Clinical trial NCT02124902
Conditions: Triple Negative Breast Neoplasms
Sponsor: Washington University School of Medicine
Start date: 2014-07-07; Completion date: 2021-12-31
Enrollment: 148 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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. Patient derived xenografts will also be developed simultaneously for the purposes of genoproteomic analysis.

Please note that Baylor College of Medicine (BCM) has a parallel study the same as this study. Baylor is expected to enroll approximately 19 participants that have complied with the inclusion and exclusion criteria for this study (excluded participants from BCM will include male participants or participants with inflammatory breast cancer). The investigators will pool participants and data from the BCM study and the study at Washington University School of Medicine. Pooling the data will potentially improve statistical power.

Detailed description:

Arms: arm 1: Docetaxel will be administered intravenously at a dose of 75mg/m2 over 60 minutes on Day 1 of each 21-day cycle. Carboplatin AUC 6 will be administered intravenously over 30 minutes on Day 1 of each 21-day cycle immediately following docetaxel infusion. A total of 6 cycles will be given. arm 2: Docetaxel will be administered intravenously at a dose of 75mg/m2 over 60 minutes on Day 1 of each 21-day cycle. Carboplatin AUC 6 will be administered intravenously over 30 minutes on Day 1 of each 21-day cycle immediately following docetaxel infusion.
Interventions: intervention 1: Docetaxel intervention 2: Carboplatin intervention 3: FDG-PET/MR
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: * Prior to initialization of Cycle 1 and completion of cycle 1 (preferably on cycle 2 day 1)
* This is not optional for final 30 participants enrolled on the study

Protocol documents:
Prot_SAP_000.pdf: 
Version 07/12/2019 
 
page 1 of 49 
 
 
 
A Co-clinical Trial in Triple Negative Breast Cancer Patients with Genoproteomic Discovery 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #:  201404107 
Version Date: 07/12/2019 
 
Principal Investigator:  
Foluso Ademuyiwa, M.D., MPH 
Phone: (314) 362-7201 
E-mail: bisiademuyiwa@wustl.edu 
 
Sub-Investigators  
 
Modality 
Cynthia X. Ma, M.D, Ph.D. 
 
Medical Oncology 
Ron Bose, M.D., PhD. 
Medical Oncology 
Rama Suresh, M.D.  
 
 
Medical Oncology 
Lindsey Peterson, M.D.   
 
Medical Oncology 
Ashley Frith, M.D. 
 
 
Medical Oncology 
Leonel Hernandez Aya, M.D.  
 
Medical Oncology 
Peter Oppelt, M.D.  
 
 
Medical Oncology 
Caron Rigden, M.D.  
 
 
Medical Oncology 
Haeseong Park, M.D.  
 
 
Medical Oncology  
Katherine Weilbaecher, M.D. 
 
Medical Oncology 
 
Jingqin Luo, Ph.D.  
Biostatistics 
Julie Margenthaler, M.D.  
 
Surgical Oncology 
Rebecca L. Aft, M.D., Ph.D. 
 
Surgical Oncology 
Amy Cyr, M.D.  
 
 
Surgical Oncology 
Timothy Eberlein, M.D. 
 
 
Surgical Oncology 
William Gillanders, M.D.  
 
Surgical Oncology 
Kooresh Shoghi, Ph.D. 
 
 
Radiology 
Farrokh Dehdashti, M.D.  
 
Radiology 
Hongyu An, Ph.D. 
 
 
Radiology 
Steven Poplack, M.D. 
 
 
Radiology 
Jieqi Wang, M.D. 
 
 
Radiology 
Study Drugs: 
 
 
Carboplatin 
Docetaxel 
Clinical Trials.gov#: 
NCT02124902 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to obtain 
informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons to 
whom the information is disclosed must be informed that the information is confidential and may not be further disclosed 
by them 


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A Co-clinical Trial in Triple Negative Breast Cancer Patients with Genoproteomic 
Discovery 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
04/28/2014 
Amendment #1 Version 
 
 
 
 
 
 
06/03/2014 
Amendment #2 Version 
 
 
 
 
 
 
04/23/2015 
Amendment #3 Version 
 
 
 
 
 
 
01/19/2016 
Amendment #4 Version 
 
 
 
 
 
 
03/28/2016 
Amendment #5 Version 
 
 
 
 
 
 
08/02/2016 
Amendment #6 Version 
 
 
 
 
 
 
05/03/2017 
Amendment #7 Version 
 
 
 
 
 
 
03/28/2018 
Amendment #8 Version 
 
 
 
 
 
 
07/25/2018 
Amendment #9 Version 
 
 
 
 
 
 
03/06/2019 
Amendment #10 Version 
 
 
 
 
 
 
07/12/2019 
 
 


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A Co-clinical Trial in Triple Negative Breast Cancer Patients with Genoproteomic 
Discovery 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research tumor biopsy for xenografting 
Pre-therapy research FDG-PET/MR imaging 
Eligible Patients 
Clinical Stage II or III Triple Negative Breast Cancer 
Treatment Plan 
Neoadjuvant IV docetaxel plus carboplatin every 3 
weeks X 6 cycles 
Post-therapy research FDG-PET/MR imaging 
(post-C1, pre-C2) 
OPTIONAL research tumor biopsy for 
molecular analysis (Cycle 1 Day 3) 
Surgery (3-5 weeks post-neoadjuvant therapy) 
Research tumor for molecular analysis 


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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 
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 


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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 
 
SCHEMA ........................................................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 8 
1.1 
Triple Negative Breast Cancer ......................................................................................... 8 
1.2 
Neoadjuvant Chemotherapy in Triple Negative Breast Cancer ....................................... 8 
1.3 
Patient-derived Xenografts (PDX) in Breast Cancer ..................................................... 10 
1.4 
Chemotherapy Agents .................................................................................................... 11 
1.5 
Study Rationale .............................................................................................................. 13 
1.6 
Correlative Studies Background..................................................................................... 15 
2.0 
OBJECTIVES .................................................................................................................... 16 
2.1 
Primary Objective .......................................................................................................... 16 
2.2 
Exploratory Objectives ................................................................................................... 16 
3.0 
PATIENT SELECTION .................................................................................................... 17 
3.1 
Inclusion Criteria ............................................................................................................ 17 
3.2 
Exclusion Criteria ........................................................................................................... 17 
3.3 
Inclusion of Women and Minorities............................................................................... 18 
4.0 
REGISTRATION PROCEDURES ................................................................................... 18 
4.1 
Confirmation of Patient Eligibility ................................................................................. 19 
4.2 
Patient Registration in the Siteman Cancer Center Oncore Database ............................ 19 
4.3 
Assignment of UPN ....................................................................................................... 19 
5.0 
TREATMENT PLAN ........................................................................................................ 19 
5.1 
Premedication Administration........................................................................................ 19 
5.2 
Agent Administration ..................................................................................................... 19 
5.3 
Anthracycline-Based Adjuvant Chemotherapy .............................................................. 20 
5.4 
General Concomitant Medication and Supportive Care Guidelines .............................. 20 
5.5 
Women of Childbearing Potential .................................................................................. 20 
5.6 
Duration of Therapy ....................................................................................................... 20 
5.7 
Duration of Follow-up .................................................................................................... 21 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 21 
7.0 
SIMULTANEOUS PET/MR IMAGING AND ANALYSIS ............................................ 21 
7.1 
Multi-Modality PET/MR Imaging ................................................................................. 22 
7.2 
Image Analysis ............................................................................................................... 22 
7.3 
Toxicities Related to FDG-PET/MR Imaging ............................................................... 23 
8.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 24 
8.1 
Definitions ...................................................................................................................... 24 
8.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
26 
8.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 26 
8.4 
Timeframe for Reporting Required Events .................................................................... 26 
9.0 
PHARMACEUTICAL INFORMATION .......................................................................... 27 
9.1 
Docetaxel (Taxotere) ...................................................................................................... 27 
9.2 
Carboplatin ..................................................................................................................... 28 
10.0 CORRELATIVE STUDIES .............................................................................................. 30 
10.1 Tumor Biopsy ................................................................................................................. 30 


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10.2 Research Blood .............................................................................................................. 31 
11.0 STUDY CALENDAR ....................................................................................................... 33 
12.0 DATA SUBMISSION SCHEDULE ................................................................................. 34 
13.0 MEASUREMENT OF EFFECT........................................................................................ 34 
13.1 Clinical Responses ......................................................................................................... 34 
13.2 Treatment Resistance ..................................................................................................... 35 
13.3 Surgery ........................................................................................................................... 35 
13.4 Diagnosis of Breast Cancer Recurrence and Other Cancer Events ................................ 35 
14.0 DATA AND SAFETY MONITORING ............................................................................ 36 
15.0 STATISTICAL CONSIDERATIONS............................................................................... 37 
15.1 Study Design .................................................................................................................. 37 
16.0 REFERENCES .................................................................................................................. 42 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 48 
APPENDIX B: Cockcroft-Gault ................................................................................................... 49 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Triple Negative Breast Cancer 
 
Triple negative breast cancer (TNBC) represents approximately 10-20% 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.  In addition, 
it is critical to identify patients who will respond to neoadjuvant docetaxel and carboplatin 
(NAC) therapy, and to avoid the use of an ineffective treatments in nonresponding patients 
with an opportunity to devise adaptive treatment strategies.    
 
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 that time, 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 creates an excellent model to assess 
pathologic tumor response and analyze tissue upon completion of systemic chemotherapy.  
Ultimately, this allows for the identification of molecular changes induced by treatment, 
and most importantly, it permits determination of predictors of chemotherapy resistance 
and chemotherapy sensitivity (CS) to better individualize management.   
 
While several clinical trials involving neoadjuvant traditional chemotherapy, biologics, or 
different dosing schedules have recently been launched in an attempt to improve the 


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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 recently indicating a role for platinum agents in the treatment 
of TNBC.  CALGB 40603, recently 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 avoided in the treatment of TNBC.  
 
 


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1.3 
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 14. 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 14-16.  To address this, patient-derived xenografts (PDX) are 
being explored as surrogates for originating tumors, as reviewed extensively by Landis and 
colleagues 17.  
 
Interestingly, several groups have found that the take rate of PDX correlate with tumor 
grade, with the most aggressive grade III and IV TNBCs having higher take rates than ER+ 
tumors 18-21.  Marangoni and colleagues used estrogen-treated Swiss nude mice to 
subcutaneously transplant tumor into the subscapular fat pad 18.  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 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 19.  Of the 2 PDX established, both maintained 
concordance with the original tumors.  Zhang and colleagues established PDX directly 
from breast cancer patient samples, using epithelium-free mammary fatpad as the 
transplantation site  20.  Again, most patients yielded triple negative PDX, though lines 
from 
other 
subtypes 
(ER-PR-HER2+, 
ER+PR+HER2–, 
ER+PR-HER2, 
and 
ER+PR+HER2+) 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. 
 
At our institution, we have successfully developed several panels of PDX (Washington 
University Human in Mouse-WHIM lines) from breast cancer patients under the umbrella 
of the Longitudinal Cancer Gene Profiling Using Sequential Tissue Biopsies breast cancer 
protocol 
(HRPO# 
04-0022 
/ 
201102244). 
Six 
patients with TNBC 
have had successful 
WHIM 
lines 
developed 
from 
their 
original 
tumors. Three of 
these patients are deceased while the other 3 achieved a pCR and are currently disease free. 
Table 1 shows characteristics of WHIMs and corresponding patients.   


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Additionally, we have previously shown that 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.  We 
have also shown that comparative whole-genome sequencing demonstrates that PDX 
preserves the genomic structural similarities to originating TNBC tumors22.  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. 
Concordant human and xenografts ER and HER2 status was demonstrated at the mRNA 
level and confirmed by western blotting.. Array-based mRNA expression data was 
generated from the originating tumors and matched early and late passage WHIM 
counterparts. In almost all cases the originating tumor and WHIM lines derived from the 
same individual clustered adjacently when subjected to unsupervised clustering. In 
addition, all structural variants (translocations, large deletions, inversions) were preserved 
upon transplantation, including complex crisscross patterns between 2 chromosomal 
regions characteristic of chromothripsis (Figure 1).  However, there were usually many 
more supporting reads for any particular structural variant in the WHIM line analysis than 
in the originating tumor because the xenograft data analysis pipeline removed all 
background sequence from the mouse genome, thereby “virtually purifying” the human 
tumor DNA from mouse stromal DNA. The preservation of variant allele frequencies from 
human to PDX suggests stable interactions between minor and major clones that were not 
influenced by the xenografting process. 
 
This study 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.  
 
1.4 
Chemotherapy Agents 
 
Chemotherapy can substantially reduce the risk of breast cancer recurrence and death in 
early stage breast cancer 23, 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 


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cyclophosphamide (TAC), reduce the risk of recurrence by 11% and the risk of death by 
16% compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) 
combinations 24. 
 
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 25. 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 26. 
 
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 27.  
 
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 
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 28 29. Most recently, SWOG 0221, compared weekly 


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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 scheduling30. 
 
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.31 
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.32 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.33 
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.34 Multiple other small studies have 
also evaluated neoadjuvant platinum-based therapy in patients with TNBC with varying 
results.35-42 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.   
 
1.5 
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 


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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 develop 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 
(CS) 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 standard of care 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 with a view to omitting anthracyclines. This strategy will avoid the 
cardiotoxicity and leukemia risk associated with anthracyclines and will develop evidence 
for a much more convenient regimen than the Gerpar 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 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 24, 
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 


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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. 
 
1.6 
Correlative Studies Background 
 
Development of new cancer therapies 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, and to use for validation of the efficacy of potential new drugs. This protocol using 
PDX models may be a unique new starting point for molecular pharmacology in TNBC 
patients. The development of these models will allow an exploration of the relationship 
between PDX phenotype and clinical outcome of patients from whom tumors arose. It will 
also enable investigating the mechanisms of response to chemotherapy through analysis of 
serial tissue using genomic and proteomic technologies, while also correlating molecular 
changes in PDX to those in originating tumors.  
 
1.6.1 Multi-parametric Positron Emission Tomography (PET) and Magnetic 
Resonance (MR) Imaging to Assess Response to Therapy 
 
Advanced quantitative imaging (QI) strategies offer an opportunity to assess and 
predict response to therapy early in the treatment.  18F-fluorodeoxyglucose (FDG), 
a glucose analogue, with PET has been extensively used to measure tumor 
metabolism as an indicator of response to therapy.  Similarly, 18F-fluorothymidine 
(FLT), a cell proliferative marker, with PET imaging is used as a marker of tumor 
proliferation via the DNA_salvage pathway.  Both have shown efficacy in assessing 
tumor response to therapy.  In particular, FDG-PET image metrics have shown 
utility in stratifying responders from non-responders 43-46 in TNBC.  More recently, 
results from the American college of radiology imaging network (ACRIN) 6688 
trial have shown that FLT-PET weakly predicted pCR in the setting of variable 
NAC and a mixed population of breast cancer patients; with the conclusion that a 
more uniform patient population/NAC plan is needed to fully assess the utility of 
FLT-PET 47.  In addition, multi-parametric MR imaging has shown efficacy in 
assessing response to therapy in breast cancer 48 49.  The primary objective of QI 
strategies to identify patients who will respond to NAC therapy, in order to avoid 
the use of ineffective treatments in nonresponding patients with an opportunity to 
devise adaptive treatment strategies.  In this context, one of the objectives of this 
trial is to initiate a pilot study to assess the utility of advanced QI methods to predict 
pCR in TNBC.   
 
The addition of a grant (U24CA209837) is to support imaging studies to assess 
response to therapy.  It is critical to identify patients who will respond to NAC 
therapy, and to avoid the use of an ineffective treatments in nonresponding 


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patients with an opportunity to devise adaptive treatment strategies.  The imaging 
methodologies have already been included in the protocol, however, they were 
optional.  With the addition of the funding, imaging will be required.  All imaging 
studies will be performed at the Center for Clinical Imaging Research (CCIR).  
We are requesting to add 30 patients to support the objectives proposed in the 
grant.  Groheux et al. 59 have shown efficacy in differentiating pCR in TNBC with 
a sample size of 20 using 18FDG PET/MR where change in SUVmax yielded an 
AUC of 0.88 and with 30% of the sample being pCR. Therefore, conservatively 
based on this data, a sample of 30 patients (30% being responders) achieves 80% 
power to detect a difference of 0.3 between the AUC under the null hypothesis of 
0.5 and an AUC under the alternative hypothesis of 0.8 using a one-sided z-test at 
a significance level of 0.05 and assuming a dropout rate of 15%. 
 
 
1.6.2 Circulating tumor DNA to predict clinical outcome 
 
ctDNA is cell-free tumor-derived fragmented DNA in the bloodstream and has 
shown promise for disease monitoring and molecular characterization in advanced 
cancers.50-56 In advanced TNBC, mutations in ctDNA show high concordance with 
those seen in primary breast biopsies.57 In early stage breast cancer, detection of 
ctDNA can detect minimal residual disease.58 We suggest that the simplicity of 
blood sampling will allow for detection and mutation tracking of ctDNA in patients 
with previously undetectable minimal residual disease at high-risk for clinical 
recurrence. We will evaluate the potential to detect and track ctDNA in early-stage 
TNBC and determine if it might predict clinical outcome. 
 
 
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.  
 
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.  
4. To assess the utility of multi-parametric FDG-PET/MR imaging in predicting response 
to therapy after one cycle of therapy. 
5. Measure circulating tumor DNA (ctDNA) somatic mutations in serial plasma samples, 
and determine if ctDNA can predict clinical outcomes. 


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3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Newly diagnosed AJCC7 clinical stage II or III breast cancer with complete surgical 
excision of the breast cancer after neoadjuvant chemotherapy as the treatment goal. 
 
2. Patients with PR+ tumors are allowed. 
 
3. HER2 negative by FISH or IHC staining 0 or 1+. 
 
4. ER less than Allred score of 3 or less than 1% positive staining cells in the invasive 
component of the tumor  
 
5. Tumor size at least 2cm in one dimension by clinical or radiographic exam (WHO 
criteria). Patients with palpable lymph nodes may be enrolled regardless of tumor size.  
 
6. At least 18 years of age. 
 
7. ECOG performance status < 2  
 
8. Normal bone marrow and organ function as defined below: 
a. Leukocytes > 3,000/mcL 
b. Absolute neutrophil count > 1,500/mcl 
c. Platelets > 100,000/mcl 
d. Serum bilirubin within (or under ) normal limits (OR total bilirubin ≤ 3.0 x IULN 
with direct bilirubin within normal range in patients with well documented Gilbert 
Syndrome) 
e. AST(SGOT)/ALT(SGPT) within (or under ) normal limits 
f. Creatinine clearance ≥ 30 mL/min/1.73 m2 
 
9. Patients may be pre- or post-menopausal. Women of childbearing potential must agree 
to use adequate contraception (hormonal or barrier method of birth control, abstinence) 
prior to study entry and for the duration of study participation.  Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she must 
inform her treating physician immediately. 
 
10. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
11. Able to tolerate PET/MRI with intravenous contrast administration and must complete 
the applicable MRI screening evaluation form. 
 
3.2 
Exclusion Criteria 


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1. Prior systemic therapy for the indexed breast cancer. 
 
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 bilateral or inflammatory breast cancer. 
 
4. Currently receiving any other investigational agents. 
 
5. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to docetaxel or carboplatin. 
 
6. 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. 
 
7. Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy test 
within 7 days of study entry if premenopausal. 
 
8. Known HIV-positivity.   
 
9. Sentinel lymph node biopsy. 
 
10. Renal insufficiency (glomerular filtration rate (GFR) < 30 mL/min/1.73 m2) measured 
within the past 60 days which precludes safe administration of the contrast agent 
 
11. On dialysis 
 
12. Prior allergic reaction to gadolinium-based MR contrast agents  
 
3.3 
Inclusion of Women and Minorities 
 
Because breast cancer occurs predominantly in women, men will not be eligible for this 
trial.  Women and members of all races and ethnic groups are eligible for this trial.  
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 


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1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below at least one business 
day prior to registering patient: 
 
1. The registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form  
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Oncore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Premedication Administration 
 
Patients receiving docetaxel should be premedicated with dexamethasone 8 mg (or its 
equivalent) PO twice a day X 3 days starting the day before docetaxel (alternatively, 
dexamethasone 10 mg IV 30 to 60 minutes before dosing), diphenhydramine 50 mg (or its 
equivalent) IV 30 to 60 minutes before dosing, and cimetidine 300 mg or ranitidine 50 mg 
(or equivalent) IV 30 to 60 minutes or before dosing.  
 
5.2 
Agent Administration 
 
Docetaxel will be administered intravenously at a dose of 75mg/m2 over 60 minutes on 
Day 1 of each 21-day cycle.  Carboplatin AUC 6 will be administered intravenously over 
30 minutes on Day 1 of each 21-day cycle immediately following docetaxel infusion.  For 
carboplatin dosing, creatinine clearance (CrCl) will be calculated according to the 
Cockcroft-Gault equation (Appendix B).  CrCl should be capped at 125 mL/min.  A total 
of 6 cycles will be given.  
 


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Surgery will take place 3 to 5 weeks after the conclusion of the neoadjuvant regimen.  
Further adjuvant chemotherapy may be given at the discretion of the treating physician, 
but we recommend that patients who have a pCR in the breast and lymph nodes do not 
receive further adjuvant chemotherapy.   
 
5.3 
Adjuvant Chemotherapy 
 
Patients who develop grade 3 neuropathy, other intolerable side effects, progressive 
disease, or who do not achieve a pCR with the docetaxel/carboplatin combination will have 
the option of receiving anthracycline-based chemotherapy (such as AC or FEC) OR 
capecitabine post-operatively at the discretion of the treating physician. These patients will 
be counted as non-pCR. 
 
5.4 
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. 
 
5.5 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum pregnancy test within 7 days prior to the first dose of docetaxel.   
 
Female patients are required to use one form of acceptable contraception during 
participation in the study and for 6 months following the last dose of chemotherapy.  
 
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 investigator must be notified in order to facilitate outcome follow-
up. 
 
5.6 
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: 


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• Documented and confirmed disease progression 
• Death 
• 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 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.7 
Duration of Follow-up 
 
Patients will be followed for survival on a yearly basis for 5 years.  Patients removed from 
study for unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event.   
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
at the discretion of the treating physician are permitted in order to keep the patient on protocol. If 
administration of chemotherapy must be interrupted because of unacceptable toxicity, drug dosing 
will be interrupted or modified according to discretion of the treating physician. 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. 
 
 
7.0 
SIMULTANEOUS PET/MR IMAGING AND ANALYSIS 
 
Patients will be studied with FDG-PET/MR centered at the level of the breasts prior to initiation 
of Cycle 1 of NAC therapy (preferably on Day 1 of Cycle 1—however, up to 2 weeks prior to the 
start of therapy will be allowed due to scheduling difficulties) and prior to initiation of Cycle 2 
(preferably on Day 1 of Cycle 2—however, imaging performed Days 15 to 21 will be allowed due 
to scheduling difficulties). The second FDG-PET/MR will be matched in regard to the fasting 
duration, FDG dose, and PET/MR imaging parameters. All imaging studies will be performed 
using the Siemens Biograph mMR PET/MRI scanner, located on the 10th floor West Pavilion of 
Barnes-Jewish Hospital at the Center for Clinical Imaging Research (CCIR).  This state-of-the-art 
scanner allows for true simultaneous image acquisition of PET and MRI data.  All subjects will 
complete an MRI screening evaluation form and have intravenous (IV) access established prior to 


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entering MRI zone 3 or the scanning room.  In the event unforeseen technical difficulties will 
prevent a patient from being scanned at baseline without causing a delay in starting NAC therapy 
(for example scanner is not operating within normal limits or FDG is unavailable) a subject can 
remain on the study and proceed with NAC therapy as planned (without baseline imaging) in order 
to address the Primary Objective and other Exploratory objectives.  A subject who does not receive 
imaging at baseline will not be asked to return for follow-up early response imaging.  Similarly, if 
technical difficulties arise at the early response imaging time point (prior to cycle 2 of therapy), 
cycle 2 of therapy should proceed as scheduled and patient may be scheduled to return for imaging 
up to 10 days after cycle 2 was administered.    
 
7.1 
Multi-Modality PET/MR Imaging 
 
This is an exploratory objective to optimize imaging parameters for simultaneous PET/MR 
imaging and using the breast coil to facilitate MR imaging.  Subjects will be positioned 
prone in the PET/MRI scanner with arms resting above the head or resting by their sides 
(bed position 1 or BPos1).  The multi-parametric PET/MR protocol listed below will be 
employed for both baseline (pre-treatment) and the early-treatment response time points 
following Cycle 1 of NAC.  All patients will fast for at least 4 hours prior to FDG-PET/MR 
imaging.  Fasting serum glucose levels prior to FDG injection must be less than 200 mg/dL 
and IV should be in the arm opposite the known breast lesion whenever possible.  
Approximately 10 mCi of FDG will be administered IV while patient rests comfortably in 
an uptake room.  The patient will be positioned prone in the scanner at BPos1.  Following 
a simple DIXON scan for attenuation correction, 35 min of dynamic PET and simultaneous 
MRI imaging will be acquired beginning approximately 35 minutes post FDG injection.    
Following BPos 1, a 2 min image acquisition of the liver will be employed in bed position 
2 (BPos 2) to develop PERCIST (PET Response Criteria in Solid Tumors) measures.   In 
parallel to PET imaging the following MR sequences will be implemented which are 
subject to change depending on study need: 
 
• T2-weighted 
• T1-weighted 
• T1/T2 mapping 
• Diffusion Tensor Imaging (DTI) (multi-shell)  
• Research dynamic contrast-enhanced (DCE) protocol—high temporal low spatial 
resolution 
• Localizer 
• Dixon 
 
Contrast injection should consist of IV administration of 0.1 mmol/kg of Dotarem, 
Multihance or other gadolinium-based MRI contrast agent   
 
7.2 
Image Analysis 
 
7.2.1 Image Co-registration 
 


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To facilitate quantitative image analysis, MR images of a given patient (pre- and 
early posttherapy) will be co-registered by employing a rigid body algorithm using 
commercially available software, thus facilitating the translation and applicability 
to other imaging centers.  Anatomical images will be inspected visually to further 
manually align images, if needed, using the outline of the breast.  Since PET and 
MR images are intrinsically co-registered (acquired simultaneously), the MR-to-
MR image co-registration transformation parameters will be applied to PET 
images.  Subsequently, each tumor will be identified by a landmark and annotated. 
 
7.2.2 Tumor Identification 
 
Target tumor lesions will be identified on PET/MR study by expert radiologists 
with one radiologist who is experienced in Breast MRI (Dr. Steven Poplack) and 
one observer with expertise in nuclear medicine (Dr. Farrokh Dehdashti). 
 
7.2.3 Quantitative Analysis 
 
In addition to measures of PERCIST measures of tumor response to therapy, we 
will quantify the pharmacokinetics of FDG in tumors using established 
methodologies.  As another layer, we will apply local masks based on multi-
parametric MR images in performing image quantification; for example, by 
limiting the analysis to regions of decreased apparent diffusion coefficient (ADC), 
and/or high perfusion, to investigate the interplay between tumor metabolism and 
perfusion in a constrained microenvironment established by multi-parametric MR.  
Through this analysis, we will identify unique and independent image features to 
explore as predictors of response to therapy. 
 
7.3 
Toxicities Related to FDG-PET/MR Imaging   
 
Likely: 
• Mild discomfort from the placement of the IV in the patient’s arm. 
• Radiation exposure: The amount of radiation exposure the patient will 
receive from one FDG-PET/MR imaging session is equivalent to a uniform 
whole-body exposure of approximately 0.6 rem (total exposure of 1.2 rem 
for 2 scans).  
 
Less Likely: 
• Discomfort from lying still on the PET imaging table.   
• There is a slight risk of bruising at sites of vein puncture.  
• Claustrophobia from lying inside the PET/MRI scanner 
 
Rare: 
• There is a remote risk of infection and an even smaller risk of blood clot at 
the site of the IV placement. 


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• There is a rare possibility of an allergic-type or other adverse reaction to 
radioactively labeled drugs.  While none have been reported to date with the 
radioactive material FDG, such a reaction could be serious and may result 
in death. 
• There is a theoretical risk of nephrogenic systemic fibrosis (NSF), which 
has been linked to gadolinium contrast agents administered in patients with 
severe renal dysfunction.  This risk is mitigated by the use of renal function 
screening. 
 
Recent information shows that repeated gadolinium use may cause collection in the 
brain. The importance of this information and how it impacts patient health are not known. 
 
 
8.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 8.2. 
 
8.1 
Definitions 
 
8.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
8.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 


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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
8.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
8.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
8.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
8.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
8.1.7 Serious Noncompliance 
 


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Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
8.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event.   
 
8.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
8.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
8.4 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 30 days following the last day of study treatment. 
   
 


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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 Dosage Form and Preparation 
 
Docetaxel injection concentrate is a sterile, non-pyrogenic, pale yellow to 
brownish-yellow solution at 20 mg/mL concentration.  Docetaxel injection 


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concentrate (20 mg/mL) requires NO prior dilution with a  diluent and is ready to 
add to the infusion solution. 
 
Using only a 21 gauge needle, aseptically withdraw the required amount of 
docetaxel injection concentrate (20 mg docetaxel/mL) with a calibrated syringe and 
inject via a single injection (one shot) into a 250 mL infusion bag or bottle of either 
0.9% sodium chloride solution or 5% dextrose solution to produce a final 
concentration of 0.3 mg/mL to 0.74 mg/mL. 
 
9.1.6 Storage and Stability 
 
Docetaxel vials should be stored between 2 and 25°C (36 and 77°F).  If the vials 
are stored under refrigeration, allow the appropriate number of vials to stand at 
room temperature for approximately 5 minutes before use.  The final dilution for 
infusion should be used within 6 hours (including the 1 hour intravenous 
administration) 
 
9.1.7 Administration 
 
Docetaxel will be administered intravenously at a dose of 75mg/m2 over 60 minutes 
on Day 1 of each 21-day cycle.  Patients receiving docetaxel should be 
premedicated with dexamethasone 8 mg (or its equivalent) PO twice a day X 3 days 
starting the day before docetaxel (alternatively, dexamethasone 10 mg IV 30 to 60 
minutes before docetaxel), diphenhydramine 50 mg (or its equivalent) IV 30 to 60 
minutes before dosing, and cimetidine 300 mg or ranitidine 50 mg (or equivalent) 
IV 30 to 60 minutes before dosing.  
 
9.1.8 Special Handling Instructions 
 
Contact of the docetaxel concentrate with plasticized PVC equipment or devices 
used to prepare solutions for infusion is not recommended.  In order to minimize 
patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be 
leached from PVC infusion bags or sets, the final docetaxel dilution for infusion 
should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, 
polyolefin) and administered through polyethylene-lined administration sets. 
 
9.1.9 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 
 


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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. 
 
9.2.3 Dosage Form and Preparation 
 
Carboplatin aqueous solution is a premixed aqueous solution of 10 mg/mL 
carboplatin.  It can be further diluted to concentrations as low as 0.5 mg/mL with 
5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. 
 
It is supplied as follows: 
50 mg/5 mL aqueous solution in multidose vials 
150 mg/15 mL aqueous solution in multidose vials 
450 mg/45 mL aqueous solution in multidose vials 
600 mg/60 mL aqueous solution in multidose vials 
 
Note: aluminum reacts with carboplatin causing precipitate formation and loss of 
potency; therefore, needles or intravenous sets containing aluminum parts that may 
come in contact with the drug must not be used for the preparation or administration 
of carboplatin. 
 
9.2.4 Storage and Stability 
 
Unopened vials of carboplatin solution are stable for the life indicated on the 
package when stored at controlled room temperature and protected from light.  The 
multidose vials of carboplatin aqueous solution are reported to maintain microbial 
and chemical stability at room temperature for up to 14 days following multiple 
needle entries. 
 
9.2.5 Administration 
 
Carboplatin will be administered over 30 minutes.  Dosing will be AUC6 on Day 1 
of each 21-day cycle for 6 cycles.  Premedication with antiemetics should happen 
on days when carboplatin dosing occurs and should follow the instructions in 
Section 5.1. 
 


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Hypersensitivity to carboplatin has been reported in 2% of patients.  These allergic 
reactions have been similar in nature and severity to those reported with other 
platinum-containing compounds, i.e., rash, urticaria, erythema, pruritus, and rarely 
bronchospasm and hypotension.  Anaphylactic reactions have been reported as part 
of postmarketing surveillance.  These reactions have been successfully managed 
with standard epinephrine, corticosteroid, and antihistamine therapy. 
 
9.2.6 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. 
 
 
10.0 
CORRELATIVE STUDIES 
 
10.1 
Tumor Biopsy 
 
Tumor biopsies and banked tissues collected on patients enrolled to the WashU protocol 
and the Baylor protocol will be processed and evaluated in the same manner. Research 
biopsies will be performed at baseline, Cycle 1 Day 3 (optional), definitive surgery, and 
at time of relapse.  Guidelines are below.  
 
10.1.1 Baseline Tumor Biopsies 
 
Those tumor specimens for human in mouse modeling will be placed in cold 
DMEM High Glucose media, chilled on wet ice and immediately sent to Dr. Li’s 
laboratory (address below) for further preparation. The procedure of tissue 
collection will be handled in a sterile fashion because the tissues will be engrafted 
into highly immunodeficient NOD/SCID mice.  
 
1) First Core—in 10% formalin for clinical or CLIA diagnostics if indicated 
2) Second Core—fresh to lab for  engrafting 
3) Third Core—immediately frozen in OCT blocks at bedside 
4) Fourth Core—fresh to lab for engrafting 
5) Fifth Core—immediately frozen in OCT blocks at bedside 
6) Sixth Core—in 10% formalin to tumor bank 
 
Optional core biopsies of the lymph nodes may be performed during baseline 
tumor biopsy for patients with nodal involvement. Guidelines are below:  
 
1) First Core—fresh to lab for engrafting 
2) Second Core—immediately frozen in OCT blocks at bedside 
3) Third Core—in 10% formalin to tumor bank 
 
Attention: Shun Li, M.D. 


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Current lab address: 
Couch Biomedical Building 3rd floor 
4515 McKinley Ave. 
St. Louis, MO 63110 
Tel: 314-747-9311(Lab) 
314-362-3244 (Office) 
314-596-8476 (Cell) 
Pager: 314-424-5911 or 314-508-7804 
E-mail: SQLI@dom.wustl.edu 
 
10.1.2 Cycle 1 Day 3, Definitive Breast Surgery, and Time of Relapse Biopsies 
 
Collection of tissue is optional on Cycle 1 Day 3 and time of relapse and mandatory 
during definitive breast surgery.  All samples should be marked with the UPN, 
initials, and date of the sample using an indelible marker. 
 
Frozen tissue suitable for gene expression and proteomic analysis 
The biopsies obtained should be snap frozen in liquid nitrogen and placed on dry 
ice.  The samples should then be immediately sent to Dr. Watson’s laboratory 
(address below).  Three frozen core biopsies should be taken and separately 
processed in OCT blocks or for the routine tissue blocks to be accessed by the 
principal investigator for analysis. 
 
10%-buffered formalin fixed tissue 
One of the samples obtained should be sent at ambient temperature in 10% buffered 
formalin to Dr. Watson’s laboratory (address below). 
  
Mark A. Watson, M.D., Ph.D. 
Siteman Cancer Center Tissue Procurement Facility 
425 S. Euclid Ave., Rm 5120 
St. Louis, MO 63110 
Phone: 314-454-7615 
Fax: 314-454-5525 
Email: tbank@pathology.wustl.edu 
 
Fresh core 
2 fresh cores for engraftment ). See instructions in Section 10.1.1. 
 
10.2 
Research Blood 
 
Blood (50 mL total) will be drawn for research purposes at baseline, Cycle 1 Day 3, at time 
of surgery, and at time of relapse. 
 
Ten mL of blood should be taken in a red/tiger top tube, allowed to clot for 30 minutes and 
then immediately centrifuged at 1200G for 10 minutes at 4°C. The serum should then be 
stored as 1 mL aliquots at -70°C and sent to TPC for analysis.   


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An additional 30 mL of blood should be taken in: 
1) a 10 mL EDTA tube (pink top) for plasma and DNA collection 
2) a 10 mL EDTA tube containing protease inhibitors (BD – P100 tube) 
3) a 10 mL lithium heparin (green top) tube for heparinized plasma 
 
 
 
Ten mL of blood should be taken in Streck Cell-Free DNA BCT for plasma circulating 
DNA at baseline, Cycle 1 Day 3, at time of surgery, at time of relapse, and every six months 
after completion of chemotherapy for 5 years.   
 
Mix these tubes several times to ensure adequate anticoagulation and place on ice. Deliver 
tubes to laboratory within 30 minutes of draw and spin as follows: pink top tubes, green 
top tubes, and the Streck tubes at 1000G for 10 min at 4°C and P100 tube at 2500G for 20 
minutes in a swing bucket or 45 degree fixed angle rotor. The plasma is aspirated off in 1 
mL aliquots and transferred to cryovials to be frozen and stored in LN2 vapor or at -70°C.  
White blood cell pellets are created with the retaining white blood cells.  Germ-line DNA 
will be processed from the white blood cell pellets. These tubes are sent to TPC lab for 
analysis.   
 
All samples should be marked with the UPN, initials, and date of the sample using an 
indelible marker. 
 
 


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11.0 
STUDY CALENDAR 
 
Baseline evaluations must be done no more than 4 weeks prior to start of treatment. 
 
 
Screening / 
Baseline 
C1D1 
C1D313 
Cycles 2-
6, Day 1 
Surgery4 
EOT9 
F/U6 
Relapse 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical exam, 
incl. ECOG PS, 
tumor 
measurement (2D) 
X 
X 
 
X 
 
X 
 
 
Vital signs, 
weight, height8 
X 
X 
 
X 
 
X 
 
 
Hematology1 
X 
 
 
X 
 
X 
 
 
CMP 
X 
X 
 
X 
 
X 
 
 
Pregnancy test2 
X 
 
 
 
 
 
 
 
Docetaxel  
 
X 
 
X 
 
 
 
 
Carboplatin3 
 
X 
 
X 
 
 
 
 
Research blood 
X 
 
X 
 
X12,14 
 
X 
X 
Research tissue 
X 
 
X5 
 
X14 
 
 
X15 
Adverse events7 
X 
X 
 
X7 
 
 
 
 
FDG-PET/MRI 
 
X10 
 
X11 
 
 
 
 
1. WBC plus differential, hemoglobin, and platelets 
2. In women of childbearing potential only. 
3. Carboplatin is to be given immediately following docetaxel  
4. To be performed between 3 and 5 weeks after completing neoadjuvant therapy 
5. Optional. 
6. Follow annually for progression and survival for 5 years, ctDNA blood drawn every six months. 
7. Collect AEs for 30 days following last day of chemotherapy. 
8. Height required at screening/baseline only. 
9. First visit after surgery. 
10. Baseline FDG-PET/MRI can be done prior to Cycle 1, preferably on Day 1 prior to initiation of therapy. 
11. Post-therapy FDG-PET/MRI should be after completion of Cycle 1, preferably on Cycle 2 Day 1 
12. If blood sample was not collected the day of surgery, the sample can be collected at the patient’s next office visit. 
13. -1 day / + 2 days window  
14. If patients discontinue treatment due to AEs before completing all 6 cycles, and go directly to surgery, blood and tissue samples 
will be obtained at the time of surgery. 
15.   Optional research biopsy


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12.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Tumor Measurement Form 
Treatment Summary Form 
(ClinPortal)  
Every cycle 
Toxicity Form 
Continuous 
Surgery Form 
Surgery 
Correlatives Form 
Baseline 
Cycle 1 Day 3 
Surgery 
Imaging Form 
Baseline 
Between Cycles 1 and 2 
Follow-Up Form 
Annually for 5 years 
 
 
13.0 
MEASUREMENT OF EFFECT  
 
13.1 
Clinical Responses 
 
Physical examination: Within 14 days of pre-registration and at the end of each 
neoadjuvant treatment cycle cycles (that is, at the end of cycles 1-6) 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 on the case report forms.   Measurements for 
clinical responses will be taken from the physical exam that is documented in the treating 
physician’s notes in the electronic medical records system. If the physician’s note indicates 
no palpable mass, we will use the dimensions of 0x0 cm. 
 
WHO 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 50% or greater decrease in the product of the bi-
dimensional measurements of the lesion (total tumor size) 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. 
 


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No Change (NC) a 50% decrease in total tumor size cannot be established nor has a 25% 
increase in the size of the lesion been demonstrated. 
 
Progressive Disease (PD): A 25% or greater increase in the total tumor size of the lesion 
from its pretreatment measurements or the appearance of new lesions.  
 
13.2 
 Treatment Resistance 
 
A patient is said to have resistant disease if progressive disease is documented any time 
during neoadjuvant endocrine therapy. 
 
13.3 
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.  
 
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. 
 
13.4 
Diagnosis of Breast Cancer Recurrence and Other Cancer Events  
 
13.4.1 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.  
 
13.4.2 Regional Recurrence 
 
Regional recurrence is defined as the cytologic or histologic evidence of disease in 
the ipsilateral internal mammary, ipsilateral supraclavicular, ipsilateral 


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infraclavicular and/or ipsilateral axillary nodes or soft tissue of the ipsilateral axilla. 
 
13.4.3 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.  
 
13.4.4 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.  
 
13.4.5 Second Primary Cancer (Non-breast) 
 
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. 
 
13.4.6 Death 
 
Underlying cause of death is to be reported. 
 
 
14.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 


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• Measures of efficacy  
• Measures of efficacy – provide a summary of tissue samples collected by site, tissue 
expected to obtain, % of tissue received, and % of tissue missing 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Study Design 
 
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.  
 
15.2 
Primary Endpoint 
 
The original primary endpoint of the trial is pCR rate which will be calculated as the 
percentage of patients who achieve pCR among all pCR evaluable patients. 
  
 
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 neoadjuvant treatment early due to refusal,  toxicity, or 
radiographic 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 neoadjuvant treatment early due to refusal, toxicity or 
radiographic evidence of progression and then receives alternative treatment. 
4. The patient discontinues study treatment, refuses surgery, or is unable to undergo 
surgery due to a co-morbid condition. 
 
Thus, any patient who does not receive alternative treatment prior to surgery and has no 
histologic evidence of invasive tumor cells in the surgical breast specimen and the axillary 
lymph nodes is considered to have a pCR. 
 


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The primary endpoint of pCR rate will be calculated with 95% CI and will be tested against 
the reference pCR rate of 35% with standard chemotherapy. 
 
15.3 
Sample Size and Trial Duration 
 
The expectation for a pathological complete response (no invasive disease in the breast or 
nodes) after neoadjuvant chemotherapy for TNBC is expected to exceed 35%.  
 
Adverse events, the pace of accrual, other scientific discoveries or changes in standard of 
care will be taken into account in any decision to terminate this trial earlier than designed. 
 
The single size phase II trial is still undergoing. Based on the 26 patients who have 
completed surgery to date, the pCR rate is currently estimated to be ~40%, lower than what 
was expected (54%) at planning the trial. We propose to increase the sample size to 100 
patients to be enrolled in WashU, with 30 of the 100 patients to support the Multi-
parametric Positron Emission Tomography (PET) and Magnetic Resonance (MR) Imaging 
study (see Section 15.3.1).  If currently the pCR of the trial achieves 40%, the enrollment 
of 100 eligible patients provides 82.1% power to test the pCR rate of 40% against the null 
pCR rate of 28% with standard chemotherapy, based on one-sided Binomial exact test at a 
target 0.05 alpha level. If 36 or more patients achieve a pCR, we conclude that the 
investigational regimen yields better efficacy than standard chemotherapy. If the pCR rate 
is higher than the current estimate of 40%, the sample size of 100 provides 90.33% power 
to test the pCR rate of 50% against the null pCR rate of 35% with standard chemotherapy, 
based on one-sided Binomial exact test at a target 0.05 alpha level (actual alpha=0.039). If 
44 or more patients achieve a pCR, we conclude that the investigational regimen yields 
better efficacy than standard chemotherapy. 
 
We anticipate that 4 patients per month with clinical stage 2 or 3 TNBC will be screened 
for trial eligibility. Approximately 75% of the patients will be eligible and enroll. Thus, we 
anticipate screening approximately 134 patients to obtain 100 eligible patients as calculated 
above.  
 
The trial has enrolled 35 eligible patients since its opening.  The period encompassing 
enrollment, study treatment, and surgery of the remaining 35 patients will be approximately 
23 months [That is, 18 months to enroll 35 eligible patients and then 5 months to await 
surgical results of last patient enrolled].   
 
The current engraftment rate of the trial is conservatively estimated to be 25~30% based 
on the 35 patients on the study. Therefore, we expect to establish a minimum of 25 PDX 
models. 
 
15.4 
Amendment to increase sample size for the Multi-parametric Positron 
Emission Tomography (PET) and Magnetic Resonance (MR) Imaging study 
 
We are requesting to add 30 patients to support the Multi-parametric Positron Emission 
Tomography (PET) and Magnetic Resonance (MR) Imaging to Assess Response to 


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Therapy objectives Groheux et al. have shown efficacy in differentiating pCR in TNBC 
with a sample size of 20 using 18FDG PET/MR where change in SUVmax yielded an 
AUC of 0.88 and with 30% of the sample being pCR. Therefore, conservatively based on 
this data, a sample of 30 patients (30% being responders) achieves 80% power to detect a 
difference of 0.3 between the AUC under the null hypothesis of 0.5 and an AUC under 
the alternative hypothesis of 0.8 using a one-sided z-test at a significance level of 0.05 
and assuming a dropout rate of 15%. 
 
15.5 
The Baylor samples 
 
Baylor College of Medicine (BCM) has a parallel protocol the same as this protocol. We 
expect to have approximately 19 patients who have been enrolled to the BCM protocol and 
complied with the WashU patient inclusion and exclusion criteria. We will pool patients 
and data from this protocol and the BCM protocol for analyses. The total sample size will 
be approximately 119 (100 from the WashU protocol and approximately 19 from the BCM 
protocol). The power with 119 evaluable patients attains 95.07% to test  the pCR rate of 
50% against the null pCR rate of 35% with standard chemotherapy, based on one-sided 
Binomial exact test with a target 0.05 alpha level  (actual alpha level = 0.046). If the total 
number of pCRs is ≥51, we conclude that the investigational regimen yields better efficacy 
than standard chemotherapy. 
 
15.6 
Secondary Clinical Outcomes  
 
Clinical response rate:  The clinical response rate will be estimated by the number of 
patients whose disease meets the WHO criteria of complete or partial response prior to 
surgery divided by the total number of eligible patients who began combination neo-
adjuvant treatment. A ninety percent confidence interval for the true clinical response rate 
will be calculated using the Duffy-Santer approach. 
 
Adverse Events:  All eligible patients that have intitiated treatment will be considered 
evaluable for assessing adverse event rate(s).  The maximum grade for each type of adverse 
event will be recorded for each patient using the NCI-CTCAE v4.0 coding scheme, and 
frequency tables will be reviewed to determine patterns.  Additionally, the relationship of 
the adverse event(s) to the study treatment will be taken into consideration. 
Grade for each type of adverse event will be recorded for each patient using the NCI-
CTCAE v4.0 coding scheme, and frequency tables will be reviewed to determine patterns.  
Additionally, the relationship of the adverse event(s) to the study treatment will be taken 
into consideration. 
 
15.7 
Explorative Studies 
 
To determine the xenografting rate from TNBC patients being treated with neoadjuvant 
chemotherapy.  The xenografting rate is expected ~50%. The sample size of 70 calculated 
to achieve the primary objective will provide 85.4% power to detect an observed 
xenografting rate of 50% against an unacceptably low xenografting rate of 30% based on 
one-sided binomial test at the 5% significance level. 


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To compare chemotherapy responses in PDX and TNBC patients being treated with 
neoadjuvant chemotherapy.  The chemotherapy response in PDX and corresponding 
TNBC will be tabulated and their association will be examined by Fisher's exact test.  The 
response rate in TNBC patients and PDX will be calculated with 95% CI. 
 
To investigate genomic and proteomic molecular changes in PDX and corresponding host 
patients with the intent to identify predictors of drug response and resistance.  Genomic 
profiling (including gene expression profiling and aCGH) of tumor tissue harvested at day 
3 and at completion of combination treatment 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. Pearson or Spearman correlation coefficient 
between the paired profiling of PDXs and their associated hosts will be calculated for 
similarity/difference. Joint unsupervised analysis of gene expression and aCGH will be 
carried for PDXs and TNBC separately by use of generalized singular value decomposition 
through which a few meta-genes will be obtained summarizing thousands of individual 
genes and meanwhile, individual genes sharing similar variation patterns in both data can 
be identified. The resulting meta-genes will then be correlated between PDXs and TNBCs 
for similarity/difference summarizing across multiple genes of both gene expression and 
copy number. Genomic profiling will be associated with endpoints at each time point. 
Differential genes/copy numbers expression (DE) analysis between responding and non-
responding subjects will be performed within PDXs and TNBCs respectively using 
significance analysis of microarray (SAM), using individual genes or meta-genes derived 
from joint analysis. The DE gene lists will be compared using Venn diagram for 
overlapping and unique genes.  The genomic profiling will also be used as predictors for 
an endpoint by using penalized logistic regression (for clinical response) or random forest 
regression (for continuous endpoints) to identify genes with important predictive effect on 
binary and continuous endpoints separately. Random forest regression has the advantage 
of making no underlying assumption on variable distributions, considering interaction 
effect and providing variable importance measure. To internally validate the gene 
signatures, leave one out cross validation procedure will be adopted for penalized logistic 
regression modeling. Breast cancer subtypes, risk of relapse score and risk group derived 
from genomic profiling will be summarized by descriptive statistics (frequency for 
categorical variables and mean, standard deviation for continuous variables) at each time 
point and the changes between time points will be summarized by correlation coefficients 
and contingency table analyses.   
 
To investigate the utility of combined FDG-PET/MR, we propose to enlist up to 30 patients 
to optimize imaging parameters for simultaneous FDG-PET/MR imaging and to optimize 
use of the breast coil to facilitate MR imaging.  Image analysis will be carried out as 
described earlier.  
 
To measure the circulating tumor DNA (ctDNA), malignant breast samples will be 
subjected to whole exome (WES) to determine driver mutations. We will analyze whether 
patient-specific mutations in the primary breast tumor are detectable in ctDNA. These 
patient-specific mutations will be prioritized according to tumor variant allele fractions 


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from breast tissue, and evaluate if levels and the presence of ctDNA mutations can predict 
clinical outcomes in pCR and non-pCR patients.  
 
15.8 
Pooled analyses with incorporation of the patients enrolled to the BCM 
protocol  
 
BCM has a parallel protocol on which 19 patients have been enrolled. To unify the 
eligibility criteria between the two protocols, we will exclude male patients or patients 
with inflammatory breast cancer, if any, who were enrolled to the BCM protocol. We will 
conduct a pooled analyses using the data collected on the patients (expected 
approximately total N=120) enrolled to both the WashU protocol (N=100) and the BCM 
protocol (N≈19). Using data from more patients will potentially improve statistical 
power. The patient demographic characteristics and tumor characteristics will be 
summarized overall and by protocol (WashU vs. BCM) using descriptive statistics 
(typically, mean and standard deviation for continuous characteristics and count and 
percentage for categorical characteristics) and difference in characteristics will be 
compared by two-sample t-test (or Wilcoxon rank sum test in presence of severe 
violation of normality assumption)  for continuous characteristics  and Fisher's exact test 
for categorical characteristics.  All the above proposed analyses for primary, secondary 
and exploratory endpoints will be performed overall pooling all the data from the two 
protocols and separately by protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: Cockcroft-Gault 
 
GFR = (140 – age) * (wt in kg) * (0.85 if female) / (72 * Cr) 
 
Calvert AUC: Total dose (mg) = (target AUC) x (GFR + 25)