Conditions: Triple-negative Breast Cancer
Keywords: TNBC, breast cancer, neoadjuvant, carboplatin, docetaxel, paclitaxel, doxorubicin, cyclophosphamide
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
Evaluate if the two carboplatin containing chemotherapy regimens will reduce the growth of breast cancer cells in women with Stage I, II, or III triple negative breast cancer.

Detailed description:
Sporadic and germline BRCA mutation associated triple-negative breast cancer share several pathological and molecular similarities which have led to the exploration of DNA damaging agents like platinum compounds in patients with triple-negative breast cancer. Recent studies demonstrate that addition of neoadjuvant carboplatin to doxorubicin/cyclophosphamide/taxane-based chemotherapy improves pathological complete response in patients with stage I-III triple-negative breast cancer but also increase toxicity.

A recent study reported encouraging pathological complete response rates with a non-anthracycline carboplatin plus docetaxel neoadjuvant chemotherapy regimen in a cohort of 49 triple negative breast cancer patients. This chemotherapy regimen of carboplatin plus docetaxel yielded an overall pathological complete response rate of 65% in unselected triple-negative breast cancer with pathological complete response rates of 61% in sporadic and 77% in germline BRCA-associated triple-negative breast cancer. The chemotherapy regimen of carboplatin/docetaxel is well tolerated and should be studied further and compared with regimens that add carboplatin to the standard anthracycline/taxane containing regimens.

This is the basis for the proposed randomized neoadjuvant phase II study to further estimate and compare pathological complete response rates of carboplatin plus docetaxel x 6 cycles to carboplatin plus paclitaxel x 4 cycles followed by doxorubicin plus cyclophosphamide x 4 cycles in stage I-III triple negative-breast cancer.

Arms:
arm 1: Paclitaxel (80mg/m2) given IV every week x12 weeks and Carboplatin (AUC 6) given IV every 21 days x 4 cycles, followed by Doxorubicin (60mg/m2) given IV and Cyclophosphamide (600mg/m2) given IV every 14 days X 4 cycles arm 2: Carboplatin (AUC 6) given IV and Docetaxel (75mg/m2) given IV every 21 days x 6 cycles

Interventions: intervention 1: Paclitaxel intervention 2: Carboplatin intervention 3: Doxorubicin intervention 4: Cyclophosphamide intervention 5: Docetaxel
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol document:
Prot_SAP_000.pdf: 
Investigator Initiated Trial 
2015-IIT- Neoadjuvant-BRST-TNBC (NeoSTOP) 
Randomized open label Phase II trial of neoadjuvant Carboplatin plus 
Docetaxel or Carboplatin plus Paclitaxel followed by Doxorubicin plus 
Cyclophosphamide in stage I-III triple-negative breast cancer (NeoSTOP: 
Neoadjuvant Study of two Platinum regimens in Triple negative breast 
cancer) 
PRINCIPAL INVESTIGATOR 
Priyanka Sharma, MD 
Associate Professor of Medicine 
University of Kansas Medical Center 
2330 Shawnee Mission Parkway, Suite 210, MS 5003 
Westwood, KS 66203 
Protocol Number:  2015-IIT-Neoadjuvant-BRST-TNBC 
Study Drugs:   
•
Doxorubicin plus Cyclophosphamide (AC)
•
Docetaxel
•
Paclitaxel
•
Carboplatin
•
Pegfilgrastim
IND Number: 
EXEMPT 
IND Holder Name: 
EXEMPT 
Initial Version:  
03-10-2015
Post-Initial Approval 
Modifications: 
Version 2 dated 01-07-2016 
Version 3 dated 03-11-2016 
Version 4 dated 05-17-2016 
NCT02413320


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
Page 2 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
LIST OF KEY PERSONNEL 
PRINCIPAL INVESTIGATOR 
Priyanka Sharma, M.D. 
SUB-INVESTIGATOR(S) 
BIOSTATISTICIAN 
. 
COLLABORATORS 
Andy Godwin, Ph.D. 
Roy Jensen, M.D. 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD  
Page 3 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
PROTOCOL AGREEMENT 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing complete and timely information, as outlined in the protocol.  It is understood that 
all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of 
the study staff and myself, I agree to maintain the procedures required to carry out the 
study in accordance with accepted GCP principles and to abide by the terms of this 
protocol. 
Protocol Number:  2015-IIT-Neoadjuvant-BRST-TNBC 
Protocol Title:  Randomized open label Phase II trial of neoadjuvant Carboplatin plus 
Docetaxel or Carboplatin plus Paclitaxel followed by Doxorubicin plus Cyclophosphamide 
in stage I-III triple-negative breast cancer (NeoSTOP: Neoadjuvant Study of two Platinum 
regimens in Triple negative breast cancer) 
Protocol Version and Date:  Version 4 dated 05-17-2016 
Investigator Signature: _______________________________ 
Date 
Print Name and Title:  
________________________ 
Site Number:  N/A 
Site Name:  The University of Kansas Cancer Center / University of Kansas Medical Center 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC Project  STUDY00002467 
Page 4 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................................................ 6 
STUDY SCHEMA .............................................................................................................................................................. 8 
STUDY SUMMARY .......................................................................................................................................................... 8 
1.0 
BACKGROUND AND RATIONALE ............................................................................................................. 10 
1.1 
DISEASE BACKGROUND .................................................................................................................................................. 10 
1.2 
STUDY AGENT(S) BACKGROUND AND ASSOCIATED KNOWN TOXICITIES ............................................................. 13 
1.3 
RATIONALE ...................................................................................................................................................................... 15 
1.4 
CORRELATIVE STUDIES .................................................................................................................................................. 16 
2.0 
STUDY OBJECTIVES ..................................................................................................................................... 17 
2.1 
PRIMARY OBJECTIVES .................................................................................................................................................... 17 
2.2 
SECONDARY OBJECTIVES ............................................................................................................................................... 17 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................................................................... 17 
2.4 
ENDPOINTS ...................................................................................................................................................................... 17 
3.0 
SUBJECT ELIGIBILITY ................................................................................................................................. 18 
3.1 
INCLUSION CRITERIA ...................................................................................................................................................... 18 
3.2 
EXCLUSION CRITERIA ..................................................................................................................................................... 19 
4.0 
TREATMENT PLAN ....................................................................................................................................... 20 
4.1 
PRE-CHEMOTHERAPY SURGICAL EVALUATION ........................................................................................................... 20 
4.2 
TREATMENT DOSAGE AND ADMINISTRATION ........................................................................................................... 20 
4.3 
SURGERY ........................................................................................................................................................................... 21 
4.4 
ADJUVANT THERAPY: ..................................................................................................................................................... 21 
4.5 
TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ...................................................................................... 22 
4.6 
CARBOPLATIN + PACLITAXEL ....................................................................................................................................... 22 
4.7 
DOSE DENSE DOXORUBICIN AND CYCLOPHOSPHAMIDE (DDAC) ........................................................................... 25 
4.8 
DOCETAXEL AND CARBOPLATIN ................................................................................................................................ 27 
4.9 
CONCOMITANT MEDICATIONS/TREATMENTS ........................................................................................................... 30 
4.10 
DURATION OF THERAPY ................................................................................................................................................ 31 
4.11 
DURATION OF FOLLOW UP ............................................................................................................................................ 31 
4.12 
REMOVAL OF SUBJECTS FROM PROTOCOL THERAPY ................................................................................................ 31 
4.13 
SUBJECT REPLACEMENT ................................................................................................................................................ 31 
5.0 
STUDY PROCEDURES .................................................................................................................................. 31 
5.1 
SCREENING/BASELINE PROCEDURES.......................................................................................................................... 31 
5.2 
PROCEDURES DURING TREATMENT ............................................................................................................................. 33 
5.3 
FOLLOW-UP PROCEDURES ............................................................................................................................................ 34 
5.4 
SCHEDULE OF EVENTS ................................................................................................................................................... 35 
5.5 
REMOVAL OF SUBJECTS FROM STUDY.......................................................................................................................... 37 
6.0 
ADVERSE EVENTS ......................................................................................................................................... 37 
6.1 
DEFINITIONS .................................................................................................................................................................... 37 
6.2 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS - ............................................................................................. 40 
7.0 
DRUG INFORMATION .................................................................................................................................. 42 
7.1 
CHEMOTHERAPY AGENTS .............................................................................................................................................. 42 
8.0 
CORRELATIVES/SPECIAL STUDIES ........................................................................................................ 46 
8.1 
SPECIMEN BANKING ....................................................................................................................................................... 46 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
Page 5 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
9.0 
MEASUREMENT OF EFFECT ...................................................................................................................... 47 
9.1 
ANTITUMOR EFFECT ...................................................................................................................................................... 47 
9.2 
SAFETY/TOLERABILITY ................................................................................................................................................. 48 
9.3 
OVERSIGHT AND MONITORING PLAN .......................................................................................................................... 48 
9.4 
SAFETY REVIEW AND OVERSIGHT REQUIREMENTS .................................................................................................. 48 
10.0 
REGULATORY CONSIDERATIONS ........................................................................................................... 49 
10.1 
PROTOCOL REVIEW AND AMENDMENTS..................................................................................................................... 49 
10.2 
INFORMED CONSENT ...................................................................................................................................................... 49 
10.3 
ETHICS AND GOOD CLINICAL PRACTICE (GCP) ........................................................................................................ 49 
11.0 
REGISTRATION PROCEDURES ................................................................................................................. 50 
11.1 
GENERAL GUIDELINES FOR KUCC AND OTHER PARTICIPATING ORGANIZATION ............................................... 50 
11.2 
REGISTRATION PROCESS FOR KUCC AND OTHER PARTICIPATING CENTERS ...................................................... 50 
12.0 
STUDY MANAGEMENT ................................................................................................................................ 51 
12.1 
INVESTIGATOR FILES AND RETENTION OF DOCUMENTS.......................................................................................... 51 
12.2 
CASE REPORT FORMS ..................................................................................................................................................... 51 
12.3 
STUDY MONITORING ...................................................................................................................................................... 51 
13.0 
STATISTICAL CONSIDERATIONS............................................................................................................. 52 
13.1 
STUDY DESIGN/STUDY ENDPOINTS ............................................................................................................................ 52 
13.2 
SAMPLE SIZE AND ACCRUAL ......................................................................................................................................... 52 
13.3 
DATA ANALYSES PLANS ................................................................................................................................................. 52 
14.0 
REFERENCES .................................................................................................................................................. 54 
15.0 
APPENDICES ................................................................................................................................................... 60 
APPENDIX A. SURGICAL EVALUATION FORM ............................................................................................................................... 60 
APPENDIX B. PERFORMANCE STATUS .......................................................................................................................................... 61 
APPENDIX C. PATIENT TRAVEL TIME COST ANALYSIS SURVEY ............................................................................................... 62 
 APPENDIX D. SUGGESTED CHEMOTHERAPY PRE-MEDICATION AND ANTIEMETIC’S………………..………………………...63 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD  
Page 6 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
LIST OF ABBREVIATIONS 
A 
Anthracycline 
AC 
Doxorubicin plus Cyclophosphamide regimen 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST 
 Aspartate Aminotransferase 
AUC 
 Area Under the Curve 
BA/BE 
 Bioavailability/Bioequivalence 
BCS 
Breast Conservation Surgery 
BID 
Twice daily 
BUN 
 Blood Urea Nitrogen 
C 
Cyclophosphamide 
CAP 
College of American Pathologists 
Cb 
 Carboplatin 
Cb+P 
 Carboplatin plus Paclitaxel 
CBC 
 Complete Blood Count 
CdD 
Carboplatin plus Docetaxel regimen 
CHF 
Congestive heart failure 
CMP 
Comprehensive Metabolic Panel 
 CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CVAP 
Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone regimen 
D5W 
5% Dextrose in Water 
DCIS 
Ductal carcinoma in situ 
ddAC 
Dose Dense Doxorubicin + Cyclophosphamide 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiography 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
DSMC 
Data and Safety Monitoring Committee 
ER 
Estrogen Receptor 
 FA 
Fanconi Anemia 
FNA 
Fine Needle Aspiration 
GFR 
Glomerular Filtration Rate 
HER2 
ERBB2 
HR 
Homologous Recombination 
HRPP 
Human Research Protections Program 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IULN 
Institutional Upper Limit of Normal 
IV 
 Intravenous 
LD 
Longest Diameter 
LFT 
Liver Function Tests 
LOH 
Loss of Heterozygosity 
 LVEF 
Left Ventricular Ejection Fraction 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multi Gated Acquisition Scan 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC Project  STUDY00002467 
Page 7 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
N+ 
Lymph node positive 
NCI 
National Cancer Institute 
PAC 
Premature atrial contractions 
pCR 
Pathological Complete Response 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PM 
Promoter Methylation 
po 
Per os/by mouth/orally 
PgR 
Progesterone Receptor 
PR 
Partial Response 
PS 
Performance Status 
PVC 
Premature ventricular contractions 
 q3w 
Every 3 week administration 
qw 
Weekly administration 
 RBC 
Red Blood Cells 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
T 
Tumor Size 
Ta 
Taxanes 
TNBC 
Triple-Negative Breast Cancer 
TPN 
Total parenteral nutrition 
ULN 
 Upper Limit of Normal 
US 
Ultrasound 
USP 
United States Pharmacopeia 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 8 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
STUDY SCHEMA 
STUDY SUMMARY 
Title 
Randomized open label Phase II trial of neoadjuvant 
Carboplatin plus Docetaxel or Carboplatin plus Paclitaxel 
followed by AC in stage I-III triple-negative breast cancer 
Short Title 
Neoadjuvant Carboplatin and Docetaxel in TNBC 
Phase 
Phase II 
Methodology 
Randomized 
Study Duration 
24 months 
Study Center(s) 
Multi-center 
Objectives 
Primary Objective: To evaluate the pathological complete 
response rates with two neoadjuvant chemotherapy regimens 
(CbDX6 and Cb+PX4 → ACX4) in patients with stage I-III 
TNBC.  
Hypothesis:  CbD and Cb+P→AC will yield comparable pCR 
rates in patient with stage I-III TNBC 
Number of Subjects 
100 patients 
Diagnosis and Main 
Inclusion Criteria 
Newly diagnosed stage I (T>1 cm), II or III TNBC who have 
not undergone definitive breast surgery and have not received 
any systemic chemotherapy 
Study Product(s), 
Dose, Route, Regimen 
Regimen A: Paclitaxel (80mg/m2) every week x12 weeks and 
Carboplatin (AUC 6, IV) every 21 days x 4 cycles, followed by 
Doxorubicin (60mg/m2, IV) and Cyclophosphamide 
(600mg/m2, IV) every 14 days X 4 cycles 
Pegfilgrastim 6mg SC Day2 during AC 
Regimen B: Carboplatin (AUC 6, IV) and Docetaxel (75mg/m2, 
IV) every 21 days x 6 cycles
Pegfilgrastim 6mg SC Day2
Duration of 
Administration 
18 to 20 weeks 
Reference Therapy 
Paclitaxel (80 mg/m2, IV) weekly x 12 weeks + Carboplatin 
(AUC 6, IV) every 3 weeks x 4 cycles + followed by 
Doxorubicin (60mg/m2, IV) and Cyclophosphamide 
(600mg/m2, IV) every 14 days x 4 cycles 
Interim Monitoring 
None 
Statistical Methodology 
Patients will be randomized 1:1 to either neoadjuvant 
Paclitaxel + Carboplatin → AC or Carboplatin plus Docetaxel. 
Pre-Surgery 
Treatment  
weeks 
Surgery  
Patients with 
stage I-III TNBC; 
T>1 cm or N+ 
N=100  
Carboplatin (AUC 6) +  
Docetaxel (75 mg/m2)  
every 21 days x 6 
Carboplatin (AUC 6) every 3 weeks x 4 
+  Paclitaxel (80mg/m2) weekly x 12 
AC every 14 days x 4  
Pathological  
response  
R 
•Breast Imaging after 4 cycles   
B 
A 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD  
Page 9 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
The primary objective will be to estimate the pCR rates in both 
arms. The estimated pCR rates in both the treatment arms is 
50% with upper bound constraints for the standard errors at 
7.5% and the upper bound constraint for the standard error of 
the difference between pCR rates of the two arms at 12%.  
The sample size required to satisfy these constraints is 45 
patients per treatment arm (Mayo et. al. 2010).  To ensure 
achieving 45 evaluable patients in each treatment arm, the 
overall maximum sample size will be inflated to 100 patients 
to account for patient drop outs. The pCR rates and MRD 
rates for each treatment arm will be estimated and 95% exact 
binomial confidence bounds will be calculated.   


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC Project  STUDY00002467 
Page 10 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
1.0 BACKGROUND AND RATIONALE 
1.1 
Disease Background 
1.1.1 Triple Negative Breast Cancer 
Breast cancer is the most commonly diagnosed malignancy and second 
leading cause of cancer mortality in American women. The lifetime risk of 
developing breast cancer is 12.2%, and the lifetime risk of breast cancer 
death is 3.3% (Harris J 1997). Triple negative breast cancer (TNBC) is 
defined by the lack of expression of estrogen receptor (ER) and progesterone 
receptor (PgR), and absence of ERBB2 (HER2) over expression and/or gene 
amplification. TNBC accounts for 15% of all breast cancer and is associated 
with poor long-term outcomes compared to other breast cancer subtypes 
(Osborne, Kannan et al. 2006, Dent, Trudeau et al. 2007, Liedtke, Mazouni 
et al. 2008). Systemic neoadjuvant chemotherapy is recommended for all 
TNBC patients with stage I (T>1cm)-III disease (NCCN 2014). Due to the lack 
of specific therapeutic targets, chemotherapy remains the mainstay of 
systemic treatment in the adjuvant setting. However, despite receiving 
standard 
anthracycline-based 
adjuvant 
chemotherapy, 
a 
significant 
proportion (approximately 30-40%) of patients with early stage TNBC develop 
metastatic disease and succumb to the cancer (Nielsen, Hsu et al. 2004, 
Haffty, Yang et al. 2006, Tan, Marchió et al. 2008). To improve outcomes for 
this subtype, we not only need novel targeted agents, but also need to identify 
predictors of response/resistance to standard chemotherapy.  
1.1.2 DNA damaging therapy in triple negative breast cancer 
Sporadic and germline BRCA mutation associated triple-negative breast 
cancer (TNBC) share several pathological and molecular similarities. These 
similarities have led to the exploration of DNA damaging agents like platinum 
compounds in the general population of patients with TNBC. Growing 
evidence suggests that platinum compounds may be active in a significantly 
larger number of TNBC patients beyond germline BRCA mutation carriers 
(Isakoff 
SJ 
2012, 
Telli 
2013). 
Currently, 
anthracyclines 
(A), 
cyclophosphamide (C) and taxanes (Ta) form the backbone of systemic 
chemotherapy for stage I-III TNBC (www.nccn.org). Recent studies 
demonstrate that addition of neoadjuvant carboplatin (Cb) to A/C/Ta-based 
chemotherapy improves pathological complete response (pCR) in patients 
with stage I-III TNBC (pCR improvement form 41% to 54% with addition of 
Cb) (Rugo, Olopade et al. 2013, Sikov, Berry et al. 2014, von Minckwitz, 
Schneeweiss et al. 2014). However, this improvement in pCR rate comes at 
the cost of increase in toxicity (dose reductions/omissions needed in 40-50% 
of patients and also increases the financial cost of chemotherapy (Sikov, 
Berry et al. 2014, von Minckwitz, Schneeweiss et al. 2014).  Furthermore, 
anthracyclines and cyclophosphamide although very active for treatment of 
breast cancer, have well known small but serious long term risks (secondary 
leukemia and myelodysplastic syndrome, cardiomyopathy, premature 
menopause) and development of effective chemotherapy regimens that are 
devoid of long term side effects is desirable.  
Furthermore, although anthracycline agents induce double-strand breaks, 
repair of these lesions appears to require non-homologous end joining, an 
error-prone double strand break repair pathway that does not require BRCA1, 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC Project  STUDY00002467 
Page 11 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
and preclinical data suggests that anthracyclines do not exhibit selective 
toxicity in BRCA1-deficient cells (Tassone, Tagliaferri et al. 2003, Rottenberg, 
Nygren et al. 2007, Schonn, Hennesen et al. 2011). Conversely, repair of 
platinum-induced 
interstrand 
crosslinks 
invokes 
BRCA1-mediated 
homologous recombination, and there is abundant clinical and in vitro 
evidence that BRCA1-deficient cells are hypersensitive to platinum agents 
(Husain, He et al. 1998, Tassone, Tagliaferri et al. 2003, Rottenberg, Nygren 
et al. 2007, Bolton, Chenevix-Trench et al. 2012). 
1.1.3 Neoadjuvant Carboplatin plus Docetaxel Pilot data 
Taxanes are an integral part of chemotherapy regimens for breast cancer 
treatment and appear to contribute particularly among patients with early 
stage TNBC (Hayes, Thor et al. 2007, Jacquin, Jones et al. 2012). Several in 
vitro studies have demonstrated synergy between platinum compounds and 
taxanes in TNBC cell lines (Corkery, Crown et al. 2009). Efficacy of 
anthracycline-devoid 
neoadjuvant 
platinum/taxane 
chemotherapy 
combination in sporadic and BRCA-associated TNBC has not been well 
studied. We recently reported encouraging pCR rates with a non-
anthracycline carboplatin plus docetaxel (CbD) neoadjuvant chemotherapy 
regimen in an observational cohort of 49 TNBC patients (Sharma P 2014). 
This chemotherapy regimen of CbD yielded an overall pCR rate of 65% in 
unselected TNBC with pCR rates of 61% in sporadic and 77% in germline 
BRCA-associated TNBC (Table 1).  
Table 1. Carboplatin/Docetaxel pathological response 
All patients (n=49) 
BRCA1/2 Wild type 
(n=36) 
BRCA mutation 
carriers (n=13) 
Pathological Complete 
Response; n (%) 
32 (65%) 
22 (61%) 
10 (77%) 
p=0.50 
Residual Cancer 
Burden 0/1; n (%) 
38 (78%) 
27 (75%) 
11 (85%) 
p=0.70 
The chemotherapy regimen of carboplatin/docetaxel is well tolerated, and is 
routinely used for HER2 positive and metastatic breast cancer, with well-
known safety profile (Slamon DJ 2001, NCCN 2014).  In our neoadjuvant 
experience, most common Grade 3/4 toxicities with carboplatin/docetaxel 
were neutropenia (4%), anemia (6%), thrombocytopenia (6%), and diarrhea 
(6%). Thus, we have recently demonstrated in an observational cohort that 
the pCR achieved with carboplatin/docetaxel chemotherapy is comparable to 
the pCR noted with addition of carboplatin to AC/paclitaxel chemotherapy and 
this regimen should be studied further in TNBC. More importantly this 
regimen should be compared with regimens that add carboplatin to the 
standard anthracycline/taxane containing regimens.  
1.1.4 Neoadjuvant chemotherapy 
Neoadjuvant (primary) chemotherapy refers to induction chemotherapy given 
before local treatment, such as surgery or radiation (Bear 1998). The biologic 
rationale for the use of neoadjuvant therapy in breast cancer is based on 
several key observations. Animal models have demonstrated that the 
removal of a primary tumor may increase the rate of growth of 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC Project  STUDY00002467 
Page 12 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
micrometastases. Fischer suggested that this accelerated growth which is 
controlled by serum growth factors, could be prevented by systemic 
chemotherapy before tumor resection (Fisher, Gunduz et al. 1983). Goldie 
and Coldman have proposed that the number of tumor cells is proportional to 
the number of chemoresistant clones, and therefore, neoadjuvant 
chemotherapy would be effective in maximizing future drug response (Goldie 
and Coldman 1979). 
Clinically, neoadjuvant chemotherapy has a number of potential advantages. 
Decreasing the size of the primary tumor may effectively downstage a mass 
to make breast preservation more likely, and may improve local control (Bear 
1998). Chemotherapy may also decrease the intensity and morbidity of 
irradiation required to treat the breast or chest wall. Additionally, it allows for 
immediate objective assessment of chemotherapy response which offers 
prognostic information, as well as guides alterations in therapy.  Finally and 
most importantly, neoadjuvant chemotherapy allows for rapid early 
assessment of new treatment approaches and to study the relationship of 
biologic markers and treatment response. 
In the landmark phase III randomized study (National Surgical and Adjuvant 
Breast Project [NSABP] B-18), it was demonstrated that in patients with stage 
I and II disease, neoadjuvant chemotherapy was equivalent to adjuvant 
chemotherapy in terms of disease free survival, distant disease free survival 
and overall survival, however, a higher percentage of breast conservation 
surgeries (67% vs. 59%) was possible with neoadjuvant chemotherapy 
(Fisher and Mamounas 1995).  For breast cancer, neoadjuvant 
chemotherapy was initially used in patients only with locally advanced or 
inoperable disease, but now is considered for patients who are candidates 
for adjuvant chemotherapy. 
It has been demonstrated that degree of tumor response and extent of 
residual disease after neoadjuvant chemotherapy are associated with relapse 
and long term survival (Fisher, Bryant et al. 1998, Kuerer, Newman et al. 
1999). Prospective trials have demonstrated that patients who achieve a 
pathologic complete response of the primary tumor with neoadjuvant 
chemotherapy have significantly improved disease free and overall survival 
when compared with patients who do not have a pCR (Fisher, Bryant et al. 
1998, Kuerer, Newman et al. 1999, van der Hage, van de Velde et al. 2001, 
Green and Hortobagyi 2002, Valero V 2002, Wang, Buchholz et al. 2002). 
Due to its value as a surrogate for survival, response to neoadjuvant 
chemotherapy is being used as a primary end point in studies that examine 
the efficacy of new drugs and novel drug combinations (Cortazar P 2012). 
1.1.5 Surgery after neoadjuvant treatment 
Approximately one third of patients thought to be in complete remission on 
clinical grounds after neoadjuvant chemotherapy still have residual disease 
at the time of pathologic examination. Therefore, pathologic examination 
following surgical excision of the suspected area of involvement is the best 
indicator of response (Fisher and Mamounas 1995). Appropriate selection of 
patients for breast conserving surgery (BCS) following neoadjuvant 
chemotherapy is important.  Absolute contraindications for BCS include 
extensive, residual, or multifocal tumor, or positive resection margins, while a 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 13 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
relative contraindication is predicted poor cosmetic outcome (Brenin and 
Morrow 1998). 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
1.2.1 Carboplatin (Paraplatin) 
Please refer to carboplatin package insert for full prescribing information. 
Carboplatin is a platinum analog that covalently binds to the DNA producing 
cross-links which leads to inhibition of DNA synthesis. It is a cell cycle non-
specific chemotherapeutic agent. Single agent carboplatin is active in 
patients with previously untreated metastatic breast cancer, producing 
response rates of 20-35% (Carmo-Pereira J 1990, Kolaric and Vukas 1991, 
Martin, Diaz-Rubio et al. 1992, Baselga, Norton et al. 1993, O'Brien, Talbot 
et al. 1993). Combination regimens of carboplatin with other chemotherapy 
agents (taxanes, gemcitabine) are also active for treatment of advanced 
breast cancer (Nasr, Chahine et al. 2004, Perez 2004, Perez, Suman et al. 
2005). Platinum compounds are considered to be especially active for triple 
negative breast cancer. Recent studies demonstrate that addition of 
neoadjuvant 
carboplatin 
to 
A/C/Ta-based 
chemotherapy 
improves 
pathological complete response in patients with stage I-III TNBC.  
1.2.2 Doxorubicin (Adriamycin) 
Please refer to doxorubicin package insert for full prescribing information. 
Description: Doxorubicin (adriamycin) is a cytotoxic anthracycline antibiotic 
different from daunorubicin by the presence of a hydroxyl group in the C-14 
position. Doxorubicin is produced by fermentation from S. peucetius var. 
caesius. Its mechanism of action is thought to be the binding of nucleic acids, 
preventing DNA and possibly RNA synthesis. 
Drug Interactions: For a comprehensive list of adverse events associated with 
doxorubicin, refer to package insert. 
Toxicity/Side Effects: Studies with doxorubicin have shown that the major 
toxic effects of this drug are alopecia, which is often total but always 
reversible; nausea and vomiting, which develops shortly after drug 
administration, occasionally persisting for 2-3 days; fever on the day of 
administration; and phlebitis at the site of the drug’s injection. Extravasation 
of the drug will lead to soft tissue necrosis. Phlebosclerosis, cellulites, 
vesication and erythematous streaking have also been seen. Mucositis may 
be seen 5-10 days after administration. Ulceration necrosis of the colon, 
particularly the cecum, with bleeding and severe infection has been reported 
with concomitant administration of cytarabine. Anorexia and diarrhea have 
also been observed. Hyperpigmentation of nail beds and dermal creases, 
onycholysis and recall of skin reaction from prior radiotherapy may occur. 
Cardiac toxicity manifested as acute left ventricular failure, congestive heart 
failure, arrhythmia or severe cardiomyopathy has been reported, but appears 
to occur predominantly in patients who receive total doses in excess of 550 
mg/m2. Myelosuppression, predominantly neutropenia, is common with nadir 
occurring approximately two weeks after a single injection; lesser degrees of 
anemia and thrombocytopenia have been reported. Renal excretion of 
doxorubicin is minimal, but enough to color the urine red. Other side effects 
include fever, chills, facial flushing, itching, anaphylaxis, conjunctivitis and 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC Project  STUDY00002467 
Page 14 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
lacrimation. The occurrence of acute leukemia has been reported rarely in 
patients treated with anthracycline/alkylator combination chemotherapy. 
1.2.3 Cyclophosphamide (Cytoxan) 
Please refer to cyclophosphamide package insert for full prescribing 
information. 
Description: Cyclophosphamide is biotransformed principally in the liver to 
active alkylating metabolites which cross-link to tumor cell DNA. 
Drug Interactions: For a comprehensive list of adverse events associated with 
cyclophosphamide, refer to package insert. 
Toxicity/Side Effects: Toxicity from cyclophosphamide includes bone marrow 
suppression which usually occurs 10-12 days after administration, nausea, 
vomiting, anorexia, abdominal discomfort, diarrhea, stomatitis, hemorrhagic 
colitis, jaundice, reversible alopecia, hemorrhagic cystitis which can 
frequently be prevented with increased hydration, hematuria, ureteritis, 
tubular necrosis, fibrosis of the bladder, cardiac toxicity which may potentiate 
doxorubicin-induced cardiotoxicity, rare anaphylactic reaction, skin rash, 
hyperpigmentation of the skin and nails, interstitial pulmonary fibrosis, and 
cross 
sensitivity 
with 
other 
alkylating 
agents. 
Treatment 
with 
cyclophosphamide may cause significant suppression of the immune system. 
Secondary malignancies, most frequently of the urinary bladder and 
hematologic systems, have been reported when cyclophosphamide is used 
alone or with other anti-neoplastic drugs. It may occur several years after 
treatment has been discontinued. It interferes with oogenesis and 
spermatogenesis and may cause sterility in both sexes which is dose and 
duration related. It has been found to be teratogenic, and women of 
childbearing potential should be advised to avoid becoming pregnant. 
Increased myelosuppression may be seen with chronic administration of high 
doses of phenobarbital. Cyclophosphamide inhibits cholinesterase activity 
and potentiates effect of succinylcholine chloride. If a patient requires general 
anesthesia within 10 days after cyclophosphamide administration, the 
anesthesiologist should be alerted. Adrenal insufficiency may be worsened 
with cyclophosphamide. Cyclophosphamide is excreted in breast milk. The 
occurrence of acute leukemia has been reported rarely in patients treated 
with anthracycline/alkylator combination chemotherapy. 
1.2.4 Paclitaxel (Taxol) 
Please refer to paclitaxel package insert for full prescribing information. 
Paclitaxel is a cytotoxic agent with proven antitumor activity in a variety of 
solid tumors, including breast cancer, ovarian cancer, and lung cancer. The 
antitumor activity of paclitaxel is based on tubulin-binding and stabilization of 
non-functional microtubule bundles, there by blocking normal mitotic spindle 
development and subsequent cell division (Ringel and Horwitz 1991). 
In breast cancer, paclitaxel is used both in combination with other agents and 
as single agent. A weekly (qw) over a three-weekly (q3w) administration 
schedule has been shown to be more effective in the metastatic as well as in 
the adjuvant setting after standard chemotherapy (Seidman, Berry et al. 
2008, Sparano, Gray et al. 2009). In these two large randomized Phase 3 
studies the overall toxicity profile was similar between the qw and q3w 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 15 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
schedule except for neuropathy (higher in qw arm) while other studies have 
described a more favorable toxicity profile with the qw administration (Eniu, 
Palmieri et al. 2005). 
1.2.5 Docetaxel (Taxotere) 
Please refer to docetaxel package insert for full prescribing information. 
Docetaxel is an anti-microtubule agent. Randomized phase III trials have 
confirmed the anti-tumor activity of docetaxel in breast cancer in neoadjuvant, 
adjuvant and metastatic settings (Bonneterre J 1997, Gradishar 1997, 
Nabholtz JM 1998, Hutcheon, Heys et al. 2003, Bear, Anderson et al. 2004, 
Malhotra, Dorr et al. 2004, Roche H 2004, Goldstein LJ 2005, Jones, Savin 
et al. 2005, Martin, Pienkowski et al. 2005). Addition of docetaxel to 
anthracycline based chemotherapy in neoadjuvant setting has universally 
been associated with improved outcome in all studies (superior complete 
clinical and pathologic response rate in all and improved survival in the 
Aberdeen study). One of the largest neoadjuvant studies, NSABPB-27, 
investigated neoadjuvant Doxorubicin/Cyclophosphamide +/- Docetaxel in 
patients with early breast cancer (T>3 cm or lymph node positive). Addition 
of neoadjuvant docetaxel to doxorubicin and cyclophosphamide was 
associated with superior clinical response rate and pCR (pCR of 27% vs. 
13%). The Aberdeen Breast Study investigated the use of neoadjuvant 
docetaxel in large or locally advanced breast cancer after treatment with 
induction cyclophosphamide, doxorubicin, vincristine, prednisolone (CVAP) 
(Hutcheon, Heys et al. 2003). Patients who were responsive to induction 
CVAP and subsequently treated with sequential docetaxel achieved a 94% 
clinical and 34% pathologic response rate versus a 66% clinical and 16% 
pathologic response rate in patients who received four additional cycles of 
CVAP therapy. Overall survival at 5 years was also superior in the docetaxel 
arm. 
1.2.6 Docetaxel + Carboplatin 
Commonly used dosing schedule of this combination in breast cancer is 
Docetaxel at 75mg/m2 and Carboplatin at AUC of 6 given every 21 days. 
Primary toxicity of this regimen is hematologic with grade 3-4 neutropenia 
occurring in up to 65% of patients and febrile neutropenia occurring in 9-10% 
of the patients (when given without growth factor support). The incidence of 
grade 3-4 neutropenia and leucopenia with carboplatin/docetaxel is lower 
compared to AC-T based chemotherapy (Slamon, Eiermann et al. 2011). 
Due to the modest risk of grade 4 neutropenia and febrile neutropenia 
prophylactic growth factor support is generally recommended for this 
combination in breast cancer (NCCN 2014). 
1.3 
Rationale 
Sporadic and germline BRCA mutation associated triple-negative breast cancer (TNBC) 
share several pathological and molecular similarities. These similarities have led to the 
exploration of DNA damaging agents like platinum compounds in the general population of 
patients with TNBC.  Recent studies demonstrate that addition of neoadjuvant carboplatin 
(Cb) to A/C/T-based chemotherapy improves pathological complete response (pCR) in 
patients with stage I-III TNBC but also increase toxicity (dose reductions/omissions needed 
in 40-50% of patients). Evaluation of the carboplatin in neoadjuvant chemotherapy for TNBC 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC Project  STUDY00002467 
Page 16 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
has been an area of intense exploration in the recent years and identifying the best 
carboplatin regimen is actively being sought. 
We recently reported encouraging pCR rates with a non-anthracycline carboplatin plus 
docetaxel neoadjuvant chemotherapy regimen in a cohort of 49 TNBC patients (Sharma P 
2014). This chemotherapy regimen of carboplatin plus docetaxel yielded an overall pCR rate 
of 65% in unselected TNBC with pCR rates of 61% in sporadic and 77% in germline BRCA-
associated TNBC. The chemotherapy regimen of carboplatin/docetaxel is well tolerated. In 
our neoadjuvant experience, most common grade 3-4 toxicities with carboplatin/docetaxel 
were neutropenia (4%), anemia (6%), thrombocytopenia (6%), and diarrhea (6%). Thus, this 
regimen should be studied further and compared with regimens that add carboplatin to the 
standard anthracycline/taxane containing regimens. 
Thus, a randomized neoadjuvant open label phase II study to further estimate and compare 
pCR rates of carboplatin plus docetaxel x 6 cycles to carboplatin plus paclitaxel x 4 
cycles→doxorubicin plus cyclophosphamide x 4 cycles in stage I-III TNBC is proposed. 
Carboplatin plus paclitaxel → AC is chosen as a comparator regimen since this was the 
regimen used in the largest randomized neoadjuvant trial which evaluated addition of 
carboplatin to A/C/Ta based chemotherapy.   
1.4 
Correlative Studies 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 17 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
2.0 STUDY OBJECTIVES 
2.1 
Primary Objectives 
To evaluate the pathological complete response (pCR) rates with neoadjuvant 
chemotherapy regimens of carboplatin plus paclitaxel x 4 cycles→ doxorubicin plus 
cyclophosphamide (AC) X 4 cycles (CbP→AC) and carboplatin plus docetaxel X 6 cycles 
(CbD) in subjects with stage I-III TNBC.  
Hypothesis: CbD and CbP→AC will yield comparable pCR rates in subjects with stage I-III 
TNBC. 
2.2 
Secondary Objectives 
To evaluate minimal residual disease (MRD) rates (Residual Cancer Burden score of 0/1) 
with two neoadjuvant chemotherapy regimens (CbP→AC and CbD) in subjects with stage I-
III TNBC.  
Hypothesis: CbP→AC and CbD regimens will yield comparable MRD rates in subjects with 
stage I-III TNBC. 
2.3 
Exploratory Objectives 
1. To compare pCR and MRD rates in subjects with germline BRCA associated and
BRCA wild type TNBC with the two neoadjuvant chemotherapy regimens.
2. Exploratory assessment of cost associated with the delivery of the two
chemotherapy regimens.
2.4 
Endpoints 
1.
Primary end point: To estimate the rates of pathological complete response in
breast and axilla (pCR) in the two treatment arms.
2.
Secondary end point: To estimate the rates of MRD in the two treatment arms


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, 
MDProject  STUDY00002467 
Page 18 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
3.0 SUBJECT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
3.1.1 Ability to understand and the willingness to sign a written informed consent 
3.1.2 Subjects with newly diagnosed stage I (T>1cm), II or III TNBC who have not 
undergone definitive breast surgery and have not received systemic 
chemotherapy will be eligible.  
3.1.3 The invasive tumor must be hormone receptor-poor, defined as both estrogen 
receptor (ER) and progesterone receptor (PgR) staining present in < 10% of 
invasive cancer cells by IHC. 
3.1.4 HER- 2 negativity will be based on the current ASCO-CAP guidelines for HER 
testing (Wolff, Hammond et al 2013) 
3.1.5 No previous chemotherapy, endocrine, therapy or radiation therapy with 
therapeutic intent for this cancer 
3.1.6 Female subjects age 18 - 70 years 
3.1.7 Performance Status of 0-1 
3.1.8 Adequate organ and marrow function as defined below: 
•
Leukocytes   ≥ 3,000/uL
•
Absolute neutrophil count ≥ 1500/uL
•
Platelets  ≥ 100,000/uL
•
Total bilirubin  ≤ 1.5mg/dL
•
AST(SGOT)/ALT(SPGT) ≤ 2 x institutional upper limit of normal
•
Creatinine  ≤ 1.5mg/dl and/or Creatinine Clearance ≥ 60mL/min
•
Serum albumin  > 3.0 g/dL
3.1.9 Women of child-bearing potential must agree to use adequate contraception 
(barrier method of birth control or abstinence – hormonal contraception is not 
allowed while participating in this study) prior to study entry, for the duration 
of study participation, and for 90 days following completion of therapy. Should 
a woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. 
3.1.9.1 A woman of child-bearing potential is any female (regardless of sexual orientation, 
having undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria: 
•
Has not undergone a hysterectomy or bilateral oophorectomy;
or
•
Has not been naturally postmenopausal for at least 12
consecutive months (i.e., has had menses at any time in the
preceding 12 consecutive months)


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD  
Page 19 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
3.1.10 Subjects must be informed of the investigational nature of the study, and must 
sign an informed consent in accordance with the institutional rules. 
3.1.11 Pretreatment lab values must be performed within 14 days of treatment 
initiation, and other baseline studies performed within 30 days prior to 
registration 
3.1.12 Subjects should have LVEF ≥ 50% by echocardiogram or MUGA scan 
performed within 4 weeks prior to treatment initiation 
3.1.13 Subjects should have breast and axillary imaging with breast MRI (preferred) 
or breast and axillary US within 4 weeks prior to treatment initiation 
3.1.14 Subjects with clinically/radiologically abnormal axillary lymph nodes should 
have pathological confirmation of disease with image guided biopsy/fine 
needle aspiration.  
3.1.15 Subjects must be already enrolled in P.R.O.G.E.C.T observational registry 
(HSC #12614) 
3.1.16 Staging to rule out metastatic disease is recommended for subjects with 
clinical stage III disease 
3.1.17 Subjects with bilateral disease are eligible if they meet other eligibility criteria. 
3.1.18 Neuropathy:  No baseline neuropathy grade > 2 
3.1.19 Cardiac function 
Subjects with congestive heart failure are not eligible, nor are subjects with 
myocardial infarction, unstable angina pectoris, an arterial thrombotic event, 
stroke or transient ischemia attack (TIA) within the past 12 months, 
uncontrolled 
hypertension 
(Systolic 
BP>160 
or 
Diastolic 
BP>90), 
uncontrolled or symptomatic arrhythmia, or grade 2 or greater peripheral 
vascular disease. 
3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
3.2.1 Current or anticipated use of other investigational agents 
3.2.2 Subject has received chemotherapy, radiotherapy or surgery for the 
treatment of breast cancer  
3.2.3 Subject with metastatic disease 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic 
composition 
to 
carboplatin, 
docetaxel, 
doxorubicin, 
cyclophosphamide, paclitaxel, or other agents used in the study. 
3.2.5 Subjects with inflammatory breast cancer 
3.2.6 Uncontrolled intercurrent illness including, but not limited to; ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 20 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements 
3.2.7 Subject is pregnant or nursing. There is a potential for congenital 
abnormalities and for this regimen to harm nursing infants. 
3.2.8 Subjects with concomitant or previous malignancies within the last 5 years 
are excluded from the study.  Exceptions include:  adequately treated basal 
or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and 
ductal carcinoma in situ (DCIS). 
3.2.9 Ejection Fraction <50% on ECHO or MUGA 
4.0 TREATMENT PLAN 
Protocol treatment is to begin within 14 days of randomization. 
4.1 
Pre-chemotherapy surgical evaluation 
Prior to beginning drug therapy, the subject will be seen and examined by the treating 
surgeon. This will include a clinical breast and lymph node examination and review 
of the imaging studies (MRI or other radiographic method) of the breast and axilla. 
After examining the subject and reviewing the pertinent radiographic studies, the 
surgeon will determine whether the subject is a breast conservation candidate. If the 
subject is not a breast conservation candidate, the reason(s) will be documented on 
the surgical evaluation form (APPENDIX A). 
4.2 
Treatment Dosage and Administration 
NEOADJUVANT THERAPY: 
In general chemotherapy premeditations and at home supportive medications to 
prevent anticipated side effects are to follow institutional guidelines. Appendix D 
describes the suggested pre-medication use with each arm of the treatment.  
4.2.1 Chemotherapy Regimen Arm A 
Carboplatin plus Paclitaxel followed by dose dense AC (Cb+P→AC) 
Agent 
Pre-medications 
Dose 
Route 
Schedule 
Cycle 
Length 
Paclitaxel 
Per institutional 
guidelines  
80 mg/m2
IV over 1 
hours 
Day 1 
weekly x 
12* 
Carboplatin# 
Per institutional 
guidelines 
AUC 6 
IV over 30 
min 
Day 1 
every 3* 
weeks x 
4 
The total duration of the above treatment should not exceed 12 weeks.  Missed doses (for any 
reason) of either paclitaxel or carboplatin should not be made up at the end of the 12 week 
treatment period. 
Doxorubicin/cyclophosphamide (see below) to start 3 weeks (+ 7 days) after the last dose of 
carboplatin and/or one week (+ 7 days) after the last dose of paclitaxel. 
Doxorubicin 
Per institutional 
guidelines  
60 mg/m2
IV push over 
3-5 min
Day 1 
Every 
14* days 
x 4 
cycles 
Cyclophosphamide 
Per institutional 
guidelines 
600 
mg/m2 
IV over 30 
min 
Day 1 
Pegfilgrastim 
6mg 
SC 
Day 2 
#The SWOG ((South West Oncology Group) guidelines must be followed for carboplatin dose 
calculation: 1) Use of Modified Cockcroft-Gault formula for calculating renal function, 2) Calculating 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC Project  STUDY00002467 
Page 21 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Modified Cockcroft-Gault with serum creatinine set to 0.8 mg/dL if actual serum creatinine < 0.8 
mg/dL, 3) Maximum GFR is 125 ml/min, 4) Limiting weight to 140% of ideal body weight for calculation 
of creatinine clearance, 5) Maximum carboplatin dose to be given is 900mg  
*+/- one day 
4.2.2 Chemotherapy Regimen Arm B 
Carboplatin plus Docetaxel (CbD) 
Agent 
Pre-
medications 
Dose 
Route 
Schedule 
Cycle 
Length 
Docetaxel 
Per institutional 
guidelines  
75mg/m2
IV over 60 
minutes 
Day 1 
Every 21* 
days x 6 
cycles 
Carboplatin# 
Per Institutional 
guidelines  
AUC 6 
IV over 30 
minutes 
Day 1 
Pegfilgrastim 
6mg 
SC 
Day 2 
#The SWOG (South West Oncology Group)  guidelines must be followed for Carboplatin dose 
calculation: 1) Use of Modified Cockcroft-Gault formula for calculating renal function, 2) Calculating 
Modified Cockcroft-Gault with serum creatinine set to 0.8 mg/dL if actual serum creatinine < 0.8 
mg/dL, 3) Maximum GFR is 125 ml/min, 4) Limiting weight to 140% of ideal body weight for calculation 
of creatinine clearance, 5) Maximum carboplatin dose to be given is 900mg  
*+/- one day  
4.2.3 Growth factor support: Erythropoietic growth factor support for fatigue/anemia 
is not allowed. Packed RBC transfusion is allowed per the discretion of the 
treating physician. Pegfilgrastim growth factor support as described above is 
included in the treatment plan. 
4.3 
Surgery 
After completion of neoadjuvant therapy, subjects will proceed with either modified radical 
mastectomy or lumpectomy.  Breast conservation eligibility as “Yes”/”No” should be 
documented prior to surgery. Surgery should take place between 3-6 weeks after the last 
chemotherapy cycle.  
All subjects with pretreatment lymph node positive disease and positive sentinel lymph node 
will undergo complete axillary lymph node dissection and/or axillary radiation. 
Histopathological examination of the surgical specimen will be done to determine the extent 
of residual disease.  Pathological complete response (pCR) will be defined as no evidence 
of disease in the breast and axilla at the time of pathology review except for DCIS. 
Prior to neoadjuvant therapy and at the end of neoadjuvant chemotherapy (prior to breast 
surgery), the surgeon will assess the subject and assess whether the subject is a candidate 
for breast conserving surgery. This must be documented in the medical record and on the 
study specific surgical assessment form (APPENDIX A). 
4.4 
Adjuvant Therapy: 
Adjuvant chemotherapy: as per recommendations of treating physician. 
Adjuvant radiation therapy: As per recommendations of the treating physician. In general 
adjuvant radiation is recommended for patients who undergo BCS, have tumors > 5 cm, 
have skin or chest wall involvement, or have pathologically positive lymph node(s) after 
neoadjuvant chemotherapy.  


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 22 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
4.5 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
subject will be assessed for the development of toxicity according to the Schedule of Events 
table. Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse 
Events (CTCAE), version 4.03. Dose modifications for chemotherapy in event of toxicity 
(sections 4.5-4.8, tables 4.6.1– 4.8.5) are applicable only if the toxicity is deemed “treatment-
related.”  This is in accordance with standard clinical practice. Dose adjustments should be 
made according to the system showing the greatest degree of toxicity.  
4.6 
Carboplatin + Paclitaxel 
Carboplatin Dose Levels 
Level 0:  AUC 6 
Level -1: AUC 5 
Level -2: AUC 4 
Paclitaxel Dose Levels 
Level 0: 80mg/m2 
Level -1:  70mg/m2 
Level -2:  60mg/m2 
There are no paclitaxel dose reductions below dose level -2. If dose reduction below dose 
level -2 is required, discontinue paclitaxel and carboplatin and begin ddAC when ANC > 
1,000/uL (and platelets≥> 75,000/uL). 
4.6.1 Hematologic Toxicities: 
Toxicity 
Treatment Modifications 
ANC < 1,000/uL  
(prior to each treatment)* 
ANC <100 or febrile 
neutropenia** (at any 
time) 
-Skip paclitaxel. Skipped doses are not made up.
-On week 4, 7 or 10, delay carboplatin for ANC <
1000/uL. When treatment resumes (ANC ≥1000uL)
continue with carboplatin every 3 weeks. If delays
result in a carboplatin dose being scheduled on wk
12, that dose will be skipped; carboplatin will not be
given on wk 12.
-If paclitaxel is skipped for 1 week, resume paclitaxel
at previous dose level when ANC  ≥ 1000/uL
-If paclitaxel is skipped for 2 consecutive weeks for
ANC < 1000/uL, decrease paclitaxel and carboplatin
by one dose level for all subsequent doses.
-If paclitaxel is skipped for 3 consecutive weeks for
ANC < 1000/uL, discontinue paclitaxel and
carboplatin and begin ddAC when ANC  ≥ 1000/uL
(and platelets  ≥ 75,000/uL)
Reduce carboplatin and paclitaxel by one dose level 
for all subsequent cycles 
Thrombocytopenia* 
• For platelets < 25,000/uL, at any time, decrease carboplatin by one dose level
for all subsequent doses.
• For platelets < 50,000/uL* on weeks 2, 3, 5, 6, 8, 9, 11 or 12 skip paclitaxel and
decrease carboplatin by one dose level for all subsequent doses. Skipped doses


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD   
Page 23 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
are not made up. 
• For platelets < 75,000/uL on weeks 4, 7 or 10 delay carboplatin until platelets
≥ 75,000/uL, then resume carboplatin with one dose level reduction for all
subsequent doses.
• When treatment with carboplatin resumes, continue with carboplatin every 3
weeks. However, if delays result in a carboplatin dose being scheduled on week
12, that dose will be skipped; carboplatin will not be administered on week 12.
• For platelets ≥ 50,000/uL and < 75,000/uL, continue paclitaxel at previous dose.
• If paclitaxel is skipped for 2 consecutive weeks for platelets < 50,000/uL, reduce
paclitaxel by one dose level for all subsequent doses.
• There are no carboplatin dose reductions below dose level -2. If dose reduction
below dose level -2 is required, discontinue carboplatin, and resume weekly
paclitaxel when platelets are ≥ 50,000/uL.
• If paclitaxel is skipped or carboplatin delayed for 3 consecutive weeks for
thrombocytopenia, discontinue paclitaxel and carboplatin, and begin ddAC when
platelets ≥ 75,000/uL (and ANC ≥ 1,000/uL).
Anemia 
During the twelve weeks of weekly paclitaxel and 
carboplatin, if the patient requires more than 2 units 
of packed red blood cells for symptomatic anemia, 
all subsequent doses of carboplatin will be reduced 
one dose level. The doses of paclitaxel will not be 
changed, nor will the doses for subsequent 
treatment with ddAC. 
*If the ANC is < 1000/uL or the platelet count is < 75,000/uL when drawn > 24 hours prior to
the scheduled treatment, the CBC should be re-checked on the day of the treatment to see if
the blood counts have recovered sufficiently to allow the scheduled treatment to be given.
** Febrile neutropenia = ANC < 1000/uL and a single temperature of > 38.3oC (101oF) or a
sustained temperature of > 38oC (100.4oF) for more than one hour.
4.6.2 Non hematologic toxicities: 
Peripheral neuropathy 
• Grade 1: continue treatment
• Grade 2: decrease the dose of paclitaxel by one
dose level for all subsequent doses. The dose of
carboplatin is not reduced.
• Grade 3: skip paclitaxel and delay carboplatin
(week 4, 7 or 10). Skipped doses are not made up.
• When neuropathy improves to < grade 2, resume
treatment with one dose level reduction of both
paclitaxel and carboplatin.
• If a carboplatin dose was delayed, the remaining
doses of carboplatin will continue every 3 weeks.
However, if delays result a carboplatin dose being
scheduled on week 12, that dose will be skipped;
carboplatin will not be administered on week 12.
• If grade 3 peripheral neuropathy, does not
improve within 3 weeks, discontinue paclitaxel +
carboplatin and begin ddAC.
• For grade 3 peripheral neuropathy that has
recurred after recovery to < grade 2, discontinue
paclitaxel + carboplatin and begin ddAC.
• Grade 4: discontinue paclitaxel + carboplatin and
begin ddAC. Recovery of neuropathy is not


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 24 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
required to begin ddAC. 
Other non-hematologic 
toxicities 
• Delay all treatment for any toxicity > grade 3 (with
the exception of fatigue), until toxicity improves to <
grade 2. When treatment is resumed, reduce the
dose of both paclitaxel and carboplatin
• If toxicity does not improve to < grade 2 within 3
weeks, discontinue paclitaxel + carboplatin and
begin ddAC when non-hematologic toxicities
(including sequelae of hypersensitivity reactions)
have improved to ≤ grade 2.
Hepatic dysfunction (prior 
to each treatment) 
• For total bilirubin > 1.5 x IULN or ALT > 5 x IULN,
skip paclitaxel. Skipped doses are not made up.
Recheck LFTs the following week. Paclitaxel can
be resumed when total bilirubin ≤ 1.5 x IULN and
ALT ≤ 5 x IULN
• For total bilirubin > 1.5 x IULN or ALT > 5 x IULN
on week 4, 7 or 10, delay carboplatin until total
bilirubin < 1.5 x IULN and ALT < 5 x IULN, then,
resume treatment with carboplatin at previous
dose. Continue with carboplatin every 3 weeks.
However, if delays result in a carboplatin dose
being scheduled on week 12, that dose will be
skipped; carboplatin will not be administered on
week 12.
• If treatment is skipped or delayed for 3
consecutive weeks for hepatic dysfunction,
discontinue paclitaxel + carboplatin and begin
ddAC when total bilirubin 
 ≤ 1.5 x IULN and ALT ≤ 
2.5 x IULN. 
4.6.3 Hypersensitivity and/or infusion reactions 
During paclitaxel infusion: 
•
Grade 1: Continue paclitaxel infusion. Consider more intensive premedication
prior to subsequent doses.
•
Grade 2: Interrupt paclitaxel infusion. Manage reaction according to
institutional procedures. Resume paclitaxel when reaction has completely
resolved. Consider more intensive premedication prior to subsequent doses.
•
Grade 3: Stop paclitaxel infusion. Manage reaction according to institutional
procedures. Do not resume paclitaxel infusion that day; delay carboplatin (if
patient is due to receive carboplatin). It is up to the treating physician to
decide whether to attempt re-treatment with paclitaxel the following week with
more intensive premedication or to discontinue paclitaxel +carboplatin and
begin ddAC.
•
Grade 4: Stop paclitaxel infusion. Manage reaction according to institutional
procedures.  Discontinue paclitaxel + carboplatin and begin ddAC.
During carboplatin infusion 
•
Grade 1 or 2: Stop carboplatin infusion. Manage reaction according to
institutional procedures. Do not resume carboplatin infusion that day. It is up
to the treating physician to decide whether to re-attempt carboplatin infusion


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD  
STUDY00002467 
Page 25 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
with next weekly paclitaxel (with or without desensitization) or to discontinue 
carboplatin and continue treatment with weekly paclitaxel only. 
•
Grade 3 or 4: Stop carboplatin infusion. Manage reaction according to
institutional procedures. Discontinue carboplatin and continue treatment with
weekly paclitaxel only.
4.7 
Dose dense Doxorubicin and Cyclophosphamide (ddAC) 
*****Growth factor support is required during ddAC (see section with title 
Treatment Dosage and Administration / NEOADJUVANT THERAPY) 
Doxorubicin and cyclophosphamide cannot be reduced below dose level -2 for 
toxicity. If dose reductions below dose level -2 are required, discontinue ddAC and 
proceed to surgery when feasible.  
Doxorubicin dose level 
Cyclophosphamide dose level 
Level 0 
60 mg/m2 
Level 0 
600 mg/m2 
Level -1 
50 mg/m2 
Level -1 
500 mg/m2 
Level -2 
40 mg/m2 
Level -2 
400 mg/m2 
Hematologic Toxicities: 
•
For ANC < 1000/uL or platelets < 75,000/uL, re-check CBC weekly and delay
doxorubicin and cyclophosphamide until ANC ≥ 1000/uL and platelets ≥
75,000/uL. If cycles 2 or 3 of doxorubicin and cyclophosphamide are delayed
for more than 1 week for hematologic toxicity, decrease doxorubicin by one
dose level and decrease cyclophosphamide by one dose level for all
subsequent doses.
•
For febrile neutropenia (a single temperature ≥ 38.3⁰C or a sustained
temperature of ≥ 38oC in the presence of ANC < 1,000/uL) that occurs
following treatment with ddAC, decrease doxorubicin by one dose level and
decrease cyclophosphamide by one dose level for all subsequent doses.
•
There will be no dose modifications for anemia of any grade.
Non hematologic toxicities 
Mucositis (grade 3-4) 
• Provide supportive measures and hold
doxorubicin and cyclophosphamide.
• Resume at current dose when toxicity
recovers to grade 0-2.
• If the subject again experiences
mucositis grade 3-4, reduce the doses
of both doxorubicin and
cyclophosphamide by one dose level.
• If, after three week delay, the toxicity is
not resolved discontinue AC
chemotherapy
Hepatic toxicity 
See below for dose reductions 
• For total bilirubin 1.5 – 3.0 mg/dL,
decrease doxorubicin by one dose
level.
• For total bilirubin > 3.0 mg/dL,
decrease doxorubicin to dose level -2.


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 26 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
• There are no dose modifications for
cyclophosphamide for total bilirubin ≤
5.0 mg/dL.
• For total bilirubin > 5.0 mg/dL, delay
all treatment until bilirubin ≤ 5.0 mg/dL.
Cardiac Dysfunction 
(grade 3-4) 
Discontinue AC therapy and remove 
the subject from protocol treatment if 
the subject has symptoms of CHF (e.g., 
dyspnea, tachycardia, cough, neck vein 
distension, cardiomegaly, 
hepatomegaly, paroxysmal nocturnal 
dyspnea, orthopnea, peripheral edema, 
etc.) and a diagnosis of CHF is 
confirmed, or if the subject has a 
myocardial infarction or a drop in LVEF 
to below the institutional limits of 
normal.  
**The presence of PACs or PVCs 
without cardiac dysfunction is not an 
indication to stop doxorubicin. Acute 
dysrhythmias, which may occur during 
and shortly after doxorubicin infusion, 
are not an indication to stop 
doxorubicin. 
Hemorrhagic cystitis 
(grade 2-4) 
If hematuria is felt to be secondary to 
cyclophosphamide therapy, delay 
treatment until grade 0-1. Provide 
adequate hydration and other 
supportive measures. Mesna can be 
used at the discretion of the 
investigator. If, after three week delay, 
the toxicity is not resolved, discontinue 
AC chemotherapy. 
Other non-hematologic 
toxicities 
For any other grade 3 or 4 toxicity (with 
the exception of fatigue, nausea or 
vomiting), delay doxorubicin and 
cyclophosphamide until toxicity 
improves to < grade 2. When treatment 
is resumed, reduce the doses of 
doxorubicin and cyclophosphamide by 
one dose level.  
• If toxicity does not improve to < grade
2 within 3 weeks, discontinue
doxorubicin and cyclophosphamide and
proceed to surgery when feasible


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD  
Page 27 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
4.7.1 Hepatic dysfunction (dose modifications based on Day 1 liver function tests) 
Liver Function Tests 
Dose Modification 
Total bilirubin < IULN  
AND 
AST/ALT > IULN but ≤ 3 x IULN 
Doxorubicin dose reduced 25%. 
Total bilirubin ≥ IULN but ≤ 3 mg/dL 
OR 
AST/ALT > 3 x IULN 
Doxorubicin dose reduced 50%. 
Total bilirubin 3.1-5 mg/dL 
Doxorubicin dose reduced 75%. 
Cyclophosphamide dose reduced 
25%. 
Total bilirubin > 5 mg/dL 
Do not administer doxorubicin or 
cyclophosphamide. Recheck labs 
every week. Resume when Total 
bilirubin < IULN  
AND 
AST/ALT > IULN but ≤ 3 x IULN.  
If does not resolve to this level within 3 
weeks stop doxorubicin and 
cyclophosphamide and proceed to 
surgery when feasible  
4.8 
Docetaxel and Carboplatin 
Carboplatin Dose Levels 
Level 0:  AUC 6 
Level -1: AUC 5 
Level -2: AUC 4 
Docetaxel Dose Levels 
Level 0: 75 mg/m2 
Level -1: 60 mg/m2 
Level -2: 45 mg/m2 
4.8.1 Hematologic Toxicities: 
Toxicitya 
Treatment Modifications 
ANCb < 1 000/uL (day 1 of cycle) 
Delay docetaxel and carboplatin until ANC 
≥1,000/uL. If counts recover to ≥ 1,000/uL 
in ≤ 1 week, resume at current dose  
If docetaxel and carboplatin are delayed for 
2 consecutive weeks for ANC < 1000/uL 
reduce docetaxel and carboplatin by one 
dose level for all subsequent cycles.  
If docetaxel and carboplatin are delayed for 
3 consecutive weeks for ANC < 1000/uL 
discontinue docetaxel and carboplatin. 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC P 
Page 28 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
ANC <100/uL or febrile 
neutropeniab (at any time) 
Reduce docetaxel and carboplatin by one 
dose level for all subsequent cycles.  
Platelets < 50,000/uL (day 1 of 
cycle) 
For platelets ≥ 50,000 and < 
75,000 (day 1 of cycle) 
Hold docetaxel and carboplatin until 
platelets ≥ 75,000/uL then resume 
docetaxel and carboplatin with one dose 
level reduction for both drugs for all 
subsequent doses. 
Hold both docetaxel and carboplatin until 
platelets ≥75,000/ul and resume docetaxel 
at previous dose and carboplatin with one 
dose level reduction for all subsequent 
doses.  
If docetaxel and carboplatin are held for 3 
consecutive weeks for platelets < 
75,000/uL, discontinue treatment.   
aThere will be no dose modifications for grade 1 – 4 anemia.  
bFebrile neutropenia: a single temperature ≥ 38.3oC or a sustained temperature of > 38oC for 
more than an hour in presence of ANC < 1,000/uL) 
4.8.2 Non-hematologic toxicities: 
Peripheral neuropathy 
• Grade 1:  continue treatment
• Grade 2:  decrease the dose of docetaxel by one
dose level for all subsequent doses. The dose of
carboplatin is not reduced.
• Grade 3: hold docetaxel and carboplatin. When
neuropathy improves to < grade 2, resume
treatment with one dose level reduction of both
docetaxel and carboplatin.
• If grade 3 peripheral neuropathy does not
improve within 3 weeks, discontinue docetaxel
and carboplatin.
• For grade 3 neuropathy that has recurred after
recovery to < grade 2, discontinue docetaxel and
carboplatin.
• Grade 4: discontinue docetaxel and carboplatin


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC P 
Page 29 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Hypersensitivity reactions 
see below for management 
Fluid retention 
There are no dose reductions for fluid retention 
(see below for management) 
Hepatic dysfunction 
(day 1 LFTs) 
See below for dose reductions chart.  Patients with 
total bilirubin > 1.5 X IULN should not receive 
docetaxel.  
Patients with AST and/or ALT > 1.5 x IULN 
concomitant with alkaline phosphatase > 2.5 x 
IULN should not receive docetaxel. 
Other non-hematologic 
toxicities 
• For any other grade 3 or 4 toxicity (with the
exception of fatigue, nausea or vomiting), delay
docetaxel and carboplatin until toxicity improves to
< grade 2. When treatment is resumed, reduce
the doses of docetaxel and carboplatin by one
dose level.
• If toxicity does not improve to < grade 2 within 3
weeks, discontinue docetaxel and carboplatin and
proceed to surgery when feasible
4.8.3 Hypersensitivity reactions 
During docetaxel infusion 
•
Grade 1: Continue docetaxel infusion. Consider decreasing the rate of
infusion Consider more intensive premedication prior to subsequent doses.
•
Grade 2: Interrupt docetaxel infusion. Manage reaction according to
institutional procedures. Resume docetaxel when reaction has completely
resolved. Consider more intensive premedication prior to subsequent doses.
•
Grade 3: Stop docetaxel infusion. Manage reaction according to institutional
procedures. Do not resume docetaxel infusion that day and delay carboplatin
dose that was to be administered that day. It is up to the treating physician to
decide whether to attempt re-treatment with docetaxel the following cycle with
more intensive premedication or to discontinue docetaxel.
•
Grade 4: Stop docetaxel infusion. Manage reaction according to institutional
procedures. Discontinue docetaxel. Carboplatin monotherapy can be
continued per the discretion of the treating physician.
During carboplatin infusion 
•
Grade 1or 2: Stop carboplatin infusion. Manage reaction according to
institutional procedures. Do not resume carboplatin infusion that day. It is up
to the treating physician to decide whether to re-attempt carboplatin infusion
with next cycle (with or without desensitization) or to discontinue carboplatin
and continue treatment with docetaxel only.
•
Grade 3 or 4: Stop carboplatin infusion. Manage reaction according to
institutional procedures. Discontinue carboplatin. Docetaxel monotherapy
can be continued per the discretion of the treating physician.


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC P 
Page 30 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
4.8.4 Management of edema/fluid retention related to docetaxel 
No dose reduction is required. Subjects developing new onset edema, progression 
of existing edema, or another sign of fluid retention (e.g. pound weight gain) can be 
treated with oral diuretics. Regimens found to be effective in the management of 
fluid retention due to docetaxel are listed below. 
•
Hydrochlorothiazide/Triamterene one capsule 25/37.5 po up to three times
per day per the discretion of the treating physician
•
Furosemide 
40 
mg 
po 
daily 
if 
edema 
progresses 
despite
hydrochlorothiazide/triamterene therapy. Potassium supplementation
should be given as needed.
•
If after a two week trial, furosemide 40 mg po daily is ineffective, the patient
may be treated with furosemide 20 mg po daily plus metolazone 2.5 mg po
daily with potassium supplementation as needed.
Further therapy should be customized depending upon the clinical situation. The 
clinical tolerance of the subject, the overall tumor response and the medical 
judgment of the investigator will determine if it is in the subject’s best interest to 
continue or discontinue treatment. 
4.8.5 Hepatic dysfunction (dose modifications based on day 1 liver function tests) 
Liver Function Tests 
Dose Modification 
Total bilirubin > 1.5 x IULN 
concomitant with alkaline phosphatase 
> 2.5 x IULN
Do NOT administer docetaxel.  If not 
resolved in one week, subject should 
be removed from protocol treatment. 
AST/ALT >2.5 x IULN by < 5 x IULN 
AND 
Alkaline phosphatase > IULN but <2.5 
x IULN 
Docetaxel dose reduced by 20% 
AST/ALT >1.5 x IULN and < 5 x IULN 
AND 
Alkaline phosphatase > 2.5 x IULN but 
<5 x IULN 
Docetaxel dose reduced by 20% 
AST/ALT > 5 x IULN  
AND/OR 
Alkaline phosphatase > 5 x IULN 
Do NOT administer docetaxel. 
If not resolved in one week, subject 
should be removed from protocol 
treatment. 
4.9 
Concomitant Medications/Treatments 
Permitted Concomitant Therapy:  In general, the use of any concomitant medication or 
therapy deemed necessary for the care of the subject is permitted.  
•
Use of anti-emetics is allowed.
•
Use of erythropoietin stimulating agents is not allowed
•
Use of goserelin for fertility preservation is allowed.
Anticoagulants 
Anticoagulants or other anti-aggregation agents may be administered under the discretion 
of the investigator. Subjects on anticoagulation with warfarin should be carefully monitored 
and have PT/INR checked every week. 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 31 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Contraceptives 
Hormonal contraceptives are not allowed for this study. Allowed contraceptive methods are 
barrier method of birth control or abstinence. 
. 
Highly effective contraception should be maintained throughout the study and for 90 days 
after study drug discontinuation. 
Other investigational therapies must not be used while the subject is on the study. Anticancer 
therapy (chemotherapy, biologic or radiation therapy and surgery) other than the study 
treatments must not be given to subjects while the subject is on the study medication. If such 
agents are required for a subject, then the subject must be discontinued from the study 
4.10 
Duration of Therapy 
In the absence of treatment delays due to adverse events, all subjects in Arm A will receive 
neoadjuvant chemotherapy with paclitaxel weekly for 12 weeks plus carboplatin given 
every 3 weeks x 4 cycles. The total duration of this treatment should not exceed 12 weeks. 
Missed doses (for any reason) of either paclitaxel or carboplatin should not be made up at 
the end of the 12 week treatment period. 
This treatment will be followed by 4 cycles of doxorubicin and cyclophosphamide given 
every 14 days.  Doxorubicin/cyclophosphamide should start 3 weeks (+7 days) after the 
last dose of carboplatin and/or one week (+7 days) after the last dose of paclitaxel. 
All subjects in Arm B will receive 6 cycles of neoadjuvant chemotherapy with carboplatin 
and docetaxel given every 21 days. 
4.11 
Duration of Follow Up 
The subjects will be followed for 6 months after completion of all local and systemic treatment 
for breast cancer (surgery +/- radiation).  
4.12 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in section with 
title Removal of Subjects from Study apply.  
Notify the Principal Investigator and document the reason for study removal and the 
date the subject was removed in the Case Report Form. The subject should be 
followed-up per protocol. Subjects who are removed from protocol therapy due to 
disease progression will be counted as a treatment failure in the efficacy analysis 
and will continue to be followed per protocol. 
4.13 
Subject Replacement 
Subjects who do not complete the study treatment due to toxicity or other reasons will not 
be replaced. 
5.0 STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the studies 
were done before informed consent was obtained. 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC P 
Page 32 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
All screening procedures must be performed within 30 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical, surgical and oncology history as well as history of 
infections are obtained at screening. Any changes from Screening (e.g. 
worsening severity or abnormal findings) are considered to be adverse events 
(AEs). 
5.1.3 Demographics 
Demographic profile will include date of birth, gender, race, and zip code. 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
All prior medications taken by the subject within 4 weeks before starting the 
study are to be recorded. Concomitant medications taken by the subject 
during the study are to be recorded up until 30 days after last study dose. If 
a reportable adverse event (see section with title ADVERSE EVENTS) occurs 
within 30 days after last study dose, recording of concomitant medications 
should continue until resolution of the adverse event. 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
and assessment of all major body systems 
5.1.7 Performance status 
Subject performance status based on ECOG criteria (Zubrod scale) will be 
evaluated prior to study entry and possibly during study. Specific criteria for 
assessing performance status can be found in APPENDIX B.  
5.1.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See 
section with title ADVERSE EVENTS for Adverse Event monitoring and 
reporting. 
5.1.9 Hematology (to be performed no more than 14 days prior to treatment start 
date) 
Hematology to include hemoglobin (Hgb), platelets, red blood cells, white 
blood cells and differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils) 
5.1.10 Serum chemistries (to be performed no more than 14 days prior to treatment 
start date) 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, 
potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin (direct 
must be collected only in case total bilirubin is elevated >ULN), total protein, 
BUN or urea. 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC P 
Page 33 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
5.1.11 Blood draw for correlative studies 
See section with title CORRELATIVES/SPECIAL STUDIES for details. 
5.1.12 Pregnancy test (for females of child bearing potential) 
See section with title SUBJECT ELIGIBILITY / Inclusion Criteria for definition. 
5.1.13 MUGA/ECHO 
Subjects assigned to Arm A of the study must have a Left Ventricular Ejection 
Fraction (LVEF) of ≥ 50% as determined by MUGA scan or ECHO 
5.1.14 Determination of eligibility for breast conservation 
Breast conservation eligibility as Yes/No should be documented 
5.1.15 Tumor assessment 
All patients must have breast and axillary ultrasound and breast MRI (unless 
MRI is contraindicated, e.g. in presence of metal hardware in body) for 
accurate assessment of the breast and axillary disease. Subjects with 
radiologically abnormal axillary lymph node(s) should have had pathological 
documentation of the nodal involvement (FNA or core needle biopsy).  
5.2 
Procedures during Treatment 
5.2.1 Prior to Each Treatment Cycle 
• Vital signs
• Hematology
• Serum chemistries
• Arm A:  Carboplatin plus paclitaxel followed by Doxorubicin plus
cyclophosphamide: Physical exam including performance status
and clinical assessment of tumor response these are only required
at pre-study, Weeks 4, 7, 10, 13, 15, 17, 19
• Arm B:  Carboplatin plus Docetaxel: Physical exam including
performance status and clinical assessment of tumor response at
pre-study and at the start of each cycle.
5.2.2 Chemotherapy 
Arm A 
Carboplatin plus paclitaxel: carboplatin administration on days 1 (week1), 22 
(week 4), 42 (week 7), 63 (week 10) paclitaxel administration every week (+/- 
one day) starting from day 1 of cycle 1. 
Doxorubicin plus cyclophosphamide (AC) to start 3 weeks (+7 days) after the 
last dose of carboplatin and/or one week (+7 days) after the last dose of 
paclitaxel. AC will be given every 14 days (+/- 1 day) x 4 cycles. During AC 
patients will receive pegfilgrastim on day 2.  
Arm B 
 Carboplatin plus docetaxel every 21 days (+/-1 day) x 6 cycles 
Pegfilgrastim on day 2 or each cycle 
5.2.3 Radiological assessment during neoadjuvant chemotherapy (breast MRI). 
Prior to first cycle of doxorubicin/cyclophosphamide (+/- 7 days) in Arm A and 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 34 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
fifth cycle of carboplatin/docetaxel (+/- 7 days) in Arm B.  In subjects with 
contraindication/intolerance to breast MRI, breast plus axillary ultrasound can 
be used for the assessment of response 
5.2.4 Patient travel time survey 
All patients will complete a travel time survey at one time point during the 
study. This survey can be completed at any time after cycle one of 
chemotherapy (preferably at Cycle 2 or 3 of chemotherapy).  
5.2.5 Breast Surgery 
After completion of neoadjuvant therapy, subjects will proceed to either 
modified radical mastectomy or lumpectomy.  Breast conservation eligibility 
should be documented prior to surgery. Surgery should take place between 
3-6 weeks after the last chemotherapy cycle.
All subjects with pretreatment lymph node positive disease and positive 
sentinel lymph node will undergo complete axillary lymph node dissection 
and/or axillary radiation. Histopathological examination of the surgical 
specimen will be done to determine the extent of residual disease. The pCR 
will be defined as no evidence of disease in the breast and axilla at the time 
of pathology review except for DCIS.  
5.3 
Follow-up Procedures 
All subjects will be followed for 6 months after completion of all local and systemic treatment 
for breast cancer (surgery, chemotherapy and radiation whichever comes last). 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 35 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
5.4 
Schedule of Events 
1 Allowed window, can be done within 14 days of starting the study treatment.
2All pre- and peri-menopausal women should have a negative urine pregnancy test prior to study entry (should be done on the day study treatment starts) 
3 In patients with contraindication/intolerance to MRI, ultrasound of the breast and axilla can be obtained instead 
4Either ECHO or MUGA 
5A subject who requires a treatment break (not to exceed 7 days) for reasons other than toxicity should resume treatment without skipping or modifying treatment 
doses; the reason for the treatment delay (family emergency, vacation, etc.) should be reported 
6Start 3 wks (+7 days) after the last dose of carboplatin and/or one week (+7 days) after the last dose of paclitaxel, unless the patient meets criteria for treatment 
delay. 
7Pegfilgrastim 6mcg SC will be given on day 2 during the period of AC. During weekly paclitaxel +/- carboplatin, filgrastim may be used at the discretion of the 
treating physician. Pegfilgrastim may not be used during weekly paclitaxel +/- carboplatin. 
8To be drawn 21 +/- 7 days after the last chemotherapy and prior to breast surgery  
9 All patients will fill a travel time survey at one time point during the study. This survey can be filled at any time after cycle one of chemotherapy (preferably at 
Cycle 2 or 3 of chemotherapy). 
Regimen A: Carboplatin + Paclitaxel followed by AC 
Required Studies 
Pre- 
study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
Wk 
17 
Wk 
18 
Wk 
19 
Wk 
20 
Physical 
History +Physical1
X
X 
X 
X 
X 
X 
X 
X 
Weight + PS1 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Notation1 
X 
X 
X 
X 
X 
X 
X 
X 
Labs 
CBC/ANC1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP1 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X2
Radiology 
Ultrasound 
breast/axilla 
X 
MRI breast3 
X 
X 
Echo/MUGA4 
X 
Treatment 5 
Carboplatin 
X 
X 
X 
X 
Paclitaxel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Doxorubicin 
X6 
X 
X 
X 
Cyclophosphamide 
X6 
X 
X 
X 
Pegfilgrastim7 
X 
X 
X 
X 
Correlative blood 
specimen8 
Travel time survey9 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 36 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Regimen B: Carboplatin + Docetaxel 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Required Studies 
Pre- 
study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
Wk 
17 
Wk 
18 
Wk 
19 
Wk 
20 
Physical 
History +Physical1
X 
X 
X 
X 
X 
X 
Weight + PS1 
X 
X 
X 
X 
X 
X 
Toxicity Notation1 
X 
X 
X 
X 
X 
X 
Labs 
CBC/ANC1 
X 
X 
X 
X 
X 
X 
CMP1 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X2 
Radiology 
  Ultrasound 
breast/axilla 
X 
  MRI breast3 
X 
X 
Treatment 
Carboplatin 
X 
X 
X 
X 
X 
X 
Docetaxel 
X 
X 
X 
X 
X 
X 
Pegfilgrastim4 
X 
X 
X 
X 
X 
X 
Correlative blood 
specimen5 
Travel time 
survey 
1Allowed window can be done within 14 days of starting the study treatment  
2All pre- and peri-menopausal women should have a negative urine pregnancy test prior to study entry. (should be done on the day study treatment starts) 
3In subjects with contraindication/intolerance to MRI, ultrasound of the breast and axilla can be obtained instead 
4Pegfilgrastim 6mcg SC will be given on day 2 
5To be drawn 21 +/- 7 days after the last chemotherapy and prior to breast surgery  
6All subjects will fill a travel time survey at one time point during the study. This survey can be filled at any time after cycle one of chemotherapy (preferably 
at Cycle 2 or 3 of chemotherapy). 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 37 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own requestor 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
5.5.1 Subject withdraws consent (termination of treatment and follow-up) 
5.5.2 Treating physician judges continuation on the study would not be in the 
subject’s best interest 
5.5.3 Subject becomes pregnant (pregnancy to be reported along same timelines 
as a serious adverse event) 
5.5.4 Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study 
6.0 ADVERSE EVENTS 
Text below in italics is verbatim from “Guidance for Industry and Investigators. Safety 
Reporting Requirements for INDs and BA/BE Studies”, issued December 2012 by U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research, and Center for Biologics Evaluation and Research.  The guidance 
may be retrieved from:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM227351.pdf?source=govdelivery 
6.1 
Definitions 
6.1.1 Adverse Event [21 CFR 312.32(a)] 
An adverse event means any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality.  An adverse event can arise with any use of the drug (e.g., off-label use, 
use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose. 
This study will use the descriptions and grading scales from Common Terminology 
Criteria for Adverse Events version 4.03 (CTCAE v 4.03) for hematologic and non-
hematologic toxicities.  Detailed information may be found on the Cancer Therapy 
Evaluation 
Program 
(CTEP) 
website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Information for adverse events, whether reported by the subject, directly observed, 
or detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported in the CRF as described in the following sections.  


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 38 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Adverse events experienced by subjects will be collected and reported from initiation 
of study treatment and throughout the study, and within 30 days of the last dose of 
study treatment. Subjects who experience an ongoing adverse event related to a 
study procedure and/or study medication beyond 30 days will continue to be 
contacted by a member of the study team until the event is resolved, stabilized, or 
determined to be irreversible by the principal investigator. Study subjects should also 
be instructed to report any new serious post-study event(s) that might reasonably be 
related to participation in this study. 
Medical conditions/diseases, or cancer related symptoms present before starting 
study treatment are considered adverse events only if they worsen after initiation of 
study treatment. Adverse clinical events occurring before starting study treatment but 
after signing the informed consent form are to be recorded on the Medical 
History/Current Medical Conditions CRF. All cancer-related symptoms that have 
occurred in the last 30 days prior to start of study drug must also be recorded on the 
CRF. 
Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms, or require therapy.  In this case they will be 
recorded on the Adverse Events CRF, along with the associated signs, symptoms or 
diagnosis. 
As far as possible, each adverse event will also be described by: 
• its duration (start and end dates),
• grading of severity,
• its relationship to the study drug,
• the action(s) taken,
• outcome.
6.1.2 Suspected Adverse Reaction [21 CFR 312.32(a)] 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of 
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug.  
Suspected adverse reactions are the subset of all adverse events for which there is 
a reasonable possibility that the drug caused the event. Inherent in this definition, 
and in the requirement to report suspected adverse reactions, is the need for the 
sponsor to evaluate the available evidence and make a judgment about the likelihood 
that the drug actually caused the adverse event.  
Factors to be considered in assessing the relationship of the adverse event to study 
treatment include: 
• The temporal sequence from study drug administration: The event should occur
after the study drug is given. The length of time from study drug exposure to event
should be evaluated in the clinical context of the event.
• Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-
challenge): Subjects response after drug discontinuation (de-challenge) or


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 39 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
subjects response after study drug re-introduction (re-challenge) should be 
considered in the view of the usual clinical course of the event in question. 
• Underlying, concomitant, intercurrent diseases: Each report should be evaluated
in the context of the natural history and course of the disease being treated and
any other disease the subject may have.
• Concomitant medication or treatment: The other drugs the subject is taking or the
treatment the subject receives should be examined to determine whether any of
them may be suspected to cause the event in question.
• The pharmacology and pharmacokinetics of the study drug: The pharmacokinetic
properties (absorption, distribution, metabolism and excretion) of the test drug(s),
coupled with the individual subject’s pharmacodynamics should be considered.
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
• Unrelated - The AE is clearly NOT related to the study treatment.
• Unlikely - The AE is doubtfully related to the study treatment.
• Possible – The AE may be related to the study treatment.
• Probable – The AE is likely related to the study treatment.
• Definite – The AE is clearly related to the study treatment.
6.1.3 Unexpected [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity that 
has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application… "Unexpected," as used in this definition, also 
refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the Particular drug under investigation. 
This definition relies entirely on a listing of the adverse events or suspected adverse 
reactions in the investigator brochure…as the basis for determining whether newly 
acquired information generated from clinical trials or reported from other sources is 
unexpected. This means that events not listed for the Particular drug under 
investigation in the investigator brochure are considered “unexpected” and those 
listed are considered “expected.”  When new adverse event information is received, 
it is the sponsor’s responsibility to determine whether the event is “unexpected” for 
safety reporting purposes. 
6.1.4 Serious [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or sponsor, it results in any of the following outcomes: 
Death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 40 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
judgment, they may jeopardize the patient or patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
6.1.5 Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the patient or 
patient at immediate risk of death. It does not include an adverse event or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
6.2 
Reporting Requirements for Adverse Events - 
6.2.1 Submitting Serious Adverse Events Reports to IRB 
For serious adverse events, the clinical research site will follow local IRB policies and 
procedures.  
6.2.2 Study Investigator Notification of Adverse Events 
All expected and unexpected serious adverse events occurring after the subject 
has signed the informed consent and has started protocol treatment must be reported 
to the study principal investigator within 24 hours of becoming aware of the event: 
Priyanka Sharma, M.D. 
University of Kansas Medical Center 
3901 Rainbow Blvd, Mail Stop 3003 
Kansas City, KS 66160-7233 
6.2.3 DSMC Notification of SAEs 
All expected and unexpected serious adverse events occurring after the subject 
has signed the informed consent and has started protocol treatment must be reported 
by phone or email to the KUCC DSMC within 24 hours of becoming aware of the 
event to: 
KUCC DSMC 
A follow-up written report in the form of MEDWATCH Form FDA 3500A is required 
within 5 days.  
6.2.4 Recording Adverse Events and Documentation in VELOS 
All expected and unexpected adverse events and serious adverse events occurring 
after the subject has signed the informed consent and has started protocol treatment 
must be fully recorded in the subject’s case record form. 
All AEs and SAEs regardless of causality must be entered in the KU implementation 
of eVELOS, called the Comprehensive Research Information System (CRIS).  All 
SAEs regardless of causality must be entered into CRIS within 24 hours. 
Unexpected and expected adverse events must be entered within 5 days and 
include:  new unexpected adverse events; worsening baseline conditions; clinically 
significant laboratory findings; disease-related signs and symptoms that were not 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 41 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
present at baseline, and any event or findings that the Investigator feels is clinically 
significant. 
Documentation must be supported by an entry in the subjects file.  A laboratory test 
abnormality considered clinically relevant, e.g., causing the subject to withdraw 
from the study, requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.  Each 
event should be described in detail along with start and stop dates, severity, 
relationship to investigational product, action taken and outcome. 
6.2.5 Reporting of Unexpected, Related SAEs for Concomitant Medications 
For concomitant medications, all unexpected, related serious adverse experiences 
will be forwarded to the product manufacturer by the investigator using the 
Voluntary MEDWATCH Form FDA 3500. 
6.2.6 Summary of Expedited Serious Adverse Event Reporting 
Relationship 
to Study 
Drug 
KUCC 
DSMC 
IRB 
PI 
Velos 
Unexpected 
SAE 
Related 
24 hrs 
Follow local 
IRB reporting 
requirements* 
24 hrs 
24 hrs 
Unexpected 
SAE 
Not-related 
24 hrs 
24 hrs 
24 hrs 
Expected 
SAE 
Related 
24 hrs 
24 hrs 
24 hrs 
Expected 
SAE 
Not-related 
24 hrs 
24 hrs 
24 hrs 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 42 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
7.0 DRUG INFORMATION 
7.1 
Chemotherapy Agents 
Please refer to individual package inserts for more comprehensive information. 
Agent 1: Carboplatin 
•
Other names: Paraplatin
•
Classification: alkylating agent/platinum coordination compound
•
Mode of action: covalently binds to DNA producing cross-links which leads to inhibition
of DNA synthesis
•
Storage and stability: Unopened vials of carboplatin injection, 10 mg/mL are stable to the
date indicated on the package when stored at 25°C (77°F), excursions permitted from
15°C-30°C (59°F - 86°F) [see USP Controlled Room Temperature]. Protect from light.
•
Preparation: Carboplatin injection is a premixed aqueous solution of 10 mg/mL
carboplatin.   Carboplatin injection, 10 mg/mL can be further diluted to concentrations
as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride
Injection (NS), USP.  When prepared as directed, carboplatin aqueous solutions are
stable for 8 hours at room temperature (25°C).Since no antibacterial preservative is
contained in the formulation, it is recommended that carboplatin aqueous solutions are
discarded 8 hours after dilution.
•
Route of administration: IV
•
Incompatibilities: amphotericin B cholesteryl sulfate complex
•
Availability: commercially available
•
Side effects:
-
Alopecia
-
Hypomagnesemia, hypokalemia, hyponatremia, hypocalcemia
-
Nausea, vomiting, stomatitis
-
Myelosuppression (dose related and dose-limiting); thrombocytopenia
(37% to 80%); leukopenia (27% to 38%)
-
Increase in alkaline phosphatase and AST (usually mild and reversible)
-
Hearing loss at high tones
-
BUN and/or creatinine increase
-
Peripheral neuropathy
•
Nursing implications: Use appropriate precautions for handling and disposal (hazardous)
Agent 2: Paclitaxel 
•
Other name(s): Taxol
•
Classification: antimicrotubule agent
•
Mode of action: promotes microtubule assembly and stabilizes tubulin polymers by
preventing their depolarization, resulting in formation of extremely stable and
nonfunctional microtubules
•
Storage and stability: Unopened vials are stored under refrigeration.  Freezing does not
adversely affect the product.  Solutions diluted to a concentration of 0.3-1.2 mg/mL in
NS, 5% dextrose, 5% dextrose and NS, or 5% dextrose in Ringer’s solution are stable
for up to 27 hours when stored at room temperature and normal room light.
•
Preparation: The concentrated solution must be diluted prior to use in normal saline, 5%
dextrose, 5% dextrose and normal saline, or 5% dextrose in Ringer's solution to a
concentration of 0.3 -1.2 mg/mL. Solutions exhibit a slight haze, common to all products


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 43 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
containing non-ionic surfactants. Glass, polypropylene, or polyolefin containers and non-
PVC-containing (nitroglycerin) infusion sets should be used. A small number of fibers 
(within acceptable limits established by the USP) have been observed after dilution. 
Therefore, a hydrophilic 0.22 micron in-line filter should be used. Analyses of solutions 
filtered through IVEX-2 and IVEX-HP (Abbott) 0.2 micron filters showed no appreciable 
loss of potency. Solutions exhibiting excessive particulate formation should not be used. 
•
Route of administration: IV
•
Incompatibilities: Avoid the use of PVC bags and infusion sets due to leaching of DEHP
(plasticizer). Prior administration of cisplatin may increase myelosuppression because of
reduced clearance of paclitaxel. Ketoconazole may inhibit paclitaxel metabolism, based
on in vitro data.
•
Availability: commercially available
•
Side effects:
-
Myelosuppression
-
Hypersensitivity
-
Arrhythmias
-
Peripheral neuropathy
-
Alopecia
-
Nausea and vomiting
-
Diarrhea
-
Stomatitis
-
Elevated LFTs
-
Fatigue
-
Arthralgias
•
Nursing implications: monitor CBC, pre-medicate with anti-emetics, monitor for
abdominal cramping occurring after administration due to risk of ischemic and
neutropenic colitis, advise about possible hair loss, monitor LFTs, advise of arthralgias
and myalgias that may occur for several days after treatment, monitor for neuropathy,
monitor for hypersensitivity reactions
Agent 3: Doxorubicin 
•
Other name(s): Adriamycin
•
Classification: anthracycline
•
Mode of action: Inhibition of DNA and RNA synthesis by intercalation between DNA base
pairs by inhibition of topoisomerase II
•
Storage and stability: intact vials (solution) refrigerate at 2oC to 8oC and protect from
light.  Intact vials (lyophilized powder) room temperature (15oC to 30oC).  Reconstituted
vials stable for 7 days at room temperature (25oC) and 15 days under refrigeration (5oC).
•
Preparation: add 5, 10, 25, 50, 75 ml of preservative-free normal saline to the 10, 20,
50, 100, or 150 mg vial to produce a solution containing 2 mg/mL
•
Route of administration: IV
•
Incompatibilities: Allopurinol, aminosyn II, amphotericin B cholesteryl sulfate complex,
cefepime, freamine III, gallium nitrate, ganciclovir, lansoprazole, pemetrexed,
piperacillin/tazobactam. Variable (consult detailed reference): Fluorouracil, furosemide,
granisetron, heparin, methylprednisolone sodium succinate, propofol, sodium
bicarbonate, TPN.
•
Availability: commercially available
•
Side effects:
-
Cardiovascular: Acute cardiotoxicity: Atrioventricular block, bradycardia, bundle


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 44 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
branch block, ECG abnormalities, extrasystoles (atrial or ventricular), sinus 
tachycardia, ST-T wave changes, supraventricular tachycardia, tachyarrhythmia, 
ventricular tachycardia 
-
Delayed cardiotoxicity: LVEF decreased, CHF (manifestations include ascites,
cardiomegaly, dyspnea, edema, gallop rhythm, hepatomegaly, oliguria, pleural
effusion, pulmonary edema, tachycardia); myocarditis, pericarditis
-
Central nervous system: Malaise
-
Dermatologic: 
Alopecia, 
itching, 
photosensitivity, 
radiation 
recall, 
rash;
discoloration of saliva, sweat, or tears
-
Endocrine & metabolic: Amenorrhea, dehydration, infertility (may be temporary),
hyperuricemia
-
Gastrointestinal: Abdominal pain, anorexia, colon necrosis, diarrhea, GI ulceration,
mucositis, nausea, vomiting
-
Genitourinary: Discoloration of urine
-
Hematologic: Leukopenia/neutropenia (75%; nadir: 10-14 days; recovery: by day
21); thrombocytopenia and anemia
-
Local: Skin “flare” at injection site, urticaria
-
Neuromuscular & skeletal: Weakness
•
Nursing implications: vesicant – do not extravasate, refer to extravasation protocol if
infiltration occurs, advise about alopecia, advise about red urine for 24 hours after drug
administration, anti-emetics, monitor CBC, assess for stomatitis which typically occurs
7-10 days post injection, Adria-flare – most commonly consisting of erythematous streak
up the vein, associated with urticarial and pruritus, monitor for signs of cardiotoxicity.
Agent 4: Cyclophosphamide 
•
Other name(s): Cytoxan (US), Procytox (Canada)
•
Classification: alkylating agent
•
Mode of action: prevents cell division by cross linking DNA strands and decreasing DNA
synthesis
•
Storage and stability: Tablets and injectable powder are stored at room temperature.
Reconstituted cyclophosphamide is chemically and physically stable for 24 hours at
room temperature or for six days under refrigeration.
•
Preparation: add 0.9% sterile sodium chloride solution if injected directly
•
Route of administration: IV
•
Incompatibilities: barbiturates, phenytoin, and choral hydrate, allopurinol, imipramine,
phenothiazines
•
Availability: commercially available
•
Side effects:
-
Alopecia
-
Amenorrhea
-
Gonadal suppression
-
Sterility
-
Abdominal pain
-
Anorexia
-
Diarrhea
-
Mucositis
-
Nausea and vomiting
-
Hemorrhagic cystitis
-
Myelosuppression


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 45 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
•
Nursing implications: monitor CBC, assess hydration and fluid balance, premedicate with
antiemetics, advise patient of metallic taste – hard candy may help
Agent 5: Docetaxel 
•
Other name(s):Taxotere
•
Classification: an anti-microtubule agent
•
Mode of action: induces apoptosis via bcl-2 phosphorylation, binds to tubulin and inhibits
microtubule depolymerization, antiangiogenic properties
•
Storage and stability: The initial diluted solution may be used immediately or stored either
in the refrigerator or at room temperature for a maximum of 8 hours.
TAXOTERE® infusion solution, if stored between 2oC and 25ºC (36oF - 77ºF) is 
stable for 4 hours. Fully prepared TAXOTERE® infusion solution (in either 0.9% 
Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours 
(including the 1 hour I.V. administration). 
•
Preparation of the initial diluted solution
1. Gather the appropriate number of vials of TAXOTERE for Injection Concentrate and
diluent (13% ethanol in water for injection). If the vials were refrigerated, allow them
to stand at room temperature for approximately 5 minutes.
2. Aseptically withdraw the contents of the appropriate diluent vial into a syringe and
transfer it to the appropriate vial of TAXOTERE for Injection Concentrate. If the
procedure is followed as described, an initial diluted solution of 10mg
docetaxel/mL will result.
3. Gently rotate the initial diluted solution for approximately 15 seconds to
assure full mixture of the concentrate and diluent.
4. The initial diluted TAXOTERE solution (10 mg docetaxel/mL) should be clear;
however, there may be some foam on top of the solution from the polysorbate 80.
Allow the solution to stand for a few minutes to allow any foam to dissipate. It is not
required that all foam dissipate prior to continuing the preparation process.
The initial diluted solution may be used immediately or stored either in the
refrigerator or at room temperature for a maximum of 8 hours.
5. Preparation of the final dilution for infusion
Aseptically withdraw the required amount of initial diluted TAXOTERE solution
(10 mg docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion
bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution
to produce a final concentration of 0.3 to 0.74 mg/mL. If a dose greater than 200
mg of TAXOTERE is required, use a larger volume of the infusion vehicle so
that a concentration of 0.74 mg/mL TAXOTERE is not exceeded.
6. Thoroughly mix the infusion by manual rotation.
7. As with all parenteral products, TAXOTERE should be inspected visually for
particulate matter or discoloration prior to administration whenever the solution and
container permit. If the TAXOTERE for injection initial diluted solution or final
dilution for infusion is not clear or appears to have precipitation, these should be
discarded.
•
Route of administration: IV
•
Incompatibilities: Amphotericin B, doxorubicin liposome, methylprednisolone sodium
succinate, nalbuphine. Variable (consult detailed reference): Ceftriaxone.
•
Availability: commercially available


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD HSC  
Page 46 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
•
Side effects:
-
neutropenia is the dose-limiting hematologic toxicity
-
during organogenesis, docetaxel is embryotoxic and fetotoxic
-
fluid retention, possibly severe; requires appropriate steroid pre-medication
-
hypersensitivity reactions can occur within minutes following administration and
subjects should be appropriately pre-medicated
-
neurotoxicity (paresthesias, dysethesias, pain)
-
alopecia
-
nausea/vomiting/diarrhea
-
transaminase or bilirubin elevation
•
Nursing implications: anti-emetics, advise about alopecia, monitor for hypersensitivity
reactions, evaluate LFTs, evaluate for sites of infiltration, peripheral neuropathy, monitor
for fluid retention
7.1.1 Return and Retention of Study Drug 
Study drug will be obtained from commercial supply and handled according 
to Institutional drug handling procedures. 
7.1.2 Drug Accountability/Subject Compliance 
Drug accountability will not be performed.  All medications administered in 
this study are IV and will be administered by clinical staff. 
8.0 CORRELATIVES/SPECIAL STUDIES 
8.1 
Specimen Banking 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 47 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
 
 
 
 
 
 
 
t 
 
9.0 Measurement of Effect 
9.1 
Antitumor Effect 
9.1.1 Response Criteria 
Primary end point of the study is pathological response in the breast and 
axilla.  
Pathologic complete response (pCR) in breast and axilla is defined as no 
evidence of disease in the breast and axillary lymph nodes at the time of 
pathology review, except for DCIS in the breast and isolated tumor cells in 
the axillary lymph nodes.  
Secondary end point of the study is assessment of minimal residual disease 
(MRD) which is defined as residual cancer burden (RCB) score of 0/1. 
Residual cancer burden score will be calculated utilizing surgical pathology 
parameters by a study personnel by using a free online tool 
(http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert
3)


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 48 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
9.2 
Safety/tolerability 
Analyses will be performed for all patients having received at least one dose of study drug. 
The study will use the CTCAE version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf) 
for reporting non-hematologic adverse events and modified criteria for hematologic 
adverse events. 
DATA AND SAFETY MONITORING 
9.3 
Oversight and Monitoring Plan 
The DSMC of the KUCC is responsible for monitoring patient safety for this trial. The DSMC 
is responsible for: 
•
Review of all clinical trials conducted by the KUCC for progress and safety
•
Review of all adverse events requiring expedited reporting as defined in the protocol
•
Submit recommendations for corrective action to the PI and the Deputy Director of
the KUCC or designee.
•
Notify external sites participating in multiple-institutional clinical trials coordinated by
the KUCC of adverse events requiring expedited reporting and subsequent
committee recommendations for study modifications.
•
The University of Kansas Cancer Center Quality Assurance Unit will audit study
activity and reported data on at least a quarterly basis for any collaborating sites.
9.4 
Safety Review and Oversight Requirements 
a) Serious Adverse Event
Serious adverse events that require expedited reporting will be reviewed by the
DSMC Chair or designee who will determine if immediate action is required.  Refer
to section with title ADVERSE EVENTS.  If determined to be necessary by the
DSMC, all participating sites will be notified of the event and any resulting action
within one working day of this determination.
b) Review of Adverse Event Rates
Once per month, adverse event rates will be monitored by the DSMC Coordinator. If
any study has had 2 or more of the same SAE reported within one month, or more
than 6 of the same SAE in 6 months, the DSMC will review summaries of SAEs, and
discuss events in detail with the PI. The DSMC chair or designee determines whether
further action is required.  The DSMC Coordinator ensures that collaborating
investigators and IRBs for all Participating sites are notified of any resulting action.
c) Study Safety and Progress – Quarterly Review
An overall assessment of toxicities as described in the protocol is reviewed at
quarterly DSMC meetings.  This review enables DSMC committee members to
assess whether significant risks are occurring that would warrant study
suspension/closure or protocol amendment.


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 49 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
10.0 
REGULATORY CONSIDERATIONS 
10.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The Principal Investigator will disseminate protocol amendment 
information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
10.2 
Informed Consent 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their participation 
in this study. The formal consent of a participant, using the IRB approved consent form, must 
be obtained before the participant is involved in any study-related procedure. The consent 
form must be signed and dated by the participant or the participant’s legally authorized 
representative, and by the person obtaining the consent. The participant must be given a 
copy of the signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file. 
10.3 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
1.
ICH Consolidated Good Clinical Practice: Guidelines (E6)
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor
mation/Guidances/UCM073122.pdf 
2.
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical
principles that have their origin in the Declaration of Helsinki
http://www.ecfr.gov/cgi-bin/text-
idx?SID=3ee286332416f26a91d9e6d786a604ab&mc=true&tpl=/ecfrbrowse/
Title21/21tab_02.tpl 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 50 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
With attention to the following specific regulations: 
•
Title 21 Part 11 – Electronic Records; Electronic Signatures
•
Title 21 Part 50 – Protection of Human Patients Title 21 Part 54 –
Financial Disclosure by Clinical Investigators
•
Title 21 Part 56 – Institutional Review Boards
•
Title 21 Part 312 – Investigational New Drug Application
3.
State laws
4.
Institutional research policies and procedures
It is understood that deviations from the protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. In such case, the deviation must 
be reported to the IRB according to the local reporting policy.  
11.0 REGISTRATION PROCEDURES 
11.1 
General Guidelines for KUCC and Other Participating Organization 
11.2 
Registration Process for KUCC and Other Participating Centers 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD HS 
Page 51 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
12.0 STUDY MANAGEMENT 
12.1 
Investigator Files and Retention of Documents 
The investigator must prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the study for each research participant. 
This information enables the study to be fully documented and the study data to be 
subsequently verified. Original source documents supporting entries in the case report forms 
include but are not limited to hospital records and clinic charts, laboratory and pharmacy 
records, ECG, signed ICFs, subject diaries and pathology reports. All study related 
documents must be retained for the maximum period required by applicable federal 
regulations and guidelines or institutional policies.  
12.2 
Case Report Forms 
Electronic case report forms (eCRFs) will be completed for each subject enrolled and 
entered into CRIS.  All eCRFs will be customized by the KU Biostatistics Department for this 
study, and will be complete and accurate. The medical chart and any other clinical 
worksheets, procedural reports, etc. are the source documentation of the data captured into 
the study database.   
12.3 
Study Monitoring 
The study will be monitored at appropriate intervals to assure compliance to GCP and to 
assess the data quality and study integrity. The frequency of monitoring may vary depending 
on enrollment rate and the quality of data collected. 
The investigator and staff are expected to cooperate and provide all relevant study 
documentation in detail at each site visit on request for review. The study monitor will have 
direct access to source data for data verification. Data verification will be conducted by 
comparing the data entered into the CRFs with source data. 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 52 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Study Endpoints 
This is a prospective, randomized, multi-centered study. 
Study end points are:  
•
Primary end point: To estimate the rates of pathological complete response in breast
and axilla (pCR) in the two treatment arms.
•
Secondary end point: To estimate the rates of MRD in the two treatment arms
13.2 
Sample Size and Accrual 
Power justification and sample size calculation: Patients will be randomized 1:1, stratified on 
nodal status (positive/negative) to ensure balance, to either neoadjuvant carboplatin  
+ docetaxel or carboplatin + paclitaxel followed by AC. The primary objective will be to
estimate the pCR rates in both arms for the purposes of designing a larger randomized
phase III comparative study. The estimated pCR rates in both the treatment arms is 50%
with upper bound constraints for the standard errors at 7.5% and the upper bound constraint
for the standard error of the difference between pCR rates of the two arms at 12%. The
sample size required to satisfy these constraints is 45 patients per treatment arm (Mayo et.
al. 2010). To ensure achieving 45 evaluable patients in each treatment arm, the overall
maximum sample size will be inflated to 100 patients to account for patient drop outs. The
pCR rates and MRD rates for each treatment arm will be estimated and 95% exact binomial
confidence bounds will be calculated.
13.3 
Data Analyses Plans 
Baseline demographic and clinical characteristics will be summarized overall and by 
treatment assignment with means, standard deviations, medians, ranges, frequency counts 
and proportions. Two sample t-tests and chi-squared tests will be used to identify any 
differences in baseline demographics and clinical characteristics between treatment 
assignment groups. Safety data will be summarized and reported on all subjects who 
received at least one dose of a study drug. 
Primary Objective Analysis: The pathological complete response rates will be estimated and 
95% exact binomial confidence bounds will be calculated in both the carboplatin plus 
docetaxel treatment group, and the carboplatin plus paclitaxel and doxorubicin- 
cyclophosphamide treatment group.  
Secondary Objective Analysis:  The MRD rates (CbD and CbP→AC) will be estimated and 
95% exact binomial confidence bounds will be calculated in both the carboplatin plus 
docetaxel treatment group, and the carboplatin plus paclitaxel and doxorubicin -
cyclophosphamide treatment group.  
Exploratory Objectives Analyses:  Two-sided binomial tests for proportions will be used to 
compare pCR and MRD rates in patients with germline BRCA associated and BRCA wild 
type TNBC with the two neoadjuvant chemotherapy regimens.  
 Exploratory assessment of cost associated with the two chemotherapy regimens. 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 53 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Cost Analysis              Our primary interest is to compare costs between Regimens A and 
B. The maintained hypothesis is that clinical outcomes from the Regimens should be 
similar, so we will conduct a cost minimization analysis (Drummond, Sculpher et al. 2005).
Costs will depend primarily on pharmaceutical costs, costs of administering 
pharmaceuticals, other medical costs related to the regimens, plus subject travel and time 
costs. To ensure that cost differences are due to differences in resource use (not variations 
in prices), medical costs will be based on the average amount paid for the drug or service 
(O'Keeffe-Rosetti, Hornbrook et al. 2013). Patient costs will be calculated using the local 
median wage rate.  


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 54 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
14.0 References 
1. Baselga, J., L. Norton, H. Masui, A. Pandiella, K. Coplan, W. H. Miller, Jr. and J.
Mendelsohn (1993). "Antitumor effects of doxorubicin in combination with anti-
epidermal growth factor receptor monoclonal antibodies." J Natl Cancer Inst 85(16):
1327-1333.
2. Bear, H. D. (1998). "Indications for neoadjuvant chemotherapy for breast cancer."
Seminars in Oncology 25(2): 3-12.
3. Bear, H. D., S. Anderson, R. E. Smith, A. Robidoux, M. S. Kahlenberg, R. G.
Margolese, S. R. Dakhil, E. R. Pajon, J. L. Hoehn, E. P. Mamounas, C. E. Geyer, T.
B. Julian and N. Wolmark (2004). "A randomized trial comparing preoperative (preop)
doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T)
and to preop AC followed by postoperative (postop) T in patients (pts) with operable
carcinoma of the breast: results of NSABP B-27." Breast Cancer Research and
Treatment 88: S16-S16.
4. Bolton, K., G. Chenevix-Trench, C. Goh, S. Sadetzki, S. J. Ramus, B. Y. Karlan, D.
Lambrechts, E. Despierre, D. Barrowdale, L. McGuffog, S. Healey, D. F. Easton, O.
Sinilnikova, J. Benítez, M. J. García, S. Neuhausen, M. H. Gail, P. Hartge, S. Peock,
D. Frost, D. G. Evans, R. Eeles, A. K. Godwin, M. B. Daly, A. Kwong, E. S. K. Ma
and C. Lázaro (2012). "Association between brca1 and brca2 mutations and survival
in women with invasive epithelial ovarian cancer." JAMA: The Journal of the
American Medical Association 307(4): 382-389.
5. Bonneterre J, M. A., Roche J, et al. (1997). "Taxotere versus 5-fluorouracil +
Navelbine in patients with metastatic breast cancer a 2nd line chemotherapy: A
phase III study." Breast Cancer Res Treat 50: 261 (abstr).
6. Brenin, D. R. and M. Morrow (1998). "Breast-conserving surgery in the neoadjuvant
setting." Seminars in Oncology 25(2 Suppl 3): 13-18.
7. Carmo-Pereira J, D. C., Keizer J et al. (1990). "Phase II trial of carboplatin in
carcinoma of the breast." Ann Oncol 1(3): 33.
8. Corkery, B., J. Crown, M. Clynes and N. O'Donovan (2009). "Epidermal growth factor
receptor as a potential therapeutic target in triple-negative breast cancer." Ann Oncol
20(5): 862-867.
9. Cortazar P, Z. L., Untch M, Mehta K, Costantino J, et al. (2012). "Meta-analysis
Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC)."
Cancer Res 72(24): 93s.
10. Dent, R., M. Trudeau, K. I. Pritchard, W. M. Hanna, H. K. Kahn, C. A. Sawka, L. A.
Lickley, E. Rawlinson, P. Sun and S. A. Narod (2007). "Triple-Negative Breast
Cancer: Clinical Features and Patterns of Recurrence." Clinical Cancer Research
13(15): 4429-4434.
11. Drummond, M. F., M. J. Sculpher and G. W. Torrance (2005). Methods for the
economic evaluation of health care programs, Oxford university press.
12. Eniu, A., F. M. Palmieri and E. A. Perez (2005). "Weekly administration of docetaxel
and paclitaxel in metastatic or advanced breast cancer." Oncologist 10(9): 665-685.
13. Fisher, B., J. Bryant, N. Wolmark, E. Mamounas, A. Brown, E. Fisher, D. Wickerham,
M. Begovic, A. DeCillis, A. Robidoux, R. Margolese, A. Cruz, J. Hoehn, A. Lees, N.
Dimitrov and H. Bear (1998). "Effect of preoperative chemotherapy on the outcome
of women with operable breast cancer." Journal of clinical oncology 16(8): 2672-
2685.
14. Fisher, B., N. Gunduz and E. A. Saffer (1983). "Influence of the Interval between
Primary Tumor Removal and Chemotherapy on Kinetics and Growth of Metastases."
Cancer Research 43(4): 1488-1492.


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 55 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
15. Fisher, B. and E. P. Mamounas (1995). "Preoperative chemotherapy: a model for
studying the biology and therapy of primary breast cancer." J Clin Oncol 13(3): 537-
540.
16. Frew, E., J. L. Wolstenholme, W. Atkin and D. K. Whynes (1999). "Estimating time
and travel costs incurred in clinic based screening: flexible sigmoidoscopy screening
for colorectal cancer." J Med Screen 6(3): 119-123.
17. Goldie, J. H. and A. J. Coldman (1979). "A mathematic model for relating the drug
sensitivity of tumors to their spontaneous mutation rate." Cancer Treat Rep 63(11-
12): 1727-1733.
18. Goldstein LJ, O. N. A., Sparano J, et al. (2005). "E2197: Phase IOII AT
(doxorubicin/docetaxel) vs. AC (doxorubicin/cyclophosphamide) in the adjuvant
treatment of node positive and high-risk node negative breast cancer " J Clin Oncol
23(7s): abstr.
19. Gradishar, W. J. (1997). "Docetaxel as neoadjuvant chemotherapy in patients with
stage III breast cancer. ." Oncology-(Huntingt). 1997 Aug; 11(8 Suppl 8): 15-8
20. Green, M. and G. N. Hortobagyi (2002). "Neoadjuvant chemotherapy for operable
breast cancer." Oncology (Williston Park) 16(7): 871-884, 889; discussion 889-890,
892-874, 897-878.
21. Haffty, B. G., Q. F. Yang, M. Reiss, T. Kearney, S. A. Higgins, J. Weidhaas, L. Harris,
W. Hait and D. Toppmeyer (2006). "Locoregional relapse and distant metastasis in
conservatively managed triple negative early-stage breast cancer." Journal of
Clinical Oncology 24(36): 5652-5657.
22. Harris J, M. M., Norton L (1997). Malignant Tumors of the Breast. Cancer: Principles
and Practice of Oncology H. S. Devita V, Rosenberg S. Philadelphia, PA, Lippincott-
Raven Publishers: 557-1582.
23. Hayes, D. F., A. D. Thor, L. G. Dressler, D. Weaver, S. Edgerton, D. Cowan, G.
Broadwater, L. J. Goldstein, S. Martino, J. N. Ingle, I. C. Henderson, L. Norton, E. P.
Winer, C. A. Hudis, M. J. Ellis and D. A. Berry (2007). "HER2 and Response to
Paclitaxel in Node-Positive Breast Cancer." New England Journal of Medicine
357(15): 1496-1506.
24. Husain, A., G. He, E. S. Venkatraman and D. R. Spriggs (1998). "BRCA1 up-
regulation 
is 
associated 
with 
repair-mediated 
resistance 
to 
cis-
diamminedichloroplatinum(II)." Cancer Res 58(6): 1120-1123.
25. Hutcheon, A. W., S. D. Heys, T. K. Sarkar, K. N. Ogston, O. Eremin, L. G. Walker
and I. D. Miller (2003). "Docetaxel primary chemotherapy in breast cancer: a five year
update of the Aberdeen trial." Breast Cancer Research and Treatment 82: S9-S9.
26. Isakoff SJ, G. P., Mayer EL, Taina T, Carey LAA, Krag KJ, Liu MC, Rugo H, Stearns
V, Come S, Finkelstein D, Hartman A-R, Garber JE, Ryan PD, Winer EP, Ellisen LW
(2012). "Impact of BRCA1/2 mutation status in TBCRC009: A multicenter phase II
study of cisplatin or carboplatin for metastatic triple negative breast cancer." Cancer
Research 72(24 supplement): 140s-141s.
27. Jacquin, J. P., S. Jones, N. Magne, C. Chapelle, P. Ellis, W. Janni, D. Mavroudis, M.
Martin and S. Laporte (2012). "Docetaxel-containing adjuvant chemotherapy in
patients with early stage breast cancer. Consistency of effect independent of nodal
and biomarker status: a meta-analysis of 14 randomized clinical trials." Breast
Cancer Res Treat 134(3): 903-913.
28. Jones, S. E., M. A. Savin, F. A. Holmes, J. A. O'Shaughnessy, J. L. Blum, S. J.
Vukelja, T. K. George, K. J. McIntyre, J. E. Pippen, J. Sandbach, R. L. Kirby, J. H.
Bordelon, W. J. Hyman, A. G. Negron, P. Khandelwal, D. A. Richards, S. Anthony,
J. E. Nugent, R. G. Mennel, M. Banerji, G. Edelman, R. L. Ruxer, M. Amare, C. E.


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 56 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Kampe, N. Koutrelakos, W. G. Meyer and L. Asmar (2005). "Final analysis: TC 
(docetaxel/cyclophosphamide, 4 cycles) has a superior disease-free survival 
compared to standard AC (doxorubicin/cyclophosphamide) in 1016 women with early 
stage breast cancer." Breast Cancer Research and Treatment 94: S20-S20. 
29. Kolaric, K. and D. Vukas (1991). "Carboplatin activity in untreated metastatic breast
cancer patients--results of a phase II study." Cancer Chemother Pharmacol 27(5):
409-412.
30. Kuerer, H. M., L. A. Newman, T. L. Smith, F. C. Ames, K. K. Hunt, K. Dhingra, R. L.
Theriault, G. Singh, S. M. Binkley, N. Sneige, T. A. Buchholz, M. I. Ross, M. D.
McNeese, A. U. Buzdar, G. N. Hortobagyi and S. E. Singletary (1999). "Clinical
Course of Breast Cancer Patients With Complete Pathologic Primary Tumor and
Axillary Lymph Node Response to Doxorubicin-Based Neoadjuvant Chemotherapy."
Journal of clinical oncology 17(2): 460.
31. Liedtke, C., C. Mazouni, K. R. Hess, F. André, A. Tordai, J. A. Mejia, W. F. Symmans,
A. M. Gonzalez-Angulo, B. Hennessy, M. Green, M. Cristofanilli, G. N. Hortobagyi
and L. Pusztai (2008). "Response to Neoadjuvant Therapy and Long-Term Survival
in Patients With Triple-Negative Breast Cancer." Journal of clinical oncology 26(8):
1275-1281.
32. Malhotra, V., V. J. Dorr, A. P. Lyss, C. M. Anderson, S. Westgate, M. Reynolds, B.
Barrett and M. C. Perry (2004). "Neoadjuvant and adjuvant chemotherapy with
doxorubicin and docetaxel in locally advanced breast cancer." Clin Breast Cancer
5(5): 377-384.
33. Martin, M., E. Diaz-Rubio, A. Casado, P. Santabarbara, J. M. Lopez Vega, E. Adrover
and L. Lenaz (1992). "Carboplatin: an active drug in metastatic breast cancer."
Journal of Clinical Oncology 10(3): 433-437.
34. Martin, M., T. Pienkowski, J. Mackey, M. Pawlicki, J. P. Guastalla, C. Weaver, E.
Tomiak, T. Al-Tweigeri, L. Chap, E. Juhos, R. Guevin, A. Howell, T. Fornander, J.
Hainsworth, R. Coleman, J. Vinholes, M. Modiano, T. Pinter, S. C. Tang, B. Colwell,
C. Prady, L. Provencher, D. Walde, A. Rodriguez-Lescure, J. Hugh, C. Loret, M.
Rupin, S. Blitz, P. Jacobs, M. Murawsky, A. Riva and C. Vogel (2005). "Adjuvant
docetaxel for node-positive breast cancer." N Engl J Med 352(22): 2302-2313.
35. Nabholtz JM, T. B., Bezwoda WR, et al. (1998). "Taxotere improves survival over
mitomycin C/vinblastine in patients with metastatic breast cancer who have failed an
anthracycline containing regimen: Final results of a phase III randomized trail." Proc
Am Soc Clin Oncol 17.
36. Nasr, F. L., G. Y. Chahine, J. G. Kattan, F. S. Farhat, W. T. Mokaddem, E. A. Tueni,
J. E. Dagher and M. G. Ghosn (2004). "Gemcitabine plus carboplatin combination
therapy as second-line treatment in patients with relapsed breast cancer." Clin Breast
Cancer 5(2): 117-122; discussion 123-114.
37. NCCN. (2014). "NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)
Breast Cancer."  3.2014. 2013, from
http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.
38. Nielsen, T. O., F. D. Hsu, K. Jensen, M. Cheang, G. Karaca, Z. Hu, T. Hernandez-
Boussard, C. Livasy, D. Cowan, L. Dressler, L. A. Akslen, J. Ragaz, A. M. Gown, C.
B. Gilks, M. van de Rijn and C. M. Perou (2004). "Immunohistochemical and Clinical
Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma." Clinical
Cancer Research 10(16): 5367-5374.
39. O'Brien, M. E., D. C. Talbot and I. E. Smith (1993). "Carboplatin in the treatment of
advanced breast cancer: a phase II study using a pharmacokinetically guided dose
schedule." J Clin Oncol 11(11): 2112-2117.


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 57 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
40. O'Keeffe-Rosetti, M. C., M. C. Hornbrook, P. A. Fishman, D. P. Ritzwoller, E. M.
Keast, J. Staab, J. E. Lafata and R. Salloum (2013). "A standardized relative
resource cost model for medical care: application to cancer control programs." J Natl
Cancer Inst Monogr 2013(46): 106-116.
41. Osborne, C. R., L. Kannan, X. J. Xie, R. Ashfaq, A. Bian and T. D. Baylor (2006).
"Neoadjuvant chemotherapy for basal-like breast cancer cohort: clinical and
pathological outcomes." Breast Cancer Research and Treatment 100: S53-S53.
42. Perez, E. A. (2004). "Carboplatin in combination therapy for metastatic breast
cancer." Oncologist 9(5): 518-527.
43. Perez, E. A., V. J. Suman, T. R. Fitch, J. A. Mailliard, J. N. Ingle, J. T. Cole, M. H.
Veeder, P. J. Flynn, D. J. Walsh and F. K. Addo (2005). "A phase II trial of docetaxel
and carboplatin as first-line chemotherapy for metastatic breast cancer: NCCTG
study N9932." Oncology 69(2): 117-121.
44. Reuben, D. B., R. C. Wong, K. E. Walsh and R. D. Hays (1995). "Feasibility and
accuracy of a postcard diary system for tracking healthcare utilization of community-
dwelling older persons." J Am Geriatr Soc 43(5): 550-552.
45. Ringel, I. and S. B. Horwitz (1991). "Effect of alkaline pH on taxol-microtubule
interactions." J Pharmacol Exp Ther 259(2): 855-860.
46. Roche H, F. P., Spielmann M, et al. (2004). "6 cycles of FEC 100 vs. 3 FEC 100
followed by 3 cycles of docetaxel for node-positive breast cancer patients: analysis
at 5 years of the adjuvant PACS 01 trial." Breast Cancer Res Treat 79: abstr.
47. Rottenberg, S., A. O. H. Nygren, M. Pajic, F. W. B. van Leeuwen, I. van der Heijden,
K. van de Wetering, X. Liu, K. E. de Visser, K. G. Gilhuijs, O. van Tellingen, J. P.
Schouten, J. Jonkers and P. Borst (2007). "Selective induction of chemotherapy
resistance of mammary tumors in a conditional mouse model for hereditary breast
cancer." Proceedings of the National Academy of Sciences 104(29): 12117-12122.
48. Rugo, H. S., O. I. Olopade, A. DeMichele, L. van 't Veer, M. Buxton, N. Hylton, D.
Yee, A. J. Chien, A. Wallace, I.-S. S. PI's, J. Lyandres, S. Davis, A. Sanil, D. Berry
and L. Esserman (2013). "Veliparib/carboplatin plus standard neoadjuvant therapy
for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL." Cancer
Res 73(24): Supplement, S5-02.
49. Russell, L. B., M. R. Gold, J. E. Siegel, N. Daniels and M. C. Weinstein (1996). "The
role of cost-effectiveness analysis in health and medicine. Panel on Cost-
Effectiveness in Health and Medicine." JAMA 276(14): 1172-1177.
50. Schonn, I., J. Hennesen and D. Dartsch (2011). "Ku70 and Rad51 vary in their
importance for the repair of doxorubicin- versus etoposide-induced DNA damage."
Apoptosis 16(4): 359-369.
51. Seidman, A. D., D. Berry, C. Cirrincione, L. Harris, H. Muss, P. K. Marcom, G.
Gipson, H. Burstein, D. Lake, C. L. Shapiro, P. Ungaro, L. Norton, E. Winer and C.
Hudis (2008). "Randomized phase III trial of weekly compared with every-3-weeks
paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2
overexpressors and random assignment to trastuzumab or not in HER-2
nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840." J
Clin Oncol 26(10): 1642-1649.
52. Sharma P, S. S., Kimler BF, Khan QJ, Connor CS, McGuinness M, Mammen J,
Wagner JL, Jensen RA, Godwin AK, Fabian CJ (2014). "Efficacy of neoadjuvant
carboplatin/docetaxel chemotherapy in sporadic and BRCA-associated triple-
negative breast cancer (TNBC)." J Clin Oncol 32(5s): suppl; abstr 1022.
53. Sikov, W. M., D. A. Berry, C. M. Perou, B. Singh, C. T. Cirrincione, S. M. Tolaney, C.
S. Kuzma, T. J. Pluard, G. Somlo, E. R. Port, M. Golshan, J. R. Bellon, D. Collyar,


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 58 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
O. M. Hahn, L. A. Carey, C. A. Hudis and E. P. Winer (2014). "Impact of the Addition
of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel
Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic
Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB
40603 (Alliance)." J Clin Oncol.
54. Slamon, D., W. Eiermann, N. Robert, T. Pienkowski, M. Martin, M. Press, J. Mackey,
J. Glaspy, A. Chan, M. Pawlicki, T. Pinter, V. Valero, M. C. Liu, G. Sauter, G. von
Minckwitz, F. Visco, V. Bee, M. Buyse, B. Bendahmane, I. Tabah-Fisch, M. A.
Lindsay, A. Riva and J. Crown (2011). "Adjuvant trastuzumab in HER2-positive
breast cancer." N Engl J Med 365(14): 1273-1283.
55. Slamon DJ, L.-J. B., Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann
W, Wolter J, Pegram M, Baselga J, Norton L. (2001). "Use of chemotherapy plus a
monoclonal antibody against HER2 for metastatic breast cancer that overexpresses
HER2." The New England journal of medicine 344(11): 783-792.
56. Sparano, J. A., V. R. Gray, L. J. Goldstein, B. H. Childs, R. Bugarini, S. Rowley, J.
Baker, S. Shak, S. Badve, F. L. Baehner, E. A. Perez, L. N. Shulman, S. Martino, J.
G. W. Sledge and N. E. Davidson (2009). "GRB7-dependent pathways are potential
therapeutic targets in triple-negative breast cancer." Cancer Research 69(2): 70s-
70s.
57. Tan, D., C. Marchió, R. Jones, K. Savage, I. Smith, M. Dowsett and J. Reis-Filho
(2008). "Triple negative breast cancer: molecular profiling and prognostic impact in
adjuvant anthracycline-treated patients." Breast Cancer Research and Treatment
111(1): 27-44.
58. Tassone, P., P. Tagliaferri, A. Perricelli, S. Blotta, B. Quaresima, M. L. Martelli, A.
Goel, V. Barbieri, F. Costanzo, C. R. Boland and S. Venuta (2003). "BRCA1
expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast
cancer cells." Br J Cancer 88(8): 1285-1291.
59. Telli, M. L. (2013). "PrECOG 0105: Final efficacy results from a phase II study of
gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy
for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer." J Clin
Oncol(31s).
60. Valero V, B. A., McNeese M, et al (2002). "Primary chemotherapy in the treatment of
breast cancer: The University of Texas M. D. Anderson Cancer Center experience."
Clin Breast Cancer 2: S63-68.
61. van der Hage, J. A., C. J. van de Velde, J. P. Julien, M. Tubiana-Hulin, C.
Vandervelden and L. Duchateau (2001). "Preoperative chemotherapy in primary
operable breast cancer: results from the European Organization for Research and
Treatment of Cancer trial 10902." J Clin Oncol 19(22): 4224-4237.
62. von Minckwitz, G., A. Schneeweiss, S. Loibl, C. Salat, C. Denkert, M. Rezai, J. U.
Blohmer, C. Jackisch, S. Paepke, B. Gerber, D. M. Zahm, S. Kummel, H. Eidtmann,
P. Klare, J. Huober, S. Costa, H. Tesch, C. Hanusch, J. Hilfrich, F. Khandan, P. A.
Fasching, B. V. Sinn, K. Engels, K. Mehta, V. Nekljudova and M. Untch (2014).
"Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early
breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial." Lancet Oncol.
63. Wang, J., T. A. Buchholz, L. P. Middleton, D. C. Allred, S. L. Tucker, H. M. Kuerer,
F. J. Esteva, G. N. Hortobagyi and A. A. Sahin (2002). "Assessment of histologic
features and expression of biomarkers in predicting pathologic response to
anthracycline-based neoadjuvant chemotherapy in patients with breast carcinoma."
Cancer 94(12): 3107-3114.


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 59 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
64. Yabroff, K. R., J. L. Warren, K. Knopf, W. W. Davis and M. L. Brown (2005).
"Estimating patient time costs associated with colorectal cancer care." Med Care
43(7): 640-648.


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC  
Page 60 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
15.0 Appendices 
Appendix A. Surgical Evaluation Form 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HS 
Page 61 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Appendix B. Performance Status 
Zubrod (ECOG) Performance Scale 
POINT 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair. 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 62 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Appendix C. Patient Travel Time Cost Analysis Survey 


2015-IIT-Neoadjuvant-BRST-TNBC 
Principal Investigator:  Priyanka Sharma, MD 
HSC 
Page 63 of 63 
2015-IIT-Neoadjuvant-BRST-TNBC 
Revised Protocol Version 4 dated 05-17-2016 
05/16 sab
Appendix D. Suggested Chemotherapy Pre-Medication and Antiemetic’s 
ARM A  
Carboplatin/Taxol 
Day 1 Day of Treatment (Weeks 1, 4,7, 10) * 
diphenhydrAMINE (BENADRYL) injection 50 mg 
famotidine (PEPCID) injection 20 mg 
dexamethasone (DECADRON) 20 mg in sodium chloride 0.9% (NS) 50 mL 
IVPB 
palonosetron(+) (ALOXI) injection 0.25 mg 
Take Home Medication 
Decadron 4-8 mg PO BID Day 2,3 (week 1,4,7, 10) 
Zofran 4 mg PO TID PRN 
Compazine 10 mg PO TID PRN 
Ativan 0.5 mg PO TID PRN 
*Patients who have uncontrolled nausea after first cycle of carboplatin
consider adding Emend (fosaprepitant dimeglumine) 150mg to chemotherapy
premedication for remaining carboplatin doses.
AC (Adriamycin and Cytoxan) 
Day 1 Day of Treatment (Weeks 13, 15, 17, 19) 
dexamethasone (DECADRON) tablet 12 mg 
palonosetron(+) (ALOXI) injection 0.25 mg 
fosaprepitant (EMEND) 150 mg in sodium chloride 0.9% (NS) 150 mL IVPB 
Take Home Medication 
Decadron 4-8 mg Day 1, 2, 3 
Zofran 4 mg PO TID PRN 
Compazine 10 mg PO TID PRN 
Ativan 0.5 mg PO TID PRN 
Arm B  
Carboplatin/Taxotere 
Day 1 Day of Treatment (Weeks 1, 4, 7, 10, 13, 16) 
LORazepam (ATIVAN) tablet 0.5-1 mg 
dexamethasone (DECADRON) 20 mg in sodium chloride 0.9% (NS) 50 mL 
IVPB 
palonosetron(+) (ALOXI) injection 0.25 mg 
Take Home Medication 
Decadron 4-8mg PO BID Day -1, 1, 2 
Zofran 4 mg PO TID PRN 
Compazine 10 mg PO TID PRN 
Ativan 0.5 mg PO TID PRN