A Randomized Phase III Post-operative Trial of Platinum Based Chemotherapy vs. Capecitabine in Patients With Residual Triple-Negative Basal-Like Breast Cancer Following Neoadjuvant Chemotherapy
Phase: PHASE3
Conditions: Estrogen Receptor Negative, HER2/Neu Negative, Invasive Breast Carcinoma, Progesterone Receptor Negative, Stage II Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage III Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Triple-Negative Breast Carcinoma
Sponsor: ECOG-ACRIN Cancer Research Group

 
EA1131 
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A Randomized Phase III Post-Operative Trial of Platinum 
Based Chemotherapy Vs. Capecitabine in Patients with 
Residual Triple-Negative Breast Cancer following 
Neoadjuvant Chemotherapy 
STUDY CHAIR: Ingrid A. Mayer, M.D., MSCI 
STUDY CO-CHAIR: Carlos L. Arteaga, M.D. 
STUDY STATISTICIAN: Fengmin Zhao, Ph.D. 
BREAST COMMITTEE  
CO-CHAIRS: 
 
Antonio Wolff, M.D. 
 Joseph Sparano, M.D. 
Angela DeMichele, M.D. 
QUALITY OF LIFE CO-CHAIRS: Amye J. Tevaarwerk, M.D. 
Sofia F. Garcia, Ph.D. 
Karen Lisa Smith, M.D., M.P.H. 
PATHOLOGY AND LABORATORY CO-CHAIR: 
LABORATORY CO-CHAIR: 
COMMUNITY CO-CHAIR: 
Fraser Symmans, M.D. 
Ben Ho Park, M.D., Ph.D. 
Brian L. Burnette, MD 
CANCER CONTROL AND SURVIVORSHIP 
COMMITTEE CHAIR: 
BREAST COMMITTEE CHAIR: 
 
Lynne Wagner, Ph.D. 
Kathy D. Miller, MD. 
 
 
Version Date:  March 1, 2021 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology  
April 29, 2015 
NRG / NRG Oncology 
 
Addendum #1 – Incorporated Prior to Activation 
SWOG / SWOG  
 
Addendum #2 – 2/16 
 
 
Addendum #3 – 6/16 
(Limited to U.S. sites only) 
 
Addendum #4 – 9/17 
NCTN STUDY CHAMPIONS 
ALLIANCE: Erica L. Mayer, M.D., M.P.H. 
SWOG: Eve Therese Rodler, M.D. 
NRG: William Sikov, M.D. 
 
Addendum #5 – 4/2018 
Addendum #6 - 11/2018 
Addendum #7 – 11/2020 
Addendum #8 
 
Agents 
IND# 
NSC# 
Supply 
Cisplatin 
IND exempt study 
119875 
Commercially available 
Carboplatin 
IND exempt study 
241240 
Commercially available 
Capecitabine 
IND exempt study 
712807 
Commercially available 
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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Triple-Negative Breast Cancer (TNBC) ...................................................... 7 
1.2 
Residual drug-resistant disease after neoadjuvant chemotherapy .......... 7 
1.3 
Platinum agents in TNBC ........................................................................... 8 
1.4 
Capecitabine in TNBC .............................................................................. 10 
1.5 
Rationale for selected approach and trial design ................................... 11 
1.6 
Chemotherapy dose selection ................................................................ 12 
1.7 
Biomarker Correlatives ........................................................................... 13 
1.8 
Patient reported outcomes (PRO) ........................................................... 15 
1.9 
Rationale for Tobacco Use Assessment .................................................. 17 
2. Objectives ......................................................................................................... 20 
2.1 
Primary Objective .................................................................................... 20 
2.2 
Secondary Clinical Objectives ................................................................. 20 
2.3 
Secondary Correlative Biomarker Objectives ......................................... 20 
2.4 
Exploratory Correlative Biomarker Objectives........................................ 21 
2.5 
Exploratory Tobacco Use Objectives ....................................................... 21 
3. Selection of Patients ......................................................................................... 22 
3.1 
Eligibility Criteria for Screening and Molecular Profiling (STEP 0) .......... 22 
3.2 
Eligibility Criteria for Randomization (Step 1): ........................................ 26 
4. Registration Procedures .................................................................................... 29 
4.1 
Screening (STEP 0) ................................................................................... 33 
4.2 
Additional Requirements ........................................................................ 33 
4.3 
Randomization (STEP 1) .......................................................................... 33 
4.4 
Data Quality Portal .................................................................................. 36 
4.5 
Instructions for Patients who Do Not Start Assigned Protocol Treatment36 
5. Treatment Plan ................................................................................................. 37 
5.1 
Administration Schedule ......................................................................... 37 
5.2 
Adverse Event Reporting Requirements ................................................. 39 
5.3 
Capecitabine Dose Modifications ........................................................... 44 
5.4 
Cisplatin or Carboplatin Dose Modifications .......................................... 49 
5.5 
PRO Administration ................................................................................. 55 
5.6 
Patient Reported Outcome Measures: Tobacco Use Assessment .......... 57 
5.7 
Duration of Therapy ................................................................................ 58 
5.8 
Duration of Follow-up ............................................................................. 59 
6. Measurement of Effect ..................................................................................... 60 
6.1 
Local, Regional Recurrence ..................................................................... 60 
6.2 
Distant Recurrence .................................................................................. 60 
6.3 
Invasive Disease-Free Survival ................................................................ 60 
6.4 
Survival .................................................................................................... 60 

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7. Study Parameters .............................................................................................. 61 
7.1 
Therapeutic Parameters .......................................................................... 61 
8. Drug Formulation and Procurement ................................................................. 65 
8.1 
Capecitabine............................................................................................ 65 
8.2 
Cisplatin ................................................................................................... 66 
8.3 
Carboplatin .............................................................................................. 68 
9. Statistical Considerations .................................................................................. 71 
9.1 
Study Objectives ...................................................................................... 71 
9.2 
Study Design ............................................................................................ 72 
9.3 
Secondary Endpoints ............................................................................... 76 
9.4 
Analysis Plan for Primary and Secondary Endpoints ............................... 77 
9.5 
Biomarker Correlative Study ................................................................... 78 
9.6 
PRO Study ................................................................................................ 80 
9.7 
Gender and Ethnicity .............................................................................. 83 
9.8 
Study Monitoring .................................................................................... 83 
10. Biological Sample Submissions ......................................................................... 85 
10.1 Submissions to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) .......................................................................................... 85 
10.2 Mandatory Submission of Peripheral Blood for CTCs to Epic Sciences .. 88 
10.3 ECOG-ACRIN Sample Tracking System .................................................... 90 
10.4 Use of Specimens in Research ................................................................ 90 
10.5 Sample Inventory Submission Guidelines ............................................... 91 
11. Biomarker Studies ............................................................................................. 92 
11.1 Rate of basal-like gene expression using PAM50 analysis by digital mRNA 
quantitation – Integral Biomarker Study ................................................ 92 
11.2 Genomic alterations identified via whole exome sequencing (WES) and 
RNA sequencing – Biomarker Study ........................................................ 94 
11.3 Blood-Based Biomarkers – Rate of CTC Detection .................................. 95 
11.4 Lab Data Transfer Guidelines .................................................................. 97 
12. Electronic Data Capture .................................................................................... 98 
13. Patient Consent and Peer Judgment ................................................................ 98 
14. References ........................................................................................................ 98 
Appendix I  Pathology Submission Guidelines ...................................................... 103 
Appendix II  Patient Thank You Letter ................................................................... 107 
Appendix III  ECOG Performance Status ................................................................ 108 
 Appendix IV  CLIA Laboratory Sample Submission Form ..................................... 109 
 Appendix V  Patient Pill Calendar ......................................................................... 111 
 Appendix VI  Ancillary for Tobacco Use Assessment: EAQ16T ............................. 113 
Appendix VII  EA1131 Collection and Shipping Kit Order Instructions .................. 124 
 

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STUDY CHAIR 
Ingrid A. Mayer, MD, MSCI, 
Vanderbilt University Medical Center/ Vanderbilt-
Ingram Cancer Center 
2220 Pierce Ave., 777 PRB  
Nashville, TN, 37232 
(615) 936-2033 (P), (615) 343-7602 (F) 
Ingrid.mayer@vumc.org 
 
 
STUDY CO-CHAIR 
Carlos L. Arteaga, M.D. 
University of Texas Southwestern Harold C. 
Simmons Cancer Center5323 Harry Hines 
Blvd.Dallas, TX 75390 (214) 648-1677 (P), (214) 
648-7084(F) 
carlos.arteaga@utsouthwestern.edu  
 
 
STUDY CHAIR LIAISON (SCL) 
Jannine Hewitt, RN 
Vanderbilt University Medical Center/ Vanderbilt-
Ingram Cancer Center 
719 Thompson Lane, suite 25000 
Nashville, TN, 37212 
(615) 875-9639 (P), (615) 875-5850 (F) 
jannine.hewitt@vumc.org 
 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
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. 
Please refer to the patient 
enrollment section of the 
protocol for detailed instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or 
https://OPEN.ctsu.org. 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
Data collection for this study will 
be done through Medidata 
Rave and the ECOG-ACRIN 
Systems for Easy Entry of 
Patient Reported Outcomes 
(EASEE-PRO) system. Please 
see the data submission 
section of the protocol for 
further instructions. 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Web site is located at   https://www.ctsu.org 
 
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Schema 
Patients with: 
• Clinical stage II/III TNBC1 at 
diagnosis
• Neoadjuvant chemotherapy2
• ≥ 1 cm in diameter of residual 
cancer in the breast at the 
time of definitive surgery
1.
TNBC: ER/PR 1 to ≤ 10% positive staining with weak intensity score, or ≤ 1% positive staining; HER2 negative per ASCO guidelines.
2.
Taxane ± anthracycline based; platinum agents or capecitabine not allowed.
3.
Tumor tissue from the residual disease on the definitive surgical specimen must have been received by ECOG-ACRIN Central Biorepository and Pathology Facility (EA CBPF) for PAM50 analysis/ 
determination of patient eligibility as outlined in Section 10. Patients cannot be randomized to treatment until institution receives confirmation of tissue receipt/ eligibility from ECOG-ACRIN.tion 10.2.
4.
Females of child-bearing potential must have a blood test or urine study within 2 weeks prior to treatment initiation to rule out pregnancy.
5.
Radiation therapy (when applicable) may be completed before or after protocol treatment. If performed before protocol treatment, it needs to be completed prior to randomization.
6.
Choice of platinum agent will be per treating physician discretion.
7.
Primary endpoint: IDFS in patient with basal-like TNBC.
8.
Secondary endpoints: IDFS in patient with non-basal-like TNBC, OS and RFS.
**Arm A closed to new accrual in Addendum #3. New patients are randomized to Arm B or C
Tissue Submission 
for PAM50 Analysis3
R
A
N
D
O
M
I
Z
 E3,4,5
Arm B6
Cisplatin 75 mg/m2 
Day 1 every Q3W x 4 cycles  
OR
Carboplatin AUC 6
Day 1 Q3W x 4 cycles
Arm A
Observation
F
O
L
L
O
W
U
   
P7,8
Stratification factors:
1) Clinical stage at diagnosis (II or III)
2) Residual cancer burden after NAC (1~3 cm or > 3 cm)
3) Planned platinum agent choice (cisplatin or carboplatin)
4) Anthracycline exposure (yes or no)
5) Administration of radiotherapy (yes or no)
Accrual = 775
1 cycle = 3 weeks 
STEP 0
STEP 1
S
C
R
E
E
N
I
N
G
CLOSED TO NEW ACCRUAL**
Arm C
Capecitabine 1000 mg/m2 
twice daily 
D1-14 every Q3wx6 cycles
 
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1. 
Introduction 
1.1 
Triple-Negative Breast Cancer (TNBC) 
Triple negative breast cancer (TNBC) is defined as estrogen and progesterone 
receptor (ER/PR) negative and not amplified for HER2 (ERBB2), and accounts 
for approximately 15% of all invasive breast cancers. Most TNBCs are high-
grade and the majority of them harbor a basal-like gene expression signature(1). 
Among young women and African-American women, its prevalence is 
elevated(2). Patients with TNBC have an increased likelihood of distant 
recurrence and death compared with women with other types of breast 
cancer(3), as well as a tendency to develop visceral metastases early in the 
course of their disease. Improved approaches to treatment of these cancers is 
critical, since less than 30% of women with metastatic breast cancer survive five 
years and virtually all women with metastatic TNBC will ultimately die of their 
disease despite systemic therapy. To date, not a single targeted therapy has 
been approved for treatment of TNBC, where cytotoxic chemotherapy remains 
the standard treatment.  
1.2 
Residual drug-resistant disease after neoadjuvant chemotherapy 
It is generally established that patients with breast cancer who achieve a 
pathological complete remission (pCR - lack of residual cancer in both breast and 
axilla) after neoadjuvant therapy exhibit a good long-term outcome(4). More 
specifically, approximately 30% of TNBC treated with anthracycline and taxane–
based neoadjuvant chemotherapy (NAC) have a pCR to treatment(5), and 
consistent with above data, achieving a pCR to NAC in this group of patients also 
has been shown to be a strongly positive prognostic factor. On the other hand, 
those patients with residual viable tumor following neoadjuvant therapy are at risk 
of metastatic recurrence and death. High residual disease burden in the post-
treatment, surgically-excised cancers has been shown to correlate with a high 
rate of recurrence and death(6,7) (Figures 1a and b). 
 

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Balko et al. recently completed a study where we profiled 89 residual tumors 
from patients with stage II (20%) and III (80%) TNBC treated with AC-T 
neoadjuvant chemotherapy (NAC)(8). Expression level for 450 genes was 
quantified by NanoString in RNA extracted from the surgical specimen. 
Molecular subtype of these residual tumors, after adjusting for HER2 
amplification (i.e. upon re-testing, all HER2 FISH amplified cancers were 
excluded) was as follows: 70% basal-like; 15% HER2-enriched; 6% luminal A, 
6% luminal B; and 5% normal-like. Basal-like status was associated with a 
trend toward worse recurrence free survival (RFS) and overall survival (OS) 
(log-rank test, P = 0.12 and 0.058, respectively). The median time to relapse 
among this high-risk group of patients with basal-like gene expression was only 
18 months (Figure 2). 
 
These data suggest that residual drug-resistant disease in the breast after 
neoadjuvant therapy is a surrogate for drug-resistant micrometastases that 
ultimately progress to clinically overt metastatic breast cancer. Therefore, more 
detailed molecular analysis of residual disease after neoadjuvant therapy may be 
useful to explain mechanisms of resistance and to identify potentially useful 
therapies. 
1.3 
Platinum agents in TNBC 
Using gene expression, a recent study from Lehmann et al. supports the notion 
that TNBC is a heterogeneous group of tumors(9). Within TNBC, about 70% are 
expected to be basal-like, by gene expression profile(10). Consistent with early 
clinical data in TNBC, breast cancer cells and xenografts with basal-like gene 
expression were particularly sensitive to cisplatin (Figure 3). 
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Platinum salts, including carboplatin and cisplatin, lead to DNA cross-link strand 
breaks, which may be especially important in cells which are deficient in 
homologous recombination repair mechanisms such as BRCA mutated cells and 
TNBC. Leong et al.(11) reported a p63-dependent tumor survival pathway that 
directly mediates cisplatin sensitivity, specifically in TNBC. To further corroborate 
these findings, Rocca et al.(12) conducted a retrospective analysis of core 
biopsies of breast cancer patients treated with neoadjuvant chemotherapy and 
showed that regimens including cisplatin yield a significantly higher rate of pCR 
in p63-positive tumors. In a small phase II study (29 patients), Silver et al. 
showed activity of neoadjuvant cisplatin as a single agent in the treatment of 
patients with locally advanced TNBC. The observed pCR was 22%, and 50% of 
patients had a partial clinical response, and 14% had a complete clinical 
response(13). In another small study, 9 of 10 patients with stage I-III breast 
cancer harboring BRCA1 mutations achieved a pCR after neoadjuvant therapy 
with cisplatin(14).  
Further evidence of the activity of platinum agents in TNBC comes from 2 phase 
II randomized trials in the neoadjuvant setting: the GeparSixto phase II 
randomized trial, in its TNBC subset (n=315), compared weekly neoadjuvant 
paclitaxel, liposomal doxorubicin, and bevacizumab to the same regimen with the 
addition of carboplatin. The pCR rate improved from 36.9% to 53.2% with the 
addition of weekly carboplatin. However, only about 50% of patients were able to 
complete treatment due to adverse events (possibly since all chemotherapy 
drugs were given concomitantly(15). The 3 year disease-free survival (DFS) for 
the patients that received carbo was 85.8%, compared to 76.1% for patients in 
the non-carbo arm [HR =0.56, 95% CI (0.33, 0.96); p=0.0350](16). CALGB 
40603 (NCT00861705) is a randomized phase II trial with a 2 x 2 factorial design 
that explored the addition of every 3 weeks carboplatin +/- bevacizumab to 
neoadjuvant weekly paclitaxel followed by dose-dense AC in in 443 patients with 
stage II/III TNBC(17). The pCR rate improved from 41% to 54% with the addition 
of carboplatin; bevacizumab had no added benefit. The concomitant use of 
platinum agents with chemo in CALGB 40603 was also associated with markedly 
higher toxicity, which resulted in significantly fewer patients receiving 11-12 
doses of paclitaxel when carboplatin was added, compared to the control group 
(< 65% in PCarbo AC vs. > 85% in P  AC). After a median follow-up of 39 

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months, the 3 year DFS for the patients that received carbo was 76%, compared 
to 71% for patients in the non-carbo arm [HR =0.84, 95% CI (0.58, 1.22); 
p=0.36](18). Of note, neither of these studies was powered to address disease-
free or overall survival benefit from the addition of carboplatin to neoadjuvant 
systemic chemotherapy, lack of precision from small sample sizes are likely 
responsible for the difference seen in DFS between these two trials. The 
chemotherapy backbone and the carboplatin dose and schedule may be critical 
to optimal efficacy, which could also explain some of the discrepancy seen in the 
results above. Long term effects of the added toxicity are also now known. 
Therefore, the addition of a platinum agent routinely in the neoadjuvant setting in 
TNBC is still an individualized decision and not yet standard of care. 
Ultimately, the reason to treat patients in the (neo) adjuvant setting is prevention 
of distant recurrence and death from breast cancer. The improvement in pCR 
rate is certainly encouraging; however, pCR may not be a clinically meaningful 
endpoint. pCR is only important to the extent that it predicts EFS. Unfortunately, 
the relationship between pCR and EFS is complicated and imperfect. Studies 
that are adequately powered to detect a DFS and OS are still important and 
needed. 
1.4 
Capecitabine in TNBC 
Capecitabine is an orally administered prodrug of 5-fluorouracil (5-FU) that is 
activated to -FU preferentially in tumor tissue due to increased expression of 
thymidine phosphorylase in tumor tissue, which contributes to the drug’s 
specificity and action against tumor cell proliferation (Wagstaff 2003, 
Drugs). Capecitabine was first approved for MBC in 1998 in patients pretreated 
with anthracyclines and taxanes. It was later approved in combination with 
docetaxel after the combination resulted in improved overall survival (OS) when 
compared with docetaxel alone20,21. Since then, capecitabine has come into wide 
use in MBC and is now approved both as monotherapy and in combination with 
docetaxel(19). 
Studies on the use of capecitabine in women with metastatic TNBC are limited, 
partly because of a current interest in platinum compounds after anthracycline 
and taxane failure for this subtype. The data available so far include a non-
randomized phase 2 trial of capecitabine plus bevacizumab as first-line therapy 
for metastatic disease which showed poor outcome in patients with TN cancers 
with a median overall survival (OS) of 7.5 months and progression-free survival 
(PFS) of 4.4 months(20), and a randomized trial of adjuvant therapy in early 
breast cancer in older women suggesting that those with the TN subtype had 4 
times the chance of relapse and a 3 times higher risk of death if treated with 
capecitabine rather than with standard chemotherapy(21). 
CREATE-X is a phase III randomized clinical trial conducted in Japan(22), that 
randomized 900 patients with HER2-negative breast cancer with lack of pCR 
post-neoadjuvant chemotherapy (anthracycline or taxane containing regimens; 
more than 80% of patients received both) to observation or capecitabine 
1250mg/m2 twice daily, 14 days on followed by 7 days off, every 3 weeks, for 24 
weeks (8 cycles). About 40% of patients were able to complete 8 cycles of 
capecitabine, and about 60% completed 6 cycles of capecitabine. As expected, 
hand-foot sd, diarrhea and neutropenia were the most common side effects in 
the capecitabine arm. For the overall patient population (ER+ and TNBC), the 
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the observation arm [HR=0.7 (95% CI 0.53 – 0.93, one sided p=0.00524)], and a 
5 year overall survival (OS) of 89.2%, opposed to 83.9% in the observation arm 
[HR=0.6 (95% CI 0.4 – 0.92, one sided p < 0.01)]. Subgroup analysis for the 296 
patients that had TNBC revealed a statistically significant improvement in DFS 
(4-year DFS of 67%) with the addition of capecitabine [HR=0.58 (95% CI 0.39 – 
0.87)], whereas the patients with ER+ BC (561) did not seem to derive significant 
benefit [HR=0.84 (95% CI 0.57 – 1.23)]. 
1.5 
Rationale for selected approach and trial design 
At present, upon completion of neoadjuvant therapy, the standard of care for 
patients with TNBC (who have no clinical evidence of metastatic disease after 
surgical excision of the cancer regardless of burden of residual disease) is 
observation. However, the significant improvement in DFS and OS provided by 
adjuvant capecitabine for patients with TNBC and residual disease post-
neoadjuvant chemotherapy seen with CREATE-X, a single phase III trial, merits 
consideration, and the addition of capecitabine in the adjuvant setting is likely to 
be adopted by oncologists for patients with TNBC and residual disease with high 
risk of recurrence post completion of neoadjuvant chemotherapy. 
Within TNBC, patients with tumors with basal-like expression are at the highest 
risk for recurrence. In preclinical models, the basal-like subtype of TNBC was the 
most sensitive to cisplatin; preliminary clinical data showed that residual cancer 
with basal-like subtype was associated with trend toward worse RFS and OS. 
Hence, the biologic rationale for this concept is strongest in the basal like 
subtype. While the GeparSixto(15) and CALGB40603(17) phase II trials have 
clearly shown the merit of adding a platinum agent to the systemic treatment of 
patients with TNBC in the neoadjuvant setting, these trials were underpowered to 
address DFS and OS. Furthermore, exposing (unselected) patients, many of 
whom will never relapse, to toxic therapy in the absence of known benefit would 
be clearly detrimental. Finally, the pooled analysis performed by Cortazar et 
al.(23) could not validate pCR as a surrogate endpoint for improved EFS and OS. 
Therefore, studies that are adequately powered to detect a DFS and OS benefit 
are still important and needed. We hypothesize that for patients with basal-like 
TNBC, with residual disease post completion of neoadjuvant chemotherapy, the 
addition of a platinum agent in the adjuvant setting will provide a higher DFS 
benefit than capecitabine. 
Our proposed NCI-sponsored phase III study is designed to have a large impact 
for patients with basal-like TNBC. The advantages of our proposed design are:  
a) This design and patient population allow us to assess the magnitude of DFS 
and OS benefit from the addition of a platinum agent in the adjuvant setting 
without requiring extremely large number of patients, since we will be 
enriching the trial with participants that are at the highest risk for recurrence;  
b) In the GeparSixto and CALGB 40603 neoadjuvant trials, only about 50-60% 
of patients were able to complete treatment due to adverse events (possibly 
since all chemotherapy drugs were given concomitantly); in our study, since 
the intervention occurs after standard of care treatment, we will potentially 
minimize toxicity from treatment and will maximize the chances that 
participants will complete treatment as planned;  
c) If positive, this trial proposal is powered to foster a change in clinical practice 
worldwide for patients with a very high risk of early recurrence and death from 
basal-like TNBC.  
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This study design will lay the groundwork (i.e. the proof of concept) for additional 
similarly designed studies as new data and new targeted agents become 
available; our study is based in biology that tests a concept as much as it tests a 
specific drug. The information gleaned from the correlates will advance the field 
irrespective of the outcome of the clinical endpoints. In addition to PAM50, this 
study design could allow us to explore other markers of platinum sensitivity, such 
as HRD (Homologous Recombination Deficiency Assay [Myriad], to identify 
tumors with HR deficiency), and Next Generation Sequencing in (residual) breast 
cancers after neoadjuvant therapy, for unbiased identification of somatic 
alterations (mutations, amplifications, deletions, indels) potentially associated 
with drug resistance, that could be targeted therapeutically in order to eradicate 
clinically silent micrometastases already present at the time of surgery. This type 
of deep molecular profiling of actionable molecular alterations could become 
standard of care in surgical specimens after neoadjuvant chemotherapy, where 
identification of these lesions in a CLIA-certified setting should be able to guide 
personalized adjuvant trials aimed at eradicating micrometastatic disease in the 
near future. 
1.6 
Chemotherapy dose selection 
The usual dose of cisplatin for a variety of tumors (ovarian, bladder, 
neuroblastoma, ostegenic sarcoma, non-small cell lung cancer, etc. ranges from 
60 – 100 mg/m2 every 3-4 weeks, and for carboplatin ranges from AUC 4 – 6, 
every 3-4 weeks. A single arm, multi-center phase II study evaluating platinum 
monotherapy (cisplatin or carboplatin) in 86 patients receiving first or second line 
treatment of metastatic TNBC(24) was recently reported, and utilized cisplatin at 
75 mg/m2 every 3 weeks and carboplatin AUC 6 every 3 weeks. These doses 
were well tolerated, without extensive grade 3 and 4 events. Considering that the 
patient population in our clinical trial would have been recently exposed to 
neoadjuvant chemotherapy and (in a good proportion of patients) radiotherapy, 
and from a treatment point of view would be very similar to patient population 
enrolled in the above phase II trial, we opted to use cisplatin at 75 mg/m2 every 3 
weeks and carboplatin AUC 6 every 3 weeks for a total of 4 cycles (12 weeks) as 
the prescribed chemotherapy regimen in this trial. 
Capecitabine was initially approved for use at a starting dosage of 1250mg/m2 
twice daily, with a dosing schedule of 14 days on followed by 7 days off despite 
frequent treatment-limiting toxicities, primarily hand-and-foot syndrome, 
stomatitis, and diarrhea at this dosage. Of note, a retrospective multivariate 
analysis by Haller and colleagues of data from three phase III trials of 5-FU, 
capecitabine and oxaliplatin for the treatment of early and advanced colorectal 
cancer show a significantly worse toxic-effect profile in patients recruited from the 
US than in those from Asia or elsewhere, for both early and advanced 
disease(25). Furthermore, a randomized trial of adjuvant therapy in early breast 
cancer in older women initially used the FDA approved capecitabine dose, but 
had to be amended to a lower dose due to excessive toxicity(21). This suggests 
that the 1250mg/m2 twice daily dosing in the CREATE-X trial may not be 
reproducible in the US from a tolerance point of view. Since the approval of 
capecitabine, moderate dosage reductions have been studied, either 
retrospectively28,29 or in small prospective trials(26-28) in order to assess both the 
efficacy and frequency of adverse effects (AEs) associated with lower dosages. 
Market research from the manufacturers of capecitabine (Roche) indicates it is 
relatively rare for US-based oncologists to prescribe the label-recommended 
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dose of capecitabine (1,250 mg/m2 twice daily for 14 days) compared with their 
European colleagues. Instead, a starting dose of 1,000 mg/m2 twice daily for 14 
days is commonplace in the US. Since the majority of patients in the CREATE-X 
trial were only able to complete 6 cycles of capecitabine, for the purposes of our 
trial capecitabine will be given for a total of 1,000 mg/m2 twice daily for 14 days 
every 3 weeks for a total of 6 cycles (18 weeks). 
1.7 
Biomarker Correlatives 
Mutational spectrum analyses suggest that TNBC has a higher mutational 
frequency than other subtypes(29-31), and our group has shown that profiling of 
TNBC post-neoadjuvant chemotherapy in a small scale is feasible and identifies 
gene alterations that may have a role in chemoresistance(8). We propose to 
perform a prospective large-scale genomic profiling of surgical tissue for patients 
enrolled in the EA1131 clinical trial. The prospective and large-scale nature of 
this proposal, in a homogeneous and highly selected high-risk patient population 
with complete clinical annotation, is a major advantage towards successful 
identification of factors that predict chemotherapy resistance and recurrence, 
which is still an overarching need in early TNBC. Early and accurate detection of 
patients at highest risk for overt metastasis development sets the stage for 
additional therapeutic interventions in the adjuvant setting. The nature of these 
interventions can be guided by the comprehensive genomic analysis proposed, 
where certain molecular alterations could be readily actionable, while others may 
give insight into development of novel therapeutics. Ultimately, these novel 
approaches (early detection and novel interventions) will significantly impact risk 
of recurrence and mortality in this group of patients at highest risk, which is our 
overall goal. 
We expect that at least 400 patients (of the planned 775 to be accrued) will have 
a) viable tissue from the surgical specimen, b) paired blood specimens from 
baseline and after treatment completion, and c) have successful assay. 
Assuming the 400 patients with surgical specimen and blood specimens are 
representative of the whole study population, it is expected that about 100 RFS 
events will occur to the 400 patients. The prospective and large-scale nature of 
this proposal, in a selected high-risk patient population with complete clinical 
annotation, is a unique opportunity to successfully identify factors that predict 
chemotherapy resistance and recurrence. This would be further enriched thanks 
to the ability to analyze paired tissue and plasma-based molecular results, which 
would be invaluable to gain insights into tumor evolution and mechanisms of 
resistance to chemotherapy. Early and accurate detection of patients at highest 
risk sets the stage for additional therapeutic interventions in the adjuvant setting. 
The nature of these interventions can be guided by the comprehensive genomic 
analysis proposed, where certain molecular alterations could be readily 
actionable, while others may give insight into development of novel therapeutics. 
Ultimately, these novel approaches will significantly impact risk of recurrence and 
mortality in this group of patients at highest risk, which is our overall goal. 
1.7.1 
Genomic Alterations in the Surgical Tumor. We aim to determine if 
genomic alterations identified via profiling of the surgical tumor 
specimen of patients in the EA1131 clinical trial correlates with RFS. 
DNA and RNA will be extracted from the surgical specimens and 
subjected to whole exome sequencing (WES) and if feasible, RNA-
sequencing (RNA-seq) analysis. Genomic alterations identified via 
profiling (i.e., mutations, CNV) will be correlated with RFS. Full 
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sequencing of residual TNBC in large scale will likely mirror the 
genomic make-up of metastatic recurrences. We expect that the 
large-scale identification of tissue genomic biomarkers of 
chemotherapy sensitivity and resistance will increase our ability to 
predict which patients with TNBC are at highest risk of relapse after 
surgery and identify clinically actionable alterations. 
We hypothesize that the genomic alterations identified via genomic 
profiling will predict relapse-free survival (RFS) for this group of 
patients at high risk of recurrence. Successful completion of this 
comprehensive profiling will a) more accurately identify patients with 
TNBC at highest risk of recurrence, and b) provide novel insights into 
future targeted interventions that could significantly impact risk of 
recurrence and mortality in patients at highest risk. 
1.7.2 
Circulating Tumor Cells (CTCs). Several assays are available that 
may detect clinically-occult tumor burden or minimal residual disease 
(MRD), but their clinical utility has not been established. Detection of 
circulating tumor DNA in the blood of cancer-free patients is one such 
assay, although the sensitivity, specificity, and positive/negative 
predictive value for predicting recurrence is currently unknown(32). 
Enumeration of CTCs in the blood (≥ 1 CTC in 7.5 ml blood) has also 
shown to be associated with recurrence when detected in patients with 
operable breast cancer who have not yet had surgery(33), particularly 
amongst those who have residual disease after neoadjuvant therapy. 
In EA1131, CTC detection before protocol therapy, after protocol 
therapy, and change (i.e., clearance of CTCs after study therapy in 
those harboring these biomarkers pre-therapy) will be correlated with 
RFS. CTC detection after completion of chemotherapy will be coded as 
a binary variable (present versus absent).  
Two Streck tubes for CTC analysis will be collected at the following 
time points: (1) baseline (prior to study therapy); 2) after completion of 
study therapy (e.g., capecitabine or platinum-based chemotherapy). 
Although the CTC enumeration must be done in real time, the results 
will not be provided to the clinician or patient for clinical decision-
making.  
Blood specimens will be forwarded to EPIC Sciences, where they will 
be prepared for subsequent sequencing and analyses for the 
corresponding mutations detected in matched primary breast tissue. 
We hypothesize that: 
a) patients whose specimens are negative for CTC detection at 
baseline will have a better RFS than patients with positive CTC 
detection at baseline. 
b) patients whose specimens are negative for CTC detection after 
protocol therapy will have a better RFS than patients with positive 
CTC detection after protocol therapy. 
We expect that the large-scale serial CTC detection will provide an 
important intermediate biomarker that will help identify patients with 
TNBC at a higher risk of relapse after surgery, identify those most 
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likely to benefit from additional adjuvant therapy, and identify 
alterations that could have clinically actionable potential. 
1.8 
Patient reported outcomes (PRO) 
EA1131 will randomly assign patients with residual TNBC to further treatment 
with platinum chemotherapy (4 cycles) or to capecitabine (6 cycles) in a high-risk 
group of triple negative breast cancer patients (e.g. those with residual disease 
after neoadjuvant anthracycline + taxane-based chemotherapy). The primary 
endpoint is iDFS and the trial is powered to test for non-inferiority of platinum-
chemotherapy, as well as superiority of platinum-chemotherapy over 
capecitabine if the primary endpoint of non-inferiority is met. Whether platinum 
agents prove superior or non-inferior to capecitabine, it will be important for 
patients and treating physicians to understand how receiving adjuvant platinum 
agents affect overall health related quality of life (HRQL)—both short- and long-
term—in order to effectively counsel patients with regards to benefit. Patient-
reported medication adherence could yield additional insights into the results of 
EA1131, as poor adherence whether due to side effects or access could limit the 
impact of capecitabine on iDFS. 
Further chemotherapy (whether capecitabine or platinum-based) is hypothesized 
to decrease the rate of cancer recurrence for this high-risk group. However, 
additional treatment will have at least short-term impact on HRQL due to the 
acute side effects of treatment. The CREATE-X trial examined 910 women 
randomized to adjuvant capecitabine vs observation. On that trial, nearly one-fifth 
of patients stopped treatment due to adverse events. Given the relatively shorter 
duration of platinum vs capecitabine chemotherapy (12 vs 18 weeks), as well as 
the well-characterized side effect profile, we believe that platinums will be better 
tolerated in the short-term, with the possible exception of neurotoxicity. Platinums 
are associated with a risk of long-term neurotoxocity(34, 35) that negatively 
affects long-term HRQL(36), while capecitabine does not carry a risk of long-term 
neurotoxocity. The patients enrolling on EA1131 will likely have had prior 
exposure to taxanes (which may also cause long-term neurotoxocity). Data exists 
regarding the risk for long-term neurotoxocity for combination taxane+platinums, 
but not for the agents given sequentially. If the platinum-chemotherapy arm 
proves non-inferior but not superior, it will be especially important to both 
oncologists and patients to be able to counsel survivors about the risks regarding 
the long-term neurotoxocity. 
EA1131 will also offer unique access to a population of relatively young women 
with breast cancer. In PrECOG 0105, the median age was 48 years (range 26-
73), and roughly 60% of participants were premenopausal. Patients enrolling on 
EA1131 may be even younger, as oncologists will preferentially elect to refer 
younger women and/or younger women may be the most desirous of further 
treatment. Thus, we expect that EA1131 will have a median age of at least 48 or 
possibly younger, with the majority (60% or more) being premenopausal at 
breast cancer diagnosis. This presents a number of unique considerations, given 
that these young women may live for decades after diagnosis if they do not 
succumb to breast cancer. These questions include: the longer-term 
neurotoxocity(34, 35) in the platinum and the impact of the agents in both arms 
on ovarian function. Little data exists regarding the effect of either capecitabine 
or platinum agents on ovarian function, despite increasing popularity and use. 
Platinum use in breast cancer includes gemcitabine + platinum [PrECOG0105] or 
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docetaxel + carboplatin + trastuzumab [TCH] for HER2+ breast cancer. 
Capecitabine use in breast or colon cancer typically occurs in the metastatic 
setting. In PrECOG0105, patients anecdotally reported little disruption of 
menses. Data for capecitabine from the colorectal world is less useful in breast 
cancer, due to sequencing capecitabine with agents known to disrupt ovarian 
functions such as anthracyclines or cyclophosphamide. Thus, due to the paucity 
of literature, oncologists experience difficulty counseling patients with regards to 
the impact of these agents on ovarian function. Ovarian function is of concern 
because (a) younger patients may desire to preserve fertility for child-bearing, (b) 
premature menopause is associated with attendant symptoms (hot flashes, 
sweats, vaginal dryness, decreased libido) that negatively impact HRQL.(37) and 
(c) premature menopause increases long term health risks (increased bone loss, 
possible cognitive, cardiac problems). There is an increased mortality risk with 
premature ovarian failure/removal in young women.(38-40) 
We hypothesize that HRQL between the groups will be superior in the platinum 
agent arm at the start of cycle 3 and at the 15-months after start of study 
treatment time-points (roughly 1 year after chemotherapy ends), and we also aim 
to describe the rate of neurotoxicity over time in the platinum arm, the rate of 
medication adherence in the capecitabine arm, and the rates of amenorrhea in 
both arms. 
To test the primary hypothesis and assess our exploratory objectives, we have 
selected the following measures: 
HRQL Measures. For both arms. Measures will be assessed at baseline, and 
start of cycle 3, as well as 6 and 15 months after the start of study treatment. 
These time-points have been chosen as they allow us to capture the acute 
difference in side-effects following receipt of chemotherapy and follow long 
enough to ensure that acute differences will have resolved. Differences in 
symptom burden and HRQL at 15 months after the start of study chemotherapy 
(roughly 12 months after chemotherapy ends) would be considered persistent 
and be considered unlikely to improve further. 
• 
NCCN-Fact FBSI-16 (16-items) is a validated 16-item scale including all 8 
items from the original FBSI and 8 additional items from Functional 
Assessment of Chronic Illness Therapy measures. The NFBSI-16 is 
formatted by subscale: Disease-Related Symptom, Treatment Side-Effect, 
and General Function and Well-Being.(41) Higher FBSI scores indicate better 
HRQL (score range, 0 to 16). 
Ovarian Function Measure. For both arms. We will use questions used in the 
ATEMPT and APT studies to capture ovarian function.37,38 Measures will be 
assessed at baseline and 15 months after adjuvant study chemotherapy starts 
(this is roughly 12 months after chemotherapy ends). Study participants will self-
report menstrual history retrospectively. Only patients aged 54 years or less at 
time of baseline survey will complete these questions, and we will screen out 
those who are not premenopausal with regular menses at diagnosis. 
• 
Menstrual Measures (4-items). We will use 4 measures adapted from the 
ATEMPT and APT studies.38 Patients aged less than 55 will be asked about 
(1) absence or presence of menses in the 12 months prior to neoadjuvant 
chemotherapy (termination of survey if no menses), (2) did they have periods 
at least every 2 months prior to neoadjuvant chemotherapy (termination of 
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neoadjuvant chemotherapy (termination of survey if no), (4) date of last 
menses, (5) frequency of menses over past 6 months, (6) receipt of BSO, or 
LHRH agonist and use of contraceptives. 
Neurotoxicity Symptom Measures. For the platinum arm only. Measures will be 
assessed at baseline, and start of cycle 3, as well as 6 and 15 months after the 
start of study chemotherapy. These time-points have been chosen as they allow 
us to capture the baseline rate due to prior taxanes, acute development of 
neuropathy following receipt of platinum chemotherapy and to follow long enough 
to ensure that acute toxicity will have resolved. Neurotoxicity at 15 months 
(roughly 12 months after chemotherapy ends) would be considered persistent 
and unlikely to improve further. 
• 
The FACT-Gynecologic Oncology Group/Neurotoxicity (FACT-GOG/Ntx; 11-
items) subscale contains 11 items and is designed to assess neurotoxicity 
resulting from platinum and taxane-based chemotherapies.(42) Lower FACT-
GOG/Ntx scores denote higher neurotoxicity (score range, 0 to 44). 
Medication Adherence Measure. For the capecitabine arm only. This item will 
be assessed only for patients receiving capecitabine chemotherapy, and will be 
done twice while on study chemotherapy (start of cycle 3 and 6), to add to our 
understanding of why or why not a patient adhered to medication. This may yield 
additional insight into the primary endpoint results. 
• 
ECOG-ACRIN Medication Adherence Scale Modified from the Morisky 
Medication Adherence Questionnaire (8-items). This measures the likelihood 
that a patient will take prescribed medications. The Medication Adherence 
Scale has been validated against medication pill count methods of assessing 
compliance and used in a variety of settings. It is an 8-item measure with a 
Likert response scale. The minimal detectable change has been defined as 
1.98 points. It will be administered to understand the reasons for non- 
adherence to protocol therapy. 
1.9 
Rationale for Tobacco Use Assessment 
NOTE: 
Please refer to Appendix VI for EAQ16T references. 
A significant proportion of cancer patients are current smokers at the time of 
cancer diagnosis,1–5 and there are known risks associated with continued 
smoking following cancer diagnosis. These include decreased survival time; 
increased complications from surgery, radiation, and chemotherapy; and 
increased risk of second primary tumors.6–11 As such, the National 
Comprehensive Cancer Network (NCCN), the American Association of Cancer 
Research (AACR) and the American Society of Clinical Oncology (ASCO) have 
identified persistent smoking as a modifiable risk factor and recommend 
cessation counseling for cancer patients who smoke. Although evidence-based 
guidelines for treating tobacco dependence exist,12 they have not yet been well-
integrated into cancer care settings. Moreover, knowledge regarding the scope 
and patterns of tobacco use among cancer patients is limited. 
Tobacco use following a cancer diagnosis compromises treatment outcomes but 
is not well understood. About 10% to 30% of cancer patients are smoking at the 
time of diagnosis,1–4,14,15 and the majority of cancer patients who smoke at 
diagnosis continue to smoke following diagnosis.3,16 Quitting smoking upon 
cancer diagnosis may improve cancer treatment effectiveness, reduce risk of 
recurrence and of developing new primary tumors,9–11,17–21 and improve chances 
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of survival.1,22–24 Conversely, continuing to smoke may result in diminished 
QOL,1,25,26 treatment delays and increased treatment complications.2,6–8,22,27–34 
Tobacco use following a cancer diagnosis may compromise patient reported 
outcomes. It is hypothesized that smoking may be used as a means of reducing 
symptom burden among cancer patients, which may be a barrier to smoking 
cessation. Relatedly, research has shown that cancer patients who are smoking 
experience more difficulty with physical and psychological symptom control, 
compared to nonsmokers. 35–38 Research is needed to examine how symptom 
levels differ, by tobacco use and exposure and how tobacco use changes may 
affect reported symptom burden. 
National initiatives emphasize the importance of identifying tobacco use in cancer 
care settings. Smoking status was designated as a core objective in the 2010 
federal government “Meaningful Use” electronic health record documentation.39,40 
In 2013, the American Association for Cancer Research (AACR) released 
guidelines emphasizing the provision of tobacco cessation services to cancer 
patients.41 The American Society of Clinical Oncology (ASCO) recommends 
cessation counseling to all smokers by their second oncology visit as a core 
quality indicator.42 The National Comprehensive Cancer Network (NCCN) 
published Smoking Cessation guidelines to formalize these initiatives.43 
Integrated, evidence-based services are needed during cancer care. The USPHS 
Practice Guidelines recommend that evidence-based tobacco treatment be 
delivered to all smokers in health care settings, yet little progress has been made 
to integrate these guidelines into cancer care.44 This is unfortunate, as cessation 
closer to the time of diagnosis results in a higher likelihood for continued 
abstinence,1,45–48 effective interventions exist,1,45–48 and many cancer patients 
who smoke want to quit smoking.45,46,49,50 Little work has been done to explore 
the delivery and effectiveness of tobacco treatment among racial/ethnic minority 
cancer patients who are at elevated risk of continued smoking.51–53 
Tobacco use is often not being assessed or intervened upon during cancer care. 
Recent surveys of oncologists and of clinical practices at comprehensive cancer 
centers and community oncology settings demonstrate that assessment of 
tobacco dependence is lacking.54–57 During treatment, most cancer patients do 
not get assistance with smoking cessation support.58–60 Tobacco use 
assessments and cessation support have not been incorporated in most 
cooperative group clinical trials.61 No one has assessed cancer patients’ reports 
of their oncology providers’ assistance behaviors. 
The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force developed 
the Cancer Patient Tobacco Use 1–4,13,14 Questionnaire (C-TUQ). We propose 
that administering selected C-TUQ items to participants enrolling in 8 Phase II 
and Phase III ECOG ACRIN (EA) therapeutic trials will add value to parent trial 
research questions by advancing the field. Specifically, among patients with 
varied cancers (tobacco-related and non-tobacco-related) and cancer treatments, 
we will administer C-TUQ questions at EA trial enrollment and 3 and 6 months 
follow-up. 
We have the following aims: 
a) Treatment toxicity: To determine the effects of tobacco, operationalized as 
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tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity 
(adverse events (both clinical and hematologic) and dose modifications). 
b) Symptom burden: To determine the effects of tobacco on patient-reported 
physical symptoms and psychological symptoms. 
c) Cessation patterns and treatment: To examine quitting behaviors and 
behavioral counseling/support and cessation medication utilization. 
d) Trial outcomes: To explore the effect of tobacco use and exposure on 
treatment duration and relative dose intensity, and on therapeutic benefit, of 8 
selected EA trials. 
The findings will advance the nascent field of tobacco use in the context of 
cancer care by: 1) longitudinal assessment of cigarette smoking, other forms of 
tobacco use and secondhand smoke exposure at trial enrollment and at 3 and 6 
month follow-up; 2) increase knowledge about the effects of tobacco use and 
exposure on treatment toxicity, physical and psychological symptoms and 3) 
oncology provider delivery, and 4) patient’s perceptions of stigma and utilization 
of behavioral and pharmacological treatment of tobacco dependence. Finally, the 
use of this assessment would provide a unique additional value to the hypothesis 
of this trial, by allowing investigation of previously unanswered questions about 
the effects of tobacco use and exposure on trial adherence and outcomes among 
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2. 
Objectives 
The study hypothesis is that patients with clinical stage II-III TNBC with more than 1 cm 
of residual disease and basal-like subtype in their surgical specimen after neoadjuvant 
chemotherapy that are treated with adjuvant platinum-based chemotherapy will have a 
longer invasive disease-free survival (IDFS) than the ones in the capecitabine arm, 
which is an appropriate standard of care based on the Create-X trial results. 
2.1 
Primary Objective 
2.1.1 
To compare the IDFS in TNBC patients with residual basal-like 
disease after neoadjuvant chemotherapy who are randomized to post-
preoperative platinum-based chemotherapy with those who are 
randomized to capecitabine. 
2.2 
Secondary Clinical Objectives 
2.2.1 
To evaluate OS and RFS in the two arms in patients with TNBC with 
residual basal-like disease after neoadjuvant chemotherapy. 
2.2.2 
To characterize the side effects and tolerability of each platinum agent 
(cisplatin and carboplatin) as well as capecitabine in patients with 
TNBC with residual disease after neoadjuvant chemotherapy.  
2.2.3 
To identify the rate of basal-like gene expression using PAM50 
analysis by digital mRNA quantitation amongst drug-resistant residual 
TNBC after neoadjuvant chemotherapy. 
2.2.4 
To compare the IDFS in TNBC patients with residual non-basal-like 
disease after neoadjuvant chemotherapy who are randomized to post-
preoperative platinum-based chemotherapy with those who are 
randomized to capecitabine (exploratory analysis). 
2.2.5 
To assess the difference in health-related quality of life (HRQL) 
between the platinum based and capecitabine chemotherapy arms. 
2.2.6 
To describe the rate of neurotoxicity over time in the platinum arm, the 
rate of medication adherence in the capecitabine arm and the rates of 
amenorrhea in both arms (exploratory). 
2.3 
Secondary Correlative Biomarker Objectives 
2.3.1 
To evaluate the association of genomic alterations identified via 
profiling of the surgical tumor specimen with RFS in patients with 
TNBC after neoadjuvant chemotherapy. 
2.3.2 
To explore whether any of the genomic alterations identified via 
profiling of the surgical tumor specimen can predict treatment benefit 
in patients with basal-like TNBC. 
2.3.3 
To determine the frequency of CTC positivity at baseline and after 
completion of study therapy in patients with TNBC with residual basal-
like disease after neoadjuvant chemotherapy.  
2.3.4 
To evaluate the associations between CTC levels at baseline, and 
after completion of chemotherapy, with RFS 
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2.3.5 
To evaluate the association between CTC change in status post-
treatment (i.e. negative to negative, negative to positive, positive to 
negative, positive to positive) and RFS. 
2.3.6 
To explore significance of CTC number/phenotype in predicting RFS. 
2.4 
Exploratory Correlative Biomarker Objectives 
2.4.1 
To determine the frequency of plasma tumor cell-free DNA (cfDNA) 
positivity at baseline and after completion of study therapy in patients 
with TNBC with residual basal-like disease after neoadjuvant 
chemotherapy.  
2.4.2 
To evaluate the associations between plasma tumor cfDNA tumor-
specific mutations (baseline and after therapy) with RFS.  
2.4.3 
To explore optimal biomarker combination for RFS prediction. 
2.5 
Exploratory Tobacco Use Objectives 
2.5.1 
To determine the effects of tobacco, operationalized as combustible 
tobacco (1a), other forms of tobacco (1b), and environmental tobacco 
exposure (ETS) (1c) on provider-reported cancer-treatment toxicity 
(adverse events (both clinical and hematologic) and dose 
modifications). 
2.5.2 
To determine the effects of tobacco on patient-reported physical 
symptoms and psychological symptoms. 
2.5.3 
To examine quitting behaviors and behavioral counseling/support and 
cessation medication utilization. 
2.5.4 
To explore the effect of tobacco use and exposure on treatment 
duration, relative dose intensity, and therapeutic benefit. 
NOTE: 
Tobacco Use objectives described above are ancillary for the 
Tobacco Use Assessment project approved by NCI. A combined 
analysis of the data from the selected ECOG-ACRIN trials is planned. 
Data collected from the tobacco use assessment in each parent study 
will not be analyzed and reported in the clinical study report. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician.  
NOTE: 
This study involves screening and randomization. Tumor tissue specimen 
must be submitted anytime during screening for PAM50 analysis. Patients will 
not be randomized without notification of receipt of tumor tissue at the ECOG-
ACRIN Central Biorepository and Pathology Facility. 
NOTE:  
Patients are allowed to participate in other therapeutic clinical trials either 
prior (neoadjuvant setting) or after full completion of EA1131 study treatment, 
but not during study treatment (except for non-cancer treatment related 
interventions). Patients enrolled in clinical trials addressing local therapy after 
neoadjuvant chemotherapy are also allowed to enroll. 
3.1 
Eligibility Criteria for Screening and Molecular Profiling (STEP 0) 
3.1.1 
Age ≥ 18 years. 
3.1.2 
ECOG Performance Status 0 or 1 within 2 weeks prior to screening. 
3.1.3 
Female and male patients must have histologically confirmed invasive 
breast cancer that meets the following criteria: 
3.1.3.1 
Clinical stage II or III (AJCC 8th edition) at diagnosis, 
based on initial evaluation by clinical examination and/or 
breast imaging; no metastatic disease (confirmed by 
biopsy) allowed. 
3.1.3.2 
ER- and PR- should meet one of the following criteria:   
1 to ≤ 10% cells stain positive, with weak intensity score 
≤ 1% cells stain positive 
3.1.3.3 
HER2 negative (not eligible for anti-HER2 therapy) will be 
defined as: 
IHC 0, 1+ without ISH HER2/neu chromosome 17 ratio OR 
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IHC 2+ and ISH HER2/neu chromosome 17 ratio non-
amplified with ratio less than 2.0 and if reported average 
HER2 copy number < 6 signals/cells OR 
ISH HER2/neu chromosome 17 ratio non-amplified with 
ratio less than 2.0 and if reported average HER2 copy 
number < 6 signals/cells without IHC) 
NOTE: 
Patients that originally present with 
synchronous bilateral tumors are eligible 
provided both tumors are TNBC, and at least 
one of them fulfills the remainder eligibility 
criteria of the protocol. Multifocal or multicentric 
breast cancers are eligible as long as all tumors 
that were tested for ER/PR/HER2 fulfill eligibility 
criteria (please note that tumors that were not 
tested already do not need to be tested for 
protocol eligibility). 
NOTE:  
Patients that have a discrepancy in 
ER/PR/HER2 status between original diagnosis 
and surgical specimen (only applicable if 
ER/PR/HER2 status were repeated; repeating it 
is not mandatory) are eligible for study 
participation as long as the surgical specimen’s 
ER/PR/HER2 status fulfills eligibility criteria. 
NOTE: 
Special histologies (i.e. metaplastic, adenoid 
cystic, apocrine, etc.) are eligible as long as 
ER/PR/HER2 testing fulfills eligibility criteria. 
NOTE: 
Patients with inflammatory TNBC at 
presentation are eligible. 
3.1.4 
Patients must have received neoadjuvant taxane +/- anthracycline. 
Patients must NOT have received cisplatin or carboplatin or 
capecitabine as part of their neoadjuvant therapy regimen. 
NOTE: 
Patients who received preoperative therapy as part of a 
clinical trial may enroll. 
NOTE: 
Patients that were not able to complete their planned 
neoadjuvant chemotherapy for any reason (i.e. toxicities, 
etc.) are eligible to participate as long as no further 
systemic standard of care therapy is planned by the treating 
physician. 
NOTE: 
Patients must have received a taxane for at least 1 cycle as 
part of their neoadjuvant therapy regimen. 
3.1.5 
Must have completed definitive resection of primary tumor.  
3.1.5.1 
Negative margins for both invasive and ductal carcinoma in 
situ (DCIS) are desirable, however patients with positive 
margins may enroll if the treatment team believes no 
further surgery is possible and patient has received 
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radiotherapy. Patients with margins positive for lobular 
carcinoma in situ (LCIS) are eligible.  
3.1.5.2 
Either mastectomy or breast conserving surgery (including 
lumpectomy or partial mastectomy) is acceptable.  
3.1.5.3 
Sentinel node biopsy either pre- or post-neoadjuvant 
chemotherapy (i.e. at the time of definitive surgery) are 
allowed. Axillary dissection is encouraged in patients with 
lymph node involvement, but is not mandatory. 
3.1.6 
Post neoadjuvant chemotherapy, patients must be found to have 
residual invasive cancer in the breast at the time of definitive surgery. 
Residual cancer is defined as a contiguous focus of residual invasive 
cancer, in the breast, measuring ≥ 1 cm in diameter, and with more 
than minimal cellularity, as per local pathologist determination. Please 
note that in patients that have multifocal or multicentric residual 
tumors these lesions cannot be added up; the biggest lesion has to 
measure ≥ 1 cm in diameter. This is required due to constraints in 
DNA extraction for PAM50 analysis. 
NOTE:  
The presence of ductal carcinoma in situ (DCIS) without 
invasion does not qualify as residual invasive disease in the 
breast. 
NOTE: 
Despite lymph node involvement if residual invasive cancer 
in the breast is < 1 cm in diameter patients are not eligible 
for participation. 
3.1.7 
Radiotherapy may be given before or after protocol treatment per 
standard of care guidelines. When radiotherapy is planned prior to 
protocol treatment administration, patients may be registered and 
screened while receiving radiation, and it has to be complete prior to 
randomization. 
Post-mastectomy radiotherapy is required for all patients with the 
following: 
Primary tumor ≥ 5 cm or involvement of lymph nodes (prior to 
neoadjuvant chemotherapy [clinically] or at the time of definitive 
surgery) or involvement of lymph nodes at the time of definitive 
surgery. 
For patients with primary tumors < 5 cm or without lymph node 
involvement prior to neoadjuvant chemotherapy and at the time of 
definitive surgery, provision of post-mastectomy radiotherapy is at the 
discretion of the treating physician. 
Radiation of regional nodal basins is at the discretion of the treating 
radiation oncologist. 
NOTE: 
Breast radiotherapy (whole breast or partial) is required for 
patients who underwent breast-conserving therapy, 
including lumpectomy or partial mastectomy. 
3.1.8 
Adequate bone marrow and organ function based on the following 
tests. Laboratory values must be obtained within 8 weeks prior to 
screening for protocol therapy. 
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3.1.8.1 
Hemoglobin (Hgb) > 9.0 g/dL 
Hgb: _____ 
Date of Test: _____ 
3.1.8.2 
Platelets > 100,000 cells/mm3 
Platelets: _____ 
Date of Test: _____ 
3.1.8.3 
Absolute neutrophil count (ANC) > 1500 cells/mm3 
ANC: _____ 
Date of Test: _____ 
3.1.8.4 
Calculated creatinine clearance of > 50 mL/min using the 
Cockcroft-Gault formula: 
Males:  (140 – Age in years) × Actual Body Weight in kg 
72 × Serum Creatinine (mg/dL) 
Females: 
Estimated creatinine clearance for females × 
0.85 
Creatinine Clearance: _____ Date of Test: _____ 
3.1.8.5 
Bilirubin ≤ 1.5 x ULN upper limit of normal (except in 
patients with documented Gilbert’s disease, who must 
have a total bilirubin ≤ 3.0 mg/dL) 
Bilirubin: _____ ULN:_____ Date of Test: _____ 
Gilberts disease?________(Yes or No) 
3.1.8.6 
Aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN 
AST: _____ ULN:_____ 
Date of Test: _____ 
3.1.8.7 
Alanine aminotransferase (ALT, SGPT) ≤ 2.5 × ULN 
ALT: _____ ULN:_____ 
Date of Test: _____ 
3.1.9 
No history of TNBC invasive breast cancer within 5 years of 
enrollment, no concurrent invasive malignancies except for 
synchronous bilateral tumors that are TNBC, skin, thyroid, or 
hematologic cancers with low metastatic/death potential (i.e. 
squamous cell or basal cell skin cancers, DCIS, CLL, etc.). Patients 
are eligible if they had any other cancers that were treated prior to 
screening and are without evidence of recurrence. 
3.1.10 
No clinically significant infections, cardiac, pulmonary, or hepatic 
dysfunction as judged by the treating investigator. Concurrent 
illnesses that are well controlled with medical management are 
allowed. 
3.1.11 
Patients with active ≥ CTCAE v.4 grade 2 neuropathy are ineligible. 
3.1.12 
Adjuvant chemotherapy after surgery other than that specified in this 
protocol is not allowed. LHRH agonists for fertility preservation or non-
cancer indications and adjuvant bisphosphonate or denosumab use is 
allowed. 
3.1.13 
Patients must have archived formalin-fixed paraffin-embedded (FFPE) 
tumor tissue specimen from the residual disease on the definitive 
surgical specimen available for PAM50 analysis. 
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3.1.13.1 
Tumor tissue specimen from the definitive surgery has 
been collected and is ready to ship to the ECOG-ACRIN 
Central Biorepository and Pathology Facility (EA CBPF) 
within 21 weeks post-surgery as indicated in Section 
10.2.1. 
The EA CBPF will notify the ECOG-ACRIN Operations 
Office and submitting institution of receipt of the tumor 
tissue specimen. 
NOTE: 
Tumor tissue must and can be submitted any 
time during screening period, even if patient is 
getting radiation. 
NOTE: 
Every effort should be made to submit the 
tumor tissue specimen to the EA CBPF 
immediately. 
Date of main surgery (i.e. subsequent surgeries for re-
excision of margins or lymph nodes or reconstruction do 
not apply): _______ 
Date tumor tissue sent to EA CBPF: _______ 
3.2 
Eligibility Criteria for Randomization (Step 1): 
Screened patients will remain on the study and be randomized if they meet the 
above and below following criteria. No specific timeframe between registration 
and randomization needs to be observed, as long as: 
• 
After assignment of randomization patients must begin Cycle 1/ Day 1 
(platinum based or capecitabine chemotherapy) within 6 weeks (30 working 
days) of the randomization date. 
• 
Randomization occurs no more than 24 weeks from main surgery date (i.e. 
subsequent surgeries for re-excision of margins or lymph nodes or 
reconstruction do not apply) 
3.2.1 
Must have confirmation from EA CBPF of receipt of formalin-fixed 
paraffin-embedded tumor tissue specimen (FFPE) of the residual 
disease in the breast resected at the time of definitive surgery. 
3.2.2 
ECOG Performance Status 0 or 1 within 2 weeks prior to 
randomization. 
3.2.3 
Radiotherapy, if applicable, may be given before or after protocol 
treatment. When radiotherapy is planned prior to protocol treatment 
administration, patients must have completed adjuvant radiotherapy ≥ 
2 weeks prior to randomization for protocol therapy, if applicable. 
3.2.4 
Patients must have completed treatment with any investigational 
agent ≥ 30 days prior to randomization for protocol therapy initiation 
(Cycle 1/ day 1). 
3.2.5 
Patients must be randomized within 24 weeks from main surgery date 
(i.e. subsequent surgeries for re-excision of margins or lymph nodes 
or reconstruction do not apply). 
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Rev. 6/16 
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Rev. 9/17 
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3.2.6 
Women must not be pregnant or breast-feeding due to risk of 
teratogenicity/ toxicity with capecitabine or platinum-based therapy. All 
females of childbearing potential must have a blood test or urine study 
within 2 weeks prior to randomization to rule out pregnancy. 
3.2.6.1 
A female of childbearing potential is defined as any woman 
that has achieved menarche at some point, regardless of 
sexual orientation or whether they have undergone tubal 
ligation, who meets the following criteria: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) 
has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months). 
Female of child bearing potential?____(Yes or No) 
3.2.6.2 
Date of pregnancy blood test or urine study (if not 
applicable, write N/A instead of date): ___________ 
3.2.7 
Women of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of 
contraception or to abstain from sexual intercourse for the duration of 
their participation in the study.  
3.2.8 
Adequate bone marrow and organ function based on the following 
tests. Laboratory values must be obtained within 4 weeks prior to 
randomization. 
3.2.8.1 
Hemoglobin (Hgb) > 9.0 g/dL 
Hgb: _____ 
Date of Test: _____ 
3.2.8.2 
Platelets > 100,000 cells/mm3 
Platelets: _____ 
Date of Test: _____ 
3.2.8.3 
Absolute neutrophil count (ANC) > 1500 cells/mm3 
ANC: _____ 
Date of Test: _____ 
3.2.8.4 
INR ≤ 3 (to be done/tested only for subjects on warfarin) 
Patient on warfarin?________(Yes or No) 
INR:___________ Date of Test:____________ 
3.2.8.5 
Calculated creatinine clearance of > 50 mL/min using the 
Cockcroft-Gault formula: 
Males: (140 – Age in years) × Actual Body Weight in kg 
72 × Serum Creatinine (mg/dL) 
Females: 
Estimated creatinine clearance for females  
× 0.85 
Creatinine Clearance: _____ Date of Test: _____ 
3.2.8.6 
Bilirubin ≤ 1.5 x ULN (except in patients with documented 
Gilbert’s disease, who must have a total bilirubin ≤ 3.0 
mg/dL) 
Bilirubin: _____ ULN:_____ Date of Test: _____ 
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Gilberts disease?________(Yes or No) 
3.2.8.7 
Aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN 
AST: _____ ULN:_____ 
Date of Test: _____ 
3.2.8.8 
Alanine aminotransferase (ALT, SGPT) ≤ 2.5 × ULN 
ALT: _____ ULN:_____ 
Date of Test: _____ 
NOTE: 
Live vaccines are not permitted during study treatment period (but are 
permitted after study treatment completion), but all others (inactivated, 
mRNA-based, adenovirus, etc.) including COVID vaccine are 
permitted before, during and after study treatment. 
NOTE: 
Use of (any) anti-coagulants are allowed during study. 
 
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4. 
Registration Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, please 
contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
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CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations. 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
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Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a Protocol Organization (PO) on the protocol. One way to search for a 
protocol is listed below. 
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• 
Click on the Protocols in the upper left of your screen 
• 
Either enter the protocol number in the search field at the top of the protocol tree 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EA1131 
• 
Click on Documents, select the Site Registration documents link, and download and 
complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE: The above submissions must include the following details: 
• Indicate all sites approved for the protocol under an assurance 
number. 
• OHRP assurance number of reviewing IRB 
• Full protocol title and number 
• Version Date 
• Type of review (full board vs. expedited) 
• Date of review. 
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• Signature of IRB official 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website. 
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
• 
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
NOTE: 
The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance 
with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with NCI or their affiliated networks. 
Patient Enrollment 
Treatment should start within 6 weeks (thirty [30] working days) following 
randomization date. 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for 
your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
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4.1 
Screening (STEP 0) 
4.1.1 
Protocol Number 
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name 
4.1.2.2 
Investigator’s name 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials (first and last) 
4.1.3.2 
Patient’s Hospital ID and/or Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Gender 
4.1.3.3.2 
Birth date (mm/yyyy) 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.1.3.3.7 
Country of residence 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.2 
Additional Requirements 
4.2.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.2.2 
Pathological materials are required to be submitted no later than 21 
weeks post-surgery for PAM50 analysis as indicated in Section 10.2. 
NOTE: 
The EA CBPF will notify the ECOG-ACRIN Operations 
Office and submitting institution of receipt of the tumor 
tissue specimen. PAM50 results will not be reported to the 
submitting institution. 
Patients cannot proceed with randomization to STEP 1 until the EA 
CBPF confirms receipt of tumor tissue for PAM50 analysis. 
Pathological materials will also be used for retrospective central review 
for confirmation of ER, PR, and HER2 status. 
4.3 
Randomization (STEP 1) 
4.3.1 
Protocol Number  
4.3.2 
Investigator Identification  
4.3.2.1 
Institution and affiliate name. 
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4.3.2.2 
Investigator’s name. 
4.3.3 
Patient Identification  
4.3.3.1 
Patient’s initials (first and last) 
4.3.3.2 
Patient’s Hospital ID and/or Social Security number 
4.3.3.3 
Patient demographics 
4.3.3.3.1 
Gender 
4.3.3.3.2 
Birth date (mm/yyyy) 
4.3.3.3.3 
Race 
4.3.3.3.4 
Ethnicity 
4.3.3.3.5 
Nine-digit ZIP code 
4.3.3.3.6 
Method of payment 
4.3.3.3.7 
Country of residence 
4.3.4 
Additional Requirements 
4.3.4.1 
Peripheral blood specimens are required to be submitted 
for defined laboratory research studies as outlined in 
Section 10. 
4.3.4.2 
Peripheral blood specimens are to be submitted for future 
undefined research studies per patient consent as outlined 
in Section 10. 
4.3.5 
Stratification Factors 
4.3.5.1 
Clinical stage at diagnosis (II or III) 
4.3.5.2 
Residual cancer burden after neoadjuvant chemotherapy 
(1~3 cm or >3 cm) 
4.3.5.3 
Planned platinum agent (cisplatin or carboplatin) 
4.3.5.4 
Anthracycline exposure in the neoadjuvant setting (yes or 
no)  
4.3.5.5 
Administration of adjuvant radiotherapy (yes or no) 
4.3.6 
Medidata Rave is a clinical data management system being used for 
data collection for this trial/study. Access to the trial in Rave is 
controlled through the CTEP-IAM system and role assignments. 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site 
of: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave 
SLA, or Rave Investigator. 
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum 
of an Associate Plus (AP) registration type; 
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• 
Rave Investigator role must be registered as a Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. If an eLearning is required and has not yet been 
taken, the link to the eLearning will appear under the study name in 
iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study 
in Rave will be granted, and a Rave EDC link will display under the 
study name. 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.3.7 
ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO) System: 
When patients consent to participate, they will be asked to provide a 
contact email address and that address along with their registration 
information will be sent directly from the parent trial’s registration 
system to EASEE-PRO, and the patient will be automatically 
registered into EASEE-PRO for participation. To activate their account 
for self-directed web entry of surveys, the system will send an 
activation message to the contact email address that will explain how 
to activate their account for self-directed web entry of surveys. After 
their account is activated, the patient will be able to complete 
questionnaires using a secure browser interface from any web 
enabled computer, tablet, or mobile device. 
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4.4 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on 
the Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization (LPO) for delinquent 
form details and reports to be available on the DQP. Site staff should contact the 
LPO Data Manager for their protocol regarding questions about Rave 
Calendaring functionality. 
4.5 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If after randomization a patient does not receive any assigned protocol treatment, 
baseline and follow-up data will still be collected and must be submitted through 
Medidata Rave and EASEE-PRO according to the schedule in the EA1131 
Forms Completion Guidelines. 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
Doses are based on actual body weight.  
Arm A Observation closed to accrual in Addendum #3 
5.1.1 
ARM B 
Cisplatin 75 mg/m2, IV infusion per institutional guidelines, day 1 
every 3 weeks for a total of 4 cycles (12 weeks) 
OR  
Carboplatin AUC 6, IV infusion per institutional guidelines, day 1 every 
3 weeks for a total of 4 cycles (12 weeks) 
NOTE: 
CALVERT FORMULA FOR CARBOPLATIN DOSING: 
Total Dose (mg) = (target AUC) x (GFR + 25) 
For the purposes of this protocol, the GFR is considered to be 
equivalent to the creatinine clearance. 
Glomerular Filtration Rate (GFR) Estimation: Calculated creatinine 
clearance of ≥ 50 cc/min using the Cockcroft-Gault formula: 
Males: 
(140 – Age in years) × Actual Body Weight in kg 
72 × Serum Creatinine (mg/dL) 
Females: Estimated creatinine clearance for females × 0.85 
With the Calvert formula, the total (final) dose of carboplatin is 
calculated in mg, not mg/m2. 
NOTE: 
Carboplatin maximum dose is based on a GFR estimate 
that is capped at 125 mL/min for patients with normal renal 
function. Based on Calvert formula, the recommended 
maximum AUC- based carboplatin dose is (or not to 
exceed or cap at): 
AUC 6 900 mg (max) 
AUC 5750 mg (max) 
AUC 4  600 mg (max) 
NOTE: 
Choice of platinum agent will be per treating physician 
discretion. Once a platinum agent is picked, no changes 
are allowed. 
NOTE: 
In case of an event that causes a patient to reschedule 
appointments, treatment cycles should be no less than 19 
days apart. 
NOTE: 
All patients (on both arms) will be followed for development 
of recurrences, second primary cancer and survival based 
on standard ECOG-ACRIN following schedules (see 
Section 7 for details). 
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5.1.2 
ARM C 
Capecitabine 1,000 mg/m2, PO twice daily, on days 1 - 14 every 3 weeks for a total of 6 cycles (18 weeks) 
NOTE: 
In case of an event that causes a patient to reschedule appointments, treatment cycles should be 
no less than 19 days apart. 
NOTE: 
Table below provides guidance on rounding the calculated dose of capecitabine as only 500 mg 
tablets should be utilized. Please prescribe capecitabine based on the “number of 500 mg 
tablets” column as per table below, not based on the “total daily dose in mg” column. 
Adjustments to capecitabine dose based on weight changes are not necessary unless there is ≥ 
10% change in weight compared to baseline. Capecitabine tablets are to be swallowed whole, 
with water, 30 minutes after a meal. Tablets should not be cut or crushed. Dose escalations of 
capecitabine after dose reductions for safety are not permitted. Missed capecitabine doses 
beyond 3 hours of regular intake time should not be taken. In case of vomiting after capecitabine 
ingestion, dose should not be replaced. Please see Section 5.3 for additional information on 
capecitabine dose modifications. 
Guidelines for Capecitabine Dose Calculation According to Body Surface Area 
BSA (m2) 
100% Dose Level of Capecitabine 
75% Dose Level of Capecitabine 
50% Dose Level of Capecitabine 
1000 mg/m2 
(BID) 
Number of 500 mg 
Tablets 
750 mg/m2 
(BID) 
Number of 500 mg 
Tablets  
500 mg/m2 
(BID) 
Number of 500 mg Tablets  
Total Daily 
Dose (mg) 
Morning 
Number of 
Tablets 
Evening 
Number of 
Tablets 
Total Daily 
Dose (mg) 
Morning 
Number of 
Tablets 
Evening 
Number of 
Tablets 
Total Daily 
Dose (mg) 
Morning 
Number of 
Tablets 
Evening 
Number of 
Tablets 
≤ 1.25 
2000 
2 
2 
1600 
2 
1 
1000 
1 
1 
1.26 – 1.37 
2600 
3 
2 
2000 
2 
2 
1300 
2 
1 
1.38 – 1.51 
2900 
3 
3 
2300 
2 
2 
1600 
2 
1 
1.52 – 1.65 
3300 
3 
3 
2300 
2  
2 
1600 
2 
1 
1.66 – 1.77 
3600 
4 
3 
2600 
3 
2 
1900 
2 
2 
1.78 – 1.91 
3800 
4 
3 
2600 
3 
2 
1900 
2 
2 
1.92 – 2.05 
4000 
4 
4 
3000 
3 
3 
2000 
2 
2 
2.06 – 2.17 
4300 
4 
4 
3300 
3 
3 
2300 
3 
2 
≥ 2.18 
4600 
5 
4 
3600 
4 
3 
2600 
3 
2 
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5.2 
Adverse Event Reporting Requirements 
NOTE: 
Effective April 1, 2018 all expedited adverse event reporting done 
via CTEP-AERS will use CTCAE version 5.0 terminology and 
grading. Routine adverse event reporting and dose modifications 
guidelines for this study will continue to be based on CTCAE 
version 4.0 terminology and grading. 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required 
as part of every clinical trial, are done to ensure the safety of the 
patients enrolled, as well as those who will enroll in future studies 
using similar agents.  
• 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial using Medidata Rave.   
• 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the agent. 
An adverse event is considered unexpected, for expedited 
reporting purposes, when either the type of event or the severity of 
the event is NOT listed in the protocol or drug package insert. 
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5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). The CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) 
• 
the FDA (1-800-FDA-1088)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
• 
 the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EA1131 and outline the 
specific expedited adverse event reporting requirements for study 
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5.2.5 
Steps to determine if an event is to be reported in an expedited 
manner – Arms B and C 
 
Identify the type and grade of the event 
using CTCAE v5.0. 
Determine if the event is related to the 
protocol treatment (attribution). 
With this information, review the chart in 
Section 5.2.6 to determine if event is 
reportable via CTEP-AERS. 
Refer to footnote b in 
Section 5.2.6 to determine 
if the event meets the 
protocol specific reporting 
requirements for this 
study. If so, report the 
event via CTEP-AERS. 
Is the event 
reportable?
No 
Yes 
Report the event via CTEP-AERS. 
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 
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5.2.6 
Expedited Reporting Requirements for Arms B and C on protocol 
EA1131 
Commercial Agents: Capecitabine, Cisplatin and Carboplatin 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
A death occurring while on study or within 30 days of the last dose of treatment requires both routine and 
expedited reporting, regardless of causality. Attribution to treatment or other cause must be provided. 
NOTE: A death due to progressive disease should be reported as a Grade 5 “Disease progression” 
under the System Organ Class (SOC) “General disorder and administration site conditions”. 
Evidence that the death was a manifestation of underlying disease (e.g. radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed possibly, 
probably, or definitely to the treatment must be reported within 7 calendar days of learning of 
the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar 
days of learning of the event. For instructions on how to specifically report these events via 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 301-897-
7497. This will need to be discussed on a case-by-case basis. 
5.2.7 
Other recipients of adverse event reports and supplemental data 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient.  
5.2.8 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
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2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the ECOG-ACRIN 
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5.3 
Capecitabine Dose Modifications 
A patient’s protocol treatment will be discontinued if more than 2 cumulative dose reductions are necessary or if 
patients are unable to restart capecitabine within 3 weeks of interruption (from the time of due scheduled cycle 
initiation; i.e. within 6 weeks from previous cycle initiation). Dose reductions will be permanent. Missed doses will 
not be made up once toxicity is resolved as per guidelines below. Only 500 mg tablets should be utilized. Please 
prescribe capecitabine based on the “number of 500 mg tablets” column as per table below, not based on the 
“total daily dose in mg” column. Adjustments to capecitabine dose based on weight changes are not necessary 
unless there is ≥ 10% change in weight compared to baseline. 
All toxicity grades below are described using the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). 
5.3.1 
Standardized, initial capecitabine dosing schedule 
Guidelines for Capecitabine Dose Calculation According to Body Surface Area 
BSA (m2) 
100% Dose Level of Capecitabine 
75% Dose Level of Capecitabine 
50% Dose Level of Capecitabine 
1000 mg/m2 
(BID) 
Number of 500 mg 
Tablets 
750 mg/m2 
(BID) 
Number of 500 mg 
Tablets 
500 mg/m2 
(BID) 
Number of 500 mg 
Tablets 
Total Daily 
Dose (mg) 
Morning 
Number of 
Tablets 
Evening 
Number of 
Tablets 
Total Daily 
Dose (mg) 
Morning 
Number of 
Tablets 
Evening 
Number of 
Tablets 
Total Daily 
Dose (mg) 
Morning 
Number of 
Tablets 
Evening 
Number of 
Tablets 
≤ 1.25 
2000 
2 
2 
1600 
2 
1 
1000 
1 
1 
1.26 – 1.37 
2600 
3 
2 
2000 
2 
2 
1300 
2 
1 
1.38 – 1.51 
2900 
3 
3 
2300 
2 
2 
1600 
2 
1 
1.52 – 1.65 
3300 
3  
3 
2300 
2 
2 
1600 
2 
1 
1.66 – 1.77 
3600 
4 
3 
2600 
3 
2 
1900 
2 
2 
1.78 – 1.91 
3800 
4 
3 
2600 
3 
2 
1900 
2 
2 
1.92 – 2.05 
4000 
4 
4 
3000 
3 
3 
2000 
2 
2 
2.06 – 2.17 
4300 
4  
4 
3300 
3  
3 
2300 
3 
2 
≥ 2.18 
4600 
5 
4 
3600 
4 
3 
2600 
3 
2 
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5.3.2 
Recommended Dose Modifications 
Worst Toxicity CTCAE v4.0 Grade (unless 
otherwise specified) 
Recommended Dose Modifications to capecitabine any time 
during a cycle of therapy 
BLOOD AND LYMPHATIC SYSTEM DISORDER 
Anemia 
Grade 1 (Hgb < LLN-10.0 g/dL) 
Maintain dose level. 
Grade 2 (Hgb < 10.0 g/dL - 8.0 g/dL) 
Maintain dose level. 
Grade 3 (Hgb < 8.0 g/dL); transfusion indicated 
Maintain dose level. 
Grade 4 (Life threatening consequences; urgent 
intervention indicated); related to study drugs  
Discontinue study treatment. 
ANC decreased (Neutropenia) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Maintain dose level. 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain dose level. 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Omit capecitabine until resolved to CTCAE Grade ≤ 2, then: 
- If resolved in ≤ 7 days, then maintain dose level.  
- If resolved in > 7 days, then reduce by 25%.  
- If second occurrence, then reduce by 25% 
Grade 4 (ANC < 0.5 x 109/L) 
Omit capecitabine until resolved to CTCAE ≤ Grade 2, then reduce 
by 25%. 
Febrile neutropenia  
Grade 3 (ANC < 1.0 x 109/L, single temperature 
of > 38.3°C or a sustained temperature of ≥ 
38.0°C) 
Omit capecitabine until resolved to CTCAE Grade ≤ 2, and no 
fever, then: 
- If resolved by ≤ 7 days, then reduce by 25%.  
- If not resolved within 7 days despite appropriate management 
including full clinically indicated course of antibiotics, if indicated, 
discontinue patient from study treatment. 
Grade 4 
Discontinue study treatment. 
Platelet count decreased (Thrombocytopenia) 
Grade 1 (PLT < LLN - 75 x 109/L) 
Maintain dose level 
Grade 2 (PLT < 75 - 50 x 109/L) 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then reduce 
by 25%. 
Grade 3 (PLT < 50 - 25 x 109/L) 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then reduce by 25%. 
- If resolved in > 7 days, then discontinue study treatment. 
Grade 4 (PLT < 25 x 109/L) 
Discontinue study treatment. 
Bleeding 
Any bleeding (related to cisplatin or carboplatin) 
resulting in a transfusion requirement 
Omit capecitabine until no further bleeding has been observed. 
Continuation of study treatment may be considered. 
INVESTIGATIONS – RENAL  
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level. 
Grade 2 (> 1.5 - 3.0 x ULN) 
Omit capecitabine until resolved to CTCAE Grade ≤ 1 or baseline, 
then 
- If resolved in ≤ 7 days, then maintain dose level. 
- If resolved in > 7 days, then reduce by 25%. 
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Worst Toxicity CTCAE v4.0 Grade (unless 
otherwise specified) 
Recommended Dose Modifications to capecitabine any time 
during a cycle of therapy 
Grade ≥ 3 (> 3.0 x ULN) 
Discontinue study treatment. 
INVESTIGATIONS – HEPATIC 
Blood Bilirubin b (for patients with Gilbert Syndrome these dose modifications apply to changes in direct bilirubin 
only)  
For patients with total bilirubin ≥ grade 3, a CT scan or equivalent imaging procedure to exclude disease progression or 
potential other liver disease should be performed. 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose level. 
Grade 2 (>1.5 – 3.0 x ULN)  
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then maintain dose level. 
- If resolved in > 7 days, then reduce by 25%. 
Grade 3 (> 3.0 – 10 x ULN) or higher 
Discontinue study treatment. 
NOTE: If CTCAE Grade 3 or 4 hyper-bilirubinemia is due to the 
indirect (non-conjugated) component only, and hemolysis 
as the etiology has been ruled out as per institutional 
guidelines (e.g. review of peripheral blood smear and 
haptoglobin determination), then reduce by 25% and 
continue treatment at the discretion of the Investigator. 
AST or ALT 
Grade 1 and 2 (up to 5.0 x ULN) 
Maintain dose level. 
Grade 3 (> 5.0 - 20.0 x ULN) 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then maintain dose level. 
- If resolved in > 7 days, then reduce by 25%. 
Grade 4 (> 20.0 x ULN) 
Discontinue study treatment. 
NERVOUS SYSTEM DISORDERS 
Neurotoxicity 
Grade 1 
Maintain dose level. 
Transient Grade 2 that improves to grade ≤ 1 on 
the day of planned therapy 
Maintain dose level. 
Grade 2 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then reduce 
by 25%. 
Grade ≥ 3 or second occurrence of Grade 2 
Discontinue study treatment. 
GI DISORDERS 
Diarrhea  
Grade 1 
Maintain dose level, but initiate anti-diarrhea treatment as clinically 
indicated 
Grade 2 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, including 
with appropriate management, then maintain dose level. 
Grade 3 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, initiate anti-
diarrhea treatment, then 
- If resolved in ≤ 48 hours, maintain dose level. 
- If resolved in > 48 hours, then reduce by 25%. 
For 2nd occurrence of diarrhea CTCAE Grade 3 for > 48 hours 
despite the use of anti-diarrhea treatment, discontinue study 
treatment. 
Grade 4 
Discontinue study treatment. 

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Worst Toxicity CTCAE v4.0 Grade (unless 
otherwise specified) 
Recommended Dose Modifications to capecitabine any time 
during a cycle of therapy 
Nausea/Vomiting 
Grade 1 
Maintain dose level, but initiate anti-emetic treatment. 
Transient Grade 2 that improves to grade 1 on 
the day of planned therapy 
Maintain dose level. 
Grade 2 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, initiate anti-
emetic treatment, then maintain dose level. 
Grade 3 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, initiate anti-
emetic treatment, then: 
- If resolved in ≤ 48 hours, maintain dose level. 
- If resolved in > 48 hours, then reduce by 25%. 
Grade 4 
Discontinue study treatment. 
GENERAL DISORDERS 
Fatigue 
Grade 1 or 2 
Maintain dose level. 
Grade 3 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, maintain dose level. 
- If resolved in > 7 days, discontinue patient from study treatment. 
Grade 4 
Discontinue study treatment. 
Dehydration 
Grade 1 
Maintain dose level. 
≥ Grade 2 
Interrupt capecitabine until dehydration is corrected. Once 
resolved, may resume at same level. 
MUCOCUTANEOUS AND DERMATOLOGIC 
Hand-Foot Syndrome 
Grade 1 or 2 
Maintain capecitabine. For intolerable grade 2 toxicity, may omit 
dose of capecitabine until resolved to CTCAE Grade ≤ 1, 
consideration of 25% dose reduction at investigator’s discretion. 
Grade 3 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then reduce 
by 25%. 
Grade 4 
Discontinue study treatment. 
Stomatitis/ Mucosal Inflammation 
Grade 1 or 2 
Maintain capecitabine. For intolerable grade 2 toxicity, may omit 
dose of capecitabine until resolved to CTCAE Grade ≤ 1, 
consideration of 25% dose reduction at investigator’s discretion. 
Grade 3 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then reduce 
by 25%. 
Grade 4 
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Worst Toxicity CTCAE v4.0 Grade (unless 
otherwise specified) 
Recommended Dose Modifications to capecitabine any time 
during a cycle of therapy 
OTHER ADVERSE EVENTS 
Grade 1 or 2 
Maintain capecitabine. For intolerable grade 2 toxicity, may omit 
dose of capecitabine until resolved to CTCAE Grade ≤ 1, 
consideration of 25% dose reduction at investigator’s discretion. 
Grade 3 
Omit capecitabine until resolved to CTCAE Grade ≤ 1, then reduce 
by 25%. 
Grade 4 
Discontinue study treatment. 
NOTE: All of the above are general guidelines. The investigator may omit a dose of drug, decrease dose level 
of drug, or remove any patient from study for any toxicity, if he/she believes that it is in the best 
interest of the patient. 
NOTE: If a patient requires a dose delay of > 21 consecutive days (from the time of due scheduled cycle initiation; 
i.e. > 42 days from previous cycle initiation) of capecitabine then the patient must be discontinued from the 
study treatment.  
NOTE: Patients who discontinue from the study for a study-related adverse event or an abnormal laboratory value 
must be followed approximately once a week for 3 weeks and subsequently approximately at 3-week 
intervals, until resolution or stabilization of the event, whichever comes first, unless stated otherwise. 
5.3.3 
Supportive Care 
5.3.3.1 
All supportive measures consistent with optimal patient 
care will be given throughout the study. 
5.3.3.2 
The clinical tolerance of the patients, and the medical 
judgment of the investigator will determine if it is in the 
patient’s best interest to continue or discontinue treatment. 
If treatment is discontinued due to any toxicity, the patient 
must be followed to monitor duration of toxicity, response 
and time to progression (even if non-protocol therapy is 
initiated). Suggested supportive care medications may be 
substituted at the discretion of the investigator based on 
drug availability. 
5.3.3.3 
Appropriate supportive measures for diarrhea should 
include Loperamide and/or Diphenoxilate/atropine, and 
should be implemented immediately to prevent 
dehydration. 
5.3.3.4 
A specific antiemetic regimen is at the discretion of the 
treating physician, provided adequate control is achieved. 
5.3.3.5 
Patients receiving concomitant capecitabine and oral 
coumarin-derivative anticoagulant therapy should have 
their anticoagulant response (INR or prothrombin time) 
monitored closely with great frequency and the 
anticoagulant dose should be adjusted accordingly. 
5.3.3.6 
Patients with certain homozygous or certain compound 
heterozygous mutations in the DPD gene that result in 
complete or near complete absence of DPD activity are at 
increased risk for acute early-onset of toxicity and severe, 
life-threatening, or fatal adverse reactions caused by 
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capecitabine (e.g., mucositis, diarrhea, neutropenia, and 
neurotoxicity). Patients with partial DPD activity may also 
have increased risk of severe, life threatening, or fatal 
adverse reactions caused by capecitabine. Withhold or 
permanently discontinue capecitabine based on clinical 
assessment of the onset, duration and severity of the 
observed toxicities in patients with evidence of acute early-
onset or unusually severe toxicity, which may indicate near 
complete or total absence of DPD activity. No capecitabine 
dose has been proven safe for patients with complete 
absence of DPD activity. There is insufficient data to 
recommend a specific dose in patients with partial DPD 
activity as measured by any specific test. 
5.3.3.7 
Capecitabine tablets are to be swallowed whole, with 
water, 30 minutes after a meal. Tablets should not be cut 
or crushed. Dose escalations of capecitabine after dose 
reductions for safety are not permitted. Missed 
capecitabine doses beyond 3 hours of regular intake time 
should not be taken. In case of vomiting after capecitabine 
ingestion, dose should not be replaced. 
5.4 
Cisplatin or Carboplatin Dose Modifications  
A patient’s protocol treatment will be discontinued if more than 2 
cumulative dose reductions are necessary or if patients are unable to 
restart cisplatin or carboplatin within 3 weeks of interruption (from the time 
of due scheduled cycle initiation; i.e. within 6 weeks from previous cycle 
initiation). Dose reductions will be permanent. Missed doses will be made 
up once toxicity is resolved as per guidelines below. 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.4.1 
Cisplatin and Carboplatin dose reduction guidelines 
 
Starting dose 
(100%) 
1st dose reduction 
(80%) 
2nd dose reduction 
(60%) 
Cisplatin 
75 mg/m2 
60 mg/m2 
45 mg/m2 
Carboplatin 
AUC 6 
AUC 5 
AUC 4 
5.4.2 
Recommended Dose Modifications 
Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
BLOOD AND LYMPHATIC SYSTEM DISORDER 
Anemia 
Grade 1 (Hgb < LLN-10.0 g/dL) 
Maintain dose level. 
Maintain dose level. 
Grade 2 (Hgb < 10.0 g/dL - 8.0 g/dL) 
Maintain dose level. 
Maintain dose level. 
Grade 3 (Hgb < 8.0 g/dL); transfusion 
Maintain dose level. 
Maintain dose level. 
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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
indicated 
Grade 4 (Life threatening 
consequences; urgent intervention 
indicated); related to study drugs  
Discontinue study treatment. 
Discontinue study treatment. 
ANC decreased (Neutropenia) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Maintain dose level. 
Maintain dose level 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain dose level. 
Maintain dose level 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 2. Then: 
- If resolved in ≤ 7 days, then 
maintain dose level 
- If resolved in > 7 days, then 
maintain dose level and consider 
prophylactic growth factor support 
per ASCO guidelines 
- If second occurrence, then ↓ 1 
dose level for subsequent cycles. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 2. 
Then: 
- If resolved in ≤ 7 days, then 
maintain dose level 
- If resolved in > 7 days, then 
maintain dose level and initiate 
prophylactic growth factor support 
per ASCO guidelines 
- If second occurrence, then ↓ 1 
dose level for subsequent cycles. 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose of cisplatin until resolved 
to CTCAE ≤ Grade 2, then ↓ 1 dose 
level; additionally, consider 
prophylactic growth factor support 
per ASCO guidelines. 
Omit dose of carboplatin until 
resolved to CTCAE ≤ Grade 2, then 
↓ 1 dose level; additionally, 
consider prophylactic growth factor 
support per ASCO guidelines. 
Febrile neutropenia  
Grade 3 (ANC < 1.0 x 109/L, single 
temperature of > 38.3°C or a 
sustained temperature of ≥ 38.0°C) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 2, and no fever, 
then:  
- If resolved by ≤ 7 days, then ↓ 1 
dose level and consider 
prophylactic growth factor support 
per ASCO guidelines. 
- If not resolved within 7 days 
despite appropriate management 
including full clinically indicated 
course of antibiotics, if indicated, 
discontinue patient from study 
treatment. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 2, and 
no fever, then:  
- If resolved by ≤ 7 days, then ↓ 1 
dose level and consider 
prophylactic growth factor support 
per ASCO guidelines. 
- If not resolved within 7 days 
despite appropriate management 
including full clinically indicated 
course of antibiotics, if indicated, 
discontinue patient from study 
treatment. 
Grade 4 
Discontinue study treatment. 
Discontinue study treatment. 
Platelet count decreased (Thrombocytopenia) 
Grade 1 (PLT < LLN - 75 x 109/L) 
Maintain dose level 
Maintain dose level 
Grade 2 (PLT < 75 - 50 x 109/L) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then ↓ 1 dose 
level   
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, then 
↓ 1 dose level   
Grade 3 (PLT < 50 - 25 x 109/L) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then then 
↓ 1 dose level.  
- If resolved in > 7 days, then 
discontinue study treatment. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then then 
↓ 1 dose level.  
- If resolved in > 7 days, then 
discontinue study treatment. 
Grade 4 (PLT < 25 x 109/L) 
Discontinue study treatment. 
Discontinue study treatment 
Bleeding 
Any bleeding (related to cisplatin or 
carboplatin) resulting in a transfusion 
requirement 
Omit dose of cisplatin until no 
further bleeding has been 
observed. Continuation of study 
Omit dose of carboplatin until no 
further bleeding has been 
observed. Continuation of study 

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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
treatment may be considered. 
treatment may be considered. 
INVESTIGATIONS – RENAL  
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level. 
Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1 or baseline, 
then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then ↓ 1 
dose level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1 or 
baseline, then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then ↓ 1 
dose level. 
Grade ≥ 3 (> 3.0 x ULN) 
Discontinue study treatment. 
Discontinue study treatment 
INVESTIGATIONS – HEPATIC 
Blood Bilirubin b (for patients with Gilbert Syndrome these dose modifications apply to changes in direct bilirubin 
only)  
For patients with total bilirubin ≥ grade 3, a CT scan or equivalent imaging procedure to exclude disease progression 
or potential other liver disease should be performed. 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain dose level. 
Maintain dose level 
Grade 2 (>1.5 – 3.0 x ULN)  
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then ↓ 1 
dose level.  
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 
1, then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then 
↓ 1 dose level. 
Grade 3 (> 3.0 – 10 x ULN) or higher 
Discontinue study treatment. 
NOTE: If CTCAE Grade 3 or 4 
hyper-bilirubinemia is due 
to the indirect (non-
conjugated) component 
only, and hemolysis as the 
etiology has been ruled out 
as per institutional 
guidelines (e.g. review of 
peripheral blood smear and 
haptoglobin determination), 
then ↓ 1 dose level and 
continue treatment at the 
discretion of the 
Investigator. 
Discontinue study treatment. 
NOTE: If Grade 3 or Grade 4 
hyperbilirubinemia is due 
to the indirect 
(unconjugated) 
component only, and 
hemolysis as the etiology 
has been ruled out as per 
institutional guidelines 
(e.g., review of peripheral 
blood smear and 
haptoglobin 
determination), then ↓1 
dose level and continue 
treatment at the discretion 
of the investigator. 
AST or ALT 
Grade 1 and 2 (up to 5.0 x ULN) 
Maintain dose level. 
Maintain dose level. 
Grade 3 (> 5.0 - 20.0 x ULN) 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, then 
maintain dose level. 
- If resolved in > 7 days, then ↓ 1 
dose level. 
Omit dose of carboplatin until 
resolved to Grade ≤1, then 
- If resolved in ≤ 7 days, then 
maintain dose level 
- If resolved in > 7 days, then ↓ 1 
dose level 
Grade 4 (> 20.0 x ULN) 
Discontinue study treatment. 
Discontinue study treatment 

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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
NERVOUS SYSTEM DISORDERS 
Neurotoxicity 
Grade 1 
Maintain dose level. 
Maintain dose level. 
Transient Grade 2 that improves to 
grade 1 on the day of planned therapy 
Maintain dose level. 
Maintain dose level. 
Grade 2 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then ↓ 1 dose 
level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, then 
↓ 1 dose level. 
Grade ≥ 3 or second occurrence of 
Grade 2 
Discontinue study treatment. 
Discontinue study treatment. 
GI DISORDERS 
Diarrhea  
Grade 1 
Maintain dose level, but initiate 
anti-diarrhea treatment as clinically 
indicated 
Maintain dose level, but initiate 
anti-diarrhea treatment as clinically 
indicated 
Grade 2 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, including with 
appropriate management, then 
maintain dose level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, 
including with appropriate 
management, then maintain dose 
level. 
Grade 3 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, initiate anti-
diarrhea treatment, then 
- If resolved in ≤ 48 hours, maintain 
dose level. 
- If resolved in > 48 hours, then ↓ 1 
dose level. 
  
For 2nd occurrence of diarrhea 
CTCAE Grade 3 for > 48 hours 
despite the use of anti-diarrhea 
treatment, discontinue study 
treatment. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, 
initiate anti-diarrhea treatment, then 
- If resolved in ≤ 48 hours, maintain 
dose level. 
- If resolved in > 48 hours, then ↓ 1 
dose level. 
  
For 2nd occurrence of diarrhea 
CTCAE Grade 3 for > 48 hours 
despite the use of anti-diarrhea 
treatment, discontinue study 
treatment. 
Grade 4 
Discontinue study treatment. 
Discontinue study treatment. 
Nausea/Vomiting 
Grade 1 
Maintain dose level, but initiate 
anti-emetic treatment. 
Maintain dose level, but initiate 
anti-emetic treatment. 
Transient Grade 2 that improves to 
grade 1 on the day of planned therapy 
Maintain dose level. 
Maintain dose level. 
Grade 2 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, initiate anti-
emetic treatment, then maintain 
dose level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, 
initiate anti-emetic treatment, then 
maintain dose level. 
Grade 3 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, initiate anti-
emetic treatment, then: 
- If resolved in ≤ 48 hours, maintain 
dose level. 
- If resolved in > 48 hours, then ↓ 1 
dose level. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, 
initiate anti-emetic treatment, then: 
- If resolved in ≤ 48 hours, maintain 
dose level. 
- If resolved in > 48 hours, then ↓ 1 
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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
Grade 4 
Discontinue study treatment. 
Discontinue study treatment. 
GENERAL DISORDERS 
Fatigue 
Grade 1 or 2 
Maintain dose level. 
Maintain dose level. 
Grade 3 
Omit dose of cisplatin until resolved 
to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, maintain 
dose level. 
- If resolved in > 7 days, 
discontinue patient from study 
treatment. 
Omit dose of carboplatin until 
resolved to CTCAE Grade ≤ 1, then 
- If resolved in ≤ 7 days, maintain 
dose level. 
- If resolved in > 7 days, 
discontinue patient from study 
treatment. 
Grade 4 
Discontinue study treatment. 
Discontinue study treatment. 
INFUSION REACTIONS 
Infusion reactions 
Grade 1 
(Transient flushing or rash, fever  
< 38 °C [<100.4 °F]; intervention not 
indicated) 
- Stop infusion 
- Treat per institutional 
guidelines.  
- May resume infusion (within 4 
hours of initial start of infusion) 
at 50% of previous under 
continuous observation. Ensure 
that there is a minimum 
observation period of 1 hour 
prior to restarting the infusion. 
- Maintain dose level. 
- If the AE recurs at the reinitiated 
slow rate of infusion, and 
despite oral pre-medication, 
then do not resume infusion. 
- Stop infusion 
- Treat per institutional guidelines.  
- May resume infusion (within 4 
hours of initial start of infusion) 
at 50% of previous under 
continuous observation. Ensure 
that there is a minimum 
observation period of 1 hour 
prior to restarting the infusion. 
- Maintain dose level. 
- If the AE recurs at the reinitiated 
slow rate of infusion, and 
despite oral pre-medication, 
then do not resume infusion. 
Grade 2 
(Intervention or infusion interruption 
indicated; responds promptly to 
symptomatic treatment [e.g., 
antihistamines, NSAIDS, narcotics]; 
prophylactic medications indicated for 
≤24 hrs) 
- Stop infusion 
- Treat per institutional 
guidelines.  
- May resume infusion (within 4 
hours of initial start of infusion) 
at 50% of previous under 
continuous observation. Ensure 
that there is a minimum 
observation period of 1 hour 
prior to restarting the infusion. 
- Maintain dose level. 
- If the AE recurs at the reinitiated 
slow rate of infusion, and 
despite oral pre-medication, 
then do not resume infusion. 
- Stop infusion 
- Treat per institutional guidelines.  
- May resume infusion (within 4 
hours of initial start of infusion) 
at 50% of previous under 
continuous observation. Ensure 
that there is a minimum 
observation period of 1 hour 
prior to restarting the infusion. 
- Maintain dose level. 
- If the AE recurs at the reinitiated 
slow rate of infusion, and 
despite oral pre-medication, 
then do not resume infusion. 
Grade 3 
Prolonged [e.g., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion]; recurrence of 
symptoms following 
initial improvement; hospitalization 
indicated for clinical 
sequelae [e.g., renal impairment, 
pulmonary infiltrates]) 
- Discontinue infusion 
immediately 
- Treat per institutional 
guidelines.  
- Discontinue patient from study. 
- Discontinue infusion 
immediately 
- Treat per institutional guidelines.  
- Discontinue patient from study. 

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Worst Toxicity CTCAE v4.0 Grade 
(unless otherwise specified) 
Recommended Dose 
Modifications to cisplatin any 
time during a cycle of therapy 
Recommended Dose 
Modifications to carboplatin any 
time during a cycle of therapy 
Grade 4 (Life-threatening; urgent 
intervention indicated) 
- Discontinue infusion 
immediately 
- Treat per institutional 
guidelines.  
- Discontinue patient from study. 
- Discontinue infusion 
immediately 
- Treat per institutional guidelines.  
- Discontinue patient from study. 
OTHER ADVERSE EVENTS 
Grade 1 or 2 
Maintain dose level of cisplatin or carboplatin. For intolerable grade 2 
toxicity, may omit dose of cisplatin or carboplatin until resolved to CTCAE 
Grade ≤ 1. 
Grade 3 
Omit dose of cisplatin or carboplatin until resolved to CTCAE Grade ≤ 1, 
then ↓ dose level of cisplatin or carboplatin. 
Grade 4 
Discontinue study treatment. 
NOTE: All of the above are general guidelines. The investigator may omit a dose of drug, decrease dose level 
of drug, or remove any patient from study for any toxicity, if he/she believes that it is in the best 
interest of the patient. 
NOTE: If a patient requires a dose delay of > 21 consecutive days (from the time of due scheduled cycle initiation; 
i.e. > 42 days from previous cycle initiation) of platinum agent then the patient must be discontinued from 
the study treatment.  
NOTE: Patients who discontinue from the study for a study-related adverse event or an abnormal laboratory value 
must be followed approximately once a week for 3 weeks and subsequently approximately at 3-week 
intervals, until resolution or stabilization of the event, whichever comes first, unless stated otherwise. 
5.4.3 
Supportive Care  
5.4.3.1 
All supportive measures consistent with optimal patient 
care will be given throughout the study. 
5.4.3.2 
The clinical tolerance of the patients, and the medical 
judgment of the investigator will determine if it is in the 
patient’s best interest to continue or discontinue treatment. 
If treatment is discontinued due to any toxicity, the patient 
must be followed to monitor duration of toxicity, response 
and time to progression (even if non-protocol therapy is 
initiated). Suggested supportive care medications may be 
substituted at the discretion of the investigator based on 
drug availability.  
5.4.3.3 
Growth factor support (filgastrim or peg-filgastrim) may be 
used in accordance with the American Society of Clinical 
Oncology (ASCO) guidelines 
5.4.3.4 
Diarrhea may occur on Arm B. Appropriate supportive 
measures for diarrhea should include Loperamide and/or 
Diphenoxilate/atropine, and should be implemented 
immediately to prevent dehydration. 
5.4.3.5 
Hydration guidelines may be modified at the discretion of 
the treating physician provided adequate pre- and post-
cisplatin hydration is achieved and renal function remains 
adequate. One suggested regimen consists of 
administering cisplatin in 250 cc to 1000 cc of IV fluids 
following adequate hydration and the establishment of 
adequate urinary output. It is suggested the pre-cisplatin 
hydration consist of NS at 500 cc/hr x 1 liter and post-
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cisplatin hydration consist of 1/2 NS + 10 meq KCl/liter + 1 
gram magnesium sulfate/liter + 25 grams mannitol/liter at 
500 cc/hr for at least one hour, followed by additional 
hydration at the discretion of the investigator.  
5.4.3.6 
Antiemetic therapy is critical for proper administration of 
cisplatin/ carboplatin. The specific antiemetic regimen is at 
the discretion of the treating physician, provided adequate 
control is achieved. However, on the day of cisplatin 
therapy the investigator should consider use of a steroid 
medication and a 5HT3 antagonist. One such regimen 
consists of 20 mg of dexamethasone and a high dose of a 
5HT3 antagonist (such as 1 mg oral of 10 mcg/kg IV 
granisetron or 8 mg ondansetron or equivalent) and 
continuing with 4 days of dexamethasone or equivalent 
steroid and 4 days of scheduled anti-emetic such as 
metoclorpramide or a 5HT3 antagonist. If this regimen is 
ineffective, consideration of the long-acting 5HT3 
antagonist palonosetron and the agent aprepitant or 
fosaprepitant should be considered at the discretion of the 
investigator. 
NOTE: 
Aprepitant or fosaprepitant should be used with 
caution in patients receiving concomitant 
medicinal products, including chemotherapy 
agents that are primarily metabolized through 
CYP3A4. Inhibition of CYP3A4 by aprepitant or 
fosaprepitant could result in elevated plasma 
concentrations of these concomitant medicinal 
products. The effect of aprepitant or 
fosaprepitant on the pharmacokinetics of orally 
administered CYP3A4 substrates is expected to 
be greater than the effect of aprepitant or 
fosaprepitant on the pharmacokinetics of 
intravenously administered CYP3A4 substrates. 
NOTE: 
Dexamethasone dose should be reduced by 
50% when administered with aprepitant or 
fosaprepitant 
5.5 
PRO Administration 
The PRO assessment includes health-related quality of life (HRQL), 
neurotoxicity, ovarian function, and adherence. The PROs assessment will be 
administered at the following time points: 
FBSI (Arms B and C), NTx (Arm B) will be assessed at: 
• 
Baseline, 
• 
Day 1, Cycle 3, 
• 
6 months after start of study chemotherapy 
• 
15 months after the start of chemotherapy. 
Ovarian function (Arms B and C) will be assessed at: 
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• 
Baseline 
• 
15-months post study chemotherapy start 
Medication Adherence Scale (Arm C) will be assessed at: 
• 
Day 1, Cycle 3, 
• 
Day 1, Cycle 6 
The timing of these assessments corresponds to standard clinic office visits of 
routine care, and assessments will be made prior to clinician visits when 
possible. It is estimated that the overall attrition rate is about 10% by the end of 
chemotherapy, 12% by 6 months after the start of chemotherapy and 20% by 15 
months after the start of chemotherapy for the PROs assessment in both arms. 
All participants (n=775) enrolled on the main study are potentially eligible for the 
HRQL PRO assessments, although only n = 362 are required to power the 
primary PRO objective. Thus, 362 participants will be recruited for the PRO 
assessments Any participants who take the PROs surveys at more than 1 time-
point will be eligible for analysis. 
Participants who develop recurrent disease during the follow-up period will be 
assessed (although they would likely go on to further therapy and/or have 
different concerns, these can be better addressed statistically if we have data on 
which to base assumptions.) 
5.5.1 
Instruments to be Administered 
We would anticipate these survey items would require between 10-20 
minutes per time-point, for a maximum of 1 hour(s) of participant time 
over the entire course of the study. 
Table 5.5.1. Overall TIMELINE and NUMBER OF QUESTIONS on Patient PRO Questionnaires 
Timing of Assessment 
Measure 
 
Medication 
Adherence 
Scale^ 
NTx&/FBSI 
Ov. 
Function* 
Total 
Baseline/On Study 
0 
27 
8 
33 
Before Cycle 3 chemotherapy (Day 1, Cycle 3)  
8 
27 
0 
37 
Before Cycle 6 chemotherapy (Day 1, Cycle 6) 
8 
0 
0 
8^ 
6 months after the start chemotherapy  
0 
27 
0 
27 
15 months after the start of chemotherapy 
0 
27 
5 
33 
^ Only patients on the capecitabine arm. 
& Only patients on the platinum arm 
* Women age < 55 yo only would answer 4 menstrual questions. 
5.5.2 
Survey Administration Instructions 
PRO assessment time-points correspond to the standard clinic office 
visits for routine care. Assessments will be done prior to the clinician 
visit when possible. The questionnaires should be administered at the 
time points listed above. The patient should be instructed to respond 
to the questionnaires in terms of her experience during the timeframe 
specified on each questionnaire. The patient should be asked to read 
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the instructions at the beginning of each questionnaire and complete 
all the items. It is permissible to assist the patient with the completion 
of the questionnaires as long as the staff person does not influence 
the patient’s responses. 
The questionnaires should be reviewed by the protocol nurse or 
research coordinator as soon as the patient completes them to ensure 
all items were marked appropriately. If more than one answer was 
marked, the patient should be asked to choose the answer which best 
reflects how she is feeling. If a question was not answered, the patient 
should be asked if she would like to answer it. The patient should 
always have the option to refuse. If the patient refuses, it should be 
indicated on the questionnaire that she declined to answer the item. If 
the patient cannot complete a questionnaire, or if the patient refuses 
to complete the questionnaire, the reason should be noted according 
to the instructions in the EA1131 Forms Completion Guidelines. 
5.6 
Patient Reported Outcome Measures: Tobacco Use Assessment 
5.6.1 
Assessments 
Assessments will be captured directly from the participants using the 
EASEE-PRO portal. When patients consent to participate, they will be 
asked to provide a contact email address and that address along with 
their registration information will be sent directly from the parent trial’s 
registration system to EASEE-PRO, and the patient will be 
automatically registered into EASEE-PRO for participation. To 
activate their account for self-directed web entry of surveys, the 
system will send an activation message to the contact email address 
that will explain how to activate their account for self-directed web 
entry of surveys. After their account is activated, the patient will be 
able to complete questionnaires using a secure browser interface 
from any web enabled computer, tablet, or mobile device. 
The Core and Extension C-TUQ items will be assessed, together with 
patient-reported physical and psychological symptoms (See Table 2). 
Specifically, these items will be administered using the EASEE-PRO 
system described in the companion EA NCORP application. The 
advantage of our virtual electronic data capture system is that our 
proposed assessments will not be limited to, or dependent upon, 
patient trial visits. Confidential and potentially stigmatizing information 
can be provided without requiring direct contact with the care team. 
The selected Core and Extension C-TUQ items (from categories of 
Basic Tobacco Use Information, Tobacco Use in Relation to Cancer 
Diagnosis and Treatment, Smoking Cessation/Cessation 
Products/Assistance Methods, Use of Other Products, and Second-
Hand Smoke Exposure) will be assessed. The 4-item Short Form 
PROMIS® for anxiety and depression, the Lung Cancer Stigma Scale, 
and six symptom items (general pain, fatigue, nausea, cough, sleep 
difficulties, shortness of breath) from FACIT (Functional Assessment 
of Chronic Illness Therapy) together with modifications of these same 
six questions to address the degree of bother associated with each 
symptom will be administered as well. Additionally, we will ask 
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participants’ perceptions of how smoking improves or worsens each of 
the six-symptom experience. All these items will be compiled into 
Survey of Tobacco Use (STU). Detailed information on various 
measures is outlined in Appendix VI. 
Contents and Corresponding Questions in Survey of Tobacco Use 
(STU) 
Dimension 
Source of Measures 
Baseline STU 
Follow-up 
STU 
Basic Tobacco Use Information 
C-TUQ 
Q1 – Q5 
Q1 – Q2 
Tobacco Use in Relation to Cancer 
Diagnosis and Treatment 
C-TUQ 
Q6 – Q7 
Q3 
Smoking Cessation, Cessation 
Products, and Assistance Methods 
C-TUQ 
Q8 – Q13 
Q4 – Q9 
Use of Other Products  
C-TUQ 
Q14 
Q10 
Second-Hand Smoke Exposure 
C-TUQ 
Q15 – Q16 
Q11 – Q12 
Psychological Symptoms 
PROMIS  
Lung Cancer Stigma Scale 
Q17 – Q18 
Q13 – Q14 
Physical Symptoms 
FACIT 
Q19 
Q15 
Sociodemographics 
 
Q20 – 21 
 
NOTE: 
In order to minimize ambiguity and assure that patients are 
oriented to answer appropriately, the specific phrasing of 
items may vary depending specific cancer type and 
treatment. 
5.6.2 
Assessment Schedule 
Survey of Tobacco Use will be administered at the following time 
points: 
• 
at baseline (trial enrollment) 
• 
at 3 months follow-up from study registration 
• 
at 6 months follow-up from study registration 
5.7 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Patient develops a local-regional or distant recurrence. 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
EA1131 Forms Packet. 
• 
Concurrent illness that prevents further administration of therapy per protocol 
• 
Patient becomes pregnant 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol anti-cancer therapies are administered. 
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5.8 
Duration of Follow-up  
For this protocol, all patients (on all arms A, B, and C), including those who 
discontinue protocol therapy early, will be followed for recurrence and second 
primary cancer, even if non-protocol anti-cancer therapy is initiated, and for 
survival for 10 years from the date of registration. All patients must also be 
followed through completion of all protocol therapy. 
 
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6. 
Measurement of Effect 
6.1 
Local, Regional Recurrence 
The development of a local or regional recurrence of breast cancer:  
Local-regional recurrence of the disease (ipsilateral or regional invasive breast 
cancer) should be cytologically/histologically confirmed, whenever possible. A CT 
scan of the chest/abdomen/pelvis or any other area as clinically indicated should 
be performed at the time of local recurrence to exclude further spread of the 
disease. Patients who develop loco-regional recurrence should discontinue study 
treatment (if recurrence during treatment period) and will continue to be followed 
for distant recurrence, new cancers, subsequent anti-cancer therapies and 
survival as per study schedule. 
6.2 
Distant Recurrence 
The development of a distant recurrence of breast cancer:  
Distant recurrence should be diagnosed by radiological examination and/or 
histopathological confirmation when metastatic lesion is easily accessible for 
biopsy. Abnormal blood studies alone (e.g., elevated transaminases or alkaline 
phosphatase) are not sufficient evidence of relapse. Disease recurrence or new 
cancers should be reported on the clinical database as soon as possible after 
they are discovered. This includes events diagnosed during study visits but also 
any event diagnosed during non-study visits. 
6.3 
Invasive Disease-Free Survival 
Date of randomization to the date of first treatment failure (local/regional or 
distant recurrence, second invasive primary cancer or death before recurrence):  
Disease free survival should be initially assessed by regular physical examination 
and clinical assessment. Recurrence event should be confirmed via radiological 
and/or cytological/histological assessment.  
NOTE: 
a subsequent diagnosis of non-invasive cancer (DCIS) would not be 
considered an IDFS event. 
6.4 
Survival 
Date of randomization to date of death from any cause. 
 

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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
NOTE: 
A window of +/- 3 working days is allowed for all below procedures unless otherwise specified in the 
calendar itself, to account for holidays, vacation, and scheduling issues. 
 
STEP 0-
Screening 
STEP 1-Randomization 
All Patients 
For  
Arms B and C 
All Patients 
Within 8 
weeks 
prior to 
Screening 
Within 2 weeks 
prior to 
Randomization 
Day 1 of 
Each 
Treatment 
Cycle1 
Day 1 
Cycle 
1 
Day 1 
Cycle 
3 
Day 1
Cycle
6 
End of Treatment 
(28 ±7 working 
days) post 
treatment 
discontinuation)13
6 months (±4 
weeks) after 
chemotherapy 
initiation 
15 months (±6 
weeks) after 
chemotherapy 
initiation 
Arm A: post 
randomization to 10 
years 
Arm B and C: 
6 months to 10 years 
from chemotherapy 
initiation7 
CLINICAL EVALUATIONS 
Demographics 
X 
 
 
 
 
 
 
 
 
 
History and Physical 
X1 
X1 
X 
 
 
 
X 
 
 
X 
Vital Signs and 
Weight 
 
X1 
X 
 
 
 
X 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
ECOG Performance 
Status 
X1 
X1 
X 
 
 
 
X 
 
 
 
Toxicity Assessments 
 
 
X 
 
 
 
X 
 
 
 
Concomitant 
Medications 
Assessments 
 
 
X 
 
 
 
X 
 
 
 
Non-Protocol Anti-
Cancer Medications 
Assessments 
 
 
X 
 
 
 
 
 
 
X11 
FBSI PRO 
 
 
 
X 
X 
 
 
X 
X 
 
Medication Adherence 
Scale PRO15 
 
 
 
 
X 
X 
 
 
 
 
NTx PRO14 
 
 
 
X 
X 
 
 
X 
X 
 
Ov Function PRO16 
 
 
 
X 
 
 
 
 
X 
 
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STEP 0-
Screening 
STEP 1-Randomization 
All Patients 
For  
Arms B and C 
All Patients 
Within 8 
weeks 
prior to 
Screening 
Within 2 weeks 
prior to 
Randomization 
Day 1 of 
Each 
Treatment 
Cycle1 
Day 1 
Cycle 
1 
Day 1 
Cycle 
3 
Day 1
Cycle
6 
End of Treatment 
(28 ±7 working 
days) post 
treatment 
discontinuation)13
6 months (±4 
weeks) after 
chemotherapy 
initiation 
15 months (±6 
weeks) after 
chemotherapy 
initiation 
Arm A: post 
randomization to 10 
years 
Arm B and C: 
6 months to 10 years 
from chemotherapy 
initiation7 
Tobacco Use 
Assessment PROs17 
See Section 5.6 
 
LABORATORY/ RADIOLOGICAL ASSESSMENTS 
Serum or Urine 
Pregnancy Test4 
 
X 
 
 
 
 
 
 
 
 
CBC with Differential1, 
2 
X 
X 
X10 
 
 
 
X 
 
 
 
Complete Metabolic 
Panel (CMP)1, 3 
X 
X 
X10 
 
 
 
X 
 
 
 
INR1,12,15 
X 
X 
X10,12,15 
 
 
 
 
 
 
 
Imaging Tests9 
Not mandatory, but recommended at any time as a standard of care procedure, at the investigator’s discretion if clinical 
concerns, to rule out a locoregional or distant recurrence 
TREATMENT ADMINISTRATION 
Platinum 
chemotherapy 
administration5,14 
 
 
X5,14 
 
 
 
 
 
 
 
Capecitabine 
administration15 
 
 
X15 
 
 
 
 
 
 
 
MANDATORY BIOLOGICAL SAMPLE SUBMISSIONS6,8,18 
Tumor Tissue – submit 
to EA CBPF 
X 
 
 
 
 
 
 
 
 
 
Peripheral Blood (two 
10mL Streck Cell-Free 
DNA tubes) – submit 
to Epic Sciences 
 
 
 
X 
 
 
 
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STEP 0-
Screening 
STEP 1-Randomization 
All Patients 
For  
Arms B and C 
All Patients 
Within 8 
weeks 
prior to 
Screening 
Within 2 weeks 
prior to 
Randomization 
Day 1 of 
Each 
Treatment 
Cycle1 
Day 1 
Cycle 
1 
Day 1 
Cycle 
3 
Day 1
Cycle
6 
End of Treatment 
(28 ±7 working 
days) post 
treatment 
discontinuation)13
6 months (±4 
weeks) after 
chemotherapy 
initiation 
15 months (±6 
weeks) after 
chemotherapy 
initiation 
Arm A: post 
randomization to 10 
years 
Arm B and C: 
6 months to 10 years 
from chemotherapy 
initiation7 
OPTIONAL BIOLOGICAL SAMPLE SUBMISSIONS8,18,19 
Peripheral Blood (two 
10mL Streck Cell-Free 
DNA tubes) – submit 
to EA CBPF 
 
 
 
X 
 
 
 
X 
 
 
1. Each cycle is a 3-week period of time. Total number of treatment cycles is 6 for the capecitabine arm and 4 for the platinum agents. 
Chemotherapy must be initiated within 6 weeks (30 working days) following randomization. CBC, chemistries and INR (INR is only necessary 
for patients on warfarin that are on Arm C) should be done ≤ 8 weeks prior to screening, ≤ 2 weeks prior to randomization, and during 
treatment, it should be done within 3 days prior to each treatment cycle. Telehealth visits are acceptable as long as ECOG status, vital signs, 
height and weight are current (i.e. performed within 8 weeks) on Day 1 of each cycle. Additionally, treatment initiation may be delayed for up to 
10 days without requiring repeat labs/ clinic visit/ clinic assessments in the following special circumstances: inclement weather, holidays, COVID-
related issues, delay in drug delivery from specialty pharmacies for patients on Arm C (capecitabine), and insurance approval delays. 
2. Pre-study CBC (with differential and platelet count) includes WBC, ANC, Platelets, Hgb, and Hct or PCV 
3. All required chemistries include sodium, potassium, chloride, bicarbonate (also known as CO2 or carbon dioxide), BUN, creatinine, glucose, total 
bilirubin, calcium, magnesium, total protein, albumin, AST, ALT, and alkaline phosphatase. 
4. For patients of childbearing potential; must be done within 2 weeks prior to randomization. 
5. Cisplatin or Carboplatin (Arm B only); per treating physician’s discretion. Growth factor use is allowed per ASCO guidelines. 
6. Tumor tissue collection is mandatory and required to be submitted to the ECOG-ACRIN Central Biorepository and Pathology Facility (EA CBPF) 
as outlined in Section 10.2. Confirmation of receipt of tumor tissue will be forwarded to the ECOG-ACRIN Operations Office and submitting 
institution. The CLIA Laboratory Sample Submission Form (Appendix IV) must be submitted with the tumor tissue. Results of PAM50 analysis 
will not be reported to the submitting institution. Two Streck tubes of peripheral blood must be collected on all patients at the following two time 
points: on or before cycle 1 day 1 of protocol chemotherapy and around 6 months after protocol chemotherapy initiation. 
7. Every 3 months (± 2 weeks) if patient is < 2 years from study randomization, every 6 months (± 4 weeks) if patient is 2-5 years from study 
randomization, every 12 months (± 6 weeks) if patient is 5-10 years from study randomization. No other specific requirements are needed if 
patient is more than 10 years from study randomization. If a recurrence (locoregional or distant) occurs prior to 10 years from randomization, 
patient will be followed for survival (until year 10) but no other protocol procedures (clinic visits, blood collections, etc.) will be necessary. 
8. All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS) as outlined in Section 10.3. 
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9. In case of a local recurrence or clinical suspicion of distant recurrence, imaging tests to exclude presence of distant recurrent disease are 
strongly recommended, but should be performed at the investigator’s discretion. 
10. If Baseline CBC, INR (INR is only necessary for patients on warfarin that are on Arm C) and CMP were performed within 3 days of Day 1 
Cycle 1 of treatment initiation, there’s no need to repeat them on Day 1 Cycle 1 
11. Determination if any anti-cancer treatment is being administered beyond 3 months from randomization, which was not specified in the protocol. 
12. Only for patients on warfarin therapy and Arm C 
13. End of treatment visit should be scheduled 28 (+/- 7 working days) from Day 1 of last administration of platinum agent in Arm B, and 28 (+/- 7 
days) from the last administered treatment dose for Arm C; regardless if patients completed treatment or if treatment was interrupted due to 
toxicities or other causes. 
14. For Arm B (platinum chemotherapy) only 
15. For Arm C (capecitabine) only 
16. Women age < 55 years old only would answer 8 questions on Day 1 Cycle 1, and 5 questions 15 months after the initiation of chemotherapy. 
17. Tobacco use assessment PROs will be collected using EASEE-PRO; no other EA1131 study PRO will be collected using EASEE-PRO. 
18. Kits will be provided for the collection and shipment of peripheral blood specimens. See Section 10 for instructions. 
19. Submit from patients who answer ‘Yes’ to ‘I agree to provide additional samples for research’ in the informed consent. 
 
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8. 
Drug Formulation and Procurement 
Capecitabine, cisplatin and carboplatin will be obtained commercially. For additional 
information, please refer to the FDA approved package insert for each drug. 
8.1 
Capecitabine 
8.1.1 
Other Names: Xeloda® 
8.1.2 
Classification: capecitabine) is a fluoropyrimidine carbamate with 
antineoplastic activity. It is an orally administered systemic prodrug of 
5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-
fluorouracil. Capecitabine is a white to off-white crystalline powder 
with an aqueous solubility of 26 mg/mL at 20ºC. 
8.1.3 
Mode of Action: Enzymes convert capecitabine to 5-fluorouracil (5-
FU) in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-
2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine 
triphosphate (FUTP). These metabolites cause cell injury by two 
different mechanisms. First, FdUMP and the folate cofactor, N5-10-
methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form 
a covalently bound ternary complex. This binding inhibits the 
formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the 
necessary precursor of thymidine triphosphate, which is essential for 
the synthesis of DNA, so that a deficiency of this compound can 
inhibit cell division. Second, nuclear transcriptional enzymes can 
mistakenly incorporate FUTP in place of uridine triphosphate (UTP) 
during the synthesis of RNA. This metabolic error can interfere with 
RNA processing and protein synthesis. 
8.1.4 
Storage and Stability: Store at 25°C (77°F); excursions permitted to 
15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. 
KEEP TIGHTLY CLOSED. Care should be exercised in the handling 
of capecitabine. Capecitabine tablets should not be cut or crushed. 
Procedures for the proper handling and disposal of anticancer drugs 
should be considered. Any unused product should be disposed of in 
accordance with local requirements, or drug take back programs. 
8.1.5 
Dose Specifics: Capecitabine will be administered at 1000 mg/m2 
twice a day, PO, on days 1 - 14 every 21 days, for a total of 6 cycles. 
8.1.6 
Route of Administration: oral, 30 minutes after a meal. 
8.1.7 
Incompatibilities: anticoagulants (warfarin), phenytoin, leucovorin, 
CYP2C9 substrates 
8.1.8 
Availability: Capecitabine is supplied as biconvex, oblong film-coated 
tablets for oral administration. Each light peach-colored tablet 
contains 150 mg capecitabine and each peach-colored tablet contains 
500 mg capecitabine. 
8.1.9 
Side Effects: 
8.1.9.1 
Hematologic: Leukopenia and thrombocytopenia occur, but 
are rarely dose-limiting; anemia. 
8.1.9.2 
Dermatologic: Hand-foot sd, dermatitis, nail disorders. 
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8.1.9.3 
Gastrointestinal: Diarrhea, nausea, vomiting, dyspepsia, 
anorexia. 
8.1.9.4 
General: fatigue, myalgias 
8.1.9.5 
Cardiac: edema. 
8.1.9.6 
Hepatic: Elevated AST and ALT, hyperbilirrubinemia. 
8.1.9.7 
Neurologic: paresthesia, headache, dizziness, insomnia. 
8.1.9.8 
Other: eye irritation 
8.1.10 
Nursing/Patient Implications 
• 
Assess labs prior to administration (esp. CBC, platelet count, 
BUN, Cr.). 
• 
Observe carefully for signs of severe diarrhea, mucocutaneous 
toxicities, neurotoxicities, cardiotoxicities. 
8.1.11 
References 
• 
NIOSH Alert: Preventing occupational exposures to antineoplastic 
and other hazardous drugs in healthcare settings. 2004. U.S. 
Department of Health and Human Services, Public Health Service, 
Centers for Disease Control and Prevention, National Institute for 
Occupational Safety and Health, DHHS (NIOSH) Publication No. 
2004-165. 
• 
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. 
Controlling Occupational Exposure to Hazardous Drugs. OSHA, 
1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 
• 
American Society of Health-System Pharmacists. ASHP 
Guidelines on Handling Hazardous Drugs: Am J Health-Syst 
Pharm. 2006;63:1172-1193. 
• 
Polovich M., White JM, Kelleher LO (eds). Chemotherapy and 
biotherapy guidelines and recommendations for practice (2nd ed.) 
2005. Pittsburgh, PA: Oncology Nursing Society 
8.2 
Cisplatin 
8.2.1 
Other Names: Platinol® 
8.2.2 
Classification: Cisplatin (cisplatin injection) (cis-
diamminedichloroplatinum) is an anti-neoplastic agent – alkylating 
agent. It consists of a heavy metal complex containing a central atom 
of platinum surrounded by two chloride atoms and two ammonia 
molecules in the cis position. It is a white powder with the molecular 
formula PtCl2H6N2, and a molecular weight of 300.05. It is soluble in 
water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. It 
has a melting point of 207°C. 
8.2.3 
Mode of Action: Its cytotoxic mode of action is mediated by its 
interaction with DNA to form DNA adducts, primarily intra-strand 
crosslink adducts, which activate several signal transduction 
pathways, including those involving ATR, p53, p73, and MAPK, and 
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8.2.4 
Storage and Stability: Aqueous cisplatin should be stored at 15 – 
25oC and protected from light. Do not refrigerate. It is supplied in a 
multi-dose vial without preservatives. Once the vial has been entered, 
the remaining cisplatin is stable for 28 days protected from light or for 
7 days if under fluorescent light at room temperature. 
8.2.5 
Dose Specifics: Cisplatin will be administered at 75 mg/m2 IV on day 1 
every 21 days, for a total of 4 doses (3 week-cycles). 
8.2.6 
Preparation: Cisplatin 10 mg/vial and 50 mg/vial of lyophilized powder 
formulation should be reconstituted with 10 and 50 ml of sterile water, 
respectively, resulting in a 1 mg/ml solution. The desired dose of 
cisplatin is often further diluted with 250 ml or more of 0.45%-0.9% 
NaCl and 5% dextrose, normal saline or 0.3% sodium chloride. 
8.2.7 
Route of Administration: Cisplatin will be administered as an 
intravenous infusion. It should be administered in 250 – 1000 mL 
NaCl, following intravenous hydration with at least 1000 mL NaCl. 
Needles, syringes, catheters or IV administration sets containing 
aluminum parts should not be used as contact with cisplatin yields a 
black precipitate. 
8.2.8 
Incompatibilities: Plasma levels of anticonvulsant agents may become 
sub-therapeutic during cisplatin (cisplatin injection) therapy. In 
a randomized trial in advanced ovarian cancer, response duration was 
adversely affected when pyridoxine was used in combination 
with altretamine (hexamethylmelamine) and cisplatin (cisplatin 
injection). Other drugs that are incompatible with cisplatin include 
amifostine, amphotericin B sulfate complex, cefepime, gallium nitrate, 
pipercallin/tazobactam, and thiotepa. Needles, syringes, catheters or 
IV administration sets containing aluminum parts should not be used 
as contact with cisplatin yields a black precipitate. 
8.2.9 
Availability: Cisplatin (Bristol-Myers Oncology Division) is 
commercially available as a lyophilized powder for injection (10 and 
50 mg/vial) and as a 1 mg/ml solution (50 and 100 mg/vial). 
8.2.10 
Side Effects:  
8.2.10.1 
Hematologic: Leukopenia and thrombocytopenia occur, but 
are rarely dose-limiting; anemia. 
8.2.10.2 
Dermatologic: Alopecia (uncommon). 
8.2.10.3 
Gastrointestinal: Nausea and vomiting are common and 
may persist for up to 24-96 hours; anorexia. 
8.2.10.4 
Renal: Nephrotoxicity is dose-related and relatively 
uncommon with adequate hydration and diuresis; elevated 
serum creatinine and BUN. 
8.2.10.5 
Hepatic: Elevated AST and ALT. 
8.2.10.6 
Neurologic: Peripheral neuropathy (paresthesias), common 
and dose-limiting when the cumulative cisplatin dose 
exceeds 400 mg/m²; rarely seizures; ototoxicity manifested 
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(dizziness) uncommon; tetany (caused by 
hypomagnesemia); rarely Lhermitte's sign. 
8.2.10.7 
Other: Hypomagnesemia, hypocalcemia, hyponatremia, 
vein irritation, papilledema, rarely retrobulbar neuritis, 
rarely anaphylaxis, fatigue. 
8.2.11 
Nursing/Patient Implications  
• 
Assess labs prior to administration (esp. CBC, platelet count, 
BUN, Cr.). 
• 
Assess urine output prior to each dose. Maintain hydration. Urine 
output should be 100-150 ml/hr. Diuretics may be ordered. 
• 
Administer antiemetics before cisplatin. Post-treatment 
antiemetics should be given as per institutional guidelines. 
• 
Observe carefully for signs of anaphylaxis. 
• 
Monitor for signs of neurotoxicity, hearing loss. 
8.2.12 
References  
• 
Ries F, Klastersky J. Nephrotoxicity induced by cancer 
chemotherapy with special emphasis on cisplatin toxicity. Am J 
Kidney Dis 1986; 8: 368-379. 
• 
Hutchison FN, et al. Renal salt wasting in patients treated with 
cisplatin. Ann Intern Med 1988; 108: 21-25. 
• 
Hansen SW, et al. Long-term neurotoxicity in patients treated with 
cisplatin, vinblastine and bleomycin for metastatic germ cell 
cancer. J Clin Oncol 1989; 7:1457-1461. 
• 
Eeles R, et al. Lhermitte's sign as a complication of cisplatin-
containing chemotherapy for testicular cancer. Cancer Treat Rep 
1986; 70: 905-907. 
• 
Schilsky RL, et al. Persistent hypomagnesemia following cisplatin 
chemotherapy for testicular cancer. Cancer Treat Rep 1982; 66: 
1767-1769. 
• 
Schaefer SD, Post JD, Close LG, et al. Ototoxicity of low- and 
moderate-dose cisplatin. Cancer 1985; 56: 1934-1939. 
• 
Wilding G, et al. Retinal toxicity after high-dose cisplatin therapy. J 
Clin Oncol 1985; 3: 1683-1689. 
8.3 
Carboplatin 
8.3.1 
Other Names: Paraplatin® 
8.3.2 
Classification: Carboplatin (carboplatin injection) (platinum, 
diammine[1,1-cyclobutanedicarboxylato(2-)-O,O′]-, (SP-4-2)) is 
platinum coordination compound, used as an anti-neoplastic agent. It 
is a second-generation tetravalent organic platinum compound. It is a 
crystalline powder with the molecular formula of C6H12N2O4Pt and a 
molecular weight of 371.25. It is soluble in water at a rate of 
approximately 14 mg/mL, and the pH of a 1% solution is 5 to 7. It is 
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8.3.3 
Mode of Action: Like cisplatin, carboplatin binds to DNA, thereby 
inhibiting DNA synthesis, in a cell cycle nonspecific manner. 
Carboplatin must first undergo activation to produce antineoplastic 
activity. Bidentate carboxylate ligands of carboplatin are displaced by 
water forming (aquation) positively charged platinum complexes which 
bind to nucleophilic sites in DNA, such as the O-6 position on 
guanine. Carboplatin produces predominantly interstrand DNA 
crosslinks rather than DNA-protein crosslinks. Intrastrand crosslinks 
result from the formation of adducts between the activated platinum 
complexes of the drug and the N-7 atom (not exclusively) atom on 
guanine to produce 1,2 intrastrand links between adjacent guanine 
molecules, between neighboring guanine and adenosine molecules, 
or between neighboring guanine molecules. Interstrand cross-linking 
within the DNA helix also occurs. Platinum adducts may inhibit DNA 
replication, transcription and ultimately cell division. 
8.3.4 
Storage and Stability: Store intact vials at room temperature at 25°C 
(77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect 
from light. Further dilution to a concentration as low as 0.5 mg/mL is 
stable at room temperature (25°C) for 8 hours in NS or D5W. Stability 
has also been demonstrated for dilutions in D5W in PVC bags at room 
temperature for 9 days; however, the manufacturer recommends use 
within 8 hours due to lack of preservative. Multidose vials are stable 
for up to 14 days after opening when stored at 25°C (77°F) following 
multiple needle entries. 
8.3.5 
Dose Specifics: Carboplatin will be administered at AUC 6 IV on day 1 
every 21 days, for a total of 4 doses (3 week-cycles). 
Calvert Formula for Carboplatin (AUC) Dosing 
Total dose (mg) = target AUC (in mg/mL/minute) * [GFR (in L/minute) 
+ 25]  
For the purposes of this protocol, the GFR is considered to be 
equivalent to the creatinine clearance. 
Glomerular Filtration Rate (GFR) Estimation: Calculated creatinine 
clearance of ≥ 50 cc/min using the Cockcroft-Gault formula: 
Males: 
140 – Age in years) × Actual Body Weight in kg 
72 × Serum Creatinine (mg/dL) 
Females: Estimated creatinine clearance for males × 0.85 
With the Calvert formula, the total (final) dose of carboplatin is 
calculated in mg, not mg/m2. 
8.3.6 
Preparation: Manufacturer’s labeling states solution can be further 
diluted to concentrations as low as 0.5 mg/mL in NS or D5W; however, 
most clinicians generally dilute dose in either 100 mL or 250 mL of NS 
or D5W. Concentrations used for desensitization vary based on 
protocol. Hazardous agent; use appropriate precautions for handling 
and disposal. Needles or I.V. administration sets that contain 
aluminum should not be used in the preparation or administration of 
carboplatin; aluminum can react with carboplatin resulting in 
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8.3.7 
Route of Administration: Carboplatin will be administered as an 
intravenous infusion. 
8.3.8 
Incompatibilities: Amphotericin B chloesteryl sulfate complex. 
Aluminum reacts with carboplatin causing precipitate formation and 
loss of potency; therefore, needles or intravenous sets containing 
aluminum parts that may come in contact with the drug must NOT be 
used for the preparation or administration of carboplatin. 
8.3.9 
Availability: Carboplatin (Bristol-Myers Oncology Division) is 
commercially available in 50, 150, and 450 mg vials. 
8.3.10 
Side Effects:  
8.3.10.1 
Hematologic: Thrombocytopenia, neutropenia, leukopenia, 
more pronounced in patients with compromised renal 
function and heavily pretreated patients; may be 
cumulative. 
8.3.10.2 
Gastrointestinal: Nausea and vomiting, treatable with 
moderate doses of antiemetics.  
8.3.10.3 
Dermatologic: Rash, urticaria. 
8.3.10.4 
Hepatic: Abnormal liver function tests, usually reversible 
with standard doses. 
8.3.10.5 
Neurologic: rarely Peripheral neuropathy. 
8.3.10.6 
Renal: Elevations in serum creatinine, BUN; electrolyte 
loss (Na, Mg, K, Ca). 
8.3.10.7 
Other: Pain, asthenia. 
8.3.11 
Nursing/Patient Implications  
• 
Monitor CBC and platelet count; nadir occurs at approximately day 
21 with recovery by day 28-30. 
• 
Premedicate with antiemetics - evaluate effectiveness. 
• 
Monitor fluid status - maintain adequate hydration. 
• 
Assess skin/mucous membranes. 
• 
Assess for signs of peripheral neuropathy - coordination, sensory 
loss. 
8.3.12 
References  
• 
Calvert AH, et al. Carboplatin dosage: Prospective evaluation of a 
simple formula based on renal function. J Clin Oncol 1989; 7: 
1748-1756. 
• 
Woloschuk DMM, Pruemer JM, Cluxton RJ. Carboplatin: A new 
cisplatin analog. Drug Intell Clin Pharm 1988; 22: 843-849. 
• 
Christian MC. Carboplatin. In: Principles and Practice of 
Oncology, PPO Updates 1989; 3(11): 1-16. 
 

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9. 
Statistical Considerations 
Three changes are made to the study design in the Amendment #7: 
• 
Basal-like subtype is no longer a stratification factor: Current data (ongoing 
monitoring) suggest that > 75% of the residual tumors tested thus far are basal 
subtype. Removing basal-like subtype as a stratification factor will speed up 
randomization and therefore will improve accrual, also allowing investigators who 
wish to pursue RT after chemotherapy completion to do so (this is particularly 
important for patients that wish to subsequently enroll in the phase III S1418 
protocol). Patients will be randomized to arm B or arm C as long as meeting all 
eligibility criteria listed in Section 3 and the EA Operations Office receives 
confirmation of receipt of tumor tissue from EA CBPF. The basal-like subtype status 
will be identified after randomization, and some patients may have assay failure and 
their basal-like subtype status will be unknown. We expect about 7% of patients will 
have assay failure based on data available as of June 24, 2019 (24 out of 365 
patients screened have had assay failure). This subgroup of patients with unknown 
disease subtype will be randomized to arm B or arm C, and they will be analyzed 
separately from patients with known disease subtypes (basal-like vs. non-basal like) 
as an exploratory objective of the study. The total sample size is updated (775 vs 
750) to reflect the impact of removing basal-like subtype from the stratification factor 
list (i.e.., about 7% of patients randomized will have assay failure) and the observed 
slightly higher proportion of basal-like disease in the patients (observed vs expected: 
78% vs 75%).  
• 
The futility monitoring rule based on Jennison and Turnbull repeated confidence 
interval (RCI) method is changed to be more conservative: The rule now is that if the 
lower boundary of the two-sided 95% RCI for the observed hazard ratio is greater 
than 0.754 (i.e., the alternative hypothesis) for arm B/arm C and the conditional 
power of rejecting HR>=1.154 (Ho) when HR=0.754 (Ha) is less than 10%, then the 
trial would be stopped due to futility.  
• 
Correlative biomarker blood studies about CTC (secondary correlative objective) 
added to the protocol. 
9.1 
Study Objectives 
The primary objective of this multi-institutional, open-label, randomized phase III 
study is to compare the two treatment arms, platinum and capecitabine, with 
respect to invasive disease-free survival (IDFS) in patients with triple-negative 
breast cancer (TNBC) treated with taxane +/- anthracycline-based neoadjuvant 
chemotherapy (NAC) who do not achieve a pathologic complete response (pCR) 
with a residual disease of more than 1.0 cm and with basal-like gene expression 
via PAM50 analysis by digital mRNA quantitation (NanoString) in the residual 
surgical specimen. IDFS is the primary endpoint, which is defined to be time from 
randomization to the earliest of documented disease recurrence (local, regional 
and/or distant), invasive contralateral breast cancer, invasive any other second 
primary cancer, or death. Cases with incomplete follow up or without adequate 
disease evaluations will be censored at the date last documented to be free of 
IDFS events. Secondary endpoints include overall survival (OS), recurrence-free 
survival (RFS), toxicity profile and PRO. Overall survival is defined as time from 
randomization to death from any cause. Cases still alive will be censored at the 
last date of known alive. 
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9.2 
Study Design 
Based on the literature, the benefit of platinum agent therapy in TNBC after NAC, 
if any, is expected to be predominantly in the basal-like subtype. Hence, the 
primary population for the primary endpoint is the basal-like subtype in this trial. 
After screening, tumor tissue will be sent to EA CBPF for molecular profile via 
PAM50 analysis by digital mRNA quantitation (NanoString) in the residual 
surgical specimen to identify its molecular subtype. At the time when the trial was 
developed, we expected at least 75% of the residual post-NAC TNBC screened 
to fall within the basal-like subtype. Based on data available as of the 2019 
Spring DSMC meeting, about 78% of the patients randomized to arms B and C 
fall in the basal-like subtype. We will use this proportion in the below sample size 
calculation. In addition, about 7% of patients screened had assay failure and their 
intrinsic subtype is unknown. We assume 7% of patients will have assay failure in 
the remaining patients as well. 
After EA CBPF sending the confirmation of receipt of tumor tissue to EA 
Operations Office, all eligible patients will then be randomized according to the 
permuted block algorithm with a 1:1 randomization ratio to platinum and 
capecitabine arms. Stratification factors include 1) clinical stage at diagnosis (II 
or III), 2) residual cancer burden after NAC (1~3 cm or > 3 cm), 3) planned 
platinum agent (cisplatin or carboplatin), 4) anthracycline exposure in the 
neoadjuvant setting (yes or no), and 5) administration of radiotherapy (yes or no). 
Since platinum is considered less toxic than capecitabine and also platinum is 
expected to be better than capecitabine on improvement of IDFS in patients with 
basal-like TNBC, a non-inferiority design with superiority alternative (a hybrid 
design33 is preferred for this trial). The primary analysis for the primary endpoint 
will test the null hypothesis of inferiority of platinum. The sample size would be 
calculated based on a modest superiority alternative hypothesis. If the hypothesis 
of inferiority of platinum is rejected in the primary analysis, the secondary 
hypothesis of no difference vs. superiority of platinum will be tested. Due to the 
closed testing procedure, no multiple-comparison adjustment is required for the 
two hypothesis tests34 
Based on the accrual rate of the CALGB 40603 trial (NCT00861705, accrued 445 
patients from 6/2010 to 8/2012), we anticipate an accrual rate of approximately 
16 TNBC patients (16*0.93*0.78=12 patients with basal-like subtype) per month 
in our study. 
9.2.1 
Non-inferiority test of platinum 
9.2.1.1 
Sample Size and Accrual  
Based on the review (by Von Minckwicz et al.(5)) of 
patients with TNBC (basal-like and non-basal-like) that do 
not achieve a pCR after neoadjuvant chemotherapy, the 
outcome contingent on tumor size in the residual disease 
show no difference between patients with pT1 and pT2; i.e. 
50% of those patients recur in ~ 60 months. Of note, that 
would support the reasoning behind allowing patients with 
residual tumors ≥ 1 cm. The ones with pT3 and pT4 mimic 
the cohort of patients with basal-like TNBC in the analysis 
by Balko et al.(8) ; where 50% of them recur in 18 months. 
The patients with pT3 and pT4 represented ~ 20% of the 
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whole number of patients (in the review by Von Minckwicz 
et al.(5)) that did not achieve a pCR. We would expect that 
20% of the patients that would potentially be accrued in 
our current trial would have a median IDFS of ~ 18 months 
and 80% would have a median DFS of ~60 months. 
Therefore, it would be reasonable to assume that a 
conservative estimate of the actual median DFS would be 
48 months (i.e., 4-year DFS rate of 50%) for the study 
patients if receiving no chemotherapy after surgery, with a 
median OS of 60 months (i.e., 5-year OS rate of 50%). 
Based on the CREATE-X trial, the 4-year DFS rate was 
67% in the 296 TNBC patients when receiving 
capecitabine (HR=0.58, 95% CI 0.39 – 0.87). Therefore, a 
conservative estimate of the 4-year IDFS rate would be 
67% (0.5^0.58=0.67) for the capecitabine arm in patients 
with basal-like TNBC disease in this trial. 
The null hypothesis for testing non-inferiority of platinum is 
defined as that the hazard ratio (HR) for 
platinum/capecitabine ≥ 1.154 (i.e., HR of 1.154 is used as 
the non-inferiority margin). This corresponds to a 4-year 
IDFS rate of ≤63% on platinum if the 4-year IDFS rate is 
67% on capecitabine arm. With a total accrual of 562 
patients (281 on each arm) and full information of 196 
IDFS events, this non-inferiority test would have about 
83% power, with a one-sided 0.025 significance level, to 
reject the null hypothesis of inferiority of platinum under the 
alternative hypothesis of HR=0.754 for 
platinum/capecitabine, i.e., the 4-year IDFS rate for 
platinum is expected to be 73.9%.  
With an average annual accrual rate of 144 patients with 
basal-like TNBC, about 3.9 years of accrual will be needed 
with an additional 3 years of follow up to reach the 
expected number of IDFS failures. The final analysis for 
IDFS comparison in the basal-like TNBC patients is 
expected to be conducted at about 7.5 years (3.9 years of 
accrual + 3 years of follow up + 0.5 years of data collection 
and cleaning) after study activation.  
We expect at least 78% of the residual post-NAC TNBC 
screened to fall within the basal-like subtype within the 
patients with successful assay, and about 7% of patients 
will have assay failure. Hence, at least 775 patients 
(=562/0.78/0.93) with residual TNBC at the time of surgery 
will be enrolled to obtain the 562 patients with basal-like 
TNBC. 
9.2.1.2 
Interim analysis plan 
The study will be monitored by the ECOG-ACRIN Data and 
Safety Monitoring Committee (DSMC) according to the 
principals of group-sequential methods. The first interim 
analysis will be performed at the first DSMC meeting when 
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at least 25% of the total information has been reported. 
Since 196 IDFS failures are required as the total 
information under the alternative hypothesis, the first 
interim analysis is estimated to take place after 49 IDFS 
failures have occurred, which corresponds to 2.9 years 
after activation of the study in calendar time, under the 
accrual and failure rate assumptions mentioned above. 
Interim analysis will be performed for each subsequent 
DSMC meeting until either the criteria for early stopping 
(described below) are met or the total planned number of 
IDFS failures has been reported. In total, this design is 
expected to incorporate 8 interim analyses and one final 
analysis for IDFS comparisons.  
The Jennison and Turnbull repeated confidence interval 
(RCI) methodology35 will be used to monitor the trial in 
favor of non-inferiority. At each interim analysis, a two-
sided 95% RCI on the log hazard ratio (logHR) for 
platinum/capecitabine will be computed using partial 
likelihood estimation method, and the critical value for each 
interim analysis (see Table 1) will be based on Lan-
DeMets error spending rate function(43) corresponding to 
the truncated version of O'Brien-Fleming boundaries(44) 
with an overall one-sided type I error rate of 0.025. The 
partial likelihood estimator of logHR and its standard error 
will be derived from stratified Cox proportional hazard 
model, where the patients will be stratified using the same 
factors as the randomization (i.e., clinical stage at 
diagnosis, residual cancer burden after NAC, planned 
platinum agent, anthracycline exposure I the neoadjuvant 
setting, and administration of radiotherapy). The 
confidence interval for the HR will be reported by 
exponentiating the logHR intervals. When the upper 
confidence limit for the HR is less than 1.154 (the pre-
defined non-inferiority margin) at any interim analysis or 
final analysis, then the null hypothesis of inferiority of 
platinum will be rejected, and we would conclude that the 
platinum therapy is non-inferior to capecitabine in terms of 
IDFS. The primary hypothesis of the trial (i.e., non-
inferiority of platinum) is then answered, and superiority 
test of platinum (i.e., secondary hypothesis of the trial) 
would be then performed (see Section 9.2.2). If this occurs 
at an interim analysis, accrual to the study will continue to 
allow a definitive answer to the secondary hypothesis test 
(superiority of platinum), i.e., the rejection of null 
hypothesis for the non-inferiority test of platinum will not 
result in early termination of the trial. 
Table 1 shows expected timing of interim analyses and 
critical values for early stopping monitoring under the 
alternative hypothesis of HR=0.754 for 
platinum/capecitabine. Because interim analyses are timed 
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meetings, these boundaries may change depending on the 
number of observed IDFS failures at that time. Also, 
because of delays in data submission and processing, it is 
likely that actual analysis times will be 6-12 months later. 
Table 1: Expected timing of interim analyses and critical values under the alternative hypothesis 
of HR=0.754 (i.e., 4-year IDFS rate of 67% on capecitabine vs. 73.9% on platinum) 
Repeated 
analysis 
Time from study 
activation (years) 
Information 
time (%) 
Number of Failures 
under alternative 
Upper boundary (critical value 
for two-sided 95% RCIs) 
1 
2.9 
0.25 
49 
3.2905 
2 
3.4 
0.34 
67 
3.2905 
3 
3.9 
0.44 
87 
3.2905 
4 
4.4 
0.55 
107 
2.9084 
5 
4.9 
0.65 
126 
2.6218 
6 
5.4 
0.74 
145 
2.4376 
7 
5.9 
0.83 
162 
2.2980 
8 
6.4 
0.92 
179 
2.1870 
Final 
6.9 
1.00 
196 
2.0962 
In addition to efficacy monitoring for the non-inferiority test, the trial 
will be monitored to allow early stopping for inferiority of platinum 
based on conditional power and the above RCI methods. At each 
interim analysis, the conditional power of the log rank test for the 
primary comparison at a one-sided type I error rate of 0.025 will be 
computed using simulation, and if the conditional power of the 
assigned treatment analysis is < 10% and the lower boundary of the 
above two-sided 95% RCI is greater than 0.754 for arm B/arm C (the 
alternative hypothesis), then the trial would be stopped due to futility 
unless there is other supporting evidence for non-inferiority of 
platinum at the time. We would conclude that the trial fail to reject the 
null hypothesis of inferiority of platinum, and platinum is inferior to 
capecitabine. If the conditional power is > 10% or the lower boundary 
of the 95% RCI is below 0.754, the trial would continue. 
9.2.2 
Superiority test of platinum 
If inferiority of platinum is rejected at an interim analysis or the final 
analysis, the primary hypothesis is answered, and a superiority test of 
platinum (i.e., the secondary hypothesis) is then performed at an 
overall one-sided type I error rate of 0.025, using the same RCIs used 
for the above non-inferiority test. For the superiority test, the null 
hypothesis is that HR=1 for platinum/capecitabine. Assuming the 
alternative hypothesis is HR=0.653 for platinum/capecitabine for the 
superiority test, with 562 basal-like TNBC patients and total 
information of 196 IDFS events, there would be at least 82% power to 
detect a 34.7% reduction in the IDFS failure hazard rate using 
stratified log rank test with an overall one-sided type I error rate of 
0.025, if the trial continues regardless of the results of non-inferiority 
test. This reduction in IDFS failure hazard rate corresponds to an 
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improvement in 4-year IDFS rate from 67% on the capecitabine 
arm5,38 to 77% on the platinum arm, under the assumption of 
exponential distribution of IDFS. 
At any interim analysis or the final analysis, when the upper 
confidence limit for the HR is less than 1, the null hypothesis of no 
difference between the two arms would be rejected and we would 
conclude that platinum is superior to capecitabine in improving IDFS 
in patients with basal-like TNBC. If this occurs at an interim analysis, 
DSMC may consider stopping the trial early for efficacy. If the RCI for 
the HR does not include the target alternative HR of 0.653 for 
platinum/capecitabine, the study may be stopped early for lack of 
benefit (i.e., fail to reject the null hypothesis for the superiority test of 
platinum). 
In summary, if, at any of the interim analyses, the null hypotheses for 
both non-inferiority test of platinum (i.e., HR ≥ 1.154) and superiority 
test of platinum (i.e., HR=1) are rejected, the DSMC may consider 
stopping the trial early. If only the inferiority of platinum is rejected and 
the superiority test of platinum dose not cross the stopping boundary, 
the trial will continue. In this case, RCIs would be computed using the 
same upper boundary listed in Table 1, but the stopping rules would 
be shifted to the equality vs. superiority difference. If criteria for early 
stopping (either for efficacy or for futility) are not met for the non-
inferiority test, the final analysis for the non-inferiority test will be 
performed when IDFS event has occurred in 196 patients. If inferiority 
of platinum is rejected at the final analysis, superiority test would then 
be performed at the final analysis. 
For the IDFS endpoint, the primary analysis will compare treatment 
groups defined by the randomized treatment assignment (intent-to-
treat analysis, ITT). A secondary analysis will be performed 
comparing groups defined by treatment received. The results will be 
creditable only if the two analyses are reasonably consistent. 
Although one-sided type I error rate of 0.025 is used for hypothesis 
test in the study design, two-sided 95% RCIs will be used in the 
DSMC and final reports for reporting purpose. 
9.3 
Secondary Endpoints 
9.3.1 
Overall Survival  
Overall survival (OS) is an important secondary endpoint in the study, 
and only superiority test of platinum is planned for OS. With a total 
accrual of 562 basal-like patients, total information of 240 deaths is 
needed to give about 80% power to detect a 30% reduction (i.e., 
HR=0.7 for platinum/ capecitabine under alternative hypothesis) in the 
OS failure hazard rate using stratified log-rank test with one-sided 
type I error rate of 0.025, without any interim analysis plan. This 
reduction in OS failure hazard rate corresponds to an improvement in 
5-year OS from 66% on capecitabine arm to 75% on platinum arm, 
under the assumption of exponential distribution of OS. The final 
analysis for OS is expected to occur at about 10.5 years after study 
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data collection and cleaning, i.e., 3 years after IDFS final analysis) to 
reach the expected number of OS failures. The OS comparison will be 
intent-to-treat analysis of all randomized patients regardless of 
eligibility status. A secondary analysis of OS will be conducted in 
eligible patients. 
9.3.2 
Toxicity 
Another secondary endpoint of the study is to evaluate toxicities in 
patients with basal-like TNBC. All patients who start protocol therapy 
(i.e., receive at least one dose of protocol treatment) will be included 
in toxicity analysis. Assuming 14 basal-like TNBC patients 
(14/281=5%) will not start protocol therapy in each arm, with 267 
evaluable patients, the binomial exact 95% confidence interval for 
toxicity rate would be no wider than 0.12, and there would be at least 
83% power to detect a 13% difference in grades 3 or higher toxicity 
rate, using Fisher exact test with one-sided type I error rate of 0.025. 
For each individual platinum agent (carboplatin or cisplatin), the 
binomial exact 95% confidence interval for toxicity rate would be no 
wider than 0.17 if about the same number of patients (n=133) take 
each agent. 
9.4 
Analysis Plan for Primary and Secondary Endpoints 
The primary endpoint is invasive disease-free survival (IDFS) in patient with 
basal-like TNBC, which is defined to be time from randomization to the earliest of 
documented disease recurrence (local, regional and/or distant), invasive 
contralateral breast cancer, invasive any other second cancer, or death. Cases 
with incomplete follow up or without adequate disease evaluations will be 
censored at the date last documented to be free of IDFS events. The secondary 
endpoints include overall survival (OS) recurrence-free survival (RFS), and 
incidence of toxicity in basal-like TNBC. The final analysis of IDFS and all 
secondary endpoints except for OS will be conducted at about 7.5 years after 
study activation (3.9 years of accrual + 3 years of follow up + 0.5 years of data 
submission and processing). The final analysis for OS will be conducted at about 
10.5 years after study activation (3.9 years of accrual + 6.1 years of follow up + 
0.5 years of data collection and cleaning). 
The distributions of IDFS, RFS and OS will be estimated using the Kaplan- Meier 
method(45). For the non-inferiority test, the primary analysis for IDFS will be 
performed using the RCI method with HR being estimated via stratified Cox 
proportional hazard model, stratifying on the randomization stratification factors. 
For the superiority tests of IDFS, OS and RFS, the primary analysis will be 
performed using stratified log-rank tests, and stratified Cox proportional-hazard 
models will also be built to estimate the HRs for treatment effect for these 
efficacy endpoints as a supportive analysis. IDFS, OS and RFS in non-basal like 
TNBC patients (n=158) and in patients with assay failure (n=35) would be 
analyzed as an exploratory analysis to examine whether the treatment effect 
appears similar between the three subsets (basal-like and non-basal like subtype 
TNBC, and patients with unknown subtype). The treatment-by-basal like subtype 
interaction would be explored using Cox proportional hazard model in the overall 
study population. In the multivariable Cox models, known prognostic factors will 
be included as covariates when appropriate, such as age, race/ethnicity, ECOG 
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excluded from modeling when the proportion of missingness is less than 5% and 
will be imputed appropriately if the proportion of missingness is ≥ 5%. 
Toxicity analysis will be conducted in all basal-like TNBC cases receiving at least 
one dose of chemotherapy (i.e., all treated population). Adverse events will be 
graded using the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. All treatment-emergent and baseline 
adverse events and hematological/biochemical toxicities based on laboratory 
measurements will be summarized for patients on each arm. The incidence of 
deaths and treatment-emergent serious adverse events will be calculated along 
with exact 95% CI based on binomial distribution and compared between 
treatment arms using Fisher exact test. Also, the incidence of adverse events 
leading to discontinuation of chemotherapy and/or withdrawal from the study will 
be summarized and listed. Toxicity in all patients (including both basal-like and 
non-basal like patients) will be summarized and compared between treatment 
arms as well.  
The proportion of basal-like TNBC in all screened TNBC patients will be 
calculated with exact 95% CI based on binomial distribution.  
9.5 
Biomarker Correlative Study 
For this correlative biomarker study, we will combine all the patients on all the 
arms since we don’t expect the prognostic value of the biomarkers of interest 
(i.e., tumor genomic alterations, CTCs) will differ by type of chemotherapy 
patients received and the intrinsic subtype. The total sample size is 775 patients 
for EA1131 (562 basal-like patients, 158 non-basal-like patients and 35 patients 
with unknown subtype). As of June 2019, about 260 patients have enrolled to the 
study. Taking into consideration of various factors (continuous enrollment in the 
upcoming months, assay failure, etc.), we expect to have successful genomic 
profiling of the surgical specimens from at least 400 patients at the end of the 
study. Per the study protocol, the final analysis of the primary endpoint of the 
EA1131 trial will take place at 3 years after accrual completion. At the final 
analyses time (6.9 years after study activation), 196 IDFS events (including 
recurrence, contralateral breast cancer, second invasive primary cancer, and 
death) are expected to have occurred to the 562 basal-like TNBC patients based 
on the alternative hypothesis of the EA1131 study. Of the 196 IDFS events, it is 
expected that approximately 75% will be recurrence or death, i.e., relapse-free 
survival (RFS) events. Assuming the same distribution of RFS in the 158 non-
basal-like patients and in the 35 patients with unknown subtype, there will be 
approximately 100 RFS events occurred to the 400 patients with successful 
genomic profiling, assuming success of genomic profiling is independent of risk 
of recurrence and basal-like subtype. 
9.5.1 
Genomic alterations in the surgical specimen  
We hypothesize that genomic alternations identified via genomic 
profiling will predict RFS for patients with TNBC at high risk of 
recurrence. The frequency of genomic alterations identified will be 
assessed via genomic profiling in TNBC patients with high risk of 
recurrence, and associations between genomic alterations and RFS 
will be assessed; we expect that we can identify some genomic 
alterations that can predict RFS in TNBC at high risk of recurrence. 
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With 400 patients and 100 RFS events, for a binary genomic 
alteration (i.e., the genomic alteration is coded as a binary variable), 
the minimal hazard ratio (HR) that could be detected with 80% power 
at two-sided type I error of 0.05 will be 1.78 assuming 50% of the 
patients have the genomic alteration and the genomic alteration 
increases risk of recurrence. The minimal HR will be 1.85, 1.75, 1.87 
and 2.06 if the proportion of genomic alteration is 20%, 40%, 60% and 
70%, respectively.  
Frequency of genomic alterations will be summarized using binomial 
proportions and 95% exact confidence interval. Association of 
genomic alterations with RFS (i.e., prognostic value of genomic 
alterations) will be analyzed using log rank test and Cox proportional 
hazard models. Available potential confounding variables will be 
adjusted in the Cox model. Due to the exploratory nature of the study, 
no adjustment will be made for multiple comparisons. All testes will be 
two-sided with significance level of 0.05. In addition to the prognostic 
value of genomic alterations, the predictive value of genomic 
alterations will also be explored via a treatment-by-biomarker 
interaction test in multivariable Cox proportional hazard models. 
These analyses will have limited statistical power without prior 
hypothesis, and they will be considered exploratory and hypothesis 
generating. 
9.5.2 
Peripheral Blood CTCs 
We hypothesize that the detection of CTCs at baseline after 
completion of protocol therapy will predict RFS for patients with TNBC 
at high risk of recurrence. Further, we predict that the percent change 
in CTC from pre to post-therapy will also predict RFS, with lower RFS 
in those who turn from positive to negative over the course of 
treatment than those who remain positive or turn positive after 
treatment. 
We will determine the proportion of, and factors associated with CTC 
detection at baseline in early stage TNBC. We will also assess the 
proportions of patients whose CTCs disappear or persist after 
chemotherapy. We will evaluate the association between detection of 
CTC after completion of chemotherapy and RFS and see whether 
persistence of CTC after chemotherapy can predict disease 
recurrence. We will also evaluate the association between change in 
CTC and RFS to see whether lack of decrease in CTC can predict 
higher risk of recurrence. 
In order to test the hypothesis about CTC and RFS, research blood is 
mandatory for all patients enrolled in the trial, and all patients with 
research blood and successful assay results about CTC will be 
included in the analysis. Of the 400 patients with successful CTC 
detection at baseline and after completion of chemotherapy, we 
expect that about 35% of them will have detectable CTCs after 
completion of adjuvant chemotherapy. CTC detection will be coded as 
a binary variable (positive versus negative), and presence of CTC is 
defined as any detectable CTC, e.g., >=1 CTC in 7.5 ml blood. With 
100 RFS events at the analysis time (assuming no RFS event before 
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completion of chemotherapy), the minimal HR for presence of CTC 
versus absence of CTC that could be detected with 80% power at 
two-sided type I error of 0.05 will be 1.75. The minimal HR that can be 
detected with 80% power will be 1.85, 1.80, 1.77, and 1.76 if the 
proportion of CTC is 20%, 25%, 30% and 45%, respectively.  
Associations between detection of CTC at completion of 
chemotherapy as well as change over the course of therapy and RFS 
will be analyzed using Cox proportional hazard models. Available 
potential confounding variables will be adjusted in the Cox models. 
Landmark method will be used for these analyses with landmark time 
point at 5 months (i.e., completion of chemotherapy in both arms). 
Factors associated with CTC detection at baseline will be analyzed 
using Chi square test and Logistic regression models. Due to the 
exploratory nature of the study, no adjustment will be made for 
multiple comparisons. All testes will be two-sided with significance 
level of 0.05. 
9.5.3 
To-be-defined Exploratory Correlative Objectives 
The association of detection of plasma tumor cell-free DNA tumor-
specific mutations prior and after study therapy, its change over time 
and long-term outcome (RFS) will be explored. An amendment or 
proposal for this and any additional correlative science studies to be 
performed on biological samples will be submitted to CTEP, NCI for 
review and approval according to NCTN guidelines. Amendments to 
the protocol and/or proposals for use of biological samples will include 
the appropriate background, experimental plans with assay details, 
and a detailed statistical section. Samples for testing will not be 
released for testing until the appropriate NCI approvals have been 
obtained. 
9.6 
PRO Study 
The study will assess the difference in health-related quality of life (HRQL) 
between two chemotherapy arms and to describe the rate of neurotoxicity over 
time in the platinum arm, the rate of medication adherence in the capecitabine 
arm and the rates of amenorrhea in both arms. 
All participants enrolled on the main study are potentially eligible for the PRO 
assessments after its activation in addendum #4. Patients (regardless of 
molecular subtype) will be enrolled consecutively for the PRO study until 
reaching the target sample size for the PRO primary endpoint (i.e., 362 patients 
with baseline PROs assessments, see Section 9.5.1). PROs assessment for 
HRQL, neurotoxicity or ovarian function will not be administered in the rest of the 
patients enrolled for the assessment of the clinical outcomes. The adherence 
measure (Medication Adherence Scale) for capecitabine will be descriptive and 
administered to all patients in this cohort. 
9.6.1 
Statistical Consideration for PRO Endpoints 
The primary objective of the PRO study is to compare HRQL between 
the chemotherapy arms. HRQL measures will be assessed at 
baseline, and at day 1 of cycle 3 (at 6 weeks), and 6 and 15 months 
after the start of study chemotherapy (dated at Day 1 of Cycle 1). 
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These time-points have been chosen as they will allow us to capture 
the acute difference in side-effects following receipt of chemotherapy, 
while following long enough to ensure that acute differences in side 
effects have resolved. Differences in symptom burden and HRQL at 
15 months would be considered persistent and unlikely to improve 
significantly with further follow up. The study hypothesis is that HRQL 
between the two arms will differ significantly at all time points after 
baseline (i.e. the platinum chemotherapy group will report higher 
HRQL at all time-points). The null hypothesis is that patients on the 
two arms have same overall HRQL at these time points. 
The primary endpoints for the PRO objective are HRQL at 6 months 
and 15 months after the start of study chemotherapy. The type I error 
rate is split between the two primary endpoints to control the overall 
one-sided type I error rate at 2.5% for the PROs analysis. Specifically, 
the one-sided type I error rate is 1.0% for HRQL test at 6 months after 
the start of chemotherapy and 1.5% for HRQL test at 15 months after 
the start of chemotherapy. 
HRQL will be measured by the FBSI Treatment Side Effects (TSE) 
subscale score in the study, an aggregate score of 4 items from the 
NCCN-FACT FBSI-16 scale. Higher score represents better HRQL 
(score range 0-16). Based on Garcia’s study (Value in Health 2012), 
the minimally important difference (MID) for the FBSI-TSE is 1.5 
points, and the standard deviation (SD) for the score is about 3.7. A 
total of 326 patients will be needed to provide a 90% power to detect 
an effect size (i.e., MID/SD) of 0.4 at 6-months post baseline, using 
two-sample t test with one-sided type I error rate of 0.01. For HRQL 
comparison at 15 months, 290 patients would be needed for this test 
with one-sided type I error rate of 0.015 and 90% power. Assuming an 
overall attrition rate of approximately 12% by 6 months after the start 
of chemotherapy and 20% by 15 months after the start of 
chemotherapy for the PROs assessment in both arms, it is expected 
that about 362 patients will be needed for the primary analysis for 
HRQL in the study to provide the 326 patients for the HRQL test at 6 
months after the start of chemotherapy and the 290 patients for HRQL 
test at 15 months after the start of chemotherapy. 
9.6.2 
Analysis Plan for PRO Endpoints 
PROs endpoints will be analyzed at the final analysis time for the 
primary endpoint. Any participants who take the PROs surveys at 
more than 1 time-point will be eligible for analysis. The primary 
endpoint for HRQL is FBSI TSE subscale score at 6 and 15 months 
after the start of chemotherapy. The primary endpoint of ovarian 
function is rate of amenorrhea at 15 months. Amenorrhea is defined 
as the absence of menses without secondary reason (e.g., 
pregnancy, oophorectomy or receipt of LHRH agonist, etc.) for the 
whole 6 months prior to the 15-month survey (i.e., no menses 
between 9 and 15 months). The primary analysis of HRQL will be 
assessed in all eligible patients. The primary analysis of rate of 
amenorrhea will be assessed in women aged 18-49 at enrollment who 
are premenopausal at cancer diagnosis. 
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Subscale scores for HRQL endpoint will be prorated by multiplying the 
sum of the subscale by the number of items in the subscale, then 
dividing by the number of items actually answered: Prorated subscale 
score= (sum of items cores) * (number of items in subscale) /(number 
of items answered). When there are missing data, prorating by 
subscale in this way is acceptable as long as more than 50% of the 
items are answered in each subscale. Standard descriptive and 
graphical analyses will be used initially to examine missing data 
patterns, and to understand the relationship between variables for 
HRQL scores. The assessment scores for the HRQL will be compared 
between the two treatment arms at all time points, using two samples 
t test (or Wilcoxon rank sum test if the distribution of the score is not 
symmetric). Change in the HRQL scores between all other time points 
and the baseline visits will be compared between the two arms using 
two sample t tests. Similar analyses will be conducted for each NCCT-
FACT FBSI subscales. The mean score and proportion of 
moderate/severe symptoms will be compared between treatment 
arms for each individual FBSI item at 6 months after the start of 
chemotherapy using Wilcoxon rank sum test and Fisher exact test, 
respectively, as an exploratory analysis. Mixed effect models will be 
constructed as another exploratory analysis to estimate the time 
profile of HRQL in the two treatment arms and to evaluate treatment-
by-time interactions. Time will be included as a continuous variable if 
there is a linear trend in HRQL over time or a set of dummy variables 
if non-linear trend exits for HRQL. Likelihood ratio test will be used for 
model selection. Adjusted covariates in the mixed effect models will 
include patient demographic and disease characteristics, such as age, 
ECOG PS, clinical stage at diagnosis, residual cancer burden, prior 
therapy, et al. 
Fisher exact test will be used to examine the difference in rates of 
amenorrhea between the arms at 15 months. Logistic models will be 
used for regression analysis for amenorrhea. Adjusted covariates in 
the logistic models will include patient demographic and disease 
characteristics, such as age, ECOG PS, clinical stage at diagnosis, 
residual cancer burden, prior therapy, et al. 
In all analyses, P-values will be two-sided. A level of 2.0% will be 
considered statistically significant for HRQL comparison at 6 months 
after the start of chemotherapy between two arms. A level of 3.0% will 
be considered statistically significant for HRQL comparison at 15 
months after the start of chemotherapy between two arms. For all 
other analysis, a level of 5% will be considered statistically significant. 
No adjustment will be made for multiple comparisons for secondary 
and exploratory endpoints. 
For neurotoxicity (platinum arm) and adherence (capecitabine arm), it 
will be descriptive only. Neurotoxicity is measured by the FACT-
GOG/NTx 11-item subscale score at each time point. The FACT-
GOG/NTx subscale score is calculated in a similar way as that for 
HRQL endpoint. Mixed effect model will be constructed as an 
exploratory analysis to estimate the time profile of neurotoxicity in the 
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adherence score will be displayed via box-and-whisker plot. The 
proportion of high, medium and low adherence will be calculated 
along with the binomial exact 95% confidence interval. The adherence 
score for each cycle will be calculated. The reasons for non-
adherence will be summarized. 
9.6.3 
Tobacco Use Assessment 
Detailed statistical considerations are outlined in Appendix VI. 
9.7 
Gender and Ethnicity  
Male breast cancer accounts for approximately 1% of all breast cancers. 
Meanwhile, some elderly male patients may not be eligible or consider trials. We 
could anticipate that about 7 male patients with TNBC could enroll out of a 
sample size of 775, and all of them are expected to be non-Hispanic White 
patients. For the 768 female patients, based on previous data from SWOG 
S0226 and ECOG E2100 studies, the anticipated accrual in subgroups defined 
by gender and race is: 
Racial Categories 
Ethnic Categories 
Total 
Hispanic or Latino 
Not Hispanic or 
Latino 
Females 
Males 
Females Males 
American Indian or Alaskan Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
15 
0 
15 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
65 
0 
65 
White 
53 
0 
635 
7 
695 
Total 
53 
0 
715 
7 
775 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual 
targets. 
9.8 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
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10. 
Biological Sample Submissions 
Tumor tissue from the residual disease on the definitive surgical specimen must be 
submitted for PAM50 analysis as defined in Section 11. The PAM50 analysis will be 
performed by the Molecular Diagnostics Laboratory (MDL) at MD Anderson Cancer 
Center and receipt of tumor tissue will be forwarded to the ECOG-ACRIN Operations 
Office and submitting institution. Results of the PAM50 analysis will not be reported to 
the submitting institution. 
Tumor tissue will also be assessed by central review of immunohistochemistry (IHC) 
expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal 
growth factor receptor (HER2) FISH to rule out conversion of these clinical markers 
following chemotherapy. 
Every effort should be made to submit tumor tissue specimen to the MDL immediately, 
as patients need to be randomized within 24 weeks from surgery.  
Patients cannot proceed to STEP 1/ randomization before the EA CBPF acknowledges 
receipt of tumor tissue for PAM50 analysis. 
Peripheral blood specimens must be submitted for defined laboratory research studies 
described in Section 11. 
Peripheral blood specimen are to be submitted per patient consent for undefined future 
research studies. 
It is required that all specimens submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (see Section 10.3). An STS shipping manifest 
form is to be included with every submission. 
All specimens must be labeled clearly with the ECOG-ACRIN protocol number 
(EA1131), ECOG-ACRIN patient sequence number, patient’s initials, date of collection 
and specimen type. 
10.1 
Submissions to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF) 
10.1.1 
Tumor Tissue Submission (Mandatory) 
Pathology specimens must be submitted as soon as possible as not 
to delay randomization, as patients need to be randomized within 24 
weeks from surgery. 
Submitting pathologist and clinical research associate may refer to 
Appendix I, which outlines the Pathology Submission Guidelines. 
Submission of pathology specimens from all patients is mandatory. 
The tumor tissue specimens and pathology report are to be labeled 
with the Pathology accession ID number and as well as the 
information above. 
10.1.1.1 Required Materials 
Forms: Must be submitted with all tumor tissue 
submissions.   
• 
STS generated shipping manifest form 
• 
Copy of the institutional surgical pathology report  
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6/16 
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• 
CLIA Laboratory Sample Submission Form (Appendix 
IV) 
10.1.1.2 
Pathological Material Submission: 
• 
FFPE tumor tissue block – breast primary specimen 
from definitive surgery (≥ 1 cm in diameter, > minimal 
cellularity as per local pathologist determination). 
NOTE: If these criteria cannot be met, please contact 
the ECOG-ACRIN CBPF 
(eacbpf@mdanderson.org) to obtain 
alternative submission requirements. 
10.1.1.3 
Notification of Tumor Tissue Receipt 
The MDL will notify the ECOG-ACRIN Operations Office 
and submitting institution of receipt of the tumor tissue 
specimen. 
CRA’s will receive an email notification when patients can 
proceed to Step 1 randomization. 
Randomization cannot occur until receipt of the tumor 
tissue specimen is acknowledged. 
10.1.2 
Optional Peripheral Blood Submissions for Future ctDNA Analysis 
Submit from patients who answer ‘Yes’ to ‘I agree to provide 
additional samples for research’ on the informed consent document. 
Kits for the collection and shipment of the peripheral blood specimens 
are ordered on-line from Cenetron Central Laboratories. Instructions 
are provided in Appendix VII. Questions regarding kits can be directed 
to projectmanagement@cenetron.com or call the Cenetron Clinical 
Trials Group at (512) 439-2000. Kits must be ordered after the patient 
has been randomized to the trial and will generally arrive within three 
(3) business days from when the order was placed. 
Peripheral blood specimens are to be collected at the following time 
points: 
• 
Prior to Start of Treatment [Cycle 1, Day 1] 
• 
Six (6) Months from Chemotherapy Initiation [+/- 2 weeks] 
Blood specimens are to be shipped at ambient temperature on the 
day of collection (Cycle 1/ Day 1 and 6 months [+/- 2 weeks] from 
chemotherapy initiation). 
10.1.2.1 
Specimen Preparation Guidelines 
• 
Confirm blood tube is not expired. Expired tubes 
should not be used for blood collection. 
• 
Draw two (2) 10mL Streck Cell-Free DNA BCT tubes of 
whole blood at each time point. Fill each tube 
completely.  
NOTE: 
The first 5mL of blood collected from the 
fresh venipuncture cannot be used for the 
collection into the Streck tubes due to 
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possibility of contaminating epithelial cells 
during venipuncture. Please ensure that at 
least one (1) blood tube of 5mL or more is 
collected prior to collection.   
• 
Ensure at least 10mL of blood is drawn in each tube. 
Avoid low volume to minimize agitation during shipping.  
• 
Immediately after collection, gently invert tubes 180 
degrees and back 10 times to ensure adequate mixing. 
• 
Label the tube with ECOG-ACRIN protocol number 
(EA1131), ECOG-ACRIN five-digit patient sequence 
number and date and time of blood draw. Unlabeled 
blood tubes may not be processed. 
• 
Maintain blood at room temperature (6ºC to 37ºC) until 
shipping. Do Not place tubes in refrigerator 
• 
Ship on day of collection in shipper provided at ambient 
temperature. 
NOTE: 
Prevention of Backflow: 
Since Streck Cell-Free DNA tubes contain 
chemical additives, it is important to avoid 
possible backflow from the tube. To guard 
against backflow, observe the following 
precautions: 
• 
Keep patient’s arm in the downward position 
during the collection procedure 
• 
Hold the tube with the stopper uppermost 
• 
Release tourniquet once the blood starts to 
flow into the tube, or within two minutes of 
application 
• 
Tube contents should not touch stopper or 
the end of the needle during the collection 
procedure 
10.1.3 
Specimen Shipping Procedures 
Pathology specimens are to be shipped at ambient temperature within 
21 weeks post-surgery. 
Peripheral blood specimens are to be shipped at ambient temperature 
Monday-Thursday via overnight courier. 
Friday shipments are ill advised, similarly shipping before 
holidays is often problematic. The laboratory is closed Saturday, 
Sunday, and holidays. 
Ship using the CBPF's FedEx account using the FedEx on-line 
Ship Manager. 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
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Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Boulevard 
Houston, TX 77030 
Toll Free Phone: (844) 744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
Access to the shipping account for shipments to the CBPF can only 
be obtained by logging into fedex.com with an account issued by the 
CBPF. For security reasons, the account number will no longer be 
given out in protocols, over the phone, or via email. If your site needs 
to have an account created, please contact the CBPF by email at 
eacbpf@mdanderson.org. 
An STS shipping manifest form must be generated and shipped with 
all specimen submissions. 
10.2 
Mandatory Submission of Peripheral Blood for CTCs to Epic Sciences 
If you have any questions concerning specimen collection and shipment, please 
contact Epic Sciences at (858) 356-6610 or partners@epicsciences.com. 
Peripheral blood specimens are to be collected at the following time points: 
• 
Prior to Start of Treatment [Cycle 1, Day 1] 
• 
Six (6) Months from Chemotherapy Initiation [+/- 2 weeks] 
Epic Sciences will be providing collection and shipping kits to include Streck Cell-
Free DNA BCT tubes, shipping containers. Please email 
partners@epicsciences.com to order kits and provide the shipping address. 
Indicate ‘EA1131/EP-001’ in the subject line of the email. Kits will generally arrive 
within seven (7) days from when the order was placed. 
Please use FedEx account number: 680817251 when shipping specimens 
to Epic Sciences for this trial only. 
10.2.1 
Specimen Preparation Guidelines 
• 
Confirm blood tube is not expired. Expired tubes should not be 
used for blood collection. 
• 
Draw two (2) 10mL Streck Cell-Free DNA BCT tubes of whole 
blood at each time point. Fill each tube completely. NOTE: The 
first 5mL of blood collected from the fresh venipuncture cannot be 
used for the collection into the Streck tubes due to possibility of 
contaminating epithelial cells during venipuncture. Please ensure 
that at least one (1) blood tube of 5mL or more is collected prior to 
collection of the CTC specimen to avoid adversely affecting the 
test results. 
• 
Ensure at least 10mL of blood is drawn in each tube. Avoid low 
volume to minimize agitation during shipping. 
NOTE: 
Epic requires minimum of 4mL of blood per time point, 
but a full 10mL tube of blood should be provided when 
possible. 
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• 
Immediately after collection, gently invert tubes 180 degrees 
and back 10 times to ensure adequate mixing. 
• 
Label the tube with ECOG-ACRIN protocol number (EA1131), 
ECOG-ACRIN five-digit patient sequence number and date and 
time of blood draw. Unlabeled blood tubes may not be processed. 
• 
Maintain blood at room temperature (6ºC to 37ºC) until shipping. 
Do Not place tubes in refrigerator 
• 
Ship on day of collection in shipper provided at ambient 
temperature. 
NOTE: 
Prevention of Backflow: 
Since Streck Cell-Free DNA tubes contain chemical 
additives, it is important to avoid possible backflow from the 
tube. To guard against backflow, observe the following 
precautions: 
• 
Keep patient’s arm in the downward position during the 
collection procedure 
• 
Hold the tube with the stopper uppermost 
• 
Release tourniquet once the blood starts to flow into the 
tube, or within two minutes of application 
• 
Tube contents should not touch stopper or the end of 
the needle during the collection procedure 
10.2.2 
Specimen Shipment Procedures 
Please use FedEx account number: 680817251 when shipping 
specimens to Epic Sciences for this trial only. 
The lab is open for specimen receipt and processing Mondays-
Saturdays. Please mark courier slip with ‘Saturday Delivery’ if 
shipping on Thursdays and Fridays. 
Clinical sites should provide email notification of specimen shipment 
to Epic Sciences on the day of collection, send notification to: 
partners@epicsciences.com 
The email should contain: 
• 
Trial Code (EA1131/EP-001) 
• 
ECOG-ACRIN 5-Digit Patient Sequence Number 
• 
Collection Date and Time 
• 
Time Point/Visit 
• 
Tracking Information 
Do not place ‘Infectious Substance’ sticker on shipper, as this can 
result in a delay of shipment. 
Ship specimens to: 
Epic Sciences 
Attn: EA1131 / EP-001 
9381 Judicial Drive, Suite 200 
San Diego, CA 92121 
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Phone: (858) 356-6610 
Fax: (858) 356-5852 
An STS shipping manifest form must be generated and shipped with 
all specimen submissions. 
10.3 
ECOG-ACRIN Sample Tracking System  
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) CTSU username and password. 
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html.   
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu.  
Study Specific Notes 
Generic Specimen Submission Form (#2981) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. Indicate the appropriate 
Lab on the submission form: 
• 
ECOG-ACRIN Central Biorepository and Pathology Facility (EA CBPF) 
• 
EPIC Sciences 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.4 
Use of Specimens in Research  
Tumor tissue specimens will be sent directly to the MDL at MDA for PAM50 
analysis and residual tumor tissue will be distributed to Vanderbilt University for 
laboratory research studies outlined in Section 11. Peripheral blood specimens 
will be sent directly to Epic Sciences for CTC Detection analysis as outlined in 
Section 11. 
Use of banked specimens will not occur until an amendment to this protocol (or 
separate correlative science protocol) is reviewed and approved in accordance 
with National Clinical Trials Network (NCTN) policies. The proposed future 
studies are: 
• 
Rate of ctDNA Detection and Significance of ctDNA-detected Mutations 
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Specimens from patients who consented to allow their specimens to be used for 
future ECOG-ACRIN approved research studies will be retained in an ECOG-
ACRIN designated central repository. 
For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microarrays (TMAs). DNA, 
RNA, serum, and plasma (if appropriate) will be isolated from the submitted 
peripheral blood specimens. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request.  
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. Pathology 
materials may be retained for documentation purposes or returned to the site. All 
other specimens will be destroyed per guidelines of the respective repository. 
10.5 
Sample Inventory Submission Guidelines 
Inventories of all specimens submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory. 
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office – Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office – Boston. 
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11. 
Biomarker Studies 
11.1 
Rate of basal-like gene expression using PAM50 analysis by digital mRNA 
quantitation – Integral Biomarker Study 
11.1.1 
Rationale for PAM50 Analysis in Surgical Residual Tumor 
Most TNBCs are high-grade and the majority of them harbor a basal-
like gene expression signature1,41. Among young women and African-
American women, its prevalence is elevated(2). We recently 
completed a study where we profiled 89 residual tumors from patients 
with stage II (20%) and III (80%) TNBC treated with AC-T neoadjuvant 
chemotherapy (NAC)8. Expression level for 450 genes was quantified 
by NanoString in RNA extracted from the surgical specimen. 
Molecular subtype of these residual tumors, after adjusting for HER2 
amplification (i.e. upon re-testing, all HER2 FISH amplified cancers 
were excluded) was as follows: 70% basal-like; 15% HER2-enriched; 
6% luminal A, 6% luminal B; and 5% normal-like. Basal-like status 
was associated with a trend toward worse RFS and OS (log-rank 
test, P = 0.12 and 0.058, respectively). The median time to relapse 
among this high-risk group of patients with basal-like gene expression 
was only 18 months. Consistent with early clinical data in TNBC, 
breast cancer cells and xenografts with basal-like gene expression 
are particularly sensitive to cisplatin(9). In summary, within TNBC, 
patients with tumors with basal-like expression are at the highest risk 
for recurrence. Hence the biologic rationale for this concept is 
strongest in the basal subtype. At present, patients with TNBC (of 
which about 70% are expected to be basal-like by gene expression 
profile(10)) that complete neoadjuvant therapy and have no clinical 
evidence of metastatic disease after surgical excision of the cancer, 
regardless of residual disease burden, are usually observed. This 
conduct might not be appropriate for patients at a very high risk of 
early recurrence such as those with a high residual disease burden in 
the residual drug-resistant tumor. Based on all the above data, we 
hypothesized that patients with clinical stage II-III basal-like triple-
negative breast cancer (TNBC) with more than 1 cm of residual 
disease in their surgical specimen after neoadjuvant chemotherapy 
that are treated with adjuvant platinum-based chemotherapy will have 
a longer disease-free survival (DFS) than the ones in the capecitabine 
arm.  
11.1.2 
PAM50 Background 
In 2009, a 50-gene set (PAM50) was proposed for standardizing 
subtype classification. The PAM50 Breast Cancer Intrinsic Classifier is 
the clinical manifestation of this gene set using a digital gene 
expression assay on the NanoString nCounter Dx Analysis System 
that has been validated on formalin-fixed, paraffin-embedded tissues. 
Multivariable analyses using the PAM50 subtypes and other clinical 
data (e.g., node status, grade, ER-status) show that the PAM50 is an 
independent predictor of survival in breast cancer(46-49). The PAM50 
test provides additional information about the tumor biology and 
quantitative data on biomarkers already used for treatment 
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decisions46,47. Along with a categorical classification of breast cancer 
subtype, the clinical PAM50 test also determines a quantitative value 
for proliferation(50). The PAM50 gene set testing will be performed 
using an Investigational Use Only (IUO) PAM50 Assay on the 
nCounter Dx Analysis System produced by NanoString Technologies. 
The IUO PAM50 assay uses the same reagents, procedures and 
algorithm as the Prosigna Gene Expression Assay, which have all 
been analytically validated and cleared for use by the FDA as a 
prognostic test in ER+ breast cancer patients who are treated with 
endocrine therapy alone. 
Within this study, we expect at least 75% of the residual post-NAC 
TNBC screened to fall within the basal-like subtype by gene 
expression profile(10). Hence, at least 750 patients (=562/0.75) with 
residual TNBC at the time of surgery will be screened to obtain the 
562 patients with basal-like TNBC. 
11.1.3 
Assay Description 
Used together, the PAM50 and nCounter Dx Analysis System are a 
nucleic acid hybridization, visualization and image analysis system 
based upon coded probes designed to detect the messenger RNA 
transcribed from 58 genes. The test input is purified RNA from FFPE 
breast tumor specimens. The PAM50 assay uses gene-specific 
probe-pairs that hybridize directly to the mRNA transcripts in solution. 
The nCounter Dx Analysis System delivers direct, multiplexed 
measurements of gene expression through digital readouts of the 
relative abundance of the mRNA transcripts. 
Specifications are included to 
control for sample quality, RNA 
quality, and process quality. The 
PAM50 assay utilizes 
prototypical expression profiles 
(centroids) which are associated 
with and define each of the four 
intrinsic subtypes of breast 
cancer. Patients are categorized 
into one of the four subtypes 
based upon how close their 
gene expression pattern is to 
each of the centroids (Luminal A, 
Luminal B, Her2-Enriched, and Basal-Like). 
11.1.4 
Specimens and Processing:  
Formalin-fixed paraffin-embedded (FFPE) tumor block from the 
residual disease on the definitive surgical specimen will be collected 
and submitted to the Molecular Diagnostics Laboratory (MDL) at MD 
Anderson Cancer Center, where H&E stain will be performed to 
assess tumor area and cellularity. After central processing, the tumor 
areas will be transposed to unstained slides. Adjacent non-tumor 
tissue will be macrodissected and RNA will be extracted with a 
manual kit and subjected to PAM50 analysis, as described above(51). 
The MDL will have a custom software configuration that is intended 
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for investigational use within this clinical trial and will output intrinsic 
subtype. 
11.2 
Genomic alterations identified via whole exome sequencing (WES) and RNA 
sequencing – Biomarker Study 
11.2.1 
Rationale and Background for WES and RNA-seq in Surgical 
Residual Tumor 
Mutational spectrum analyses suggest that TNBC has a higher 
mutational frequency than other subtypes(29-31), and our group has 
shown that profiling of TNBC post-neoadjuvant chemotherapy in a 
small scale is feasible and identifies gene alterations that may have a 
role in chemoresistance(8). We propose to perform a prospective 
large-scale genomic profiling of surgical tissue from patients enrolled 
in the EA1131 clinical trial; we hypothesize that the genomic 
alterations identified via genomic profiling will predict relapse-free 
survival for this group of patients at high risk of recurrence. Successful 
completion of this comprehensive profiling will a) more accurately 
identify patients with TNBC at highest risk of recurrence, and b) 
provide novel insights into future targeted interventions that could 
significantly impact risk of recurrence and mortality in patients at 
highest risk. 
We will assess the frequency of genomic alterations (VAFs, copy 
number, and patterns of mutant allele expression) identified via 
genomic profiling in TNBC patients with high risk of recurrence, and 
assess associations between genomic alterations and clinical 
outcome; we expect that we can identify some genomic alterations 
that can predict relapse free survival in TNBC at high risk of 
recurrence. We will use the WES methods developed by Griffith(52), 
which will deliver ~100x average coverage of targeted regions. We 
will use established RNA-seq methods(53), and enrich WES data by 
assessing expression and relevance of mutations identified by WES. 
Missense mutations expressed at RNA level are more likely to be 
relevant than those not expressed. We will also be able to identify 
expressed gene fusions through RNA-seq; which would be more 
sensitive/specific than WES for detecting gene fusions and novel 
cryptic fusions. Gene’s normalized expression level will be assessed. 
11.2.2 
Specimens and Processing 
The surgical tumor specimens will be subjected to whole genome 
sequencing (WES) and RNA-seq. Future analysis will be performed 
on the DNA and RNA extracted from the formalin-fixed paraffin-
embedded (FFPE) tumor specimens submitted from patients who: 
• 
Registered prior to activation of Addendum #6 and answered 
“Yes” to “My samples and related information may be kept in a 
Biobank for use in future health research.” 
OR 
• 
Registered following activation of Addendum #6 and answered 
“Yes” to “I agree that my samples and related information may be 
used for the laboratory studies described above.” 
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11.3 
Blood-Based Biomarkers – Rate of CTC Detection 
11.3.1 
Rationale and Background 
We hypothesize that the detection of CTC after completion of adjuvant 
chemotherapy and change in CTC prior to and after completion of 
adjuvant chemotherapy will predict RFS for patients with TNBC at 
high risk of recurrence. 
In 2004, the seminal work by Cristofanilli et al. demonstrated that CTC 
count was an independent prognostic factor for progression-free 
survival (PFS) and OS in metastatic BC(54). In a large study involving 
2,026 primary BC patients, CTCs have been detected in the 
peripheral blood of approximately 22% of patients after surgery and 
before adjuvant therapy(55). In adjuvant setting, CTC detection (≥ 1 
CTC in 7.5 mL of blood) before chemotherapy has shown to be an 
independent predictor of disease-free survival (DFS) and OS and, not 
only the presence but also the quantity of CTCs has proven to be 
associated with worse outcome. Moreover, the persistence of CTCs 
after adjuvant treatment significantly correlates with a decreased 
DFS(33, 55). CTCs evaluation in patients with early-stage BC could 
provide useful information for adjuvant treatment decision-making. 
However, in this particular context, CTCs are observed with low 
frequency thus, CTC detection methods with higher sensitivity could 
be necessary for their clinical use. Moreover, further studies are 
needed to better define its efficacy in both the prediction of outcome 
and monitoring the effect of therapy. 
The Epic Sciences CTC detection and characterization platform 
enables enumeration of CTCs as well as evaluation of protein 
biomarker expression and subcellular localization when used with 
their 1) 4 or 5-color immunofluorescence assays, 2) gene 
amplifications, deletions or rearrangements by DNA FISH and 3) 
genomic aberrations via mutation or copy number variation (CNV) 
analysis via next-generation sequencing (NGS). 
Analytical validation in terms of assay performance, accuracy, 
linearity, specificity and precision of CTC enumeration was published 
in by Werner et al(56). An excerpt of data that highlights the 
performance of key parameters is shown below. 
Performance 
Characteristics 
Assessment 
Parameter 
Spike-In CLCs 
Measured Parameter 
Accuracy 
Recovery of nucleated 
cells 
0 to 300 CLSs/slide 
(7 serial dilutions) 
% Recovery of 
Nucleated Cells 
Linearity (Reportable 
Range) 
Assay Linearity 
0 to 300 CLCs/Slide 
(7 serial dilutions) 
Linear Regression of 
CLC Count 
Specificity 
False Positive CLC 
Detection 
Unspiked healthy donor 
slides 
CLC Count 
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Performance 
Characteristics 
Assessment 
Parameter 
Spike-In CLCs 
Measured Parameter 
Precision/Repeatability 
Intra-Assay (n=3 
replicate tests / run) 
Inter-Assay (n=5 runs / 
3 operators) 
Intra-Operator (n=3 
runs / operator) 
Inter-Operator (n=3 
runs / 3 operators) 
(i) 25 CLCs/slide 
(ii) 300 CLCs/slide 
% CV CLC Count 
These are the analytical characteristics assessed to benchmark the 
performance of the Epic Sciences CTC detection and characterization 
platform. Varying concentrations of COLO-205 cell line cells (CLCs) 
were spiked into healthy donor blood, red blood cells were lysed, and 
3 x 106 nucleated cells were deposited onto slides, ranging from 0-
300 CLCs/slide. Slides were stained with a cocktail of CK, CD45 and 
DAPI antibodies. Assay accuracy, linearity, specificity and precision 
were determined as described in the methods. For each analysis, a 
“run” is comprised of three tests, with each test consisting of two 
replicate slides. 
CTC enumeration on the Epic Sciences platform consists of: 
 
1. Slide Prep: Upon receipt of patient blood specimen, whole blood 
is lysed and nucleated cells are deposited on up to 12 microscope 
slides that are frozen at -80 ºC until analysis. 
2. Cell Staining and Scanning: Slides are immunofluorescently 
stained and scanned by Epic’s rapid fluorescent scanning method, 
which images each nucleated cell. 
3. CTC Identification and Biomarker Analysis: A digital pathology 
algorithm, which includes protein expression and morphology, 
differentiates candidate CTCs from surrounding white blood cells 
(WBCs). CTCs are confirmed and classified into one of the 
following categories (1) Traditional CTCs, (2) CTC clusters, (3) 
CK(-) CTCs and (4) Apoptotic CTCs (see CTC basics to review 
these different classes of CTCs). 
The Epic Sciences' platform analyzes all nucleated cells within a 
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blood specimen are deposited on replicate glass slides and 
compared for morphological features, expression of biomarkers 
and nuclear integrity, using immunofluorescent staining. Guided 
by cell phenotype and marker expression, CTCs are individually 
recovered from the slide surface. Their genomes are amplified 
(WGA) and analyzed by next-generation sequencing (NGS) for 
the presence of point mutations, copy number alterations, genome 
wide chromosomal instability, ploidy or genome wide scarring. 
1. Slide Prep: Upon patient blood specimen receipt at Epic 
Sciences, whole blood is lysed and nucleated cells are deposited 
onto microscope slides. 
2. Cell Staining and CTC Identification: Cells are stained for 
immunofluorescence to identify CTCs and other biomarkers in the 
study. Coordinates of all CTCs on the slide are preserved. 
3. Genomics Analysis: Coverslips are removed and cell 
coordinates are used to relocate CTCs. Once relocated, cells are 
picked and placed into individual wells of an assay-ready 96 well 
plate. 
11.4 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research study will be 
submitted electronically using a secure data transfer to the ECOG-ACRIN 
Operations Office – Boston by the Investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. 
 

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12. 
Electronic Data Capture 
Please refer to the EA1131 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed in Medidata Rave and EASEE-PRO (for 
tobacco use assessment). 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application. 
Reports are due January 31, April 30, July 31, and October 31. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
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A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. 
Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer 
following Neoadjuvant Chemotherapy 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981v3) 
 

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Guidelines for Submission of Pathology Materials 
EA1131 A randomized phase III post-operative trial of platinum-based chemotherapy vs. 
observation in patients with residual basal-like triple-negative breast cancer 
following neoadjuvant chemotherapy 
The following materials must be submitted within 21 weeks post-surgery. 
1. Pathology Submission: 
• 
FFPE tumor tissue block (≥ 1 cm in diameter, > minimal cellularity as per local 
pathologist determination) from the residual disease on the definitive surgical 
specimen – submission is mandatory. 
NOTE: If these criteria cannot be met, please contact the ECOG-ACRIN CBPF 
(eacbpf@mdanderson.org) to obtain alternative submission 
requirements. 
The following items are to be included with the pathology materials. 
2. Forms and Reports: 
• 
Copy of institutional surgical pathology report. 
• 
STS generated shipping manifest form.  
• 
CLIA Laboratory Sample Submission Form (Appendix IV) 
NOTE:  
Adequate patient identifying information must be included with every 
submission. It is strongly recommended that full patient names be 
provided. The information will be used only to identify patient materials, 
for interactions between the ECOG-ACRIN CBPF, the central testing 
laboratory and the site, and will help to expedite any required 
communications with the institution (including site pathologists). 
3. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN 
Room G1.3598 
1515 Holcombe Boulevard 
Houston, TX 77030 
If you have any questions concerning the above instructions or if you anticipate any 
problems in submitting the required pathology material, contact the Pathology 
Coordinator at the ECOG-ACRIN CBPF by telephone: (844) 744-2420, by fax: (713) 
563-6506, or by email: eacbpf@mdanderson.org. 
 
Rev. 2/16 
Rev. 6/16 
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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA1131:  A randomized phase 
III post-operative trial of platinum based chemotherapy vs. 
capecitabine in patients with residual basal-like triple-negative breast 
cancer following neoadjuvant chemotherapy 
 
A patient has been entered onto an ECOG-ACRIN protocol by 
________________________ (ECOG-ACRIN Investigator). This protocol requires the 
submission of pathology materials for PAM50 analysis, central review, and defined 
laboratory research studies. 
Return the surgical pathology report(s), the slides and/or blocks and any other required 
material to the Clinical Research Associate (CRA). The CRA will forward all required 
pathology materials to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF). 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN CBPF 
for future undefined research studies. Paraffin blocks will be returned upon written 
request for purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the ECOG-ACRIN 
CBPF at (844) 744-2420 or Fax (713) 563-6506. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 

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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
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A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. 
Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer 
following Neoadjuvant Chemotherapy 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we may improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
 

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A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. 
Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer 
following Neoadjuvant Chemotherapy 
 
Appendix III 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 

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A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. 
Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer 
following Neoadjuvant Chemotherapy 
 
Appendix IV 
 
CLIA Laboratory Sample Submission Form 
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Department of Pathology 
Tissue Qualification Laboratory 
T 713-745-4901 F 713-745-4925 
T 844-744-2420 (Toll Free) 
Unit 0085 
1515 Holcombe Blvd 
Room G1.3597 
Houston, Texas 77030 
CLIA Laboratory Sample Submission Form 
The information on this form is required for results reporting from the CLIA laboratory.  This form MUST be 
completed and submitted with all specimens.  Failure to submit this form will result in a delay in specimen 
processing and a delay in the reporting of results to the ordering physician. 
SECTION I.  TRIAL INFORMATION       
ECOG-ACRIN TRIAL NUMBER: ______________ 
ECOG-ACRIN Patient ID: ______________________ 
Section II.  SITE’S TIME ZONE INFORMATION 
Time Zone:  
 Atlantic    
 Eastern    
 Central   
 Mountain    
 Pacific   
 Alaska    
 Hawaii-Aleutian 
                    
 Other:  ________________________ Is Daylight Saving Time observed:      
 Yes     
 No 
Section III.  PATIENT INFORMATION 
Last Name: ________________________________ 
First Name: _________________________________ 
Date of Birth (MM/DD/YYYY):  ___________________ 
Gender: 
 Female     
 Male 
Section IV. SITE CONTACTS 
Sections A and B must be completed. 
If applicable, has or will the tissue submitted be reviewed by a local pathologist?             
 Yes            
 No 
If yes, Section C must be completed and a copy of the local pathology report must be uploaded into Medidata Rave 
within 5 days of submission of the tissue or per protocol instructions. 
Section A 
Ordering Physician 
Section B 
Site CRA or Research Contact 
Section C 
Pathology Group 
Last Name: 
Last Name: 
Last Name (optional): 
First Name: 
First Name: 
First Name (optional): 
NPI: 
 
 
Phone: 
Phone: 
Phone: 
Fax: 
Fax: 
Fax (optional): 
Institution: 
Institution: 
Institution: 
Department: 
Department: 
Department: 
Street Address Line 1: 
Street Address Line 1: 
Street Address Line 1: 
Street Address Line 2: 
Street Address Line 2: 
Street Address Line 2: 
City: 
City: 
City: 
 State: 
Zip Code: 
 State: 
Zip Code: 
 State: 
Zip Code: 
Physician E-mail (optional): 
Research Contact E-mail (optional): 
Pathologist E-mail (optional): 
Office Contact Name (optional): 
Office Contact Name (optional): 
Office Contact Name (optional): 
Office Contact E-mail (optional): 
Office Contact E-mail (optional): 
Office Contact E-mail (optional): 

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A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. 
Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer 
following Neoadjuvant Chemotherapy 
 
Appendix V 
 
Patient Pill Calendar 
NOTE: 
This pill calendar is for patients randomized to Arm C ONLY. 
Pill Calendar Directions 
1. Take your schedule dose of pill 
2. If you forget, the missed pills will not be taken later. 
3. Please bring the empty bottle or any leftover pills and your pill calendar to your next clinic 
visit. 
4. When taking Capecitabine: 
• 
Capecitabine pills are to be swallowed whole with water within 30 minutes after a meal 
• 
Do not crush or cut capecitabine pills 
 
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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of pills you take each day. 
You should take your schedule dose of each pill. Note the times and the number of pills that 
you take each day. If you develop any side effects, please record them and anything you would 
like to tell the doctor in the space provided. 
Cycle: ______ 
Prescribed dosage: _____ 
Bring any unused pills and your completed pill calendar to your doctor’s visits. 
CYCLE
DAY 
Date 
Times Pills 
Taken 
Number of Pills 
Taken 
Use the space below to make 
notes about things you would 
like to tell the doctor 
(including unusual symptoms 
you experience, other 
medicine you have taken and 
anything else you think would 
be of interest.) 
(Month / Day / 
Year) 
AM 
PM 
AM 
PM 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
Patient Signature: __________________________________ Date: _______________ 
Number of pills returned: _____ 
Administrator Signature: __________________________________ Date: _______________ 

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A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. 
Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer 
following Neoadjuvant Chemotherapy 
 
Appendix VI 
 
Ancillary for Tobacco Use Assessment: EAQ16T 
Study Co-Chairs: Elyse Park, Ilana Gareen, Lynne Wagner, Jamie Ostroff, Ben Herman 
Patients registered to selected ECOG-ACRIN trials are eligible to participate in this ancillary 
study, once the appropriate amendment incorporating the study is activated. 
The Ancillary for Tobacco Use Assessment is a project that seeks to address questions about 
patient-reported tobacco use and smoking behaviors that may span several studies and/or 
diseases. The tobacco use ancillary is embedded into parent protocols, with participation in the 
ancillary informed in the parent consent form and participation determined via providing email 
address to the sites. The general objectives of the tobacco use ancillary are not specific to any 
single parent protocol; however, specific objectives may be included in the parent or related 
parent protocols. 
A significant proportion of cancer patients are current smokers at the time of cancer diagnosis,1–
5 and there are known risks associated with continued smoking following cancer diagnosis. 
These include decreased survival time; increased complications from surgery, radiation, and 
chemotherapy; and increased risk of second primary tumors.6–11 As such, the National 
Comprehensive Cancer Network (NCCN), the American Association of Cancer Research 
(AACR) and the American Society of Clinical Oncology (ASCO) have identified persistent 
smoking as a modifiable risk factor and recommend cessation counseling for cancer patients 
who smoke. Although evidence-based guidelines for treating tobacco dependence exist,12 they 
have not yet been well-integrated into cancer care settings. Moreover, knowledge regarding the 
scope and patterns of tobacco use among cancer patients is limited. As a critical step in closing 
this knowledge gap, the NCI-AACR Cancer Patient Tobacco Use Asssessment Task Force 
developed the Cancer Patient Tobacco Use 1–4,13,14 Questionnaire (C-TUQ). Through this 
ancillary, the modified C-TUQ measures will be administered to participants enrolling in selected 
Phase II and Phase III ECOG ACRIN (EA) therapeutic trials. 
The major questions may be summarized: 
1. What is the smoking status of cancer patients enrolled on EA clinical trials? 
2. Do patients quit smoking or try to quit smoking after receiving a cancer diagnosis? 
3. What forms of tobacco use do patients engage in? 
4. What assistance do patients use or receive to try to quit? 
5. How does tobacco use, other forms of tobacco use, and/or environmental tobacco exposure 
affect patient’s treatment toxicity, patient-reported physical and psychological symptoms, 
trial adherence, and therapeutic outcomes? 
When patients consent to participate, they will be asked to provide a contact email address and 
that address along with their registration information will be sent directly from the parent trial’s 
registration system to ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO), and the patient will be automatically registered into EASEE-PRO for 
participation. To activate their account for self-directed web entry of surveys, the system will 
send an activation message to the contact email address that will explain how to activate their 
account for self-directed web entry of surveys. After their account is activated, the patient will be 
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able to complete questionnaires using a secure browser interface from any web enabled 
computer, tablet, or mobile device. 
Measures 
The selected Core and Extension C-TUQ items will be assessed. The 4-item Short Form 
PROMIS® for anxiety and depression, the Lung Cancer Stigma Scale, and six symptom items 
(general pain, fatigue, nausea, cough, insomnia, shortness of breath) from FACIT (Functional 
Assessment of Chronic Illness Therapy)) together with modifications of these same six 
questions to address the degree of bother associated with each symptom will be administered 
as well. Additionally, we will ask participants’ perceptions of how smoking improves or worsens 
each of the six symptom experience. All these items will be compiled into Survey of Tobacco 
Use (STU) (baseline and follow-up). 
Contents and Corresponding Questions in Survey of Tobacco Use (STU) 
Dimension 
Source of Measures 
Baseline STU 
Follow-up STU 
Basic Tobacco Use Information 
C-TUQ 
Q1 – Q5 
Q1 – Q2 
Tobacco Use in Relation to Cancer 
Diagnosis and Treatment 
C-TUQ 
Q6 – Q7 
Q3 
Smoking Cessation, Cessation 
Products, and Assistance Methods 
C-TUQ 
Q8 – Q13 
Q4 – Q9 
Use of Other Products  
C-TUQ 
Q14 
Q10 
Second-Hand Smoke Exposure 
C-TUQ 
Q15 – Q16 
Q11 – Q12 
Psychological Symptoms 
PROMIS  
Lung Cancer Stigma 
Scale 
Q17 – Q18 
Q13 – Q14 
Physical Symptoms 
FACIT 
Q19 
Q15 
Sociodemographics 
 
Q20 – 21 
 
NOTE: 
In order to minimize ambiguity and assure that patients are oriented to answer 
appropriately, the specific phrasing of items may vary depending specific cancer type 
and treatment. 
Tobacco Use. The selected Core and Extension C-TUQ items (from categories of Basic 
Tobacco Use Information, Tobacco Use in Relation to Cancer Diagnosis and Treatment, 
Smoking Cessation/Cessation Products/Assistance Methods, Use of Other Products, and 
Second-Hand Smoke Exposure) will be assessed in the baseline and follow-up Survey of 
Tobacco Use. 
Oncology Provider Assistance. C-TUQ Question 13 assesses “cancer doctors” Advise. We 
will add 4 As to assess participants’ reported 5As (Ask (Q12a), Advise (Q12b), Assess (Q12c), 
Assist (Q12d-Q12f), and Arrange follow-up (Q12g), as in Baseline STU).80 
Psychological Symptom Assessment. Anxiety & Depression: (The Patient Reported 
Outcomes Measurement Information System (PROMIS®)). We will administer the 4-item Short 
Form PROMIS® for anxiety and depression (Q17 in Baseline STU). Stigma: The Lung Cancer 
Stigma scale measures the extent to which shame is internalized (Q18 in Baseline STU).81 
Physical Symptom Assessment Physical Symptom Assessment (Functional Assessment of 
Chronic Illness Therapy (FACIT)). FACIT, a measurement system with a collection of quality-of-
life questionnaires, expands the more familiar FACT (Functional Assessment of Cancer 
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individual questions to assess various symptoms from the patient perspective. We will use 6 
FACIT items, selected based on the therapeutic regimens, expected toxicity, and malignancy 
type of the parent trials. In addition, we have created modifications of these same six questions 
to address the degree of bother associated with each symptom” The symptoms of general pain, 
fatigue, nausea, cough, sleep difficulty, and shortness of breath will be assessed, first using the 
standard and validated FACT item, and then asking the degree of “bother” imposed by each 
symptom, on the same 5-point scale. These clusters of symptoms were specifically chosen 
based on potential interactions between tobacco use and longitudinal symptoms. 
Sociodemographic Variables. Sociodemographic variables, including age, sex, zip code, and 
race/ethnicity are collected for all NCTN trial participants at registration. At baseline, participants 
will provide information on marital status (Q20 in Baseline STU) and education level (Q21 in 
Baseline STU) as part of the tobacco supplemental assessment. 
Cancer Treatment Variables. Clinical variables including date of diagnosis, malignancy type 
(smoking related vs. non-smoking related, cancer stage), and treatment details (i.e. types and 
dates of surgery, chemotherapy, and/or radiation received), along with disease status and 
survival, will be captured in Medidata Rave via the parent protocol and will be available for 
analysis of the ancillary. Provider-assessed adverse events will also be captured via the parent 
protocol in Medidata Rave, using case report forms commonly used across the NCTN and using 
standard data elements. 
Assessments 
All items in Survey of Tobacco Use will be administered using the EASEE-PRO system. The 
advantage of our virtual electronic data capture system is that our proposed assessments will 
not be limited to, or dependent upon, patient trial visits. Confidential and potentially stigmatizing 
information can be provided without requiring direct contact with the care team. 
Timing of Assessments 
Given the critical questions that remain13 about the timing of conducting tobacco use 
assessments, we have carefully chosen to collect tobacco assessment data at trial enrollment, 3 
and 6 month follow-up. For tobacco treatment trials, 6 month follow-up is the recommended 
primary outcome time point. By 6 month follow-up, most cancer treatment-related quitting 
activity62, cancer treatment initiation of therapy, and FDA-approved smoking cessation 
medication regimens will be completed. Adverse events during treatment will have been 
observed. 
Statistical Considerations and Analysis Plans 
The analysis plans described below are planned for a combined analysis of the data from the 8 
selected ECOG-ACRIN trials. Consistency in the effects over the studies would be examined in 
this analysis. 
1. CHANGES IN SMOKING STATUS AND EXPOSURE. At baseline, combustible tobacco use 
(1a) will be characterized by smoking status (never smoker, former smoker, and current 
smoker based on Baseline STU Qs 1 and 5), other forms of tobacco use (1b) will be a 
composite variable determined by non-cigarette items (based on Baseline STU Q7 and 
Q14), and environmental tobacco smoke (ETS) level (1c) will be determined by current 
household and work exposure (Baseline STU Qs 15-16). At follow-up, combustible tobacco 
use (1a) will be examined by smoking status (Follow-up STU Qs 1 and 2), other forms of 
tobacco use (1b) will be determined by Follow-up STU Q10, and ETS level (1c) will be 
determined by 30 day household and work exposure (Follow-up STU Qs 11-12). We will 
examine tobacco use at baseline, 3 and 6 month follow-up, and change in status 
(abstinence in combustible tobacco, abstinence of other forms of tobacco use, and change 

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in exposure to smoke-free home and work) using summary statistics (frequency and 
proportion). We will explore the effects of sociodemographic and cancer treatment factors 
on smoking status using logistic regression (comparing smokers and non-smokers). We will 
also evaluate factors associated with changes in smoking status. 
2. TREATMENT TOXICITY. The selected trials capture information about adverse events 
during treatment using NCI’s Common Terminology Criteria for Adverse Events, Version 4. 
Toxicities are measured at each treatment visit and graded according to severity, with grade 
1 corresponding to mild toxicity and grade 5 signifying a lethal adverse event. We will 
determine each patient’s worst degree toxicity across all event types and treatment visits 
and will compare the distribution of worst degree grades between smokers and non-
smokers and between patients with environmental tobacco exposure and those without 
exposure using exact tests. We will also examine the distribution of worst degree grades 
between users with different form of tobacco use. In addition, we will explore the effects of 
tobacco use on dose modifications (yes vs. no) using logistic regression, with each patient’s 
dose modification status determined across all treatment visits. 
3. SYMPTOM BURDEN. Tobacco variables will be conceptualized as described in the section 
of CHANGES IN SMOKING STATUS AND EXPOSURE. Tobacco use status (as measured 
at baseline, 3 and 6 months follow-up) will be compared to physical and psychological 
symptom burden (as measured at each corresponding time points). At 3 and 6 months 
follow-up, we will also examine the association between tobacco use changes and changes 
in symptom burden. We will explore the effects of sociodemographic and cancer treatment 
factors on symptom burden using repeated measures mixed effects models. As an example 
of statistical power, we consider the PROMIS SF-4 depression measure. We assume that 
1500 patients will be enrolled across the 8 parent studies over 13 months, and that 20% are 
smokers. We assume that 85% of patients will have assessments at 6 months. Given 
groups of these sizes (26 quitters and 230 still-smokers) and standard deviation of 4.08 for 
the PROMIS SF-4 depression scale, there will be 83% power to detect a difference in 
change scores of 2.5 between groups using a two-sample t-test with Type I error of 5%. The 
minimally important difference for this instrument is 2.2.79 
4. CESSATION PATTERNS AND TREATMENT. At baseline we will explore pre-treatment 
combustible tobacco use patterns (STU Q6a and Q6b), quitting behaviors (STU Q13), 
behavioral program utilization (STU Q11) and oncology provider support (5As, STU Q12), 
and smoking cessation medication use (STU Q10). At follow-up we will explore post-
treatment combustible tobacco use patterns (STU Q3a-Q3e), quitting behaviors (STU Q9), 
behavioral program utilization (STU, Q7) and oncology provider support (5As, STU Q8), and 
smoking cessation medication use (STU Q6). We will explore the effects of 
sociodemographic and cancer treatment factors on these variables. We will examine 
associations of quitting behaviors and behavioral and medication utilization with tobacco use 
status (as outlined in the section of CHANGES IN SMOKING STATUS AND EXPOSURE) at 
baseline and on respective 3 and 6 month tobacco outcomes. These analyses will be 
descriptive in nature. Summary statistics (frequency, proportions, and 95% confidence 
intervals) will be used. 
5. TRIAL OUTCOMES. We will compare treatment duration between smokers and non-
smokers and between patients with environmental tobacco exposure and those without 
exposure. Cumulative incidence/competing risk methods will be used to estimate time to 
treatment discontinuation for adverse events, disease progression, completion per protocol, 
or other causes. Gray’s test will be used to test for differences in the cumulative incidence 
distributions.78 Differences in the distribution of reasons for discontinuation of treatment will 
be examined using exact tests. Relative dose intensity is defined as the ratio of actually 
delivered dose intensity to the planned dose intensity. The effects of tobacco use and 

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exposure on relative dose intensity (≥ 90% vs. < 90%) will be explored using logistic 
regression. Differences in the primary endpoint and important secondary endpoints will be 
examined using log rank test and exact test (as appropriate). 
Data collected in the tobacco use project will support a range of analyses. Precise estimates of 
power will depend on the prevalence of smoking at baseline among study participants, the 
proportion whose smoking status changes, and the duration and adequacy of follow-up. 
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37. Albers AB,  Biener L, Siegel M, Cheng OM, Rigotti N. Household smoking  bans and 
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38. Thorndike AN, Regan S, Rigotti NA. The treatment of smoking by US physicians during 
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cancer survivors. Semin Oneal Nurs. 2008;24(3):180-192.  
doi:10.1016/j.soncn.2008.05.006. 
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51. Cancer Facts and Statistics I American Cancer Society. 
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52. de Dios MA, Anderson BJ, Stanton C, Audet DA, Stein M. Project Impact: a 
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53. Park ER, Japuntich SJ, Traeger L, Cannon S, Pajolek H. Disparities between blacks and 
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54. Warren GW, Marshall JR, Cummings KM, Toll B, Gritz ER, Hutson A, Dibaj S, Herbst R, 
Dresler C, IASLC Tobacco  Control and Smoking  Cessation  Committee.  Practice patterns 
and perceptions   of thoracic oncology providers on tobacco use and cessation in cancer 
patients. J Thorac Oneal Off Pub/ Int Assoc  Study  Lung  Cancer.  2013;8(5):543-548.  
doi:10.1097/JTO.Ob013e318288dc96. 
55. Warren GW, Marshall JR, Cummings KM, Toll BA, Gritz ER, Hutson A, Dibaj S, Herbst R, 
Mulshine JL, Hanna N, Dresler CA. Addressing tobacco use in patients with cancer: a 
survey of American Society of Clinical Oncology members. J Oneal Pract Am Soc Clin 
Oneal. 2013;9(5):258-262. doi:10.1200/JOP.2013.001025. 

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Strategies to Improve Smoking Cessation Support for Cancer Patients. J Thorac Oneal Off 
Pub/ Int Assoc Study Lung Cancer. 2015;10(11 ):1532-1537. 
doi:10.1097/JT0.0000000000000659. 
58. Bjurlin MA, Goble SM, Hollowell CMP. Smoking cessation assistance for patients with 
bladder cancer: a national survey of American urologists. J Ural. 2010; 184(5):1901-1906. 
doi: 10.1016/j.juro.2010.06.140. 
59. Weaver KE, Danhauer SC, Tooze JA, Blackstock AW, Spangler J, Thomas L, Sutfin EL. 
Smoking cessation  counseling  beliefs and behaviors of outpatient  oncology  providers.  
The Oncologist.  2012; 17(3):455-462. doi: 10.1634/theoncologist.2011-0350. 
60. Simmons VN, Litvin EB, Unrod M, Brandon TH. Oncology healthcare providers' 
implementation of  the 5A's model of brief intervention for smoking cessation: patients' 
perceptions. Patient Educ Couns. 2012;86(3):414-419. doi: 10.1016/j.pec.2011.06.016. 
61. Peters EN, Torres E, Toll BA, Cummings KM, Gritz ER, Hyland A, Herbst RS, Marshall JR, 
Warren GW. Tobacco assessment in actively accruing National Cancer Institute Cooperative 
Group Program Clinical Trials. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(23):2869-
2875. doi: 10.1200/JC0.2011.40.8815. 
62. Park ER, Japuntich S, Temel J, Lanuti M, Pandiscio J, Hilgenberg J, Davies D, Dresler C, 
Rigotti NA. A smoking cessation intervention for thoracic surgery and oncology clinics: a 
pilot trial. J Thorac Oncol Off Pub/ Int Assoc Study Lung Cancer. 2011;6(6):1059-1065. 
doi:10.1097/JTO.Ob013e318215a4dc. 
63. Haas JS, Linder JA, Park ER, Gonzalez  I, Rigotti NA, Klinger EV, Kontos EZ, Zaslavsky  
AM,  Brawarsky P, Marinacci LX, St Hubert S, Fleegler EW, Williams DR. Proactive tobacco 
cessation outreach to smokers of low socioeconomic status: a randomized clinical trial. 
JAMA Intern Med. 2015; 175(2):218-226. doi:  10.1001/jamainternmed.2014.6674 
64. Park ER, Puleo E, Butterfield RM, Zorn M, Mertens AC, Gritz ER, Li FP, Emmons KM. A 
process evaluation of a telephone-based peer-delivered smoking cessation intervention for 
adult survivors of childhood cancer: the partnership for health study. Prev Med. 
2006;42(6):435-442.doi: 10.1016/j.ypmed.2006.03.004. 
65. Emmons KM, Puleo E, Park E, Gritz ER, Butterfield RM, Weeks JC, Mertens A, Li FP. Peer-
delivered smoking counseling for childhood cancer survivors increases rate of cessation: the 
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among young adults with breast or colorectal cancer. Cancer. 2014; 120(15):2255-2263. 
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72. Mouli S, Hickey R, Thornburg B, Sato KT, Desai K, Gabr A, Kallini JR, Niemeri H, Kircher S, 
Mulcahy MF, Benson Iii AB, Gupta R, Salem R, Lewandowski RJ. Single- versus Triple-Drug 
Chemoembolization for Hepatocellular Carcinoma: Comparing Outcomes by Toxicity, 
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73. Hickey R, Lewandowski RJ, Prudhomme T, Ehrenwald E, Baigorri B, Critchfield J, Kallini J, 
Gabr A, Gorodetski B, Geschwind J-F, Abbott A, Shridhar R, White SB, Rilling WS, Boyer B, 
Kauffman S, Kwan S, Padia SA, Gates VL, Mulcahy M, Kircher S, Nimeiri H, Benson AB, 
Salem R. 90Y Radioembolization of Colorectal Hepatic Metastases Using Glass 
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Gates VL, Atassi B, Vouche M, Atassi R, Desai K, Hohlastos E, Sato K, Habib A, Kircher S, 
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75. Hickey R, Mulcahy MF, Lewandowski RJ, Gates VL, Vouche M, Habib A, Kircher S, 
Newman S, Nimeiri H, Benson AB, Salem R. Chemoradiation of hepatic malignancies: 
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Primary Care Provider-Delivered Smoking Cessation Interventions and Smoking Cessation 

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A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. 
Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer 
following Neoadjuvant Chemotherapy 
Appendix VII 
 
EA1131 Collection and Shipping Kit Order Instructions 
Specimen Collection/Shipping Kits are being provided by CENETRON CENTRAL 
LABORATORIES and are to be ordered ONLINE. 
Starter kits are not available. Kit requests are to be made AFTER patient randomization 
(preferred) but can be ordered after patient consent. 
Questions regarding kits can be directed to projectmanagement@cenetron.com or call 
the Cenetron Clinical Trials Group at (512) 439-2000.  
Ordering Process: 
• 
Following randomization of the patient to the trial, go to the website 
www.cenetron.com and click on the ‘Order Kits’ button at the top right. It is 
recommended that kits be ordered same day as patient randomization. 
• 
The order form is not study specific and can be used for any study. Complete the 
online form as follows: 
o Sponsor (REQUIRED): ECOG-ACRIN 
o Contact Name (REQUIRED): Name of the institution kit contact.  
o Protocol Number (REQUIRED): EA1131 
o Phone Number (REQUIRED): Phone number of the kit contact. Please ensure 
that this is a number that can be reached from an external caller. 
o Site Number (REQUIRED): Institution NCI Site ID 
o FAX Number: Fax number of the kit contact 
o Investigator: Last name of the kit contact is adequate 
o Email (REQUIRED): Email of the institution kit contact. Must be entered twice to 
confirm. 
o Date Supplies Needed (REQUIRED): Add three (3) business days or more to 
order date. (Reminder that weekends and holidays must also be considered in 
this timeline) 
o KIT NAME (REQUIRED): EA1131 Collection Kit 
o Quantity: 1 
o 
Comments: Provide EA1131 Patient Case ID# and full shipping address 
• 
‘Patient Case ID =’ ##### 
• 
‘Ship Kit to’ name of the individual to whom the kit is being shipped. (May be different 
than the kit contact provided above) 
• 
Full street address, town, state and zip code 
o Answer the security question 
Please complete this form correctly, including the valid ECOG-ACRIN patient case 
number and complete shipping address. If information is missing the kit processing will 
be delayed. 
Rev. Add6 
Rev. Add8