documentation must include the NCI protocol 
number, the CTEP-AERS ticket number, and the protocol-specific patient ID number 
provided during trial registration. 
Note:  All secondary malignancies should also be reported on the B-47 Form F (see 
Section 13.6). 
13.3.7 Second malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting online on the B-47 Form F (see Section 13.6). 
13.3.8 Expedited reporting of pregnancy, fetal death, and death neonatal occurring during 
study therapy 
Any pregnancy, fetal death, or death neonatal occurring while the patient is receiving 
study therapy or within 6 months following the last dose of study therapy, if the patient is 
in Arm 1, or within 7 months following the last dose of study therapy, if the patient is in 
Arm 2, must be reported via CTEP-AERS as a medically significant event.  Definitions 
and reporting instruction for these events are provided in the Cancer Therapy Evaluation 
Program's (CTEP) revised NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements (Section 5.5.6) located at the following CTEP website: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines. 
pdf). 
Upon learning of a pregnancy, fetal death, or death neonatal that occurs during study or 
within 6 months following the last dose of study therapy, if the patient is in Arm 1, or 
within 7 months following the last dose of study therapy, if the patient is in Arm 2, the 
investigator is required to: 
• 
Call the NRG Oncology Clinical Coordinating Department (see Information 
Resources).  Patients must immediately discontinue receiving study therapy. 
• 
Within 5 working days of learning of the event, and as required by the NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements (Section 5.5.6): 
- 
Create and submit an CTEP-AERS report;  
- 
Complete the Pregnancy Information Form (located in the NSABP Members' 
Area in Protocol B-47 "Forms and Supporting Documents"); and  
- 
Fax the completed Pregnancy Information Form with all available supporting 
documentation to the NRG Oncology SDMC's expedited fax number at  
412-622-2113. 
• 
The pregnancy outcome for patients on study should be reported via CTEP-AERS at 
the time the outcome becomes known, accompanied by the same Pregnancy 
Information Form used for the initial report. 
• 
For questions concerning AE reporting, contact the AE Reporting Nurse  
(see Information Resources). 


 
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13.4 
Routine reporting of adverse events 
13.4.1 Online reporting on the B-47 Treatment and Adverse Event Report form  
(Form TRTAE) 
• 
Direct online reporting of adverse events is done through the Online Data Entry 
function located in the Study Management Area of Coordinator Online in the 
Members' Area of the NSABP Web site. 
• 
Any grade 1 AE that required trastuzumab to be held or discontinued (see  
Table 29) and all ³ grade 2 adverse events not reported via CTEP-AERS that 
occurred during study therapy or during the 30 days following the last dose of study 
therapy must be reported on the B-47 Treatment and Adverse Event Report form 
(Form TRTAE). 
• 
Supporting documentation for each adverse event must be maintained in the patient's 
research record.  When submission of supporting documentation to the NRG 
Oncology SDMC is required, the online software will provide a transmittal form that 
must be printed.  Fax this transmittal form with the supporting documentation to  
412-622-2111.  Remove patient names and identifiers such as social security number, 
address, telephone number, etc. from reports and supporting documentation. 
13.4.2 Schedule for submission of the B-47 Form TRTAE 
Form TRTAE is submitted online to the NRG Oncology SDMC, even if no AEs were 
experienced by the patient, according to the following schedule: 
• 
All patients receiving chemotherapy with or without trastuzumab 
- 
During TC and AC: Submit Form TRTAE at the end of each cycle of 
chemotherapy. 
- 
During paclitaxel: Submit Form TRTAE after every 3 doses. 
- 
After the final dose of chemotherapy for patients not receiving trastuzumab:  
Submit Form TRTAE 30 days after the final dose of chemotherapy. 
• 
All patients receiving trastuzumab 
- 
During trastuzumab (given without chemotherapy): Submit Form TRTAE every  
9 weeks, if no treatment delay. 
- 
After the final dose of trastuzumab: Submit Form TRTAE 30 days after the final 
dose of trastuzumab.  (The final Form TRTAE will include the time period from 
the most recent Form TRTAE through 30 days after the last trastuzumab dose.) 
13.5 
Reporting selected late cardiac adverse events on the B-47 Follow-up Form (Form F) and 
Form CR 
Beginning at year 3 and continuing through year 10, the selected late cardiac adverse events listed 
below will be reported online on B-47 Form F and Form CR for all patients.  (Also, refer to 
Section 5.6 regarding required additional follow-up when late heart failure or left 
ventricular systolic dysfunction are reported.) 
• 
³ grade 3 acute coronary syndrome 
• 
³ grade 2 heart failure 
• 
³ grade 3 left ventricular systolic dysfunction 
• 
³ grade 3 myocardial infarction 


 
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Note: Supporting documentation must be submitted for each adverse event listed above and must 
be maintained in the patient's research record.  When submission of supporting documentation to 
the NRG Oncology SDMC is required, the online software will provide a transmittal form that 
must be printed.  Fax this transmittal form with the supporting documentation to 412-622-2111.  
Remove patient names and identifiers such as social security number, address, telephone number, 
etc. from reports and supporting documentation. 
13.6 
Reporting breast cancer recurrence, secondary malignancies, and second primary cancer 
Report breast cancer recurrence, secondary malignancies (including leukemia secondary to 
oncology chemotherapy, myelodysplastic syndrome, and treatment-related secondary malignancy 
previously reported through CTEP-AERS), and second primary cancer (a malignancy which is 
unrelated to the treatment of a prior malignancy and which is not a metastasis from the initial 
malignancy) online on the B-47 Form F.  Fax supporting documentation, unless previously faxed 
to the NRG Oncology SDMC with an CTEP-AERS report, that confirms the breast cancer 
recurrence or second primary cancer diagnosis with the transmittal form (provided by the online 
software and printed) to 412-622-2111. 


 
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14.0 
DOCUMENTATION OF BREAST CANCER RECURRENCE AND SECOND 
MALIGNANCIES 
14.1 
General instructions 
• 
Documentation of a breast cancer recurrence requires meeting at least one of the criteria 
defined below.  Suspicious findings do not provide adequate documentation of a breast 
cancer recurrence, and should not be an indication to alter protocol therapy. 
• 
Tumor marker evaluations alone do not document breast cancer recurrence. 
• 
Treatment of a breast cancer recurrence or second primary cancer will be at the discretion of 
the investigator. 
14.2 
Local recurrence 
Note: If the first local recurrence is non-invasive breast cancer, the first invasive breast cancer 
must also be reported. 
Recurrent local tumor is defined as evidence of invasive breast cancer or DCIS in the ipsilateral 
breast or invasive breast cancer in the skin of the ipsilateral breast.  Patients who develop clinical 
evidence of local recurrence in the ipsilateral breast must have a biopsy confirmation of 
recurrence.  However, if a patient also meets criteria for regional or distant metastatic disease, 
results of clinical exams alone will be sufficient to document local recurrences. 
14.2.1 Ipsilateral breast tumor recurrence (IBTR) 
An IBTR event is defined as recurrent invasive or non-invasive breast cancer in the 
ipsilateral breast parenchyma or invasive breast cancer in the skin of the breast occurring 
after lumpectomy. 
Acceptable documentation includes core, incisional or excisional biopsy.  Cytology alone 
will not be adequate to establish IBTR. 
14.2.2 Other local recurrence 
Defined as recurrence in the skin of the chest wall (exclusive of the breast) or chest wall. 
Acceptable documentation includes core, incisional or excisional biopsy, as well as 
cytology. 
14.3 
Regional recurrence 
Defined as the development of tumor in the ipsilateral internal mammary, ipsilateral 
supraclavicular, ipsilateral infraclavicular and/or ipsilateral axillary nodes, as well as the soft 
tissue of the ipsilateral axilla, following surgery.  Recurrence must be confirmed by biopsy or 
cytology.  However if a patient meets criteria for distant metastatic disease, results of clinical 
exams alone will be sufficient to document regional recurrences. 


 
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14.4 
Distant recurrence 
Defined as evidence of tumor in all areas, with the exception of those described in Sections 14.2 
and 14.3.  The first distant recurrence and the first central nervous system recurrence will 
be reported.  Further treatment for distant metastasis, with or without evidence of local-regional 
recurrence, will be at the discretion of the investigator.  
14.4.1 Skin, subcutaneous tissue, and lymph nodes (other than local or regional) 
Acceptable documentation includes positive cytology, aspirate or biopsy, or radiologic 
evidence of metastatic disease. 
14.4.2 Bone marrow 
Acceptable documentation includes positive cytology, aspirate, biopsy, or MRI scan. 
14.4.3 Lung 
Acceptable documentation includes: (i) positive cytology, aspirate, or biopsy, or (ii) 
radiologic evidence of multiple pulmonary nodules that are judged to be consistent with 
pulmonary metastases. 
Note: If a solitary lung lesion is found and no other lesions are present on lung 
tomograms, CT scan, or MRI scan, further investigations, such as biopsy, needle 
aspiration, PET-CT scan, or PET scan should be performed.  Proof of neoplastic pleural 
effusion must be established by cytology or pleural biopsy. 
14.4.4 Skeletal 
Acceptable documentation includes: (i) x-ray, CT, or MRI evidence of lytic or blastic 
lesions consistent with bone metastasis, (ii) biopsy proof of bone metastases, or (iii) bone 
scan, PET-CT scan, or PET scan clearly positive for bone metastases. 
Note: If the diagnosis is equivocal by bone scan or radiologic evaluation, a biopsy is 
strongly recommended.  A bone scan with uptake limited to joints or in a recent area of 
trauma (surgical or otherwise) cannot be used as a criterion for breast cancer recurrence. 
14.4.5 Liver 
Acceptable documentation includes: (i) abdominal CT scan, liver scan, ultrasound, MRI, 
PET-CT scan, or PET scan consistent with liver metastases, or (ii) liver biopsy 
confirmation of the metastatic disease. 
Note: If the radiologic findings are not definitive (especially with solitary liver nodules), 
a liver biopsy is recommended; however, if a biopsy is not performed, serial scans must 
be obtained to document stability or progression. 
14.4.6 Central nervous system 
Acceptable documentation includes: (i) positive CT scan, PET-CT scan, PET scan, or 
MRI scan, usually in a patient with neurological symptoms, or (ii) biopsy or cytology (for 
a diagnosis of leptomeningeal involvement). 


 
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14.5 
Contralateral breast cancer 
Contralateral breast cancer is defined as evidence of invasive breast cancer or DCIS in the 
contralateral breast or chest wall.  The diagnosis of a contralateral breast cancer must be 
confirmed by core, incisional, or excisional biopsy.  Cytology alone will not be adequate to 
document a contralateral breast cancer. 
14.6 
Second primary cancer 
Second primary cancer is defined as any invasive non-breast cancer other than squamous or basal 
cell carcinoma of the skin.  The diagnosis of a second primary cancer must be confirmed 
histologically whenever possible. 
14.7 
Documentation requested following death 
• 
Autopsy reports should be secured whenever possible and should be submitted to the NRG 
Oncology SDMC. 
• 
A copy of the death certificate should be forwarded to the NRG Oncology SDMC if it is 
readily available or if it contains important cause-of-death information that is not documented 
elsewhere. 
• 
Please submit the last clinic/office note made before the death or the investigator’s note 
summarizing events resulting in death. 


 
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15.0 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
Note: Accrual closed on February 10, 2015, following achievement of the sample size goal. 
15.1 
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>. 
15.2 
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>. 
15.3 
CTSU registration procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 


 
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15.3.1 IRB approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ website by entering credentials 
at https://www.ctsu.org.  For sites under the CIRB initiative, IRB data will automatically 
load to RSS. 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing or amendment review.  This information will be provided to 
the CTSU Regulatory Office from the CIRB at the time the site’s Signatory Institution 
accepts the CIRB approval.  The Signatory site may be contacted by the CTSU 
Regulatory Office or asked to complete information verifying the participating 
institutions on the study.  Other site registration requirements (i.e., laboratory 
certifications, protocol-specific training certifications, or modality credentialing) must be 
submitted to the CTSU Regulatory Office or compliance communicated per protocol 
instructions. 
15.3.2 Downloading site registration documents 
Site registration forms may be downloaded from the NSABP B-47 protocol page located 
on the CTSU members’ website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the NCTN Groupname link to expand, then select trial protocol NSABP  
B-47 
• 
Click on the Site Registration Documents link 
15.3.3 Requirements for protocol number site registration 
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the 
NCI CIRB) 
15.3.4 Submitting regulatory documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org (Members' area) ® Regulatory Tab ® 
Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 


 
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15.3.5 Checking your site's registration status 
Check the status of your site's registration packets by querying the RSS site registration 
status page of the members' section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members' area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
15.4 
Patient consent form 
Before the patient is enrolled, the consent form, including any addenda, must be signed and dated 
by the patient and the person who explains the study to that patient. 
15.5 
Patient enrollment 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility criteria 
have been met, and the study site is listed as ‘approved’ in the CTSU RSS. 
15.6 
Required submission of tumor samples 
As part of the B-47 consent form, all patients have agreed to allow the submission of tumor 
blocks (see Section 7.1). 
15.7 
Regulatory requirement for Canadian institutions 
Any Canadian institution that will utilize PET scans in the conduct of this study must indicate the 
intent to do so to the NRG Oncology Department of Regulatory Affairs prior to initiating patient 
enrollment at the institution (and any satellites).  Use of PET scans as part of this study may 
require submission by NRG Oncology of specific documentation to Health Canada before 
activation of the trial at the institution. 
15.8 
Oncology Patient Enrollment Network (OPEN) 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data.  OPEN can be accessed at https://open.ctsu.org 
or from the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. 


 
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Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  (Site staff should 
use the registration forms provided on the NRG Oncology or CTSU Web site as a tool to 
verify eligibility.) 
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration, 
including the Patient ID number for the study, and treatment information.  Please print this 
confirmation for your records.  Additionally, a transmittal form to be used when faxing the 
signed consent form to the NRG Oncology SDMC will be provided.  If it is necessary to 
reprint the randomization confirmation or the transmittal form, they can be reprinted through 
Coordinator Online via the View a Patient Entry Report under Patient Entry. 
Further instructional information is provided on the OPEN tab of the CTSU members' side of the 
CTSU Web site at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
15.9 
Patient study number 
After randomization, the institution will receive the Patient ID number for the study. 
15.10 Patient-initiated discontinuation of study therapy 
Even after a patient agrees to take part in this study, she may stop study drug or withdraw from 
the study at any time.  If study therapy is stopped but she still allows the study doctor to submit 
information, study data and other materials must be submitted according to the study schedule, 
including any Menstrual History study and Host Factors study assessments and blood samples, as 
well as any correlative science tumor and blood samples. 
15.11 Withdrawal from the study 
If a patient chooses to have no further interaction regarding the study (i.e., allow no future  
follow-up data to be submitted to NRG Oncology SDMC), the investigator must provide the 
NRG Oncology SDMC with written documentation of the patient’s decision to fully withdraw 
from the study. 
15.12 Investigator-initiated discontinuation of study therapy 
In addition to the conditions outlined in the protocol, the investigator may require a patient to 
discontinue study drug if one of the following occurs: 
• 
the patient develops a serious side effect that she cannot tolerate or that cannot be controlled 
with other medications, 
• 
the patient’s health gets worse, 
• 
the patient is unable to meet the study requirements, or 
• 
new information about the study drug or other treatments for breast cancer becomes 
available. 
If study therapy is stopped but she still allows the study doctor to follow her care, she should 
continue to be followed according to the study schedule. 


 
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16.0 
REQUIRED DATA COLLECTION 
16.1 
Data collection 
B-47 data collection will include the following elements: 
• 
Patient characteristics 
• 
Menstrual history as described in Section 8.2 
• 
Concomitant medications 
• 
Tobacco and alcohol use 
• 
Comorbid conditions 
• 
Weight and height 
• 
Characteristics of the breast cancer 
• 
AJCC TNM stage 
• 
Study treatment administered 
• 
Other treatment including RT and endocrine therapy 
• 
LVEF assessments 
• 
Cardiac events as described in Sections 5.4, 5.5, and 5.6 
• 
Adverse events as described in Section 13.0 
• 
Breast cancer events (local, regional, and distant) 
• 
Second primary cancer events 
• 
Survival 
16.2 
Instructions for completion and submission of B-47 forms and materials 
• 
Submit all completed CRFs (with the exception of patient enrollment forms), clinical reports, 
and other documents directly to the NRG Oncology SDMC.  Submission of study data 
directly to NRG Oncology is done through the Online Data Entry function located in the 
Study Management Area of Coordinator Online in the Members' Area of the NSABP Web 
site.  Contact the Support Desk at support@nrgoncology.org for an account.  When 
submission of supporting documentation to the NRG Oncology SDMC is required, fax to 
412-622-2111.  Remove patient names and identifiers such as social security number, 
address, telephone number, etc. from reports and supporting documentation. 
• 
The NRG Oncology SDMC will send query notices and delinquency reports directly to the 
site for reconciliation.  Please send query responses and delinquent data to the NRG 
Oncology SDMC and do not copy the CTSU Data Operations.  If the query is sent with fax 
transmittal form, return the data to the fax number on the transmittal form, otherwise fax to 
412-624-1082. 
• 
Data form worksheets and specimen transmittal forms, as well as instructions for completion 
and submission of data and materials, are available in the Members' Area of the NSABP Web 
site, http://www.nsabp.pitt.edu.  (CTSU investigators should refer to the NSABP B-47 Web 
page located on the CTSU Member site.)  Sites must use the current form versions and adhere 
to the instructions and submission schedule outlined in the protocol. 
16.3 
Data monitoring for CTEP 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  CTEP has 
assigned abbreviated CDUS reporting: no AE reporting (routine or expedited) is required via any 
of the CDUS mechanism.  Cumulative CDUS data will be submitted quarterly by the NRG 
Oncology SDMC by electronic means.  Reports are due January 31, April 30, July 31, and 
October 31. 


 
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17.0 
STATISTICAL CONSIDERATIONS 
17.1 
Primary endpoint 
The primary endpoint for efficacy analysis is invasive disease-free survival (IDFS) (see  
Section 3.1). 
17.2 
Secondary endpoints 
Secondary efficacy endpoints include disease-free survival (DFS-DCIS), breast cancer-free 
survival (BCFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), and 
overall survival (OS).  Secondary safety endpoints include the frequency and severity of adverse 
events graded according to the CTCAE v4.0.  (See Section 17.9 for additional endpoints related 
to the Menstrual History and Host Factors sub-studies.) 
17.3 
Stratification and randomization 
Assignment of treatments to patients will be balanced with respect to IHC score (1+, 2+), 
pathologic nodal status (0-3, 4-9, 10+ positive nodes), hormone receptor status (ER-positive 
and/or PgR-positive, ER- and PgR-negative), and intended chemotherapy regimen  
(TC, AC®WP) as specified prior to randomization, using a biased-coin minimization 
algorithm.101 
17.4 
Patient cohorts 
The primary objective of this trial is to show that the addition of trastuzumab to chemotherapy 
(either TC [Groups 1A and 2A] or AC®WP [Groups 1B and 2B]) improves IDFS.  Patients will 
be entered in one of these two chemotherapy cohorts based on the investigator's preference, 
which must be indicated prior to randomization. 
17.5 
Sample size calculation 
17.5.1 Estimates of annual hazard rates 
We have estimated yearly hazard rates for IDFS events in breast cancer patients treated 
with TC reported in Jones et al.61  We approximated the total person years by first 
multiplying the number of patients in the TC arm by the median follow-up in months and 
then by dividing it by 12 to make it an annual rate, i.e., (506 x 66)/12=2783. 
Based on this estimate of the total person years, the annual hazard rate was estimated as  
0.028 (=79/2783).  Here the 79 events include recurrence or second primary cancer, and 
death without recurrence from Table 2 in Jones et al.61 
17.5.2 Accrual rate and total sample size 
This protocol will be attractive to patients similar to those who participated in the 
NSABP B-36 and B-38 trials.  Based on our experience in those trials, it is realistic to 
assume an eventual steady-state accrual of 100 patients per month.  To account for delays 
in getting the trial approved by local IRBs and initiated at each potential site of accrual, 
we assume linear ramp-up from 10 to 100 patients per month during the first year of 
accrual.  A steady monthly accrual of 100 patients was assumed thereafter. 
The total accrual to the trial will be 3,260 patients.  This sample size will provide 
statistical power of 0.9 to detect a 33% reduction in the hazard rate among the 
chemotherapy plus trastuzumab group compared to the chemotherapy alone group using 
a one-sided alpha level of 0.025.  The projected time to reach this accrual goal is 3 years 
and 2 months. 


 
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17.6 
Statistical analysis 
17.6.1 Primary efficacy analysis: Compare the chemotherapy plus trastuzumab group to the 
control group (chemotherapy alone) with respect to IDFS 
Timelines: We will perform the definitive analysis comparing chemotherapy plus 
trastuzumab to Control (chemotherapy alone), using IDFS as the primary endpoint, when 
262 events have occurred in total on the Control + chemotherapy/trastuzumab arms.  The 
comparison will be performed using a log rank test. 
• 
The estimated time required to accrue 3,260 patients is 3 years, 2 months. 
• 
The estimated time to reach the required number of events is 5 years and 6 months 
from the start of accrual. 
• 
Allowing an additional 6 months for reporting and data lock, the total time from start 
of accrual to analysis will be roughly 6 years. 
17.6.2 Interim efficacy analyses 
There will be three interim analyses.  The first interim analysis will take place at the first 
regularly scheduled meeting of the NRG Oncology Data Monitoring Committee (DMC)  
when 66 events have occurred in total on the Control (chemotherapy alone) + 
chemotherapy/trastuzumab arms.  Subsequent interim analyses will take place according 
to the schedule outlined on Table 33. 
 
TABLE 33.  Interim monitoring schedule 
Interim and final 
analysis 
(k) 
Approximate number 
of events 
in each comparison 
Lower 
significance level 
(for futility) 
Upper 
significance level 
1 
66 
0.01 
0.0001 
2 
131 
0.05 
0.00025 
3 
197 
0.3 
0.00025 
Final analysis 
262 
N/A 
0.0246 
At each interim analysis, the experimental arm (chemotherapy plus trastuzumab) will be 
compared to the control arm (chemotherapy alone) using IDFS as the primary endpoint.  
At each interim analysis, crossing the upper boundary will indicate that the experimental 
arm is significantly better than the control arm at a pre-specified nominal level given in 
Table 33.  If that happens, the DMC will consider declaring the experimental treatment to 
be superior to the control and terminating the study.  We expect that one-sided type I 
error probability for the definitive analysis will be approximately 0.0246. 
At each interim analysis, the experimental arm will also be tested against the control arm 
to see whether the study should be stopped due to futility (see Table 33).  For example, at 
the first interim analysis, consideration will be given to stopping the study if the 
experimental arm is significantly worse than the control arm with one-sided significance 
level of 0.01. 
Under our data management system, summary files are locked every 3 months for 
approval, so in practice the numbers of events at each interim analysis may differ slightly 
from the numbers given in Table 33.  If significant deviations are necessary, the 
parameters will be adjusted by alpha-spending102 to insure that the type 1 error control 
criteria cited above are maintained. 


 
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17.7 
Monitoring of adverse events 
The occurrence of adverse events, including toxicities and deaths, will be monitored.  Summaries 
of all adverse events will be prepared and discussed at regularly scheduled meetings of the NRG 
Oncology Medical Affairs Division. 
In addition, throughout the periods in which the protocol is open to accrual or patients are 
receiving therapy, semi-annual progress reports will be made to the NRG Oncology DMC.  These 
reports will include an assessment of toxicities, including cardiac events as described in  
Sections 5.4, 5.5, and 5.6 and deaths during study therapy; a comparison of actual and projected 
accrual; and an assessment of data quality, including data delinquency and rates of eligibility.  
After accrual is closed, reports of adverse events, together with the results of planned interim 
analyses of the primary endpoints will be presented in semi-annual progress reports to the DMC. 
17.8 
Sample size considerations and analysis plan for correlative studies dealing with HER2 
mRNA and Fcγ receptor polymorphism 
A sample size of 2,500 will be sufficient to evaluate an interaction between HER2 mRNA and 
treatment.  This is based on the conservative case of dichotomized expression level thereby 
dealing with a 2-by-2 table.  We assume that the probability of falsely rejecting the null 
hypothesis of no interaction is 10%.  By using the results proposed in Peterson and George103 
with the sample size of 2,500, the probability of detecting the interaction hazard ratio of 0.5 is 
expected to be 81%.  The same cohort of patients will be used to validate Fcγ receptor 
polymorphism as a predictor. 
The interaction between treatment effect and HER2 mRNA level will be evaluated in the 
proportional hazards model104, which would include an indicator for treatment group and the 
HER2 mRNA level as a continuous variable, and the corresponding interaction term.  The  
log-hazard ratio plot for the interaction term with 95% confidence intervals will be used to 
determine the cut-off of the HER2 mRNA level that would determine a subset of the patients who 
would benefit from the adjuvant trastuzumab therapy.  The polymorphism of the Fcγ 158 receptor 
gene will be dichotomized as V/V (valine) vs. other genotypes and the polymorphism of the Fcγ 
131 receptor gene will be dichotomized as H/H (histidine) vs. other genotypes to evaluate an 
interaction between treatment group and Fcγ polymorphism.  The Kaplan-Meier method105 will 
be used to estimate the distribution of the primary endpoints stratified by the dichotomized 
subgroups, and the log-rank test106 will be used to statistically compare the time-to-event 
distributions. 
The potential association between response with anthracycline and HER2 level could impact on 
estimated trastuzumab benefit differently in the two chemotherapy groups.  To investigate this, an 
interaction between HER2 level and treatment with/without anthracycline will be evaluated.  If 
there is a significant interaction at the 2-sided level of 0.05, it will be included as an adjusting 
factor for the main analysis. 


 
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17.9 
Statistical considerations for Menstrual History and Host Factors sub-studies 
17.9.1 Menstrual History sub-study analyses 
The primary endpoints for the MH sub-study are amenorrhea (cessation of menses for  
³ 6 months), circulating ovarian hormone suppression (the following set of conditions: 
low levels of estradiol and elevated levels of FSH), and duration of amenorrhea.  The 
time to amenorrhea and time to hormone suppression will be censored if a patient 
undergoes a hysterectomy with or without oophorectomy, and will also be censored at the 
time of a new cancer event, death, or last follow-up in the absence of any of the specified 
events.  Statistical tests will be two-sided.  The two primary analyses will be tested at 
significance level 0.05/2.  All secondary and exploratory analyses will be performed at 
significance level 0.05, without adjustment for multiple comparisons, and reported as 
secondary or exploratory.  In the Cox regressions described below, we will test the 
proportional hazards assumption by creating an artificial time-dependent covariate and 
testing its interaction with other covariates, as described in Klein and Moeschberger, and 
will explore more appropriate models if the assumption is not satisfied.107 
Hypotheses in Section 8.2.7 will be tested as follows.  Primary hypothesis (a) will be 
tested using a kappa test for agreement between two raters, to determine whether patients 
with amenorrhea are more likely to have hormone suppression, including data from 6 and 
12 months to determine whether amenorrhea and hormone suppression have occurred.  
This test will be performed without regard to treatment assignment or other predictors of 
amenorrhea because the objective is to determine whether these two approaches to 
detecting amenorrhea coincide, although in exploratory analyses we may examine 
whether the approaches have greater agreement within subgroups of patients.  For 
primary hypothesis (b), the fraction of patients with amenorrhea will be compared 
between treatment groups according to the random assignment using a Binomial test of 
two proportions.  An exploratory examination will consider only patients with positive 
ER status.  For this analysis and for secondary hypothesis (b), we will use the full time 
course of amenorrhea.  The denominator for the proportions will be the number of 
patients who had at least one MH follow-up.  However, any bias in the compliance with 
MH assessments between treatment groups will also bias these analyses because more 
assessments provide a greater opportunity to observe amenorrhea.  We will address this 
as described below under “Missing Data.” 
Secondary hypothesis (a) will be tested using Cox proportional hazards regression of the 
time from establishment of amenorrhea (time at which ³ 6 months of amenorrhea are first 
observed; that is, 6 months after the last bleeding) to the resumption of menses, with 
explanatory factors age (< 40, 40–49, ≥ 50), TC regimen, use of tamoxifen, or ovarian 
suppression therapy (e.g., GnRH analog therapy), and baseline hormonal profile (i.e., low 
estradiol and elevated FSH).  We will also include ER and PR status and two-way 
interactions of those with TC regimen.  This analysis includes only those patients who 
have amenorrhea. 
For secondary hypothesis (b), we will use Cox proportional hazards regression of the 
time from randomization to onset of amenorrhea (date of last period before > 6 months of 
amenorrhea as reported by the patient to the coordinator), with explanatory factors TC 
regimen (the factor of interest), age (< 40, 40–49, ≥ 50), use of tamoxifen, or ovarian 
suppression therapy (e.g., GnRH analog therapy), and baseline hormonal profile (i.e., low 
estradiol and elevated FSH).  We will also include ER and PR status and two-way 


 
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interactions of those with the TC regimen.  The analysis of time to onset of hormone 
suppression will be handled differently because hormone suppression will only be 
detected as of the time of a blood draw.  We will use ordinal logistic regression 
(classifying onset time as 6 months, 12 months, etc.), including the same list of 
explanatory variables. 
To test secondary hypothesis (c), we will conduct model building and internal validation 
using four-fold cross-validation.108  We first randomly divide the sub-study patients into 
four subsets of equal size, stratified by age (< 40, 40–49, ≥ 50) and TC regimen. 
Combining three of the subsets into a training set, we will perform weighted logistic 
regression, classifying women as having developed early, permanent amenorrhea (no 
return of menses at 36 months, with amenorrhea duration ³ 30 months) versus all others.  
A fraction of women will not be evaluable for permanent amenorrhea due to cancer 
recurrence, death, or missing data for other reasons.  Women whose disease-free survival 
is shorter than 36 months will not be considered in this analysis, and the results will be 
viewed as conditional on being alive and disease-free at 36 months. To account for data 
that are missing for other reasons, we will use a propensity score approach, first 
performing a logistic regression for evaluable status using the same factors listed below 
for this hypothesis.  The propensity scores will then be used to define weights for the 
logistic regression of permanent amenorrhea.  Explanatory variables will be demographic 
and behavioral factors (age, weight, ethnicity, current tobacco use, prior hormone use), 
medical (treatment assignment-cytoxan duration), menstrual history (bleeding patterns in 
year prior to diagnosis), and baseline ovarian hormones.  Variables that are not 
significant at the 0.10 level in this multivariable analysis will be removed from the final 
model.  (A liberal significance level is used because prediction is the goal rather than 
model parsimony or tests of the significance of individual variables.)  To evaluate 
whether the predictive model is useful, we will then apply the estimated factor 
coefficients to the data in the remaining quarter subset (the test set) and compute the 
sensitivity, specificity, and the negative and positive predictive values.  This process of 
model building and testing will be repeated three additional times by leaving out one-
quarter each time.  The means and standard errors of sensitivity, specificity, and the 
negative and positive predictive values will be reported.  A final model will then be 
constructed using the same approach, including all evaluable patients. 
To test secondary hypothesis (d), we will conduct a landmark Cox regression analysis of 
the time from the 6-month blood draw to the first invasive cancer event or death.  The 
time will be censored at the last follow-up in the absence of an invasive cancer event or 
death.  The explanatory factors will be circulating hormone suppression as of the 6-month 
sample, chemotherapy and trastuzumab treatment, stratification factors used in the 
randomization, and interaction terms between hormone receptor status and TC regimen.  
The same 6-month landmark analysis will be used to test the prognostic significance of 
amenorrhea at 6 months.  However, for this analysis we will consider women 
amenorrheic if their most recent bleeding occurred at least 3 months prior.  (In this way, 
we will include amenorrhea that began in response to chemotherapy.) 
To test secondary hypothesis (e), we will assess associations between genetic variants 
and CRA (defined as no periods between the end of chemotherapy and the last available 
menstrual follow-up).  We will pool our genome-wide association data with data from 
other large clinical trials to obtain a sample size of 2800.  Analyses will be adjusted for 
study, time from last dose of chemotherapy to last follow-up, BMI, age, chemotherapy 
regimen (grouping those with similar doses of alkylating agents and anthracyclines), and 


 
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endocrine therapy (including time on and time since last ovarian function suppression 
medication administration) because other studies have shown that these variables may all 
impact risk of CRA.  An individual’s genotype for each SNP will be coded to represent 
the number of copies of the minor allele that she carries.  We will assign individuals to 
major racial groups by comparing genome-wide genotypes to 1000 Genome reference 
data using the software STRUCTURE and REAP.  These methods provide estimates of 
the probability a patient belongs to a major racial group, and we assign each patient to a 
genetically defined race group based on the maximum probability.  We will focus the 
primary analysis on genetically defined White and non-Hispanic patients to optimize our 
power.  To further adjust for population stratification within a genetically defined race 
group, we will estimate principal components based on all SNPs, using EIGENSTRAT 
software.109  Then, stratifying on race, we will evaluate whether additional covariates 
associated with the CRA should be used as adjusting factors.  Covariate selection will be 
performed within each stratum based on p-values for covariates < 0.1 (a somewhat liberal 
threshold). 
Once each stratum of race has clearly defined principal components and adjusting 
covariates, we will perform a GWAS analysis within White non-Hispanics.  Tests of 
association between SNPs and CRA will be performed using R or PLINK statistical 
software, based on logistic regression.  We will explore other tools appropriate for  
data-rich situations including approaches that assess for an over-abundance of small  
p-values within specific pathways identified in the literature, and using classification and 
regression trees to identify other combinations of SNPs associated with CRA.  To reduce 
false positives, we will adhere to the common practice of using a p-value threshold of 
5x10-8. 
To test secondary hypothesis (f), we will evaluate AMH as a biomarker for CRA.  We 
will pool these data with data from other clinical trials (total N=2900), and treat AMH as 
a continuous covariate in a logistic model for CRA, adjusting for other covariates  
(e.g., age, BMI, chemotherapy regimen received, endocrine therapy, and months of 
ovarian function suppression).  We will assess whether or not AMH should be modeled 
with a linear effect versus a more flexible model using natural cubic splines.  Two-sided 
p-values < 0.05 will be considered significant.  We also plan an exploratory analysis of 
the association of AMH with time to menstruation using a Cox proportional hazards 
model with time-dependent covariates, and we will model the interaction between AMH 
and each of the SNPs that were found to be associated with CRA. 
17.9.2 Host Factors sub-study analyses 
The primary endpoint for the Host Factors sub-study is invasive disease-free survival 
(defined in Section 3.1).  Time is measured from randomization except in landmark 
analyses described below.  Primary and secondary hypotheses will be tested using Cox 
proportional hazards regression.  General statistical considerations will follow those in 
Section 17.9.  Hypotheses in Section 8.3.7 will be tested as follows. 
For primary hypothesis (a), the explanatory factors will be baseline BMI, tobacco and 
alcohol use, comorbid conditions, trastuzumab group, chemotherapy regimen, and 
stratification factors.  Primary hypothesis (b) will be tested with a landmark analysis in 
which event time will be measured from 1 year and the analysis will include only those 
patients who are alive and free of invasive cancer as of 1 year.  The explanatory variables 
will be the same as for hypothesis (a) except with the addition of the slope of BMI from 


 
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baseline to 1 year.  The effect of overweight in hypothesis (a) and effect of weight change 
in hypothesis (b) will be tested at significance level 0.05/2. 
For secondary hypothesis (a), explanatory variables will include baseline use of 
metformin, aspirin, NSAIDs, beta blockers, ACE inhibitors, and ARBs, as well as 
baseline BMI, tobacco use, alcohol, and comorbid conditions.  Exploratory analyses will 
include interactions among metformin, aspirin, NSAIDs, ACE inhibitors, and ARBs, and 
beta blockers, and will also consider the use of these agents over time as a time-varying 
factor.  Hypothesis (b) will be tested with two Cox regression analyses: one using only 
baseline CRP elevation (and other factors listed above), and the second using elevation of 
CRP at baseline and/or 12 months, using a landmark approach at 12 months.  The 
landmark analysis will include only patients who are alive and free of invasive cancer at 
12 months and who are evaluable for CRP at both baseline and 12 months.  In addition, 
we will test whether the effect of BMI is mediated by its impact on CRP.  To do this, we 
will add CRP elevation to the model with BMI.  If the effect of BMI is diminished, that 
will support mediation.  The development and validation of the predictive model for 
hypothesis (c) will follow the four-fold cross-validation approach described above for 
amenorrhea.  The modeling will be performed with Cox regression as in other analyses 
for this sub-study.  For hypothesis (d), all above primary and secondary analyses will be 
repeated with a secondary endpoint, recurrence-free interval (defined in Section 3.2.3), 
using competing risk models if needed. 
17.9.3 Evaluable data for Menstrual History and Host Factors analyses 
All analyses will be performed including all enrolled patients who have data available for 
the given analysis.  Analyses involving blood markers will be conducted only with 
patients who consented to providing blood samples for this research. 
17.9.4 Missing MH or Host Factors data 
Completion of all scheduled questionnaires is part of the routine delinquency assessment 
for centers collaborating in B-47.  Adherence to the questionnaire assessment schedule 
will be encouraged by means of proactive reminders to the participating institutions and 
other measures that have previously been found effective.110  The NRG Oncology 
SDMC staff will continue to monitor proportions of missing information occurring in 
each treatment arm at different assessment points.  If a decline in follow-up assessments 
is observed in specific centers or specific trial arms, interventions will be developed to 
address problems in the data collection process.  If all efforts to collect a scheduled 
questionnaire fail, the center will be required to submit a missing data form.  This form 
will capture the reason for the missing data and will enumerate the attempts made by 
clinic staff to collect the questionnaire. 
Despite these precautions, some missing data is expected.  Because the analysis for 
secondary hypothesis (c) for the MH sub-study requires data at 36 months, and is 
therefore most likely to have missing data, that analysis includes propensity score 
weighting as described above.  In general, information from patients with missing data 
will be reviewed to detect sources of bias.  Patients with missing data will be reviewed 
for imbalances in factors such as trial arm, treatment adherence, collaborating center, and 
reasons for non-adherence.  If no missing data mechanism can be detected, the data will 
be analyzed assuming the missing data are at random.  If a missing data mechanism 
appears to be present, we will develop an appropriate analytic strategy to control for the 


 
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potential bias and, if possible, to impute the missing values.  The appropriateness of 
alternative strategies will depend upon both the pattern (e.g., item non-response versus 
intermittent missing forms versus complete dropouts) and the severity of the missing data 
problem.111-113  For example, an appropriate strategy could involve the stratification of 
the patients in the study in terms of the completeness of their data for key time periods 
(e.g., 6 months or 1 year) and the comparison of results from separate analyses for each 
group or it could involve the implementation of more sophisticated imputation 
procedures designed to model a missing data mechanism.114,115  We will also present 
sensitivity analyses based on varying assumptions about the missing-data mechanism. 
17.9.5 Statistical power for MH and Host Factors sub-studies 
We expect to enroll 1500 patients who will be eligible for the MH sub-study.  In NSABP 
B-30, sufficient follow-up data were available to analyze 87% of enrolled MH sub-study 
patients.  An evaluable sample size of 1500x87%=1305 will provide 80% power to detect 
a kappa coefficient of 0.09 against a null value of 0, assuming that the percentage of 
women with amenorrhea by 12 months is approximately 79% (as in the AC®T arm of  
B-30).  (The power calculation applies for percentages in the range of 20-80%, as seen in 
various treatment groups of B-30.)  For primary hypothesis (b), n=1305 will provide 80% 
power to detect a difference in the proportion amenorrheic of 0.79 versus 0.86 or 0.79 
versus 0.71 (tested at the 0.025 significance level).  For secondary hypothesis (a), 
assuming 79% of women become amenorrheic at some point during the study, the sample 
size will be 79% x 1305=1031.  This will provide 80% power to detect the effect of a 
variable, assuming that variable has standard deviation 1.0, the hazard ratio is 1.33, other 
variables in the regression model have a joint R2 of 0.1, and 10% of patients resume 
menses during the study (again, using observations from B-30). 
In the Host Factors sub-study, the sample size for the questionnaire data is 3260  
(all B-47 patients).  With 262 events at the time data are locked for the primary analysis 
for the parent B-47 study (see Section 17.6.1), this will provide 80% power to detect the 
effect of BMI, assuming the hazard ratio is 1.22 corresponding to a one standard 
deviation change in BMI, and assuming that when BMI is regressed on other variables in 
the model, the R2 is 0.1.  For the second primary analysis, the following considerations 
apply.  We expect 3168 patients to be alive and free of invasive disease at one year, and 
therefore eligible for the landmark analysis (using the expected annual event rate of 0.028 
per Section 17.5.1).  We assume that a random sample of 90%, or 2851, will also have 
adequate questionnaire data at 1 year (a conservative assumption relative to rates of 
questionnaire compliance in past NSABP studies; note that the 87% figure cited above 
also included attrition due to disease events).  Among those patients, we would expect 
154 (90%) of the remaining 171 IDFS events expected to occur after 1 year and before 
the data lock.  This will provide 80% power to detect the effect of the slope of BMI, 
assuming the hazard ratio is 1.30, and other assumptions are as above.  Power 
calculations were performed in PASS 2002 (Kaysville, UT). 
The power to detect genetic associations with a binary trait depends on the frequency of 
the risk allele/genotype and the size of per-allele odds ratio of the genetic effect.  To 
approximate power by the exemplary method to detect additive effects of alleles, we use 
a sample size of 2800 patients, anticipating that 60% will have CRA, and consider a 
range of MAFs, with p-value < 5x10-8 to claim genome-wide significance.  We have 
80% power to detect a SNP with a per-allele OR >1.5 for MAF of 0.2, or OR=1.7 for 
MAF=0.1, or OR=2.0 for MAF=0.05.  These are consistent with effect sizes found in 


 
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other GWAS evaluations of toxicities.  We will validate these findings in separate cohorts 
of patients as well. 
With 2900 total pre-chemotherapy AMH levels in women with follow-up menstrual data, 
and using p-value < 0.05, we will have 80% power to detect a minimum OR of 1.11, 
where the OR represents the change in risk of CRA according to one standard deviation 
change in the pre-chemotherapy AMH.  Another way to view this is that we will have 
80% power to detect a difference in the mean AMH between patients with versus without 
CRA when the difference in means is at least 0.11 standard deviations of the  
pre-chemotherapy AMH.  Because we expect only 2700 women (from this trial and 
others with both pre-chemotherapy and 1-year follow-up AMH levels, and using  
p-value < .05, we will have 80% power to detect a minimum OR of 1.12, where the OR 
represents the change in risk of CRA according to one standard deviation change in the 
difference between AMH at one year and AMH pre-chemotherapy.  Another way to view 
this is that we will have 80% power to detect a difference in the mean AMH change 
between patients with versus without CRA, where the difference in means is at least 0.12 
standard deviations of change in AMH. 
17.10 Issues relating to racial and ethnic differences 
Possible racial and ethnic variation in response to the treatment under consideration is of great 
concern to African-Americans.  Researchers have noted poorer survival rates for African-
American breast cancer patients as compared to Caucasians.116,117  This difference has been 
attributed to many factors, including more advanced disease at the time of diagnosis,118 social 
and economic factors,119 or specific tumor characteristics such as ER positivity.120,121  Although 
outcomes tend to be less favorable for African-Americans, significant race-by-treatment 
interactions have not been previously reported suggesting that, where treatment efficacy exists, 
both groups appear to benefit.  Previous NSABP investigations of the relationship between race 
and prognosis support these conclusions.122,123 
Potential for the enrollment of minority patients in this protocol is enhanced by the NRG Oncology's 
recognition of the importance of increasing minority accrual.  To this end, we provide educational 
opportunities for NRG Oncology investigators and coordinators to increase their awareness and skills 
related to recruitment of racial and ethnic minority populations.  The distributions of ethnicity and race 
for B-47 are projected from the NSABP B-28 study.  The ethnicity distribution of the NSABP B-28 
population consisted of 3% Hispanic and 97% non-Hispanic.  The racial distribution in the B-28 study 
was 86% white; 8% black, not of Hispanic origin; 4% Asian or Pacific Islander descent; and 2% 
American Indian or Alaskan Native.  The prognostic effect of race/ethnicity will be evaluated using 
statistical models.  Unfortunately, because of power limitations, we will not be able to compare effects 
separately for the different cultural or racial groups. 


 
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TABLE 34.  Expected racial and ethnic composition of NSABP B-47 
Ethnic Category 
Total 
Hispanic or Latino 
98 
Not Hispanic or Latino 
3,162 
Ethnic Category: Total of all subjects 
3,260 
Racial Category 
 
American Indian or Alaskan Native 
65 
Asian 
98 
Black or African American 
261 
Native Hawaiian or other Pacific Islander 
32 
White 
2804 
Racial Category: Total of all subjects 
3,260 
Ethnic 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central  
Categories: 
American, or other Spanish culture or origin, regardless of race. 
 
Not Hispanic or Latino 
Racial 
American Indian or Alaskan Native – a person having origins in any of the original 
Categories: 
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. 
 
Black or African American – a person having origins in any of the black racial 
Groups of Africa. 
 
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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18.0 
PUBLICATION INFORMATION AND ADMINISTRATIVE AGREEMENTS 
The trastuzumab 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/industry) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
• 
Trastuzumab may not be used for any purpose outside the scope of this protocol, nor can 
trastuzumab be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for trastuzumab are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies utilizing 
investigational trastuzumab 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. 
• 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational 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".): 
- 
NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, 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. 
- 
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 investigational Agent. 
- 
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 
investigational Agent. 
• 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order.  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. 
• 
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 Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
• 
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. 


 
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• 
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: 
E-mail: mailto: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. 
 


 
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19.0 
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Perez EA, Romond EH, Suman VJ, et al.  Updated results for the combined analysis of NCCTG 
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Jones S, Holmes FA, O'Shaughnessy J, et al.  Docetaxel with cyclophosphamide is associated with 
an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of 
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Jones SE, Savin MA, Holmes FA, et al.  Phase III trial comparing doxorubicin plus 
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Jones SE, Collea RP, Oratz R, et al.  Preliminary toxicity results of a Phase II trial of adjuvant 
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Jones SE, Collea RP, Oratz R, et al.  Cardiac safety results of a Phase II trial of adjuvant 
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Swain SM, Jeong J-H, Geyer CE, et al.  NSABP B-30:  definitive analysis of patients outcome from 
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111. Little RJA, Rubin DB.  Statistical Analysis with Missing Data.  New York: John Wiley and Sons, 
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112. Jones, RH.  Longitudinal Data with Serial Correlation: A State-Space Approach.  London: 
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115. Wu M, Bailey K. Analyzing changes in the presence of informative right censoring by death and 
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120. Crowe JP Jr, Gordon NH, Hubay CA, et al.  The interaction of estrogen receptor status and race in 
predicating prognosis for stage I breast cancer patients.  Surgery 1986; 100:599-605. 
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122. Dignam JJ, Redmond CK, Fisher B, et al.  Prognosis among African-American women and white 
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6:230 Abstr 905. 


 
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APPENDIX A 
ASSESSMENT OF PERFORMANCE STATUS AND ACTIVITIES OF DAILY LIVING 
1.0 
PERFORMANCE STATUS 
ECOG or Zubrod Scale 
 
Karnofsky Score 
0 
Fully active; able to carry on all pre-
disease performance without 
restriction 
90-100% 
1 
Restricted in physically strenuous 
activity but ambulatory 
70-80% 
2 
Ambulatory and capable of self-care; 
but unable to carry out any work 
activities. 
50-60% 
3 
Capable of only limited self-care; 
confined to bed or chair more than 
50% of waking hours 
30-40% 
4 
Completely disabled 
10-20% 
 
 
2.0 
ACTIVITIES OF DAILY LIVING 
The following definitions for activities of daily living (ADL) should be used when the  
CTCAE v4.0 grading criteria are based on ADL: 
• 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
• 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 


 
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APPENDIX B 
HYPERTENSION MANAGEMENT RECOMMENDATIONS 
1.0 
SUGGESTIONS FOR ACCURATE BP ASSESSMENT 
• 
Caffeine, exercise, and smoking should be avoided for at least 30 minutes before BP 
measurement. 
• 
Patients should be seated for at least 5 minutes in a chair (rather than on an examination 
table), with feet on the floor, and arm supported at heart level. 
• 
An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be used 
to ensure accuracy. 
• 
Palpated radial pulse obliteration pressure should be used to estimate systolic and diastolic 
BP. 
- 
The cuff should be inflated 20 to 30 mmHg above the level for the auscultatory 
determinations. 
- 
The cuff deflation rate for auscultatory readings should be 2 mmHg per second. 
• 
Systolic BP is the point at which the first of 2 or more Korotkoff sounds is heard, and the 
disappearance of Korotkoff sound is used to define diastolic BP. 
2.0 
MANAGEMENT OF HYPERTENSION 
The information provided in Table B1 was adapted from the JNC7 Report.  For the complete 
article refer to: 
Chobanian AV, Bakris GL, Black HR, et al.  The Seventh Report of the Joint National Committee 
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 
Report.  JAMA 2003; 289(19):2560-2572. 
TABLE B1.  Classification and management of blood pressure for adults aged 18 years or older 
Blood Pressure Criteria 
Blood Pressure Management* 
BP Classification 
Systolic BP 
(mm Hg)* 
Diastolic BP 
(mmHg)* 
Lifestyle 
Modification 
Initial Drug Therapy 
Pre-hypertension 
120-139 
or 
80-89 
Yes 
No antihypertensive drug indicated 
Stage 1 
Hypertension 
140-159 
or 
90-99 
Yes 
Thiazide-type diuretics for most; 
may consider ACE inhibitor, ARB, 
b-blocker, CCB, or combination 
Stage 2 
Hypertension 
³ 160 
or  
³ 100 
Yes 
2-Drug combination for most 
(usually thiazide-type diuretic and 
ACE inhibitor or ARB or  
b-blocker or CCB)§ 
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; BP, blood pressure; 
CCB, calcium channel blocker. 
* Treatment determined by highest BP category. 
§ Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. 
 


 
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APPENDIX C 
DETERMINATION OF MENOPAUSAL STATUS 
 
The following criteria will be used in B-47 to define postmenopausal: 
• Age 56 or older with no spontaneous menses for at least 12 months prior to study 
entry; or 
• Age 55 or younger with no spontaneous menses for at least 12 months prior to study 
entry (e.g., spontaneous or secondary to hysterectomy) and with a documented 
estradiol level in the postmenopausal range according to local institutional/laboratory 
standard; or 
• Documented bilateral oophorectomy. 
 
Women failing to meet one of these criteria will be classified as pre-menopausal. 


 
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APPENDIX D 
CTCAE GRADE 2 CARDIAC DISORDER ADVERSE EVENTS 
THAT PROHIBIT TRASTUZUMAB THERAPY 
Trastuzumab will not be continued (Groups 2A and 2B) following any grade 2 cardiac AE listed in the 
table below.  (Trastuzumab should be administered following any of the other grade 2 AEs listed in the 
Cardiac Disorders section of the CTCAE v4.0 but not listed in this appendix or in Section 11.3.) 
Note: See Sections 11.3 and 11.4 for trastuzumab therapy following ³ grade 3 cardiac AEs listed in the 
Cardiac Disorders section of the CTCAE v4.0. 
CARDIAC DISORDERS – CTCAE v4.0 
Adverse Event 
Grade 2 Criteria 
Acute coronary syndrome 
Symptomatic, progressive angina; cardiac enzymes normal; 
hemodynamically stable 
Atrioventricular block complete 
Non-urgent intervention indicated 
Chest pain - cardiac 
Moderate pain; limiting instrumental ADL 
Heart failure 
Symptoms with mild to moderate activity or exertion 
Mobitz (type) II atrioventricular block 
Symptomatic; medical intervention indicated 
Mobitz type I 
Symptomatic; medical intervention indicated 
Myocardial infarction 
Asymptomatic and cardiac enzymes minimally abnormal and 
no evidence of ischemic ECG changes 
Myocarditis 
Symptoms with mild to moderate activity or exertion 
Pericarditis 
Symptomatic pericarditis (e.g., chest pain) 
Right ventricular dysfunction 
Symptoms with mild to moderate activity or exertion 
Sick sinus syndrome 
Non-urgent intervention indicated 
Sinus bradycardia 
Symptomatic, medical intervention indicated 
Ventricular arrhythmia 
Non-urgent medical intervention indicated 
Ventricular tachycardia 
Non-urgent medical intervention indicated 


 
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APPENDIX E 
TRASTUZUMAB INFORMATION AND INSTRUCTIONS FOR ALL IRELAND CO-
OPERATIVE ONCOLOGY RESEARCH GROUP (ICORG) 
The NCI will not supply trastuzumab to ICORG for the B-47 study.  ICORG investigators must follow 
Appendix E trastuzumab drug supply information and instructions.  Refer to Protocol Section 12.2.9 for 
trastuzumab warnings and contraindications; also refer to Sections 13.1 and 13.2 for information 
regarding expectedness of adverse events (including the trastuzumab CAEPR list).  For additional 
information about possible side effects, refer to the current Investigator's Brochure for trastuzumab (see 
Protocol Section 12.2). 
1.0 
DESCRIPTION OF TRASTUZUMAB (HERCEPTIN®) 
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively 
binds with high affinity in a cell-based assay (Kd=5 nM) to the extracellular domain of the human 
epidermal growth factor receptor 2 protein, HER2.  The antibody is an IgG1 kappa that contains 
human framework regions with the complementarity-determining regions of a murine antibody 
(4D5) that binds to HER2. 
The humanized antibody against HER2 is produced by a mammalian cell (Chinese Hamster 
Ovary [CHO]) suspension culture in a nutrient medium containing the antibiotic gentamicin.  
Gentamicin is not detectable in the final product. 
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for 
intravenous (IV) administration.  Each trastuzumab vial contains 150 mg trastuzumab,  
a,a-trehalose dihydrate, L-histidine HCl, L-histidine, and polysorbate 20. 
2.0  
PROCUREMENT OF TRASTUZUMAB 
Trastuzumab will be supplied free-of-charge to ICORG investigators by F. Hoffmann-La Roche, Ltd. 
and distributed by the Roche Distribution Network.  A starter shipment of trastuzumab will be 
dispatched directly to the investigator following study initiation by ICORG at the site.  Thereafter, 
investigators will request trastuzumab by utilizing their usual ICORG-specific procedures for requesting 
study drug supply.  Trastuzumab will be shipped directly to the address of the treating investigator on 
file with NRG Oncology. 
3.0 
SHIPPING 
Vials of trastuzumab are shipped with qualified, time controlled shippers Monday through 
Wednesday, and must be placed in a 2°–8°C (36°–46°F) refrigerator immediately upon receipt to 
ensure optimal retention of physical and biochemical integrity.  
4.0 
STORAGE/STABILITY 
Vials of trastuzumab are stable at 2°–8°C (36°–46°F) prior to reconstitution.  Do not use beyond 
the expiration date stamped on the vial.  After reconstitution with SWFI (not supplied), the 
reconstituted solution should be used immediately.  Any remaining reconstituted solution should 
be discarded.  Do not freeze trastuzumab that has been reconstituted. 
Solutions of trastuzumab for infusion are physically and chemically stable in polyvinylchloride, 
polyethylene or polypropylene bags containing sodium chloride 0.9% solution for injection for  
24 hours at temperatures not exceeding 25°C. 
From a microbiological point of view, the reconstituted solution and trastuzumab infusion 
solution should be used immediately.  The product is not intended to be stored after reconstitution 
and dilution unless this has taken placed under controlled and validated aseptic conditions. 


 
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APPENDIX E (continued) 
5.0 
RECONSTITUTION AND ADMINISTRATION (TRASTUZUMAB 150 MG POWDER) 
5.1 
Reconstitution 
Each vial of trastuzumab (150 mg) is reconstituted with 7.2 mL of SWFI (not supplied).  
Use of other reconstitution solvents should be avoided.  This yields a 7.4 mL solution for 
single-dose use, containing approximately 21 mg/mL trastuzumab. 
Shaking the reconstituted trastuzumab or causing excessive foaming during the addition 
of diluent may result in problems with dissolution and the amount of trastuzumab that can 
be withdrawn from the vial.  Use appropriate aseptic technique when performing the 
following reconstitution steps: 
• 
Trastuzumab should be carefully handled during reconstitution.  Using a sterile 
syringe, slowly inject 7.2 mL of SWFI into the vial containing the lyophilized cake of 
trastuzumab.  The stream of SWFI should be directed into the lyophilized cake. 
• 
Swirl the vial gently to aid reconstitution.  Trastuzumab may be sensitive to  
shear-induced stress, e.g., agitation or rapid expulsion from a syringe.  DO NOT 
SHAKE. 
• 
Slight foaming of the product upon reconstitution is not unusual.  Allow the vial to 
stand undisturbed for approximately 5 minutes.  The reconstituted trastuzumab 
results in a colorless to pale yellow transparent solution and should be essentially free 
of visible particulates. 
• 
The appropriate amount of solution should be withdrawn from the vial and added to 
an infusion bag containing 250 mL of 0.9% sodium chloride solution.  Do not use 
with glucose-containing solutions.  The bag should be gently inverted to mix the 
solution in order to avoid foaming.  Parenteral solutions should be inspected visually 
for particulates and discoloration prior to administration.  Once the infusion is 
prepared, it should be administered immediately.  If diluted aseptically, it may be 
stored for 24 hours (do not store above 25°C). 
5.2 
Administration 
See Protocol Sections 9.2 (Group 2A patients) or 9.4 (Group 2B patients). 
6.0  
DRUG TRANSFER 
ICORG policy does not permit the transfer of trastuzumab outside the scope of this protocol, nor 
can trastuzumab be transferred or licensed to any party not participating in this clinical study. 
7.0  
DRUG RETURN/DESTRUCTION 
Unused or expired drug will be destroyed in the Pharmacy service of each center as per each 
center's policy and guidelines, or returned to the vendor in cases where it is not possible for the 
site to destroy the drug locally. 
8.0  
DRUG ACCOUNTABILITY 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of receipt, disposition, and return of the trastuzumab received through the B-47 study.  
ICORG sites must use ICORG drug accountability logs provided.  These logs include the dates 
the study medications are received from the manufacturer, the dates dispensed for the individual 
patient, and the dates destroyed at the site per institutional policy and guidelines (or returned to 
manufacturer/supplier if authorized).  Patient number, date of infusion, investigator name, batch 
or lot numbers, expiry date, quantity, pack number (if applicable) of the study medication must be 
documented on the logs.  Drug accountability logs will be provided to sites in the study files at 
the time of study initiation.