CADENCE: Carboplatin and Docetaxel in Neoadjuvant Treatment of ER-Negative, HER2-Negative Breast Cancer: A Co-Clinical Trial With Genoproteomic Discovery
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Mothaffar Rimawi

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CADENCE: Carboplatin And Docetaxel in Neoadjuvant 
Treatment of ER Negative, HER2 Negative Breast Cancer 
 
A Co-clinical Trial with Genoproteomic Discovery 
Principal Investigator:  Mothaffar Rimawi, MD 
 
 
 
 
                     
Co-Principal Laboratory Investigators: 
Matthew J. Ellis MB., B.Chir, PhD. 
 
Michael Lewis, PhD. 
 
 
 
 
 
 
 

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Carboplatin And Docetaxel in Neoadjuvant Treatment of Patients  
with ER Negative, HER2 Negative Breast Cancer 
 with Genoproteomic Discovery 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
06/11/2015 
Amendment 1   
 
 
 
 
 
 
08/22/2016 
Amendment 2  
 
 
 
 
 
 
04/06/2017 
 
 

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 CADENCE TRIAL SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pretreatment research tumor 
Eligible Patients 
ER Negative HER2 Negative Breast Cancer 
Tumor size ≥ 2cm   
Treatment Plan 
Neoadjuvant docetaxel and 
carboplatin every 3 weeks x 6 cycles 
Research tumor biopsy  
(Cycle 1 Day 7 ± 3 days) 
Surgery (4-6 weeks post-completion 
of neoadjuvant therapy) 

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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BUN 
Blood urea nitrogen 
CALGB 
Cancer and Leukemia Group B 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMP 
Complete metabolic panel 
CNS 
Central nervous system 
CR 
Complete respose 
CRF 
Case report form 
CS 
Chemo sensitive 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DFS 
Disease-free survival 
DNA 
deoxyribonucleic acid 
DOB 
Date of birth 
DSM 
Data and Safety Monitoring  
EBCTCG 
Early Breast Cancer Trialists’ Cooperative Group 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FWA 
Federal wide assurance 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor, filgrastim (Neupogen) 
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 

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IRB 
Institutional Review Board 
IV 
Intravenous  
LD 
Longest diameter 
LDH 
Lactate dehydrogenase 
MRI 
Magnetic resonance imaging 
NCCN 
National Cancer Center Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSABP 
National Surgical Adjuvant Breast and Bowel Project 
OHRP 
Office of Human Research Protections  
OS 
Overall survival 
pCR 
Pathologic complete response 
PD 
Progressive disease 
PDX 
Patient-derived xenograft 
PET 
Positron emission tomography 
PI 
Principal investigator 
PR 
Partial response 
PR 
Progesterone receptor 
PS 
Performance status 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SCID 
Severe combined immunodeficiency 
SD 
Stable disease 
TNBC 
Triple-negative breast cancer 
UPN 
Unique patient number 
US 
Ultrasound 
WBC 
White blood cell (count) 
WHIM 
Washington University Human in Mouse 
WHO 
World Health Organization 
 
 

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Table of Contents 
CADENCE TRIAL SCHEMA .................................................................................................................. 3 
1.0 
BACKGROUND AND RATIONALE ........................................................................................ 10 
1.1 
Triple Negative Breast Cancer ........................................................................................... 10 
1.2 
Neoadjuvant Chemotherapy in Triple Negative Breast Cancer .............................. 10 
1.3 
Chemotherapy Agents.......................................................................................................... 12 
1.4 
Study Rationale ..................................................................................................................... 14 
1.5 
Correlative Studies Background ...................................................................................... 15 
2.0 
OBJECTIVES .............................................................................................................................. 18 
2.1 
Primary Objective .................................................................................................................. 18 
2.2 
Exploratory Objectives ......................................................................................................... 18 
3.0 
PATIENT SELECTION .............................................................................................................. 19 
3.1 
Inclusion Criteria .................................................................................................................. 19 
3.2 
Exclusion Criteria ................................................................................................................. 20 
4.0 
REGISTRATION PROCEDURES ........................................................................................... 21 
4.1 
Guidelines for Lead Institution ......................................................................................... 21 
4.2 
Guidelines for Other Institutions ..................................................................................... 21 
4.3 
Eligibility exceptions ............................................................................................................ 22 
5.0 
STUDY PROCEDURES ............................................................................................................ 22 
5.1 
Screening assessments ....................................................................................................... 22 
5.2 
Cycle 1 Day 1 .......................................................................................................................... 23 

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5.3 
Cycle 1 Day 7 .......................................................................................................................... 23 
5.4 
Cycles 2,3,4,5, and 6 Day 1 ............................................................................................... 24 
5.5 
End of Treatment .................................................................................................................. 24 
5.6 
Follow up procedures ........................................................................................................... 25 
6.0 
TREATMENT PLAN ................................................................................................................... 25 
6.1 
Premedication Administration .......................................................................................... 25 
6.2 
Agent Administration ........................................................................................................... 25 
6.3 
Anthracycline-Based Adjuvant Chemotherapy ........................................................... 25 
6.4 
General Concomitant Medication and Supportive Care Guidelines ..................... 26 
6.5 
Women of Childbearing Potential .................................................................................... 26 
6.6 
Duration of Therapy ............................................................................................................. 26 
6.7 
Duration of Follow-up .......................................................................................................... 27 
7.0 
DOSE DELAYS/DOSE MODIFICATIONS .......................................................................... 28 
8.0 
REGULATORY AND REPORTING REQUIREMENTS ...................................................... 35 
8.1 
General ..................................................................................................................................... 35 
8.2 
Definitions ............................................................................................................................... 35 
8.3 
Reporting Procedures ........................................................................................................... 37 
9.0 
PHARMACEUTICAL INFORMATION.................................................................................... 38 
9.1 
Docetaxel (Taxotere) ............................................................................................................. 38 
9.2 
Carboplatin ............................................................................................................................. 39 
10.0 CORRELATIVE STUDIES ........................................................................................................ 40 
10.1 Tumor Biopsy ......................................................................................................................... 40 

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10.2 Research Blood ...................................................................................................................... 40 
10.3 Specimen Storage and Banking ....................................................................................... 41 
10.4 
Planned analyses ................................................................................................................... 42 
11.0 STUDY CALENDAR ................................................................................................................... 45 
12.0 MEASUREMENT OF EFFECT ............................................................................................... 46 
12.1 Clinical Responses ................................................................................................................ 46 
12.2 Surgery ..................................................................................................................................... 46 
12.3 Diagnosis of Breast Cancer Recurrence and Other Cancer Events ...................... 47 
13.0 DATA AND SAFETY MONITORING ...................................................................................... 49 
13.1 Data Management and Reporting .................................................................................... 49 
13.2 Meetings ................................................................................................................................... 49 
13.3 Monitoring ............................................................................................................................... 49 
14.0 REGULATORY CONSIDERATIONS ...................................................................................... 50 
14.1 Protocol Review and Amendments .................................................................................. 50 
14.2 Informed Consent .................................................................................................................. 50 
14.3 Ethics and GCP ...................................................................................................................... 50 
15.0 MULTI-CENTER GUIDELINES .............................................................................................. 51 
15.1 Study Documentation .......................................................................................................... 51 
15.2 Records Retention ................................................................................................................. 51 
15.3 Publication .............................................................................................................................. 52 
16.0 STATISTICAL CONSIDERATIONS ........................................................................................ 53 
16.1 Study Design .......................................................................................................................... 53 

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17.0 REFERENCES ............................................................................................................................ 55 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Triple Negative Breast Cancer 
Triple negative breast cancer (TNBC) represents approximately 10-15% of breast cancers worldwide and 
affects approximately 200,000 women annually [1].  It is defined by a lack of expression of the estrogen 
receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) 
receptor.  The disease is more common in young black women and in women with a deleterious mutation 
in the BRCA1 gene [2, 3]. 
Established targeted therapies in breast cancer are directed against a nuclear or a surface receptor, such 
as tamoxifen or trastuzumab, respectively.  However, no established targets currently exist for TNBC, so 
patients receive chemotherapy for systemic control of their disease [4].  Despite neoadjuvant 
chemotherapy trials showing that TNBC has higher pathological complete response (pCR) rates compared 
to hormone-receptor-positive subtypes [5], TNBC remains extremely difficult to treat in many cases, and 
patients have high rates of relapse, particularly due to chemotherapy resistance within the first few years 
[6].  TNBC patients suffer from a worse initial prognosis among all other breast cancer subtypes, and there 
is a dire need to develop new treatment strategies for TNBC, particularly for those with disease that is 
resistant to standard chemotherapy.      
1.2 
Neoadjuvant Chemotherapy in Triple Negative Breast Cancer 
Neoadjuvant chemotherapy describes primary systemic therapy that is utilized prior to surgery. It was 
initially used for patients with locally advanced, inoperable breast cancer in an effort to improve local 
control and decrease distant metastases when used in combination with surgery [7].  A few years later, 
the National Surgical Adjuvant Breast and Bowel Project (NSABP) began a clinical trial (B-18) to evaluate 
the efficacy of neoadjuvant chemotherapy compared to adjuvant therapy in patients with operable breast 
cancer.  Approximately 1500 women were randomized to receive chemotherapy either pre- or post-
operatively [8].  Although there were no survival differences or differences in rates of ipsilateral tumor 
recurrence after lumpectomy, preoperative chemotherapy led to an improvement in rates of breast 
conservation.  Since then, numerous studies have confirmed the utility of neoadjuvant chemotherapy in 
patients with locally advanced inoperable disease as well as those with operable disease who desire 
breast-conserving therapy [9, 10].  In addition, the neoadjuvant platform is an excellent model to assess 
pathologic tumor response and for serial tissue acquisition.  Ultimately, this allows for the identification 
of molecular changes induced by treatment, and most importantly, it permits determination of predictors 
of resistance and sensitivity to therapy, which may lead to more individualized management.   

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While several clinical trials involving neoadjuvant traditional chemotherapy, biologics, or different dosing 
schedules have recently been launched in an attempt to improve the outcome of patients with TNBC, the 
initial phase of neoadjuvant studies did not restrict entry criteria to only patients with TNBC. However, a 
large proportion (41%) of the study population in NSABP protocol B-40 was classified as having TNBC [11]. 
The goals of this study were to determine if the addition of capecitabine or gemcitabine to docetaxel 
followed by doxorubicin and cyclophosphamide (AC) would increase pCR rates in patients with palpable 
and operable HER 2-negative disease and also to determine whether the addition of bevacizumab to 
docetaxel-based regimens followed by AC will increase pCR rates. In the chemotherapy alone arms, the 
addition of capecitabine or gemcitabine to docetaxel versus docetaxel alone did not increase the pCR 
rates (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Similarly, the Gepar Trio study reported by 
Huober et al. showed a pCR rate of 39% in the TNBC patients in a trial that sought to determine the effect 
of switching neoadjuvant chemotherapy depending on mid-course response on pCR at time of surgery 
[12]. Patients received 2 cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), followed by either 
4 or 6 more cycles of TAC in responders or 4 cycles of TAC versus capecitabine plus vinorelbine in non-
responders. In non-responders, pCR rates were less than 10% in both groups, suggesting a lack of benefit 
of switching chemotherapy to these non-standard agents or even providing further chemotherapy in the 
adjuvant setting to that subset of patients.  
In contrast to the lack of data that capecitabine, vinorelbine or gemcitabine improve pCR rates, there is 
increasing data indicating a role for platinum agents in the treatment of TNBC.  CALGB 40603, presented 
at San Antonio Breast Cancer Symposium 2013, evaluated the impact of the addition of carboplatin and/or 
bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC on pCR rates in TNBC. This was 
a 2 X 2 factorial design in which patients on Arm A received weekly paclitaxel at 80 mg/m2 for 12 weeks 
followed by dose dense AC for 4 cycles, patients on Arm B received weekly paclitaxel 80 mg/m2 for 12 
weeks plus bevacizumab followed by dose dense AC for 4 cycles, patients on Arm C received weekly 
paclitaxel 80 mg/m2 for 12 weeks plus carboplatin followed by dose dense AC for 4 cycles, and patients 
on Arm D received weekly paclitaxel 80 mg/m2 for 12 weeks plus carboplatin and bevacizumab followed 
by dose dense AC for 4 cycles. While there was no clear benefit from the addition of bevacizumab, pCR 
rates increased from 41% to 54% in patients receiving carboplatin.  Similarly, a significant improvement 
in pCR rate (58.7% vs 37.9%, p<0.05) in TNBC was observed with the addition of carboplatin (AUC 1.5 
weekly) to 18 weeks of weekly paclitaxel (80mg/m2) plus non-pegylated liposomal doxorubicin (20mg/m2) 
in the GeparSixto trial [13].   
In this trial, we therefore aim to develop predictors of response (pCR vs. non-pCR) to neoadjuvant taxane 
and carboplatin.  If sensitive tumors could be identified prospectively, a trial designed to show that the 
addition of platinum improves survival could be considered.  This could lead to a simplified regimen 
whereby the doxorubicin-based component could be possibly avoided in the treatment of TNBC.  

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1.3 
Chemotherapy Agents 
Chemotherapy can substantially reduce the risk of breast cancer recurrence and death in early stage 
breast cancer [14], and there are many chemotherapy regimens with established efficacy and safety data. 
The value of chemotherapy has been consistently demonstrated from the data of individual randomized 
trials and affirmed in the Early Breast Cancer Trialists’ Collaborative Group’s (EBCTCG) 15-year meta-
analyses combining data from the individual chemotherapy trials. The meta-analyses have shown that 
anthracycline-containing therapies, such as sequential doxorubicin and cyclophosphamide (AC) followed 
by taxanes, and combination regimens such as docetaxel, doxorubicin, and cyclophosphamide (TAC), 
reduce the risk of recurrence by 11% and the risk of death by 16% compared with cyclophosphamide, 
methotrexate, and fluorouracil (CMF) combinations [15]. 
CALGB 9344 and NSABP B-28 established the role of taxanes as a component of adjuvant therapy of breast 
cancer. Between May 1994 and April 1999, the CALGB randomized 3121 patients in a 3x2 factorial design 
to cyclophosphamide combined with one of three doses of doxorubicin given every 3 weeks for 4 cycles 
followed by paclitaxel on an every-3-week schedule or observation. No differences in efficacy based on 
doxorubicin dose were observed. However, adding paclitaxel to the AC regimens led to reductions in 
hazard for recurrence and death of 17% and 18%, respectively [16]. NSABP B-28 randomized 3060 women 
with resected, node-positive breast cancer to receive 4 cycles of AC followed by 4 cycles of paclitaxel on 
the every-3-week schedule vs. 4 cycles of AC. The addition of paclitaxel significantly reduced the hazard 
for disease-free survival (DFS) events by 17% (relative risk 0.83; 95% CI, 0.72– 0.95; p=0.006), but overall 
survival (OS) was similar for both groups [17]. 
NSABP B-27 evaluated the potential benefit of administering docetaxel (T) following AC as preoperative 
therapy for 2411 women with palpable, operable breast cancer. The addition of preoperative or 
postoperative T after preoperative AC showed a non-significant trend toward improving DFS, primarily by 
decreasing the incidence of local recurrences, but did not improve OS. Concurrent use of tamoxifen may 
have limited the impact of adding T [18].  
ECOG E1199 employed a 2x2 factorial design to compare paclitaxel to docetaxel following 4 cycles of AC 
and a weekly schedule vs. an every-3-week schedule of the taxanes in nearly 5,000 women with node-
positive or high-risk node-negative breast cancer. Patients were randomly assigned to receive one of the 
following taxane treatments: docetaxel 35 mg/m2 once a week; docetaxel 100 mg/m2 once every 3 weeks; 
paclitaxel 80 mg/m2 once a week; or paclitaxel 175 mg/m2 once every 3 weeks. The primary comparisons 
showed no differences between the taxanes (paclitaxel vs. docetaxel: HR 1.032; p=0.61) or schedule (q3w 
vs. q1w: HR 1.062; p=0.33). However, a Cox proportional hazards model, which included the taxane 
administered, the taxane schedule and their interaction, showed the interaction of docetaxel and the 
weekly schedule was significant for both DFS (p=0.003) and OS (p=0.01). This complicated the 
interpretation of the primary endpoints so comparisons were made between the standard every-3-week 

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paclitaxel schedule and each of the other three arms. As compared with the group receiving paclitaxel 
every 3 weeks, there was better DFS in the group receiving weekly paclitaxel (HR 1.27; p=0.006) and in 
the group receiving every-3-week docetaxel (HR 1.23; p=0.02). However, while OS was significantly better 
in the group receiving weekly paclitaxel (HR 1.32; p=0.01), it was not evident in the group receiving 
docetaxel every 3 weeks (HR 1.13; p=0.25). Serious adverse effects of treatment developed in 71% of 
patients treated with docetaxel every 3 weeks, and only 28% of patients treated with paclitaxel once a 
week. The increase in adverse events with docetaxel was primarily due to febrile neutropenia and 
neutropenia-associated infections which can be substantially diminished with the use of primary 
prophylactic G-CSF [19, 20]. Most recently, SWOG 0221, compared weekly paclitaxel to dose-dense (every 
2 week) scheduling as adjuvant breast cancer treatment and showed no difference in efficacy endpoints 
with either method of delivery. Patients had higher rates of grade 3 and 4 neuropathy (17% vs. 10%) with 
dose-dense delivery and higher rates of hematologic toxicity with weekly scheduling[21]. 
As sporadic TNBC is clinically similar to BRCA-1 associated breast cancer, there has been significant 
interest in using platinum compounds in TNBC. BRCA-1 associated breast cancers are sensitive to these 
agents since they cause double-strand breaks in DNA and these cancers are deficient in homologous 
recombination mediated DNA repair mechanisms. Several neoadjuvant trials have evaluated platinum 
agents in TNBC patients. Alba et el. investigated whether the addition of carboplatin to standard 
chemotherapy in patients with TNBC would lead to an increase in the pCR rates in the neoadjuvant 
setting.[22] Patients received epirubicin plus cyclophosphamide (EC) followed either by docetaxel or 
docetaxel plus carboplatin. The addition of the platinum did not improve pCR rates (35% versus 30%) in 
this study. Silver et al. evaluated the efficacy of neoadjuvant cisplatin in 28 patients with TNBC.[23] All 
patients received 4 cycles of cisplatin preoperatively, followed by definitive surgery, and then adjuvant 
chemotherapy and/or radiation as per their treating physicians. The pCR rate was 21% (6 of 28 patients), 
while 64% (18 of 28) achieved either a clinical complete or partial response. The efficacy of neoadjuvant 
cisplatin in TNBC versus non-TNBC was also compared in a small retrospective study by Sirohi et al.[24] 
Complete response rates by clinical exam were higher for those with TNBC (88%) versus the non-TNBC 
group (51%). Paradoxically survival outcomes were worse for the TNBC group despite higher rates of initial 
response to chemotherapy. This has also been seen in a study that showed despite a higher rate of 
chemosensitivity, patients with TNBC had a worse outcome than those with ER positive disease.[25] 
Multiple other small studies have also evaluated neoadjuvant platinum-based therapy in patients with 
TNBC with varying results.[26-33] While current data provides insufficient evidence for the routine use of 
platinums in patients with TNBC, the pCR improvements observed in the neoadjuvant setting have created 
a conundrum and some physicians are now routinely adding carboplatin.  However, until survival data for 
the addition of carboplatin is available, the use of carboplatin is still considered investigational by other 
physicians. Since the most significant issue remains the identification of platinum sensitivity, this protocol 
is therefore designed to have high clinical and scientific impact.   

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1.4 
Study Rationale 
While improvements in adjuvant therapy have remarkably improved the outcome of women with 
resectable breast cancers over the past two decades, biologically defined subsets of patients at a high risk 
of recurrence and death continue to exist. Improving upon our ability to eradicate micrometastases and 
prevent recurrences in these high risk individuals, particularly those with TNBC remains a challenge. The 
relapse rate for patients treated with adjuvant therapy on clinical trials has declined, due, in part, to 
improvements in treatment. Unfortunately, testing new drugs in the adjuvant setting in breast cancer 
requires large number of patients as well as long follow up periods. The neoadjuvant platform allows the 
opportunity to assess clinically meaningful responses in vivo, therefore enabling more rapid identification 
of effective drugs and consequently changes to established standards of care. In fact, to facilitate early 
access of potentially active drugs for patients with high risk disease such as TNBC, the Food and Drug 
Administration (FDA) has recently outlined a pathway for accelerated drug approval based on pathologic 
complete response (pCR) from neoadjuvant trials. Additionally, the neoadjuvant platform allows us to 
obtain serial tissue and blood samples before and after treatment, which may allow identification of 
subsets of patients less or more likely to benefit from a given treatment.  
As TNBC lacks an identified therapeutic target, most individuals receive chemotherapy as part of their 
systemic management. Unfortunately a large proportion develops recurrences due to chemotherapy 
resistance, therefore there is a need to develop more effective chemotherapy regimens and also identify 
predictors of CR and chemotherapy sensitivity to better individualize management. The use of proteomic 
and genomic analysis in the design of trials evaluating mechanisms of CR are lacking. By being able to 
assess pathologic tumor response and molecular changes induced by treatment, the neoadjuvant 
platform creates an excellent model for such a study. Typical clinical trial experimentation recruiting 
individuals to adjuvant drug studies, and then assessing survival may not be the most efficient method. 
Additionally, although cell lines are informative, they do not accurately reflect tumor morphology or 
heterogeneity in vivo. To address this, PDX are being explored as surrogates for originating tumors.  
This research proposal investigates a potential new therapeutic option for patients with curable TNBC 
using a combination of docetaxel and carboplatin in the neoadjuvant setting. We propose to treat patients 
with a similar backbone as the CALGB 40603 regimen by administering six 3-week cycles of docetaxel in 
combination with 6 cycles of carboplatin to improve pCR. If successful, this strategy may help avoid 
anthracyclines with the associated cardiotoxicity and leukemia risk, and will develop evidence for a 
regimen that is more convenient to administer than the Gepar Sixto protocol of 18 weeks of weekly 
carboplatin and paclitaxel. 
It has been postulated that DNA-damaging agents like platinum salts may be particularly effective in TNBC 
due to its similarities with BRCA-1 associated breast cancer. Studies utilizing taxanes and platinum salts 

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have been performed in unselected breast cancer patients and have shown higher response rates than 
single agent taxanes and good tolerance with a low incidence of serious side effects.  
In addition, PDX models will be developed from tumors from individual patients on this trial. This study is 
therefore based on the hypotheses that neoadjuvant docetaxel and carboplatin will achieve a pCR rate of 
54%, similar to the CALGB 40603 carboplatin-containing arms, and that PDX are accurate replicas of 
originating tumors and can recapitulate chemotherapy response. The promise of this novel strategy is that 
PDX may be used as drug discovery platform for chemotherapy-resistant patients.  
To understand the potential clinical impact of this study, it is valuable to consider a clinical scenario. After 
diagnosis, a TNBC patient may be treated with neoadjuvant chemotherapy with the ultimate goal of 
minimizing the risk of disease recurrence. While these treatments are associated with a 20-38% decrease 
in breast cancer mortality amongst all subtypes [15], patients with TNBC that do not respond to 
chemotherapy continue to have a substantial risk of recurrent disease within the first 5 years. A novel 
personalized strategy to assess drug responsiveness will be to develop a PDX model from a particular 
patient, either shortly before or during neoadjuvant treatment, treat the PDX model with a view to 
determining chemotherapy response in the PDX. This then may be able to be a surrogate for whether the 
TNBC patient will likely respond to the drug being administered. In addition, drug discovery using the PDX 
platform as a living replica may also be utilized for those with chemotherapy resistant TNBC, thus allowing 
for individualized management. 
1.5 
Correlative Studies Background 
1.5.1 
Patient-Derived Xenografts (PDX) in Breast Cancer 
Despite progress in our understanding of cancer biology, the translation of research findings into new 
therapies for cancer is still an enormous barrier.  Recent data suggests a 90% rate failure rate for oncology 
products in clinical development [34]. In part, the development of new therapies in breast cancer is 
constrained by the scarcity of reliable in vivo models of human breast cancer with which to study the 
biology of tumors and how they spread.  Breast cancer cell lines, although informative, do not reliably 
reflect breast cancer heterogeneity or morphology in vivo, and thus poorly predict how drugs will perform 
in the clinical setting [34-36].  To address this, patient-derived xenografts (PDX) are being explored as 
surrogates for originating tumors, as reviewed by Landis and colleagues [37].  
Interestingly, several groups have found that the take rate (rate of engraftment) of PDX correlate with 
tumor grade, with the most aggressive TNBCs having higher take rates than ER+ tumors [38-41].  
Marangoni and colleagues used estrogen-treated Swiss nude mice to subcutaneously transplant tumor 
into the subscapular fat pad [38].  A 12.5% rate of engraftment was observed (25 out of 200 samples), 
with almost all PDX displaying an aggressive phenotype.  PDX response rate compared to patient response 
to treatment was concordant in 5/7 of cases, supporting the utility in these models to predict patient 

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response to therapeutics. Bergmaschi and colleagues used estrogen supplementation and transplantation 
into the interscapular fat pad of severe combined immunodeficiency (SCID) mice, resulting in a 7% take 
rate [39].  Of the 2 PDX established, both maintained concordance with the original tumors.  Our group, 
in collaboration with others successfully established PDX directly from breast cancer patient samples, 
using epithelium-free mammary fatpad as the transplantation site [40].  Again, most patients yielded triple 
negative PDX, though lines from other subtypes were also established.  PDX were phenotypically 
consistent with their tumor of origin, and of the 27 lines fully evaluated, 48% developed metastatic lesions 
to the lungs. 
Investigators at Washington University in St. Louis have also successfully developed several panels of PDX 
from breast cancer patients. Six patients with TNBC have had successful PDX developed from their original 
tumors.  
Whole genome sequencing of a breast cancer primary, brain metastasis, and PDX basal-like breast cancer 
in one patient demonstrated a PDX model that efficiently captured almost all of the genome-wide somatic 
mutations from the original tumor and was enriched for mutations present in the metastatic sample.  They 
have also shown that comparative whole-genome sequencing demonstrates that PDX preserves the 
genomic structural similarities to originating TNBC tumors [42].  A panel of PDX from patients with 
treatment-resistant breast cancer was established to study the genomic, biological, and pharmacological 
characteristics of advanced breast cancer 
This trial is based on the hypothesis that PDX are accurate replicas of originating tumors and can 
recapitulate chemotherapy response.  The ability to effectively utilize innovative PDX models may be a 
unique new starting point for molecular pharmacology in TNBC patients.  The development of these 
models, as outlined here, will allow an exploration of the relationship between PDX phenotype and clinical 
outcome of patients from whom tumors arose.  It will elucidate the mechanisms of response to 
chemotherapy through analysis of serial biopsies using proteomic technologies, while also correlating 
molecular changes in PDX to those in originating tumors. The profound impact of this study to clinical 
breast cancer research is that ultimately, drug discovery using PDX as a living replica may be done more 
efficiently, especially for those with chemotherapy-resistant TNBC, thus allowing for uniquely 
individualized management.  
1.5.2 
Cell-free circulating tumor DNA 
Cell-free circulating tumor DNA has been proposed as a surrogate biological material to define the genetic 
aberrations of a primary tumor and/or metastases in a given cancer patient, and to serve as a biomarker 
for diagnosis, prognostication, and monitoring of response to therapy.  Recent studies have demonstrated 
that mutations in PIK3CA and/or TP53 can be identified in the ctDNA from plasma samples of the vast 
majority of patients with advanced breast cancer and in approximately 50% of patients with early stage 
breast cancer. 

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Our hypotheses are that plasma ctDNA analysis may provide a means to predict relapse after primary 
breast cancer systemic therapy and to characterize the genetic composition of the resistant clones. 
Furthermore, ctDNA analysis has been shown to constitute a source of DNA that allows for the 
investigation of the repertoire of somatic mutations found in micrometastatic and metastatic disease.  
ctDNA may also prove useful as an indicator of pCR before surgery.  This could improve surgical decision 
making and allow for de-escalation of local therapy. 
 
 
 
 
 
 
 

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2.0 
OBJECTIVES 
2.1 
Primary Objective 
To determine whether neoadjuvant docetaxel and carboplatin will increase the pCR rate in TNBC 
compared to historical controls. Pathologic complete response (pCR) will be defined as no residual 
invasive breast cancer in the breast and ipsilateral axillary lymph node (ypT0-is ypN0). 
2.2 
Exploratory Objectives 
1. To determine the xenografting rate from TNBC patients being treated with neoadjuvant 
chemotherapy.   
2. To compare chemotherapy responses in PDX and TNBC patients being treated with 
neoadjuvant chemotherapy 
3. To investigate genomic and proteomic molecular changes in PDX and corresponding host 
patients with the intent to identify predictors of drug response and resistance.  
 
 

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3.0 
PATIENT SELECTION 
3.1 
Inclusion Criteria 
1. All patients must be 18 years of age or older. 
2. All patients must be diagnosed with invasive breast cancer. 
3. Breast cancer must be ER-negative, and HER-2 negative according to CAP/ASCO biomarkers 
testing guidelines. Tumors may be PgR positive with an Allred score of less than 5. 
4. Primary breast tumor size at least 2 cm in one dimension by clinical or radiographic exam. 
Patients who have multicentric breast cancer are eligible if each lesion is ER-negative and 
HER2-negative. In that case, one lesion needs to be identified as the index lesion to be 
followed for clinical response.  The index lesion must also be the lesion from which core 
biopsies are obtained.   
5. Patients with inflammatory breast cancer are eligible if they meet both of the following 
criteria: 
a. Patient has an underlying, clinically palpable breast mass of at least 2cm, AND 
b. a corresponding lesion is visualized on mammogram or ultrasound 
6. Normal bone marrow and organ function as defined below: 
a. Leukocytes > 3,000/mcL 
b. Absolute neutrophil count > 1,200/mcl 
c. Platelets > 100,000/mcl 
d. Serum bilirubin ≤ institutional 1.5 times ULN (OR for patients with documented Gilbert 
Syndrome, total bilirubin ≤ 3.0 times ULN with direct bilirubin ≤ ULN)  
e. AST(SGOT)/ALT(SGPT) ≤ 2.5 times ULN 
f. Creatinine ≤ 1.5 ULN         
7. Women of childbearing potential (defined as women under the age of 55 with intact ovaries 
and uterus) must agree to use adequate contraception prior to study entry and for the 

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duration of study participation. They must also have a negative urine pregnancy test within 7 
days of starting treatment. 
8. Ability to understand and willingness to sign an IRB approved written informed consent 
document and follow study procedures including willingness to undergo study biopsies. 
 
3.2 
Exclusion Criteria 
1. Any prior systemic therapy for breast cancer within 5 years. 
2. A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous 
cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of 
the cervix. 
3. Patients with known bilateral invasive breast cancer. Patients with contralateral in situ breast 
carcinoma are eligible. 
4. Patients with confirmed stage IV disease. 
5. Currently receiving any other investigational agents. 
6. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to docetaxel or carboplatin. 
7. Known to be seropositive for HIV, HCV, or HBV.   
8. Any prior treatment with Taxotere or Carboplatin. 
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.  
10. If the patient is otherwise not deemed a good study candidate by sole discretion of the 
principal investigator. 
11. Patient is pregnant or breastfeeding.   
 
 
 

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4.0 
REGISTRATION PROCEDURES 
4.1 
Guidelines for Lead Institution 
Patients should be registered in the electronic database (available at: https://oncore.research.bcm.edu/) 
as soon as the patient has signed the informed consent.  Following registration, the patient’s enrollment 
status in the electronic database will be listed as pending. Prior to enrollment in the electronic database, 
the eligibility worksheet must be reviewed and signed by the study coordinator and a Breast Center 
physician, in accordance with Lester & Sue Smith Breast Center standard operating procedures. Eligibility 
data will then be entered in the electronic database and the subject will be designated as “on study”. 
Study treatment may begin only after eligibility has been confirmed by both a study coordinator and a 
Breast Center physician.  Once eligibility has been reviewed, the study treatment must begin according to 
the timeframe designated by the screening procedures listed in the study calendar (Section 5.1).  
4.2 
Guidelines for Other Institutions 
Participants MUST be registered with the Leading Institution prior to the start of protocol treatment. 
Subject registration will be managed by the lead study coordinator at the Lester & Sue Smith Breast Center 
(LSSBC) as described below. 
Potential study subjects who have signed the Informed Consent document should be registered in the 
electronic database Oncore.  Registration should occur as soon as possible after signed consent is 
obtained, in order to ensure that the potential subject is assigned the correct study number. The Lead 
Coordinator will then assign the subject with the study number.  
Once a potential subject has completed all required screening procedures, the responsible study 
coordinator should complete the Eligibility Worksheet, which will be provided to sites upon site activation.  
The eligibility worksheet should be reviewed by both the site study coordinator and the local principal 
investigator for accuracy.  Completed worksheets, along with de-identified source documentation, should 
be transmitted to the lead study coordinator at the Lester & Sue Smith Breast Center for confirmation of 
eligibility. Once eligibility data are entered in the electronic database and confirmed, the subject will be 
designated “on study”. Study treatment may not begin until eligibility has been confirmed by a 
representative from the Lester & Sue Smith Breast Center.  
Patients found to be ineligible for participation after being consented will be considered screen failures, 
and documented as such in the Screening and Enrollment Log.  These patients will not be eligible to receive 
study treatment.   
 

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4.3 
Eligibility exceptions 
Any requests for protocol exceptions must be approved in writing by Dr. Mothaffar Rimawi at the Lester 
& Sue Smith Breast Center.  Request for protocol exceptions must be made via email or fax to the lead 
study coordinator.  Both Dr. Rimawi and the local PI should be copied on all requests and associated 
correspondence.  Once a determination has been made, the site study coordinator and local PI will be 
notified in writing.  In the event that an eligibility exception is granted by the coordinating center, the 
local site must submit the exception to their local IRB in accordance with institutional standard operating 
procedures.   
 
5.0 
STUDY PROCEDURES 
Patients enrolled on study will have the following study assessments and procedures performed as 
described.  For a summary of required assessments, please refer to the study calendar located in Section 
11.0. 
5.1 Screening assessments 
A signed, written informed consent must be obtained before any study-specific assessments are initiated.  
Results from assessments performed prior to written consent as part of a patient’s routine diagnostic 
workup may be used for screening purposes. The following assessments will be obtained at screening, 
within 28 days prior to beginning study medication, unless otherwise noted: 
 
Signed, written informed consent 
 
Subject demographic information, to include age, ethnicity, and race 
 
Medical history, including past and current conditions, and past surgical history 
 
Physical exam, to include vital signs, weight, a clinical breast exam, and palpation of lymph nodes. 
– For patients with palpable breast masses, tumor measurements (as assessed by 
palpation)/calipers MUST be recorded in the clinic progress note 14 days prior to initiation 
or treatment 
– Please see Section 12.1 for tumor measurement guidelines 
 
Laboratory assessments to include: 
– CBC/differential/platelets 
– Serum chemistry profile (should include sodium, potassium, chloride, calcium, glucose, 
blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine 
transaminase (ALT), alkaline phosphatase, total bilirubin, total protein, and albumin)   

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– Serum βHCG (for pre- or perimenopausal subjects with an intact uterus).  NOTE – If 
screening HCG performed more than 7 days prior to Day 1, serum HCG must be repeated 
on Day 1 prior to beginning study medication. 
 
Bilateral mammogram (may be obtained within 6 weeks prior to Day 1 of study treatment). A full, 
diagnostic mammogram must be performed to fulfill this requirement.  Mammograms performed 
to verify clip placement, or mammograms containing only spot compression images, will not be 
accepted for study purposes. 
 
Breast ultrasound (unilateral, unless a bilateral ultrasound is clinically indicated; may be obtained 
within 6 weeks prior to Day 1 of study) 
 
Bone imaging, if patient is experiencing bone pain, or if bone imaging is otherwise clinically 
indicated.  If bone imaging is not clinically indicated, the treating physician must document as 
such in the source documents. 
 
Chest imaging (A CT chest, Chest X-ray PA & Lateral, or PET/CT are acceptable imaging 
techniques), to be performed if clinically indicated 
 
Review of all underlying AEs taken within 28 days of planned treatment start date 
 
If the above studies are within acceptable parameters as defined by the eligibility criteria, the participant 
will undergo a breast biopsy as described in Section 10.1 and research blood will be collected as descibed 
in Section 10.2.  If eligible, the patient will begin the combination of docetaxel and carboplatin as descibed 
in Section 6.  
5.2 Cycle 1 Day 1 
The following assessments should be performed within 3 days prior to the start of study medication: 
 
Physical exam, to include vital signs, weight, a clinical breast exam, and palpation of lymph nodes. 
– For patients with palpable breast masses, bidimensional tumor measurements (as 
assessed by palpation)/calipers) MUST be recorded in the clinic progress note (may be 
performed up to 3 days prior to C1D1) 
 
Laboratory assessments to include a CBC/differential/platelets and serum chemistry panel, as 
defined in Section 5.1. 
 
Record compliance to study medications and infusion schedule 
 
Non-serious and serious adverse events should be recorded and graded appropriately as 
discussed in Section 8. 
 
Serum pregnancy test if not performed 7 days priot to initiation of study treatment.  
 
5.3 Cycle 1 Day 7 
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▪ Core needle biopsy (optional) 
▪ Research blood draw (mandatory) 
5.4 Cycles 2,3,4,5, and 6 Day 1 
The following assessments should be performed within 3 days prior to the start of study medication: 
 
Physical exam, to include vital signs, weight, a clinical breast exam, and palpation of lymph nodes. 
– For patients with palpable breast masses, bidimensional tumor measurements (as 
assessed by palpation)/calipers) MUST be recorded in the clinic progress note (may be 
performed up to 3 days prior to each cycle) 
 
Laboratory assessments to include a CBC/differential/platelets and serum chemistry panel, as 
defined in Section 5.1. 
 
Record compliance to study medications and infusion schedule 
 
Non-serious and serious adverse events should be recorded and graded appropriately as 
discussed in Section 8. 
5.5 End of Treatment 
The following assessments should be performed within 2 weeks of the completion of last cycle. These 
assessments should also be performed for patients who discontinue treatment prematurely prior to the 
initiation of alternate treatment, if applicable.  
 
Physical exam, to include vital signs, weight, a clinical breast exam, and palpation of lymph nodes. 
– For patients with palpable breast masses, tumor measurements (as assessed by 
palpation)/calipers) MUST be recorded in the clinic progress note. 
 
Laboratory assessments to include a CBC/differential/platelets and serum chemistry panel as 
defined in section 5.1.   
 
Unilateral mammogram and breast ultrasound will be performed to further assess clinical 
response in the primary tumor and to document response to treatment.  A diagnostic 
mammogram is necessary to fulfill the mammogram requirement. 
 
Collect research blood 
 
Non-serious and serious adverse events should be recorded and graded appropriately as 
discussed in Section 8 of the protocol. 
 
At this point, patients will have completed study treatment and should proceed with definitive surgery. In 
the event of early discontinuation, patients who require additional neoadjuvant treatment will have an 
option to undergo a core needle biopsy for research purposes.  For patients proceeding directly to surgery, 
surgery should be scheduled between 4 and 6 weeks after the last dose of study treatment. If surgery is 

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delayed for a time period greater than 65-weeks following study completion, a core needle biopsy may 
be performed in lieu of surgical specimen collection if the patient has residual disease amenable to biopsy.  
5.6 
Follow up procedures 
The following assessments should be performed within 2 months (+/- 1 week) of the completion of last 
cycle, and then annually for five years or until disease recurrence, whichever comes first: 
▪ Research blood collection 
All subjects will be followed for survival at approximately 1 year intervals from the date of diagnosis.  
Survival follow-ups may be conducted by phone, email, or clinic visit, and will be discontinued in the event 
of subject death or withdrawal of consent. At each follow-up, disease and vital status will be documented.  
If patient has experienced disease recurrence or progression, the sites of recurrence/progression will be 
recorded. 
 
 
6.0 
TREATMENT PLAN 
6.1 
Premedication Administration 
Patients receiving docetaxel should be premedicated according to institutional standards to prevent or 
decrease the chance of reactions. Premedications must include steroids orally or intravenously.  
6.2 
Agent Administration 
Docetaxel will be administered intravenously at a dose of 75mg/m2 on Day 1 of each 21-day cycle.  
Carboplatin AUC 6 will be administered intravenously on Day 1 of each 21-day. For carboplatin dosing, 
creatinine clearance (CrCl) will be calculated according to the modified Cockcroft-Gault equation using 
actual body weight.  CrCl should be capped at 125 mL/min.  A total of 6 cycles will be given. A 3 day window 
will be allowed for the 21 day cycle, if deemed appropriate by the treating physician.  
Surgery will take place after the conclusion of the neoadjuvant regimen, ideally within 4-6 weeks.  Further 
adjuvant chemotherapy may be given at the discretion of the treating physician.   
6.3 
Anthracycline-Based Adjuvant Chemotherapy 
Patients who develop any of the following will have the option of receiving anthracycline-based 
chemotherapy pre- or post-operatively at the discretion of the treating physician, after an end of 
treatment biopsy. Due to the infeasibility of evaluating pathologic response in participants who receive 

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non-protocol therapy prior to surgery, such patients will be counted as non-pathologic complete 
responses for the purpose of statistical analysis. 
 
Grade 3 neuropathy 
 
Other intolerable side effects 
 
Progressive disease 
 
Failure to achieve a pCR following treatment with docetaxel/carboplatin 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
Physicians will perform standard monitoring for toxicity to chemotherapy administration. Patients will be 
treated for toxicities at the discretion of the physician. Growth factor support with either filgrastim or 
pegfilgrastim is at the discretion of the investigator. 
6.5 
Women of Childbearing Potential 
Women of childbearing potential (defined as women under the age of 55 with intact ovaries and uterus) 
are required to have a negative serum pregnancy test within 7 days prior to the first dose of 
docetaxel/carboplatin.   
Female patients are required to use acceptable contraception during participation in the study. 
If a patient is suspected to be pregnant, chemotherapy should be immediately discontinued.  In addition 
a positive urine test must be confirmed by a serum pregnancy test.  If it is confirmed that the patient is 
not pregnant, the patient may resume dosing. 
If a female patient becomes pregnant during therapy or within 6 months after the last dose of 
chemotherapy, the principal investigator must be notified in order to facilitate outcome follow-up. 
6.6 
Duration of Therapy 
If at any time the constraints of this protocol are considered to be detrimental to the patient’s health 
and/or the patient no longer wishes to continue protocol therapy, the protocol therapy should be 
discontinued and the reason(s) for discontinuation documented in the case report forms. 
In the absence of treatment delays due to adverse events, treatment may continue for 6 cycles or until 
one of the following criteria applies: 
 
Documented and confirmed disease progression 

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 
Adverse event(s) that, in the judgment of the investigator, may cause severe or permanent harm 
or which rule out continuation of study drug 
 
General or specific changes in the patient’s condition render the patient unacceptable for further 
treatment in the judgment of the investigator 
 
Suspected pregnancy 
 
Serious non-compliance with the study protocol as determined by the principal investigator. 
 
Lost to follow-up 
 
Patient withdraws consent 
 
Principal investigator removes the patient from study 
 
Death 
 
Study closure. 
Patients who prematurely discontinue treatment for any reason will be followed as indicated in the study 
calendar. 
6.7 
Duration of Follow-up 
Patients will be followed for survival on a yearly basis for 5 years. This can be achieved during routine 
clinical follow up visits, phone contact, or checking the electronic medical record.  Patients removed 
from study for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.   
 
 

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7.0 
DOSE DELAYS/DOSE MODIFICATIONS 
For patients who are unable to tolerate the protocol-specified dosing schedule, it is strongly 
recommended that dose modifications be made according to the dose adjustment schedule detailed in 
the table below.  Deviations from the recommended modifications are permitted in the event that they 
are deemed medically necessary by the treating physician, with prior approval by the principal 
investigator.  Medical necessity and PI approval must be documented in the patient’s medical record.  If 
carboplatin is to be delayed, administration of docetaxel shall be omitted as well.  Toxicity will be assessed 
using the NIH-NCI Common Terminology Criteria for Adverse Events, version 4.0. 
Table 1: Dose levels for docetaxel and carboplatin 
 
Dose Level 0 
Starting Dose 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Docetaxel (mg/m2) 
75 
60 
50 
Discontinue 
Carboplatin (AUC) 
6 
5 
4 
Discontinue 
 

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Table 2: Dose modifications/delays for DOCETAXEL and CARBOPLATIN 
Important table instructions: 
• Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs present on the 
scheduled cycle Day 1 (column 3). 
• MODIFICATIONS APPLY TO BOTH CARBOPLATIN AND DOCETAXEL UNLESS SPECIFIED OTHERWISE. 
• Dose modifications must be based on the AE requiring the greatest modification. 
NCI CTCAE v4.0 
Category/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a)  
Modifications for AEs that 
REQUIRE A DELAY IN ADMINISTRATION 
OF THE TREATMENT CYCLE 
(See footnote b) 
Neutrophil count decreased: 
Grade 2 (1000-1199/mm3), 
Grades 3, 4 
 
 
Maintain dose 
ANC: Hold until ≥  1200/mm3.  If recovery 
takes: 
1-3 wks – maintain dose and add G-
CSF 
If receiving G-CSF and recovery takes: 
1 wk – maintain dose 
2-3 wks –  ↓ one dose level 
Platelet count decreased: 
Grades 2, 3 
 
Maintain dose 
Platelets: Hold until ≥  75,000/mm3.  If 
recovery takes: 
1 wk – maintain dose;  
2 to 3 wks - ↓ one dose level 
 
Grade 4 
 
↓ one dose level 
Hold until ≥  75,000/mm3. 
↓ one dose level 
GI (if related to 
chemotherapy): 
Diarrhea 
Grade 2 
 
 
 
Maintain dose 
 
 
 
↓ one dose level 

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Important table instructions: 
• Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs present on the 
scheduled cycle Day 1 (column 3). 
• MODIFICATIONS APPLY TO BOTH CARBOPLATIN AND DOCETAXEL UNLESS SPECIFIED OTHERWISE. 
• Dose modifications must be based on the AE requiring the greatest modification. 
NCI CTCAE v4.0 
Category/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a)  
Modifications for AEs that 
REQUIRE A DELAY IN ADMINISTRATION 
OF THE TREATMENT CYCLE 
(See footnote b) 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ two dose levels or discontinue 
↓ two dose levels or discontinue 
Mucositis - oral 
Grade 2 
 
Maintain dose 
 
↓ one dose level 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ two dose levels or discontinue 
↓ two dose levels or discontinue 
Vomiting (despite 
antiemetics) 
Grade 2 
 
↓ one dose level (optional) 
 
↓ one dose level 
Grades 3, 4 
↓ one dose level or discontinue 
↓ two dose levels or discontinue 
Investigations (hepatic): 
Bilirubin, AST, alk phos 
 
Grade 2 
 
 
 
↓ one dose level 
Hold until bilirubin returns to the baseline 
grade and AST and alk phos have 
returned to ≤ grade 1. 
↓ one dose level 
Grade 3 
↓ two dose levels 
Hold until bilirubin returns to the baseline 
grade and AST and alk phos have 
returned to ≤ grade 1. 
↓ two dose levels 

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Important table instructions: 
• Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs present on the 
scheduled cycle Day 1 (column 3). 
• MODIFICATIONS APPLY TO BOTH CARBOPLATIN AND DOCETAXEL UNLESS SPECIFIED OTHERWISE. 
• Dose modifications must be based on the AE requiring the greatest modification. 
NCI CTCAE v4.0 
Category/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a)  
Modifications for AEs that 
REQUIRE A DELAY IN ADMINISTRATION 
OF THE TREATMENT CYCLE 
(See footnote b) 
Grade 4 
Discontinue 
Discontinue 
Infection or febrile 
neutropenia: 
Grade 2 
(N/A for febrile neutropenia) 
 
Maintain dose and add G-CSF 
prophylaxis for subsequent 
chemotherapy cycles if 
neutropenia was present.c 
 
Grade 3 
Maintain dose and add G-CSF 
prophylaxis 
with 
subsequent 
chemotherapy cycles.  If already 
receiving prophylactic G-CSF, ↓ one 
dose level. 
 
Grade 4 
Maintain dose or ↓ one dose level 
and add G-CSF prophylaxis with 
subsequent chemotherapy cycles.  
If receiving prophylactic G-CSF, ↓ 
one dose level or discontinue. 
 
 
Investigations: 
Creatinine increased 
Grades 2, 3 
Hold until serum creatinine is ≤ 
grade 1 and calculated creatinine 
clearance is ≥ 30 mL/min. 
− 
If creatinine clearance is > 
50 mL/min, maintain 
dose. 
− 
If creatinine clearance is 
30-50 mL/min, ↓ 
carboplatin one dose 
level. 
 

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Important table instructions: 
• Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs present on the 
scheduled cycle Day 1 (column 3). 
• MODIFICATIONS APPLY TO BOTH CARBOPLATIN AND DOCETAXEL UNLESS SPECIFIED OTHERWISE. 
• Dose modifications must be based on the AE requiring the greatest modification. 
NCI CTCAE v4.0 
Category/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a)  
Modifications for AEs that 
REQUIRE A DELAY IN ADMINISTRATION 
OF THE TREATMENT CYCLE 
(See footnote b) 
 
If calculated creatinine clearance is 
< 30 mL/min but all other non-renal 
function AEs have resolved to ≤ 
grade 1 on the scheduled Day 1, 
carboplatin must be held and 
docetaxel may be administered.  If 
calculated 
creatinine 
clearance 
subsequently improves to ≥ 30 
mL/min by Day 1 of the next 
scheduled cycle, carboplatin may 
be resumed with docetaxel.  The 
missed carboplatin dose will not be 
made up. 
Grade 4 
Discontinue 
 
Other clinically significant 
AEsd: 
Grade 2 
 
 
Maintain dose or ↓ one dose level 
 
Grade 3 
↓ one dose level 
↓ one dose level 
Grade 4 
↓ two dose levels or discontinue 
Discontinue 
a 
Resolved means that all AEs are ≤ grade 1 (except ANC/AGC [which must be ≥ 1200/mm3] and bilirubin 
[which must be ≤ the baseline grade]) on Day 1 of the next scheduled cycle (i.e., treatment can be given 
without delay). 
b 
Hold and check weekly.  With exception of ANC/AGC and bilirubin, resume treatment when toxicity is  
≤ grade 1.  If toxicity has not resolved after 3 weeks of delay, discontinue docetaxel and carboplatin. 

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Important table instructions: 
• Dose modifications must be based on AEs that occurred during the cycle (column 2) and AEs present on the 
scheduled cycle Day 1 (column 3). 
• MODIFICATIONS APPLY TO BOTH CARBOPLATIN AND DOCETAXEL UNLESS SPECIFIED OTHERWISE. 
• Dose modifications must be based on the AE requiring the greatest modification. 
NCI CTCAE v4.0 
Category/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT TREATMENT CYCLE 
(See footnote a)  
Modifications for AEs that 
REQUIRE A DELAY IN ADMINISTRATION 
OF THE TREATMENT CYCLE 
(See footnote b) 
c 
If grade 2 criteria for infection include topical antibiotics or other local treatment, use of G-CSF is at the 
investigator's discretion. 
d     Determination of "clinically significant" AEs is at the discretion of the investigator. 
 
Table 3: Treatment management for docetaxel-related neuropathy 
Nervous System Disorders 
Paresthesias 
Peripheral sensory neuropathy 
1-7 Days Duration 
Persistent for > 7 Days or 
Caused the Next Cycle  
to be Delayed 
Grade 1 
Maintain docetaxel dose 
Grade 2 
Maintain docetaxel dosea 
Decrease docetaxel  
one dose levelb 
Grade 3 
First episode: 
Decrease docetaxel one dose levela 
Second episode: 
Discontinue docetaxel 
Discontinue docetaxel 
Grade 4 
Discontinue docetaxel 
a 
Must be resolved to ≤ grade 1 on Day 1 of the next cycle. 
b 
Hold chemotherapy (docetaxel and carboplatin) for persistent grade 2 neuropathy.  When  
≤ grade 1, resume treatment with dose modification for docetaxel (no dose reduction for carboplatin).  If 
grade 2 toxicity persists after 3 weeks of delay, discontinue docetaxel.   
 

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Table 4: Treatment management for docetaxel-related musculoskeletal pain 
Musculoskeletal and 
Connective Tissue Disorders 
Arthralgia 
Myalgia 
1 – 7 Days Duration 
Persistent for > 7 Days or Caused the 
Next Cycle to be Delayed 
Grade 1 
(despite analgesics) 
Maintain docetaxel dose 
Grade 2 
(despite analgesics) 
Maintain docetaxel dose 
Maintain docetaxel dose 
or 
Decrease docetaxel one dose level* 
Grade 3 
(despite analgesics) 
First episode: 
Decrease docetaxel one dose level 
Second episode: 
Discontinue docetaxel 
First episode: 
Decrease docetaxel one dose level* 
or 
Discontinue docetaxel 
Second episode: 
Discontinue docetaxel 
* 
Hold docetaxel for persistent grade 2 or 3 musculoskeletal pain.  When ≤ grade 1, resume treatment with 
dose modification for docetaxel.  If grade 2 or grade 3 toxicity persists after 3 weeks of delay, discontinue 
docetaxel. 
 
 
 

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8.0 
REGULATORY AND REPORTING REQUIREMENTS 
8.1 
General 
This study will use the descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v4.0) that is available at http://ctep.cancer.gov/reporting//ctc.html. 
Information on all adverse events, whether reported by the participant, directly observed, or detected by 
physical examination, laboratory test or other means, will be collected, recorded, followed and reported 
as described in the following sections.  
Adverse events experienced by participants will be collected and reported from initiation of study 
medication, throughout the study, and within 30 days of the last dose of study medication, as described 
in the Case Report Form Completion Guidelines. Participants 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 
participating investigator.  
Participants should be instructed to report any serious post-study event(s) that might reasonably be 
related to participation in this study. The investigator should notify the IRB and any other applicable 
regulatory agency of any unanticipated death or adverse event occurring after a participant has 
discontinued or terminated study participation that may reasonably be related to the study. 
8.2 
Definitions 
8.2.1 
Adverse Events (AEs) 
An adverse event is any undesirable sign, symptom or medical condition or experience that develops or 
worsens in severity after starting the first dose of study treatment or any procedure specified in the 
protocol, even if the event is not considered to be related to the study.  
8.2.2 
Serious Adverse Event (SAE) 
 A serious adverse event is an undesirable sign, symptom, or medical condition which: 
 
is fatal or life-threatening; 
 
requires or prolongs inpatient hospitalization; 
 
results in persistent or significant disability/incapacity; 
 
constitutes a congenital anomaly or birth defect; or 
 
jeopardizes the participant and requires medical or surgical intervention to prevent one of the 
outcomes listed above.  
 
Any other event, which, in the opinion of the investigator, could be considered serious. 

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Events not considered to be serious adverse events are hospitalizations for: 
 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission 
 
respite care 
8.2.3 
Expectedness  
 
Expected:  Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the package insert or is included in the 
informed consent document as a potential risk. 
 
Unexpected:  An adverse event is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current adverse event list, the package insert or when 
it is not included in the informed consent document as a potential risk. 
8.2.4 
Attribution  
The investigator will determine the relationship of each adverse event, if any, to investigational treatment 
or study procedure.  Causality should be assessed using the following categories: Unrelated, Unlikely, 
Possible, Probable, or Definite.   
The degree of certainty with which an adverse experience is attributed to drug treatment (or alternative 
causes, e.g. natural history of the underlying diseases, concomitant therapy, etc.) will be determined by 
how well the experience can be understood in terms of the following: 
 
Known pharmacology of the drug 
 
Reaction of similar nature being previously observed with this drug or class of drug 
 
The event having often been reported in literature for similar drugs as drug related (e.g. skin 
rashes, blood dyscrasia) 
 
The event being related by time to drug administration terminating with drug withdrawal 
(dechallenge) or reproduced on rechallenge. 
The investigator may change his/her assessment of causality in light of follow-up information.  All adverse 
events will be recorded, regardless of whether the event is thought to be related to investigational 
treatment.  Attribution will be assigned as follows: 
 
Definite – The AE is clearly related to the study treatment. 

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 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment.  
 
Unlikely - The AE is doubtfully related to the study treatment. 
 
Unrelated - The AE is clearly NOT related to the study treatment. 
8.3 Reporting Procedures 
8.3.1 
General 
Adverse events will be captured in both the source documents and on the appropriate study-specific case 
report forms (CRFs).  Given that each of the medications being utilized in this trial has a well-established 
safety profile, this protocol will utilize targeted AE reporting for all non-serious adverse events, as 
described below. 
8.3.2 
  AE reporting requirements 
▪ AE of any grade that requires a modification to treatment (e.g. dose modification, dose delay, or 
drug discontinuation) 
▪ All grade 3 and 4 AEs, regardless of causality 
▪ Any clinically significant laboratory abnormality, defined as an abnormality requiring medical 
intervention or further diagnostic work-up, as determined by the treating physician. 
▪ All serious adverse events (SAEs). 
8.3.3 
Serious Adverse Events 
Any serious adverse events that occur during the clinical study or within 30 days of receiving the last dose 
of study medication, whether or not related to the study drug, must be reported by the investigator. In 
addition, any SAEs which occur as a result of protocol specific diagnostic procedures or interventions must 
also be reported. 
All serious adverse events must be reported to the FDA within 1 business day of becoming aware of the 
event. Events should be reported using a MedWatch form (FDA Form 3500A), which is available for 
download on the FDA website.   
The SAE report should comprise a full, written summary detailing relevant aspects of the adverse events 
in question.  Where applicable, information from relevant hospital case records and autopsy reports 
should be included.  Follow-up information and follow-up reports should be forwarded to all appropriate 
entities within 24 hours. A copy of all documents submitted to the FDA should be sent to the Lead Site. 
Serious adverse events should be reported to the Institutional Review Board within 24 hours if they meet 
the reporting criteria set forth in the IRB Policy Manual. 
 

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9.0 
PHARMACEUTICAL INFORMATION 
9.1 
Docetaxel (Taxotere) 
9.1.1 
Docetaxel Description 
Docetaxel is an antineoplastic agent belonging to the taxoid family.  The chemical name for docetaxel is 
(2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,13α-
hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate.  Docetaxel is a white to almost-white 
powder with an empirical formula of C43H53NO14·3H2O and a molecular weight of 861.9.  It is highly 
lipophilic and practically insoluble in water. 
9.1.2 
Clinical Pharmacology 
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is 
essential for mitotic and interphase cellular functions.  Docetaxel binds to free tubulin and promotes the 
assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly.  This leads 
to the production of microtubule bundles without normal function and to the stabilization of 
microtubules, which results in the inhibition of mitosis in cells.  Docetaxel’s binding to microtubules does 
not alter the number of protofilaments in the bound microtubules, a feature which differs from most 
spindle poisons currently in clinical use. 
9.1.3 
Pharmacokinetics and Drug Metabolism 
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 
mg/m2 to 115 mg/m2 in phase 1 studies.  The area under the curve (AUC) was dose proportional following 
doses of 70 mg/m2 to 115 mg/m2 with infusion times of 1 to 2 hours.  Docetaxel’s pharmacokinetic profile 
is consistent with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases 
of 4 min, 36 min, and 11.1 hr, respectively.  Mean total body clearance was 21 L/h/m2.  In vitro drug 
interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism 
may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized 
by cytochrome P450 3 A4. 
9.1.4 
Supplier(s) 
Docetaxel is commercially available. 
9.1.5 
Administration 
Docetaxel will be administered intravenously at a dose of 75mg/m2 on Day 1 of each 21-day cycle.  
Premedication will be administered according to institutional guidelines but must include oral or 
intravenous steroids.  

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9.1.6 
Expected Adverse Events 
The most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, 
febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, 
anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, 
skin reactions, and myalgia. 
9.2 
Carboplatin 
9.2.1 
Carboplatin Description 
Carboplatin is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of carboplatin.  Carboplatin 
is a platinum coordination compound.  The chemical name for carboplatin is platinum, diamine [1,1-
cyclobutane-dicarboxylato(2-)-0,0’]-,(SP-4-2).  It has a molecular formula of C6H12N2O4Pt and a molecular 
weight of 371.25.  It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution 
is 5 to 7.  It is virtually insoluble in ethanol, acetone, and dimethylacetamide. 
9.2.2 
Supplier(s) 
Carboplatin is commercially available. 
9.2.1 
Administration 
Carboplatin dosing will be AUC6 on Day 1 of each 21-day cycle for 6 cycles.  Premedication with 
antiemetics should be in accordance with institutional standards. 
9.2.2 
Expected Adverse Events 
Myelosuppression, nausea and vomiting (moderately emetogenic), peripheral neuropathy (occurring in < 
10% of patients, mild in severity), hepatotoxicity (mild, reversible elevations in liver function tests), and 
allergic reactions. 
 
 

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10.0 CORRELATIVE STUDIES 
10.1 Tumor Biopsy 
Research biopsies will be performed at baseline, Cycle 1 Day 7, and definitive surgery.  The Cycle 1 Day 7 
biopsy will be optional.  For patients with multicentric disease, all core needle biopsy samples should be 
taken from the index lesion, for all biopsy timepoints.  Collection should be performed according to the 
following guidelines.  
Based on previous experience, we estimate that not all single core needle biopsies will contain tumor 
tissue.  In order to maximize the likelihood of sufficient tissue, approximately 4-6 cores should be taken 
at each biopsy time-point. Two cores will be frozen on dry ice in OCT blocks at bedside, two will be fixed 
in formalin, and two (at the baseline and end of treatment biopsies) will be collected in media and placed 
on wet ice. Biopsies will be performed under local anesthesia, using the same entry point, but reorienting 
the needle.  
Breast tissue will be obtained by core needle biopsy, which will be performed on an outpatient basis.  The 
procedure will be performed by either an experienced breast medical oncologist or a member of the 
breast imaging staff.    The procedure will be described to the participant prior to each procedure, and the 
participant will be given the opportunity to ask questions.  The procedure will be performed as follows.  
The skin will be cleaned with an antiseptic solution (Betadine).  A local anesthetic (1% or 2% lidocaine) will 
be injected to the area that will be biopsied.  A small incision will be made into the skin using a scalpel.  
Next, the biopsy needle will be inserted through the incision and tissue cores will be obtained.  
Moderate pressure will be applied to the biopsy site for about 10 minutes.  The incision site is Steri-
Stripped and a 2x2 gauze pressure bandage is applied. No suture is required to close the small wound. 
The procedure is routinely done in the physician’s office, and the patient is released home after the 
procedure. Potential complications include bleeding, pain, or infection.  These risks are discussed with the 
patient prior to the beginning of each procedure. 
Following the procedure, the collected tissue specimens will be delivered to the Lester & Sue Smith Breast 
Center Tissue Bank, where they will be processed and stored.  In the event that baseline or surgical tissue 
samples are found to contain an insufficient amount of tumor for analysis, archival tissue may be 
requested. 
10.2 Research Blood 
Blood (50 mL total) will be drawn for research purposes at the following timepoints: 
 
Baseline 
 
Cycle 1 Day 7 (+/- 3 days) 

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 
at end of treatment, as per the study calendar 
 
2 months following definitive surgery, +/- 1 week, 
 
annually for five years or until disease recurrence, whichever comes first 
 
Blood will be collected as follows at each of the above time points: 
 
10 mL tiger top tube  
 
a 10 mL EDTA tube for plasma and DNA collection 
 
a 10 mL EDTA tube containing protease inhibitors (BD – P100 tube) 
 
a 10 mL lithium heparin (green top) tube for heparinized plasma 
 
a 10 mL Streck Cell-Free DNA BCT for plasma circulating DNA 
Collected blood specimens will be processed as detailed in the laboratory manual.  Specimens will be 
delivered to the Lester & Sue Smith Breast Center Tissue Bank, where they will be stored until further use. 
10.3 Specimen Storage and Banking 
Blood and tissue specimens obtained for this study will be delivered to the Lester & Sue Smith Breast 
Center Tissue Bank.  The physical address for the Tissue Bank is: 
Breast Center Tissue Bank 
Alkek Building, N1110 
One Baylor Plaza 
Houston, TX 77030 
 
Once received in the Tissue Bank, specimens will be processed and stored until utilized as per protocol.  
Samples will not contain any traditional patient identifiers; however, samples will be coded such that 
specimens are traceable back to the patient.  The link between the specimen code and the patient will be 
maintained in a secure area, accessible only to the Tissue Bank Coordinator.   
At the conclusion of the protocol-specified analyses, any leftover study blood and tissue samples may be 
stored indefinitely in the Tissue Bank for future research studies, provided that the participant has 
consented to future use.  The subjects will be given the opportunity to consent to future use of samples 
in the consent form for the study.  Samples will only be released for use in future studies after approval 
by the Principal Investigator and other regulatory bodies, as appropriate.  Any specimens that remain after 
this protocol is closed with the IRB may be transferred to BCM protocol # H-12573, provided that the 
participant has consented to storage and future use of donated tissue. 

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10.4 
Planned analyses 
Collected tissue and blood specimens will be analyzed as described below.  Additional analyses other than 
those listed below may be performed in the event of new information.   
10.4.1 Patient-Derived Xenografts 
Xenografts will be established from the biopsy specimens collected at baseline and end of treatment.  
Tissue collected from the Cycle 1 Day 7 biopsy will be used for genomic and proteomic analyses to study 
molecular changes and identify markers of response and resistance. Tissue collected from the Cycle 1 Day 
7 biopsy will be used for genomic and proteomic analyses to study molecular changes and identify markers 
of response and resistance.   Once obtained, specimens will be delivered to the Tumor Bank as quickly as 
is feasible following collection, but no later than 1 day after collection, as described in the laboratory 
manual.  For fragment transplantation, samples will be minced into approximately 1 mm3 fragments and 
transplanted directly into epithelium-free “cleared” fat pads of recipient SCID/Bg (Charles River 
Laboratories), or NSG mice (Jackson Laboratories) per patient.   Mice will be palpated weekly and tumor 
growth measured using calipers.  
Once established, xenografts will be characterized according to the methods described in Zhang, et al[43]. 
10.4.2 Genomic and proteomic analyses 
Genomic and proteomic analyses will be performed on the established xenografts using the techniques 
available at the time analysis is conducted.  Results obtained from these analyses will be compared to 
similar data from patient tumors.  Genomic profiling (including gene expression profiling and aCGH) of 
tumor tissue will be performed to explore the relationship between genoproteomic factors and endpoints 
including response, etc as well as to explore the longitudinal changing patterns in profiling.   
10.4.3 Whole genome sequencing 
Both tumor and matched normal blood will be collected from each patient for the comparison of germline 
and tumor genotypes to verify that any detected mutations are of somatic origin. Strict requirements of 
quality, quantity, purity, and avoidance of necrotic tissue is essential, and only samples with greater than 
50% tumor cellularity will be used to generate 5 mcg of genomic DNA from immediately flash frozen 
biopsies. Whole genome amplification (WGA) will be performed on smaller biopsies if required, by which 
the original DNA sample is amplified in a specific way from nanogram concentrations to microgram, while 
conserving the sequence representation of the template. At BCM-HGSC, the discovery phase uses support 
oligonucleotide ligation detection (SOLiD) sequencing instruments (Applied Biosystems, Inc.). A high-
throughput SOLiD pipeline has been established at HGSC since 2008 for the purpose of supporting whole 
genome sequencing activities, and is now being implemented for identification of mutations in autosomal 
dominant ataxias, ovarian, breast, and pancreatic cancers and glioblastoma.  

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Data generated from whole genome sequencing will be uploaded into a controlled-access database, 
maintained by Baylor College of Medicine.  The BCM database will only be accessible by BCM personnel 
working on this project.  All data downloaded by BCM personnel will reside behind a secure, firewall 
protected server.  Sequencing data may eventually be uploaded into an online repository, maintained by 
the National Institute of Health (NIH). In this situation, the information in this database will be available 
only to researchers and institutions who have received approval from an NIH Data Access Committee after 
certifying their adherence to patient data protection policies for the project. Please note that traditionally-
used identifying information about the patient, such as name, address, telephone number, or social 
security number, will NOT be put into any database used for this project.   
10.4.4 Cell-free circulating tumor DNA 
Cell-free circulating tumor DNA has been proposed as a surrogate biological material to define the genetic 
aberrations of a primary tumor and/or metastases in a given cancer patient, and to serve as a biomarker 
for diagnosis, prognostication, and monitoring of response to therapy.  Recent studies have demonstrated 
that mutations in PIK3CA and/or TP53 can be identified in the ctDNA from plasma samples of the vast 
majority of patients with advanced breast cancer and in approximately 50% of patients with early stage 
breast cancer. 
 
Our hypotheses are that plasma ctDNA analysis may provide a means to predict relapse after primary 
breast cancer systemic therapy and to characterize the genetic composition of the resistant clones.  Cell-
free circulating tumor DNA analysis reflects disease burden and offers a substantial lead-time over 
radiologic detection for the detection of metastatic disease of up to 13.5 months.  Furthermore, ctDNA 
analysis has been shown to constitute a source of DNA that allows for the investigation of the repertoire 
of somatic mutations found in micrometastatic and metastatic disease.  ctDNA may also prove useful as 
an indicator of pCR before surgery.  This could improve surgical decision making and allow for de-
escalation of local therapy. 
To address our hypotheses, mandatory plasma samples from enrolled patients will be collected at baseline 
prior to start of chemotherapy, when chemotherapy has been competed and then 2 months after surgery 
has been completed.  Samples will also be taken yearly for a total of 5 years or until relapse.  DNA will be 
extracted from the plasma samples following validated protocols.  In brief, 10 mL blood samples collected 
in Streck Cell-Free DNA BCT tubes and will be sent to the Breast Center Tissue Bank.  Cell-free circulating 
tumor DNA (ctDNA) will be extracted and analyzed following established protocols. 
 
In order to identify tumor DNA variants that will be used for personalized ultra-sensitive ctDNA assays for 
each patient in the study, DNA will be extracted from the primary tumor and subjected to targeted capture 
followed by massively parallel sequencing.  We will focus the targeted capture approach on genes most 
frequently mutated in breast cancer.  Based on a re-analysis of The Cancer Genome Atlas (TCGA) breast 

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cancer dataset, 100 most frequently mutated genes in breast cancer have been identified. A customized 
bait library based on these data could generate an informative ctDNA assay in > 96% of all breast cancers.  
The repertoire of somatic mutations obtained through targeted capture massively parallel sequencing of 
each primary cancer will be the basis for the development of a personalized ctDNA assay.  This may be 
based on the digital droplet PCR approach; however, technology in this field is advancing rapidly.  Since 
this field is rapidly evolving, the exact platform for analysis will be determined based on available 
technology. Since translocations and deletions provide the most specific analytes for ctDNA assays current 
efforts to search for recurrent translocations in breast cancer using combined DNA and RNA sequencing 
are very relevant to the development of the final assay that will be deployed. Changes in ctDNA will be 
correlated to outcomes. 
 
 
 

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11.0 STUDY CALENDAR 
Baseline evaluations must be performed within 28 days prior to the start of treatment, unless otherwise 
noted: 
 
Screening / 
Baseline 
C1D113 
C1D7 
(+/- 3 days) 
Cycles 2-6, 
Day 113 
Surgery3 
EOT12 
F/U5 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical exam, tumor measurement 
(2D) 
X2 
X 
 
X 
 
X 
 
Vital signs, weight, height 
X 
X 
 
X 
 
X 
 
Mammogram10 
X 
 
 
 
 
X 
 
Breast Ultrasound11 
X 
 
 
 
 
X 
 
Chest Imaging (optional) 7 
X 
 
 
 
 
 
 
Bone imaging8 
X 
 
 
 
 
 
 
Hematology1 
X 
X 
 
X 
 
X 
 
Comprehensive metabolic panel 
X 
X 
 
X 
 
X 
 
Serum Pregnancy test9 
X 
X 
 
 
 
 
 
Docetaxel  
 
X 
 
X 
 
 
 
Carboplatin 
 
X 
 
X 
 
 
 
Research blood 
X 
 
X 
 
 
X 
X 
Research tissue 
X 
 
X4 
 
X 
 
 
Adverse events6 
X 
X 
 
X 
 
X 
 
1. 
WBC plus differential, hemoglobin, and platelets 
2. 
Breast tumor measurements must be performed within 14 days prior to Cycle 1 Day 1.  
3. 
To be performed between 3 and 5 weeks after completing neoadjuvant therapy 
4. 
Optional. 
5. 
Follow annually for survival for 5 years.  Research blood draw should be collected 2 months (+/- 1 week) after the 
patient’s definitive surgery, and then annually for five years or until disease recurrence, whichever comes first.   
6. 
Collect AEs for 30 days following last day of chemotherapy. 
7. 
Staging CT chest or CXR should be performed if clinically indicated, as determined by the treating physician.  Optional 
unless clinically indicated.  PET or PET/CT is permitted as an alternative to CXR or CT chest. 
8. 
Bone imaging via PET/CT or nuclear medicine bone scan is required if one of the following criteria are met: a) Patient 
has unexplained bone pain; b) ALP > ULN. 
9. 
Serum HCG only required for WOCBP.  Required on C1D1 if it has been greater than 7 days since previous HCG 
10. Bilateral mammogram required at baseline; unilateral mammogram may be performed at EOT.  Bilateral breast MRI 
may be substituted for mammogram at the discretion of the treating physician.  May be performed within 6 weeks 
prior to start of treatment. 

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11. Ultrasound required only of affected breast.  May be performed within 6 weeks prior to treatment start. 
12. EOT procedures must be performed within 2 weeks of completion of last cycle.  In the event of early discontinuation, 
EOT procedures should be performed prior to the initiation of alternate treatment, if applicable.  Breast imaging 
procedures are not required in the event of early discontinuation, but may be performed at the discretion of the 
treating physician. 
13. May be perfomed 3 days prior to chemotherapy treatment.  
 
12.0 MEASUREMENT OF EFFECT  
12.1 Clinical Responses 
Physical examination: The longest axis and the perpendicular axis of the measurable lesion should be 
measured and recorded in metric notation by tape, ruler or caliper technique in the source documents 
and on the case report forms.  Breast tumor measurements should be taken at baseline (within 14 days 
prior to C1D1), on Day 1 of each subsequent cycle, and again following the completion of Cycle 6 (prior to 
surgery). 
Radiographic evaluation of tumor size:  Mammogram and ultrasound imaging will be performed within 42 
days of Cycle 1 Day 1, and again at the end of cycle 6 combination therapy.   
RECIST 1.1 criteria will be used to assess clinical response  
Complete Response (CR) is defined as the disappearance of all known disease based on a comparison 
between the pre-treatment measurements and the measurements taken at the completion of neo-
adjuvant therapy. In addition there is no appearance of new lesions.  
Partial Response (PR) is defined as a 30% or greater decrease in the longest diameter of the breast tumor 
between the pre-treatment measurements and the measurements taken at the completion of neo-
adjuvant therapy. In addition there can be no appearance of new lesions or progression of any lesion. 
Stable Disease (SD) Changes between a 30% decrease and a 20% increase in the longest diameter of the 
primary tumor, without appearance of new lesions.. 
Progressive Disease (PD): A 20% or greater increase in the total tumor size of the lesion from its 
pretreatment measurements or the appearance of new lesions at any point in study treatment.  
12.2 Surgery 
A pathologic complete response (pCR) is defined as no histology evidence of invasive tumor cells in the 
surgical breast specimen and sentinel or axillary lymph nodes.  

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All eligible women who have been treatment with combination therapy are included in the analysis of 
pCR. A patient is considered to not to have a pCR if any of the following are true: 
1. There is histologic evidence of invasive tumor cells in the surgical breast specimen or the 
axillary lymph nodes. 
2. The patient has discontinued neo-adjuvant treatment early due to refusal, toxicity, or 
radiographic or clinical evidence of progression and then goes straight to surgery where there 
is histologic evidence of invasive tumor cells in the surgical breast specimen and the axillary 
lymph nodes. 
3. The patient has discontinued neo-adjuvant treatment early due to refusal, toxicity or 
radiographic or clinical evidence of progression and then receives alternative treatment. 
4. The patient refuses surgery or is unable to undergo surgery due to a co-morbid condition. 
12.3 Diagnosis of Breast Cancer Recurrence and Other Cancer Events  
12.3.1 Local Recurrence  
Local recurrence is defined as histologic evidence of ductal carcinoma in situ or invasive breast cancer in 
the ipsilateral breast or chest wall.  
12.3.2 Regional Recurrence 
Regional recurrence is defined as the cytologic or histologic evidence of disease in the ipsilateral internal 
mammary, ipsilateral supraclavicular, ipsilateral infraclavicular and/or ipsilateral axillary nodes or soft 
tissue of the ipsilateral axilla. 
12.3.3 Distant Recurrence 
Distant recurrence is defined as the cytologic, histologic, and/or radiographic evidence of disease in the 
skin, subcutaneous tissue, lymph nodes (other than local or regional metastasis), lung, bone narrow, 
central nervous system or histologic and/or radiographic evidence of skeletal or liver metastasis.  
12.3.4 Second Primary Breast Cancer  
Second primary breast cancer is defined histologic evidence of ductal carcinoma in situ or invasive breast 
cancer in the contralateral breast or chest wall.  
12.3.5 Second Primary Cancer (Non-breast) 

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Any non-breast second primary cancer other than squamous or basal cell carcinoma of the skin, 
melanoma in situ, or carcinoma in situ of the cervix is to be reported and should be confirmed 
histologically whenever possible. 
12.3.6 Death 
Underlying cause of death is to be reported. 
 
 

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13.0 DATA AND SAFETY MONITORING 
13.1 Data Management and Reporting 
In compliance with the Dan L Duncan Cancer Center Data and Safety Monitoring Plan, the Principal 
Investigator will provide a Data and Safety Monitoring (DSM) report to the Dan L Duncan Cancer Center 
Data Review and Safety Committee (DRC) annually starting from the date the trial is activated.  Adverse 
events reported on this study will also be reviewed on a biweekly basis at the Lester & Sue Smith Breast 
Center Clinical Research and Data Review meetings. 
All patients who received any amount of study drug will be included in the safety analysis.  Subjects will 
be monitored at each clinic visit and at any contact with the subject throughout the study for the 
occurrence of AEs and SAEs. The investigator or staff will inquire about the occurrence of AEs/SAEs at 
every clinic visit or contact during the study.  Adverse events will be graded according to the NCI Common 
Terminology Criteria v. 4.0.   All AEs that occur during active treatment will be recorded in subject source 
documents and on CRF, according to the guidelines specified in Section 8 of the protocol.  Non-serious 
adverse events that occur within the 30 day follow-up period will only be recorded on the CRFs if the 
investigator believes there to be a possible relationship to study medication.   Serious adverse events 
should be recorded, regardless of relationship to drug. 
Safety analyses will include summaries of adverse event rates (both frequency and incidence tables), 
baseline laboratory parameters and changes from baseline, frequency of CTC toxicity grades for both 
laboratory and non-laboratory data. The investigators and others responsible for patient care should 
institute any supplementary investigations of major adverse events based on their clinical judgment of 
the likely causative factors. 
13.2 Meetings  
We will utilize the Data and Safety Monitoring Plan of the Dan L. Duncan Cancer Center at Baylor College 
of Medicine. During the clinical trial, clinical data on all participants enrolled on the study will be reviewed 
in our monthly breast center Data and Safety Monitoring Meeting.  
We will have the trial reviewed at our Data Review Committee which will review accruals, serious adverse 
events, and cumulative toxicity data. The DRC will make recommendations about safety and tolerability. 
13.3 Monitoring 
As the lead site, Baylor College of Medicine will monitor all participating sites. Monitoring visits will 
occur at the following timepoints and can be conducted via phone or physically at the participating sites, 
at the discretion of the lead site: 

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1. After accrual of the first patient to each participating site. 
2. After the last patient at each site completes study treatment. 
3. At study close out. 
4. At other intervals per discretion of the lead site. 
14.0 REGULATORY CONSIDERATIONS 
14.1 Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional Review Board (IRB) 
per the current institutional standards of each participating center. 
Any changes to the protocol will be made in the form of an amendment and must be approved by the IRB 
of each institution prior to implementation.   
The Protocol Chair (or his designee) is responsible for the coordination and development of all protocol 
amendments, and will disseminate this information to the participating centers. 
14.2 Informed Consent 
The investigator (or his/her designee) will explain to each subject the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved and any discomfort 
it may entail.  Each subject will be informed that participation in the study is voluntary, that s/he may 
withdraw from the study at any time, and that withdrawal of consent will not affect her subsequent 
medical treatment or relationship with the treating physician(s) or institution.  The informed consent will 
be given by means of a standard written statement, written in non-technical language, which will be IRB 
approved.  The subject should read and consider the statement before signing and dating it, and will be 
given a copy of the document.  No subject will enter the study or have study-specific procedures done 
before his/her informed consent has been obtained. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the consent 
document) will include a subject authorization to release medical information to the study sponsor and 
supporting agencies and/or allow these bodies, a regulatory authority, or Institutional Review Board 
access to subjects’ medical information that includes all hospital records relevant to the study, including 
subjects’ medical history. 
 
14.3 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as described in: 

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1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 
1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to adhere 
to the principles of Good Clinical Practice that it conforms to. 
 
15.0 MULTI-CENTER GUIDELINES 
15.1 Study Documentation  
Each participating site is responsible for submitting copies of all relevant regulatory documentation 
to the Coordinating Center. The required documents include, but are not limited to the following: 
local IRB approvals (i.e., protocol, consent form, amendments, patient brochures and recruitment 
material, etc.), IRB membership rosters, summary of unanticipated problems or protocol deviations, 
and documentation of expertise of the investigators. The Coordinating Center will provide each 
participating site with a comprehensive list of the necessary documents. It is the responsibility of the 
participating sites to maintain copies of all documentation submitted to the Coordinating Center. 
 
The requirements for data management, submissions, and monitoring are outlined below. 
 
All data collected will be entered by the participating site into the Coordinating Center Electronic 
Database (eCRF), via ONCORE. 
15.2 Records Retention  
Following closure of the study, each participating center will maintain a copy of all site study records 
in a safe and secure location. Records must be maintained for at least 5 years following the conclusion 
of the study, or in accordance with institutional policy, whichever is longer. The Coordinating Center 
will inform the investigator at each site at such time that the records may be destroyed. 

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15.3 Publication  
It is understood that any manuscript or releases resulting from the collaborative research will be 
circulated to all participating sites prior to submission for publication or presentation. 

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16.0 STATISTICAL CONSIDERATIONS 
16.1 Study Design 
16.1.1 Purpose 
This is a single arm open label phase II study in women with clinical stage 2 or 3 triple negative breast 
cancer to assess the anti-tumor activity (in terms of pathologic complete response rate) of neoadjuvant 
docetaxel in combination with carboplatin.  
16.1.2 Primary Endpoint 
The primary endpoint of this trial is pathological complete response (pCR), as defined in section 10.2. All 
eligible women who begin combination treatment will be included in the analyses of the primary study 
endpoint.  
16.1.3 Sample Size and Trial Duration 
In this trial, we will use an admissible Simon-like two-stage decision rule[44] in order to allow early 
stopping in the event of futility. We will enroll up to 44 pCR-evaluable participants. If there are fewer than 
8 pCR’s in the first 22 pCR-evaluable cases, the trial will stop. Otherwise, at the end of the trial, if there 
are 20 or more pCR’s out of 44 participants, the new therapy will be deemed to be effective, while fewer 
than 20 will lead to a negative conclusion. The sample size is based on comparing the observed pCR rate 
to a rate of 35% that would be expected with standard chemotherapy, and the decision rules stated above 
will provide 90% power (alpha=10%, one-tailed) to detect a difference if the true pCR rate is 55% or better.  
We anticipate that 3 patients per month will be screened for trial eligibility. Approximately 50% of the 
patients will be eligible and enroll. Thus, we anticipate screening about 90 patients to obtain 44 eligible 
and pCR-evaluable patients as calculated above. We expect accrual will be steady and will not be paused 
to wait for the last patient in the first stage to be evaluated for pCR. 
The period encompassing enrollment, study treatment, and surgery will be 36 months [30 months to 
enroll 44 eligible patients and 5-6 months to await surgical results of last patient enrolled].   
16.1.4 Statistical Analysis Plan 
16.1.4.1 
Primary outcome 
pCR rate: The outcome of the trial will be evaluated using the decision rules decribed above. In the event 
that the realized pCR-evaluable sample size is different from planned, methods such as proposed by Green 
et al [45] will be used. The primary endpoint of pCR rate and the associated 95% confidence interval will 
be estimated from the number of pCR evaluable participants who are pCR’s or not, using the method of 
Jung  and Kim [46] to account for the two-stage nature of the design. 

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16.1.4.2 
Secondary outcomes 
Clinical response rate:  The clinical response rate and associated 95% confidence interval will be estimated 
by the number of patients whose disease meets the RECIST 1.1 criteria of complete or partial response 
prior to surgery divided by the total number of eligible patients who began combination neoadjuvant 
treatment.  
Radiological response rate: The radiological response rate and associated 95% confidence interval will be 
estimated by the number of patients whose disease meets with RECIST 1.1 criteria for complete or partial 
response at the evaluation prior to surgery divided by the total number of eligible patients who began 
combination neoadjuvant therapy.  
Adverse Events:  All eligible patients that received any chemotherapy will be considered evaluable for 
assessing adverse event rate(s).  As described in Section 6.3.1 targeted reporting will be used. The 
maximum grade for each type of reportable adverse event will be recorded for each patient using the NCI-
CTCAE v4.0 coding scheme. AE’s by grade and attribution will be summarized descriptively as frequency 
tables. 
16.1.4.3 
Exploratory Studies 
A number of exploratory or correlative studies are proposed for this study. Collection and establishment 
of patient derived xenograft lines is an important biologic outcome that will allow detailed examination 
of molecular markers of response and ‘co-clinical trial’ testing of other therapies in the future. Tumor 
engraftment rates will be estimated for tumor samples taken before and during chemotherapy.  A paired 
analysis will compare rates. Successful xenografts will be fully characterized molecularly in order to allow 
exploratory analyses of potential predictive biomarkers. 
  
 
 

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