A Phase II Study of Neoadjuvant Carboplatin/Paclitaxel Followed by Dose-Dense Doxorubicin/Cyclophosphamide in Patients With Hormone Receptor Negative, HER2 Receptor Negative Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer, Triple Negative Breast Cancer
Sponsor: University of Wisconsin, Madison

 
A Phase II Study of Neoadjuvant Weekly Carboplatin/Paclitaxel followed by Dose-Dense 
Doxorubicin/Cyclophosphamide in Patients with Hormone Receptor Negative, HER2 Receptor 
Negative Breast Cancer  
 
NCT03301350  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI: Kari B. Wisinski, MD 
November 26, 2019 
 

 
 
 
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CLINICAL STUDY PROTOCOL 
 
 
  
 
A Phase II Study of Neoadjuvant Weekly Carboplatin/Paclitaxel followed by Dose-Dense 
Doxorubicin/Cyclophosphamide in Patients with Hormone Receptor Negative, HER2 Receptor 
Negative Breast Cancer 
 
 
Study PI:  Kari B. Wisinski, MD 
Study Chair:  Yee Chung Cheng, MD 
 
 
Version 8, November 26, 2019 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board 
approval and informed consent, or as required by Federal and state laws. Persons to whom 
this information is disclosed should be informed that this information is privileged and 
confidential and that it should not be further disclosed. 
 
 
 
 
 

 
 
 
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Title: A Phase II Study of Neoadjuvant Weekly Carboplatin/Paclitaxel followed by 
Dose-Dense Doxorubicin/Cyclophosphamide In Patients with Hormone 
Receptor Negative, HER2 Receptor Negative Breast Cancer 
Protocol #: UW16112 
Coordinating Center:   
University of Wisconsin Carbone Cancer Center  
FDA IND #.: n/a   
IND Sponsor: n/a 
 
Study Principal Investigator (PI): 
  
Kari B. Wisinski, MD 
Associate Professor of Medicine 
Hematology/Oncology Division 
UW School of Medicine and Public Health 
UW Carbone Cancer Center 
WIMR Room 6033 
1111 Highland Avenue 
Madison, WI 53705-2275 
Phone: 608-262-2876 
Fax: 608-265-6905 
Email: kbwisinski@medicine.wisc.edu  
 
Study Chair:  
 
 
 
 
Yee Chung Cheng, MD 
Associate Professor 
Division of Hematology and Oncology 
Department of Medicine 
Medical College of Wisconsin 
Milwaukee, Wisconsin 
Tel: 414-805-8924 
Fax: 414-805-4606 
Email: ycheng@mcw.edu 
 
Study Co-Investigator: 
 
 
  
Christopher R. Chitambar, MD 
Professor 
Division of Hematology and Oncology 
Department of Medicine 
Medical College of Wisconsin 
Milwaukee, Wisconsin 
Tel: 414-805-4600 
Fax: 414-805-4606 
Email: cchitamb@mcw.edu 
 
 
 
Study Co-Investigator: 
Carmen Bergom, MD, PhD 
Assistant Professor 
 

 
 
 
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Department of Radiation Oncology 
Medical College of Wisconsin 
Milwaukee Wisconsin 
Tel: 414-805-4450 
Email: cbergom@mcw.edu 
 
Statistician: 
 
 
Emmanuel Sampene, Ph.D. 
 
600 Highland Avenue, H6/546 
UW Carbone Cancer Center  
Madison, WI  
Telephone: 608-265-8725 
Fax: 608-265-5579 
Email:sampene@biostat.wisc.edu  
 
Study Coordinator:  
 
 
 
Tammy Koehn 
600 Highland Avenue, CSC K4/6 
Telephone: 608-265-2999 
Fax: 608-571-1035 
Email: tmkoehn@medicine.wisc.edu 
 
WON Contact: 
Courtney Thom 
600 Highland Avenue, CSC K4/6 
Telephone: 608-265-2867 
Fax: 608-265-5676 
Email: 
affiliatecoordinators@uwcarbone.wisc.edu 
 

 
 
 
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PROTOCOL SUMMARY 
Title: 
A Phase II Study of Neoadjuvant Weekly Carboplatin/Paclitaxel 
followed by Dose-Dense Doxorubicin/Cyclophosphamide In 
Patients with Hormone Receptor Negative, HER2 Receptor 
Negative Breast Cancer 
Protocol Number: 
UW16112 
IND Sponsor: 
n/a  
Principal Investigator/ 
Study Chair: 
Kari B. Wisinski, MD/ Yee Chung Cheng, MD 
Study Sites: 
UWCCC, MCW and Wisconsin Oncology Network 
Clinical Trial Phase: 
II 
Study Disease: 
Breast Cancer 
Main Eligibility 
Criteria: 
1. Biopsy proven invasive breast cancer that is cM0 and either a) at 
least T2 if node negative or b) any T if ipsilateral regional node 
positive   
2. Candidate for neoadjuvant chemotherapy approach 
3. ER- and PR-negative (Defined as <1%)  
4. HER2-negative by either IHC or ISH. If ISH is used, ratio < 2 is 
considered negative.  
5. LVEF ≥ institutional LLN  
6. Adequate liver and renal function 
Study Rationale: 
CALGB40603 study showed that the addition of Carboplatin 
(AUC=6) every 3 weeks x 4 cycles to the standard weekly Paclitaxel 
followed by dose dense AC regimen in neoadjuvant setting of triple-
negative breast cancer increased the pathologic complete response 
(pCR) rate from 34% to 55%. However, 36% of subjects had to skip 
at least 2 doses of weekly Paclitaxel due to the prolonged cytopenia 
from Carboplatin. We hypothesize the use of low dose weekly 
Carboplatin/Paclitaxel followed by dose-dense AC regimen will 
minimize the prolonged cytopenia, allow the regular treatment 
schedule and result in a similar pCR rate seen with the every 3 
weeks Carboplatin schedule.  
Primary Objective: 
pCR rate 
Secondary Objectives: 
1. Number of cycles, doses and delays of chemotherapy 
administered 
2. Treatment-related toxicity 
3. 2-year Invasive disease-free survival  
4. 2-year Overall survival 

 
 
 
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Primary Endpoint: 
pCR rate 
Study Design: 
Phase II single arm prospective trial 
Study Agent/
Intervention 
Description: 
Carboplatin (AUC=2) and Paclitaxel 80 mg/m2 IV weekly x 12 doses 
(Regimen A), then Doxorubicin 60 mg/m2 and Cyclophosphamide 
600 mg/m2 IV every 2 weeks with pegfilgrastim or filgrastim (or 
biosimilar) support x 4 cycles (Regimen B), then primary breast +/- 
axillary surgery (Regimen C). 
Number of Subjects: 
50 
Subject Participation 
Duration: 
6 months 
Duration of Follow up 
2 years after primary breast surgery  
Estimated Time to 
Complete Enrollment: 
24 months 
Statistical 
Methodology: 
 
A sample size of 48 achieves 80% power to detect a 20% difference 
using a one-sided binomial test at an alpha significance level of 
0.025. These results assume that the population proportion under 
the null hypothesis is 0.34, which is the reported pCR rate with 
standard anthracyclines and taxane regimen in triple-negative breast 
cancer.  Allowing for drop-out rate of 5%, a total of 50 subjects is 
planned.   
Safety Assessments 
Subjects will be followed every 2-3 weeks during chemotherapy for 
treatment related morbidities.  
Efficacy Assessments 
Tolerability of the chemotherapy is determined by the number of 
cycles, doses and delays subject receives. Efficacy of the 
chemotherapy is determined by pathology at the time of final 
breast/axillary surgery.  
Unique Aspects of this 
Study 
This is a multicenter prospective study to evaluate the addition of low 
dose weekly Carboplatin to standard anthracyclines/taxane regimen 
in subjects with triple-negative breast cancer who receive 
neoadjuvant chemotherapy.  
 
 
 
 
 
 
 
 
 
 

 
 
 
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SCHEMA 
 
 
 
 
There are no stratification factors 
 
Accrual = 50 subjects 
________________________________________________________________________________ 
 
1. Subjects must meet the eligibility criteria outlined in Section 4 prior to registration 
2. Subjects are expected to complete Regimens A and B within 6 months (allowing for potential dose 
delays) 
3. It is recommended subjects undergo surgery 3-6 weeks after the last dose of chemotherapy 
4. Subjects will be followed every 6 months (+/- 30 days) for 2 years after date of surgery or last date 
of study treatment  
Registration1
Regimen A2
Carboplatin 
(AUC=2) and 
Paclitaxel 80 
mg/m2 IV 
weekly x 12 
doses 
Regimen B2
Doxorubicin 
60 mg/m2 and 
Cyclophosph-
amide 600 
mg/m2 IV 
every 2 weeks 
x 4 cycles
Regimen C3
primary breast 
+/- axillary 
surgery
Follow up4

 
 
 
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TABLE OF CONTENTS 
1 BACKGROUND ............................................................................................................................................ 10 
2 OBJECTIVES ................................................................................................................................................ 13 
2.1 PRIMARY OBJECTIVE ............................................................................................... 13 
2.2 SECONDARY OBJECTIVES ........................................................................................ 13 
3 STUDY DESIGN ........................................................................................................................................... 13 
3.1 GENERAL DESCRIPTION ........................................................................................... 13 
3.2 SECONDARY ENDPOINT(S) ....................................................................................... 14 
4 SUBJECT SELECTION ............................................................................................................................... 14 
4.2 INCLUSION CRITERIA ................................................................................................ 15 
4.3 EXCLUSION CRITERIA .............................................................................................. 17 
5 STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES .......................................................... 18 
5.1 STUDY ENTRY PROCEDURES .................................................................................... 18 
5.2 STUDY PROCEDURES DURING TREATMENT ................................................................ 19 
5.3 POST-TREATMENT ................................................................................................... 20 
5.4 STUDY WITHDRAWAL PROCEDURES .......................................................................... 21 
6 TREATMENT PLAN ..................................................................................................................................... 22 
6.1 CHEMOTHERAPEUTIC AGENTS ADMINISTRATION ........................................................ 22 
6.2 CONCOMITANT PRE-MEDICATION AND SUPPORTIVE CARE GUIDELINES ........................ 24 
6.3 FOLLOW-UP PERIOD ................................................................................................ 26 
7 DOSING DELAYS/DOSE MODIFICATIONS ........................................................................................... 26 
7.1 MONITORING AND TOXICITY MANAGEMENT ................................................................ 26 
8 ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS ....................................... 29 
8.1 ADVERSE EVENT ATTRIBUTION ................................................................................. 29 
8.2 KNOWN ADVERSE EVENTS LIST ................................................................................ 30 
8.3 TIME PERIOD AND GRADE OF ADVERSE EVENT CAPTURE ........................................... 30 
8.4 MONITORING AND RECORDING AN ADVERSE EVENT ................................................... 30 
9 DATA AND SAFETY MONITORING PLAN (DSMP) .............................................................................. 31 
9.1 OVERSIGHT AND MONITORING PLAN ......................................................................... 31 
9.2 MONITORING AND REPORTING GUIDELINES ............................................................... 32 
9.3 REVIEW AND OVERSIGHT REQUIREMENTS ................................................................. 32 
9.4 EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS ............................................. 34 
10 PHARMACEUTICAL INFORMATION..................................................................................................... 38 
10.1 CARBOPLATIN ....................................................................................................... 38 
10.2 CYCLOPHOSPHAMIDE ............................................................................................. 39 
10.3 DOXORUBICIN ....................................................................................................... 40 
10.4 PACLITAXEL .......................................................................................................... 42 
11 REPORTING AND DOCUMENTING RESULTS ................................................................................... 43 

 
 
 
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11.1      EVALUATION OF EFFICACY DURING CHEMOTHERAPY ............................................ 43 
11.4 EVALUATION OF SAFETY ...................................................................................... 44 
12 STATISTICAL CONSIDERATIONS ........................................................................................................ 44 
12.1 STUDY ENDPOINTS .............................................................................................. 44 
12.2 STUDY DESIGN ................................................................................................... 44 
12.4 DETERMINATION OF SAMPLE SIZE AND POWER ESTIMATE ....................................... 45 
12.5 ACCRUAL ESTIMATES .......................................................................................... 45 
12.6 INTERIM ANALYSES AND STOPPING RULES ............................................................ 45 
12.7 ANALYSES PLANS ................................................................................................ 45 
12.9 STUDY RESULTS ................................................................................................. 46 
13 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT ......................................... 46 
13.1 ETHICAL STANDARD ............................................................................................ 46 
13.2 REGULATORY COMPLIANCE .................................................................................. 46 
13.3 PRESTUDY DOCUMENTATION................................................................................ 47 
13.5 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ............... 49 
13.7 INVESTIGATOR COMPLIANCE ................................................................................ 51 
14 DATA HANDLING AND RECORD KEEPING ....................................................................................... 51 
14.1 OVERVIEW .......................................................................................................... 51 
14.4 SOURCE DOCUMENTS .......................................................................................... 52 
14.5 CASE REPORT FORMS  ........................................................................................ 53 
14.6 STUDY RECORD RETENTION ................................................................................ 53 
14.7 WON SITE OVERSIGHT  ....................................................................................... 54 
15 CORRELATIVE STUDIES…........................................................................................................................51 
REFERENCES ................................................................................................................................................. 56 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ............................................................................... 58 
APPENDIX 2. SPECIMEN COLLECTION ................................................................................................... 59 
APPENDIX 3. STUDY CALENDAR .............................................................................................................. 60 

 
 
 
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1 BACKGROUND 
Triple-Negative Breast Cancer  
Breast cancer is the most common non-skin cancer in females and is estimated to 
have 246,660 new cases in 2016. It is also the second most common cancer-related 
mortality in females and is estimated to cause 40,450 deaths in 2016 1. Breast 
cancer is a heterogeneous group of diseases and is traditionally divided into different 
subtypes according to the receptor profile, namely the estrogen receptor (ER), 
progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). 
Different subtypes of breast cancer present with different clinical behavior, response 
to standard treatment and prognosis.  
 
The worst outcome is currently associated with the triple-negative group, which is 
defined as lack of expression of ER, PR and HER2. The lack of these specific 
targets makes the traditional cytotoxic chemotherapy as the only modality of 
systemic treatment in this subgroup. Triple-negative breast cancer (TNBC) only 
accounts for about 15-20% of all breast cancer cases. Patients with TNBC have a 
higher chance of harboring a breast cancer gene (BRCA) mutation. TNBC also more 
commonly occurs in premenopausal women or African Americans 2. In 2012, a study 
reported the outcome of a total of 15,204 patients with breast cancer who presented 
to NCCN institutions between Jan 2000 to Dec 2006. The TNBC had the worst 
breast cancer specific survival (HR = 2.99) and overall survival (HR = 2.72) 
compared to other subtypes. It also had the highest risk of death within the 2 years 
of diagnosis 3.  
 
Traditionally, treatment for early stage TNBC was upfront surgery followed by 
adjuvant chemotherapy. Studies showed that the use of adjuvant chemotherapy in 
TNBC significantly reduced the risk of recurrence and the risk of death which in turn 
improved the disease-free survival and overall survival 4. For locally advanced 
cases, the use of neoadjuvant chemotherapy followed by surgery became the 
standard of care to improve surgical options.  Both increased rates of breast 
conservation and reduced axillary surgery are feasible after neoadjuvant 
chemotherapy 5. Thus, neoadjuvant chemotherapy has become a standard 
approach for the majority of patients with TNBC 6. The standard chemotherapy used 
for TNBC contains both anthracyclines and taxanes. One of the commonly used 
regimens in the United States is the dose-dense Doxorubicin/Cyclophosphamide 
every 2 weeks with filgrastim or pegfilgrastim (or biosimilar) support for 4 cycles and 
weekly Paclitaxel for 12 doses. An additional study has shown that receiving a 
taxane before anthracycline is associated with improved pathologic complete 
response (pCR) compared with receiving an anthracycline first 7. 
 
In 2012, the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) working 
group reported the meta-analysis of 12 randomized neoadjuvant trials which 
included 12,993 patients 8. It was found that patients who achieved a pathologic 
complete response (pCR) had significant improvements in event-free survival (HR = 
0.48) and overall survival (HR = 0.36) compared with patients who did not. In the 

 
 
 
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subgroup analysis, TNBC had a pCR rate of 34% and those who achieved a pCR to 
neoadjuvant chemotherapy had improved event-free survival (HR = 0.24). Since 
chemotherapy is the only standard treatment modality for TNBC and majority of 
TNBC patients will receive chemotherapy as part of their treatment, one of the major 
investigative areas in TNBC is to improve the pathologic complete response rate to 
neoadjuvant therapy with the anticipation that this will result in improved overall 
survival. 
 
Clinical Data of Additional Chemotherapy 
Multiple chemotherapeutic agents have been studied to determine whether they 
could improve the pathologic response rate when added to the standard 
neoadjuvant anthracycline/taxane based regimens in breast cancer. A German 
study, the GeparQuattro trial, included 1421 patients who received 4 cycles of 
Epirubicin/Cyclophosphamide and then randomized to Docetaxel alone, concurrent 
Docetaxel/Capecitabine or sequential Docetaxel/Capecitabine.  This trial 
demonstrated no difference in pCR rate 9. Another study, the NSABP B-40 trial, 
included 1206 patients who were randomized to Docetaxel alone, 
Docetaxel/Gemcitabine or Docetaxel/Capecitabine, then followed by 4 cycles of 
Doxorubicin/Cyclophosphamide. This study also showed no difference in pCR rate 
10. Therefore, the addition of either Capecitabine or Gemcitabine did not improve the 
response rate to standard neoadjuvant chemotherapy in breast cancer.  
 
However, 2 studies utilizing Carboplatin in addition to standard neoadjuvant 
chemotherapy showed an increase of pCR rate in TNBC. The GeparSixto trial 
included 315 patients with TNBC who received 18 doses of weekly combined 
liposomal Doxorubicin/Paclitaxel/Bevacizumab and then randomized to addition of 
weekly Carboplatin or not 11. Those who received the addition of Carboplatin had a 
statistically significant higher pCR rate (53% vs 37%, OR = 1.97) but also higher 
treatment discontinuation rate (40% vs 36%). The CALGB 40603 trial included 443 
patients with TNBC who received standard weekly Paclitaxel x 12 doses, followed by 
dose-dense Doxorubicin/Cyclophosphamide x 4 cycles and then randomized to 
addition of Carboplatin every 3 weeks x 4 cycles or not in combination with the 
Paclitaxel 12. There was a second randomization for bevacizumab. Patient who 
receiving Carboplatin had a statistically significant higher pCR rate than those did 
not (54% vs 41%, OR = 1.71), but 36% of those received the addition of Carboplatin 
had to skip at least 2 doses of weekly Paclitaxel due to the prolonged cytopenia.          
Known and Potential Risks and Benefits 
Based on the clinical data of GeparSixto and CALGB 40603 trials, the addition of 
Carboplatin to standard anthracycline/taxane based regimen increased the pCR rate 
of TNBC in neoadjuvant approach. However, either the use of high dose Carboplatin 
(AUC=6) every 3 weeks or the use of low dose weekly Carboplatin (AUC=2) but 
combined with anthracycline and taxane concurrently had a significant side effect of 
prolonged cytopenia, which precluded patients from receiving chemotherapy as 
scheduled. GeparOla, a randomized study presented at ASCO 2019, included a 

 
 
 
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control arm of weekly paclitaxel with carboplatin at the same doses and number of 
cycles utilized in this study, which was then followed by 4 cycles epirubicin and 
cyclophosphamide. This study arm only included 27 patients with TNBC, but pCR 
rates in this subset was 59.3% (41.7-75.2%).  Importantly, serious adverse events 
were reported in 19/37 (51.3%) patients treated with the carboplatin and paclitaxel 
regimen, primarily due to cytopenias.19  Therefore, the benefit of improved response 
rate to chemotherapy carries the risk of delaying the treatment, prolonging the 
duration of treatment, or potential for increased complications such as infection or 
bleeding due to the cytopenia side effect.   
Rationale of the Study 
The effect of Carboplatin on the bone marrow causing clinical significant prolonged 
myelosuppression is dose dependent 13. Another factor in prolonged 
myelosuppression is the concomitant use of other myelosuppressive 
chemotherapeutic agents. Therefore, the combination of low dose weekly 
Carboplatin and Paclitaxel for 12 doses followed by Doxorubicin/Cyclophosphamide 
separately may limit  the severe myelosuppressive effect of the chemotherapy and 
allow patients to continue chemotherapy as scheduled. The low dose weekly 
Carboplatin regimen would be anticipated to have the same response rate as the 
high dose Carboplatin regimen given every 3 weeks. Furthermore, there is data that 
dose dense chemotherapy (defined as increasing dose frequency while the dose per 
cycle and overall dose remains the same) may result in better cancer outcomes 14, 
15.   
Hypothesis of the Study 
The use of low dose weekly Carboplatin/Paclitaxel followed by dose-dense 
Doxorubicin/Cyclophosphamide in subjects with TNBC in neoadjuvant setting will 
result in less dose reductions or chemotherapy delays and similar pCR rate seen 
with the every 3 week carboplatin schedule. 
Exploratory Study: Cytokines as the Biomarkers 
Studies have showed that there is subpopulation of cells in breast cancer that 
display stem cell properties. These cancer stem cells are capable of self-renewal, as 
well as differentiation into non-self-renewing cells forming the tumor bulk. Therefore, 
the cancer stem cells play crucial roles in multiple aspects of cancer development 
including angiogenesis, growth, metastasis and even treatment resistance.  
According to a widely-accepted idea called soil (tumor microenvironment) and seed 
(cancer cells) hypothesis 16, all these cancer cells including the cancer stem cells are 
regulated by complex interactions with the tumor microenvironment through the 
cytokines and growth factors.  
 
Cytokines are highly inducible secretory proteins that mediate intercellular 
communication in the immune system as well as the microenvironment. Certain 
cytokines such as IL-6, IL-8, CCL2 and TGF-beta are frequently elevated in breast 

 
 
 
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cancer. Preclinical data suggests that the growth of triple negative breast cancer is 
depended on IL-6 and IL-8 17. High circulating IL-6 levels are correlated with a poor 
prognosis in breast cancer 18. Therefore, the cytokine profile could serve as a target 
for therapy and as a biomarker for treatment monitoring in breast cancer patients 
receiving systemic chemotherapy.  
 
2 OBJECTIVES 
2.1 Primary Objective 
To determine the pathologic response rate to low dose weekly Carboplatin in 
combination with weekly Paclitaxel regimen (Regimen A) followed by dose dense AC 
(Regimen B) given in neoadjuvant setting for women with TNBC.  
2.2 Secondary Objectives 
2.2.1 To evaluate the number of cycles, doses and delays of low dose weekly 
Carboplatin/Paclitaxel regimen administered. 
2.2.2 To describe any treatment-related toxicity from the low dose weekly 
Carboplatin/Paclitaxel regimen. 
2.2.3 To evaluate two-year invasive disease-free survival after treatment with this 
neoadjuvant regimen.   
2.2.4 To evaluate the two-year overall survival after treatment with this neoadjuvant 
regimen.  
2.3 Exploratory Objectives 
2.3.1 To store blood and tumor tissue for future studies to explore biomarkers of 
response to carboplatin and paclitaxel in TNBC.    
3 STUDY DESIGN 
3.1 General Description 
This is a phase II single-arm, open-label, prospective study to evaluate the efficacy of 
the low dose weekly Carboplatin/Paclitaxel followed by dose-dense 
Doxorubicin/Cyclophosphamide in subjects with triple-negative breast cancer in 
neoadjuvant setting.  
3.1.1 Number of Subjects  
There will be 50 subjects enrolled. Subject accrual will be via the Wisconsin Oncology 
Network. 

 
 
 
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3.2 Primary Endpoint 
Pathologic complete response (pCR) rate which is defined as no invasive disease in the 
breast and the ipsilateral regional lymph nodes.  
3.3 Secondary Endpoint(s) 
3.3.1 The number of cycles, doses and delays of chemotherapy administered. 
3.3.2 Any treatment-related toxicity during chemotherapy.   
3.3.3 2-year invasive disease-free survival defined as lack of any ipsilateral invasive 
breast cancer recurrence in the breast, regional nodes, chest wall or skin; any distant 
metastatic disease; any death; contralateral invasive breast cancer; or second primary 
invasive non-breast cancer.  
3.3.4 2-year overall survival   
3.4 Study Timeline 
Once the neoadjuvant chemotherapy regimen is started, subject is expected to finish 
the treatment within 6 months (allowing for potential dose delays). Then 3-6 weeks after 
the last dose of chemotherapy, the subject will undergo primary breast +/- axillary 
surgery (Regimen C). After surgery, subject will be followed according to the current 
standard of care for recurrence and survival up to 2 years.   
3.5  Primary Completion 
The study will reach primary completion 30 months from the time the study opens to 
accrual. 
3.6  Study Completion 
The study will reach study completion 54 months from the time the study opens to 
accrual. 
4 PATIENT SELECTION 
Use the below checklist to confirm a patient’s eligibility. For each patient, this checklist 
must be completed and maintained in the subject’s chart.  
 
 

 
 
 
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4.1 
Eligibility Criteria  
 
Subjects must have baseline evaluations performed prior to the first dose of 
chemotherapy and must meet all inclusion and exclusion criteria. In addition, the subject 
must be thoroughly informed about all study aspects, including the study visit schedule 
and required evaluations and all regulatory requirements for informed consent. The 
written informed consent must be obtained from the subject prior to enrollment. The 
following criteria apply to all subjects enrolled onto the study unless otherwise specified.  
4.2   Inclusion Criteria 
____ 1. Subjects must have histologically or cytologically confirmed invasive breast 
cancer which meets the following criteria:  
a)  Estrogen Receptor (ER) and Progesterone Receptor (PR)-negative as 
defined by local standard clinical immunohistochemistry (IHC) < 1%. 
b)  HER2-negative using local standard testing.  Negative is defined as IHC 0 
or 1+ (if 2+, must reflex to ISH method).  If ISH method is used, ratio < 2 is 
considered negative. 
c)  Clinical tumor size of at least 2.1 cm (T2) by palpation or imaging, 
regardless of the ipsilateral regional lymph node status, or any tumor size 
but with ipsilateral regional lymph nodes involved by the tumor (any T if 
ipsilateral regional node positive). Subjects with inflammatory breast cancer 
are eligible. If bilateral breast cancer is present, the subject is eligible if the 
contralateral tumor is DCIS only (without any invasive disease on biopsy) or 
another invasive breast cancer of any size that is also ER, PR and HER2 
negative.   
d)  Any radiographic abnormal ipsilateral regional lymph nodes or any clinically 
concerning ipsilateral regional lymph nodes with the exception of internal 
mammary nodes, should be sampled with a percutaneous biopsy, but no 
sentinel axillary lymph node mapping/biopsy is allowed before 
chemotherapy.  If clinically node negative (cNO), pre-chemotherapy 
ipsilateral sentinel axillary lymph node mapping/biopsy is not allowed.  
 
_____ 2. Candidate for neoadjuvant chemotherapy. 
 
_____ 3. Age > 18 years and < 75 years. 
_____ 4. ECOG Performance Status < 1. 
 
_____ 5. Left ventricular ejection fraction (LVEF) ≥ LLN (per institutional normal) 
determined by echocardiogram or nuclear medicine scan, within 30 days of 
registration. 
 
 
 
 
 

 
 
 
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_____ 6. Adequate organ and marrow function as below: 
 
Organ and Marrow Function Table 
Adequate bone marrow function: 
Hemoglobin  
> 9.5 g/dL 
Absolute neutrophil count 
> institutional lower limit 
Platelets 
> institutional lower limit 
Adequate hepatic function: 
Total bilirubin 
< 1.25 x institutional upper limit 
AST(SGOT)/ALT 
< 2.5 times institutional upper limit 
Adequate renal function: 
Serum creatinine or 
creatinine clearance 
< institutional upper limit or  
> 60 mL/min creatinine clearance for patients with 
serum creatinine > institutional upper limit 
 
 
_____7. Non-Pregnant. Women of childbearing potential must have a negative 
pregnancy test (HCG serum or urine) within 30 days prior to study registration 
and to be repeated if not done within 7 days of starting chemotherapy.  
 
 
 
It is not known what effects this treatment has on human pregnancy or 
development of the embryo or fetus. Therefore, female subjects participating in 
this study should avoid becoming pregnant, and male subjects should avoid 
impregnating a female partner. Non-sterilized female subjects of reproductive 
age and male subjects should use effective methods of contraception through 
defined periods during and after study treatment as specified below.  
Female subjects must meet one of the following:  
 
 
Natural postmenopausal before the screening visit defined as no menses 
at any time in the preceding 12 consecutive months, or 
 
Prior bilateral oophorectomy or bilateral tubal ligation, or 
 
If they are of childbearing potential, agree to practice two effective 
methods of contraception per discussion with the treating physicians from 
the time of signing of the informed consent form through three months 
after the last dose of study drug, or 
 
Agree to practice true abstinence when this is in line with the preferred 
and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, 
ovulation, symptothermal, post ovulation methods] and withdrawal are not 
acceptable contraception methods.) 
Male subjects, even if surgically sterilized (i.e., status post vasectomy) must 
agree to one of the following: 
 
Practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last study drug dose, or 

 
 
 
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 
Agree to practice true abstinence when this is in line with the preferred 
and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post ovulation methods] and withdrawal are not 
acceptable methods of contraception.)  
 
_____ 8. Ability to understand a written informed consent document, and the willingness 
to sign it. 
 
 
4.3 Exclusion Criteria 
A potential subject who meets any of the following exclusion criteria is ineligible to 
participate in the study. 
_____ 1. Prior chemotherapy or radiation therapy for invasive breast cancer within 6 
months before registration. 
 
_____ 2. Prior investigational drugs or interventions for invasive breast cancer treatment 
within 6 months before registration are not allowed.  Prior participation in 
window-of-opportunity trials without therapeutic intent is allowed if intervention 
is no more than 3 weeks in duration.   
 
_____ 3. Stage IV metastatic breast cancer 
 
_____ 4. History of allergic reactions attributed to compounds of similar chemical 
composition to chemotherapy to be used in this study. 
 
_____ 5. Breastfeeding women. Cytotoxic chemotherapy is drug with the potential for 
teratogenic or abortifacient effects. Due to unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with 
cytotoxic chemotherapy, breastfeeding should be discontinued.  
_____ 6. Baseline peripheral neuropathy of severity > grade 1 
_____ 7. Other invasive cancer diagnosis within the past 5 years other than non-
melanoma skin cancer.   
_____ 8. Prior axillary lymph node dissection that preclude patient from surgical 
evaluation of axillary lymph node status 
 
 
_____________________________________________             _____________ 
Investigator Signature 
 
 
 
 
      Date 
 
 
_____________________________________________             _____________ 
Coordinator Signature 
 
 
 
 
      Date 
 
 

 
 
 
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5. STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES 
5.1 Study Entry Procedures 
5.1.1 Required Preregistration Screening Tests and Procedures 
The study-specific assessments are detailed in this section and outlined in the Study 
Calendar (appendix 7). Screening assessments must be performed within 30 days prior 
to registration. Any results falling outside of the reference ranges may be repeated at 
the investigator’s discretion. All on-study visit procedures are allowed a window of 7 
days unless otherwise noted. Treatment or visit delays for public holidays or weather 
conditions do not constitute a protocol violation. 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will 
be filed in the medical record. The original will be kept on file with the study records.  
All subjects who are consented will be registered in OnCore®, the UWCCC and WON 
Cancer Center Clinical Trial Management System. The system is password protected 
and meets HIPAA requirements. 
5.1.2 Registration Process 
Each subject enrolled in the study is to be registered into the UWCCC OnCore 
Database prior to starting protocol treatment. Research personnel at WON sites who 
enter data into OnCore must have completed human subjects training and Health 
Insurance Portability and Accountability Act (HIPAA) training. WON site research 
personnel receive training from the UWCCC OnCore Support Team on how to enter 
subject data into OnCore.  
At the time of registration, the following will be required and verified by (UWCCC): 
• Subject eligibility 
• Signed informed consent form 
• Signed HIPAA 
After registration, the subject must begin treatment within 14 days.  
5.1.3 Pretreatment Period 
Screening Assessments 
 
The screening procedures and assessments must be completed within 30 days prior to 
registration.  Once registered, the subject should start study treatment within 14 days. 
 

 
 
 
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 Physical examination 
 Vital signs (weight, temperature, blood pressure, heart rate) 
 Height (can be obtained at screening or Cycle 1 Day 1 of Chemotherapy) 
 Complete medical history 
 Documentation of disease assessment (disease-specific staging criteria) 
 ECOG Performance Status 
 Measurable disease (primary breast mass, axillary nodes, etc.)  
 Result of tumor tissue biopsied, including ER, PR and HER2  
 Complete blood count (CBC) with differential and platelet count 
 Blood chemistry assessment, including:  
 
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase 
(ALT/AST), total bilirubin, calcium, blood urea nitrogen (BUN), creatinine, total 
protein, albumin, glucose, potassium, sodium, chloride, bicarbonate.   
 If a woman of childbearing potential, must have a negative pregnancy prior to 
randomization. 
 Serum or urine pregnancy test within 7 days prior to the start of first dose of 
chemotherapy for premenopausal subjects 
 MRI or mammogram or ultrasound of breast for tumor/lesion assessment 
 Cardiac assessment of LVEF (ECHO, MUGA, etc.) 
 CT scan of body (i.e. chest, abdomen, pelvis) and Bone scan or PET/CT if 
clinically indicated. 
 
All blood tests other than pregnancy test are accepted within 14 days prior to the Cycle 
1 Day 1 of chemotherapy 
 
5.2   Study Procedures during Treatment 
 Subjects must meet eligibility criteria on Cycle 1 Day 1 to be started on 
treatment.  
 Optional tumor tissue (archived from biopsy) and blood collection for research as 
per Appendix 2 and 3 
5.2.1 Study Procedures Cycle 2, 3, 4 Day 1 (Regimen A) 
 Physical examination 
 Vital signs (weight, temperature, blood pressure, heart rate) 
 ECOG Performance Status 
 Clinical assessment of measurable disease sites  

 
 
 
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 Evaluation of adverse events 
 CBC with differential and platelet count 
 Blood chemistry assessment, including:  
 
Alkaline phosphatase, ALT/AST, total bilirubin, calcium, BUN, creatinine, 
glucose, potassium, sodium, chloride, bicarbonate. 
 
5.2.2 Study Procedures, Cycle 1, 2, 3, 4, Days 8, 15 (Regimen A) 
 CBC with differential and platelet count (may do ANC rather than full differential 
per MD discretion) 
 
5.2.3 Study Procedures Cycle 5, 6, 7, 8 Day 1 (Regimen B) 
 Physical examination 
 Vital signs (weight, temperature, blood pressure, heart rate) 
 ECOG Performance Status 
 Clinical assessment of measurable diseases 
 Evaluation of adverse events 
 CBC with differential and platelet count 
 Blood chemistry assessment, including: 
   
Alkaline phosphatase, ALT/AST, total bilirubin, calcium, BUN, creatinine, 
glucose, potassium, sodium, chloride, bicarbonate. 
 MRI, Ultrasound, or Mammogram of breast for tumor/lesion assessment if 
clinically indicated within 45 days before the final breast surgery. 
 
5.2.4 Surgery (Regimen C) 
The surgical intervention for management of breast cancer (primary breast tumor 
and ipsilateral regional lymph nodes) including diagnosis will be determined by the 
surgical team; and the recommendation is for it to  occur 3-6 weeks after the last 
dose of chemotherapy.Patients who cannot proceed to surgery will be deemed in-
evaluable for the primary endpoint.   
 
5.3   Post-treatment 
 
5.3.1  Follow-Up Visit after Surgery 
 
Subjects will be followed within 30 days after the final surgery. The following procedures 
will be performed at the Follow-up Visit: 

 
 
 
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 Review of the final pathologic result 
 Physical examination 
 Vital signs (weight, temperature, blood pressure, heart rate) 
 ECOG Performance Status 
 Evaluation of adverse events 
 CBC with differential and platelet count, if clinically indicated 
 Blood chemistry assessment, if clinically indicated:   
 
Alkaline phosphatase, ALT/AST, total bilirubin, calcium, BUN, creatinine, 
glucose, potassium, sodium, chloride, bicarbonate. 
 Optional tumor tissue (archived from surgery) and blood collection for research 
as per Appendix 2 and 3 
Any other clinical trials being considered before the final surgery will need the approval 
of study chair and/or study PI.  
 
Patient is allowed to participate in other clinical trials after the final surgery, if eligible. 
 
5.3.2 Subsequent Follow-Up Visits up to 2 years 
Subjects will be followed according to the standard of care (SOC) recommended by 
NCCN guidelines.   
 
To meet study objectives, each subject’s disease status and overall survival status and 
any interval systemic anti-cancer treatment will be collected every 6 months (+/- 30 
days) for 2 years after date of surgery or last date of study treatment. This includes all 
subjects who do not complete all cycles of the study treatment unless they are 
withdrawn from study.  This information may be collected via record review or by 
contacting the subject. 
 
5.4 Study Withdrawal Procedures 
5.4.1 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 
or until:  
 Disease progression 
 General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the investigator’s judgment.  

 
 
 
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 Inter-current illness that prevents further treatment administration 
 Subject decides to withdraw from the study 
 Significant subject noncompliance with protocol 
 Unacceptable adverse event(s) 
 
5.4.2 
Subject-Initiated Withdrawal:  A subject may decide to withdraw from the 
study at any time by informing the study PI. 
 
5.4.3 Investigator-Initiated Withdrawal:  The Investigator will withdraw a subject 
whenever continued participation is no longer in the subject’s best interests. Reasons 
for withdrawing a subject include, but are not limited to, disease progression, the 
occurrence of an adverse event or a concurrent illness, a subject’s request to end 
participation, a subject’s noncompliance or simply significant uncertainty on the part of 
the Investigator that continued participation is prudent. There may also be 
administrative reasons to terminate participation, such as concern about a subject’s 
compliance with the prescribed treatment regimen.   
Subjects withdrawn from study treatment will be asked to return for a 30 day follow up 
visit.  These subjects will be followed every 6 months per the follow up schedule, which 
can be done via medical record review.   If a subject is withdrawn from regimen A or B 
and receives non-protocol chemotherapy and/or radiotherapy prior to surgery, or never 
undergo breast surgery, they will be taken off study and no additional follow up will be 
conducted.Withdrawal Documentation Procedure:  The reason for study withdrawal 
and the date the subject was removed from the study must be documented in the case 
report form. 
6. 
TREATMENT PLAN 
6.1 
Chemotherapeutic Agents Administration  
           Treatment will be administered on an outpatient basis. 
 

 
 
 
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Regimen A (Cycles 1 – 4) Description* 
Study Drug 
Premedication; 
precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Carboplatin 
Same 
premedication as 
Paclitaxel. 
Paclitaxel is given 
before Carboplatin  
AUC=2 
Intravenous 
Days 1, 8, 
15 of  
cycle 1, 2, 
3, 4 
3 weeks 
(21 
days) 
Paclitaxel 
Premedicate with 
steroids, H1 and 
H2 blocker per 
institutional SOC 
80 mg/m2 Intravenous 
Days 1, 8, 
15 of  
cycle 1, 2, 
3, 4* 
3 weeks 
(21 
days) 
Regimen B (Cycles 5 – 8) Description 
Doxorubicin3 
Baseline LVEF 
before the start of 
1st dose 
60 
mg/m2 
Intravenous 
Day 1 of  
cycle 5, 6, 
7, 8 
2 weeks 
(14 
days) 
Cyclophos-
phamide4 
Hydrate with 
normal saline 
before and after 
the infusion 
600 
mg/m2 
Intravenous 
Day 1 of  
cycle 5, 6, 
7, 8 
2 weeks 
(14 
days) 
Pegfilgrastim 
 
Given 
approximately 24-
48 hours after 
chemotherapy is 
completed.  
Filgrastim or 
biosimilar such as 
tbo-filgrastim 
given daily is 
allowed as 
substitute per 
institutional SOC.   
6 mg 
SC 
Day 2-3 of  
cycle 5, 6, 
7, 8 
2 weeks  
(14 
days) 
 
 
1. Paclitaxel 80 mg/m2 per dose; administer intravenously in a volume of 0.9% sodium 
chloride injection (NS), or 5% dextrose injection (D5W) sufficient to produce a 
concentration within the range 0.3-1.2 mg/ml, over 60 minutes, or per institutional 
infusion time standard, for 3 doses, on day 1, 8, 15, every 3 weeks. 
2. Carboplatin (calculated dose) AUC = 2; administer intravenously in 0.9% NS or 5% 
D5W 100-500 ml over 30-60 minutes, or per institutional infusion time standard, for 3 
doses, on day 1, 8, 15 after completing Paclitaxel, every 3 weeks. For dose 

 
 
 
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calculation, it is preferred to determine creatinine clearance with Cockcroft Gault 
using adjusted body weight (see below).  Rounding of all chemotherapy dosing per 
institutional standards is also permitted.   
 
Adjusted Body Weight  
Step 1: Estimate Ideal Body Weight (IBW) in (kg) 
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. 
Step 2: Determine Adjusted Body Weight (AdjBW) 
AdjBW = IBW + 0.4(Actual Body Weight - IBW) 
If a subject’s actual body weight is less than the calculated ideal body weight, it is 
preferred that the actual body weight is used for calculating the creatinine clearance. 
 
Determine Creatinine Clearance (Cockcroft Gault) using AdjBW  
 
CCr={((140 –age) x AdjBW)/(72x SCr)}x 0.85 (if female) 
 
***Minimum Serum Creatinine (SCr) = 0.6mg/dL 
 
Determine Carboplatin dose (Calvert)  
 
Carboplatin Dose (mg)*** = AUC (2) X (GFR + 25) 
 
***Maximum Carboplatin Dose = 300mg 
*  There is a one week break between the end of cycle 4 (Regimen A) and the 
beginning of cycle 5 (Regimen B). 
3.  Doxorubicin 60 mg/m2; administer by intravenous injection over 3-5 minutes or per 
institutional standards on day 1, every 14 days.  Of note, baseline LVEF is only 
required once for protocol eligibility and does not need to be repeated prior to 
starting AC, unless clinically indicated.   
4.  Cyclophosphamide 600 mg/m2; administer intravenously in 100-500 ml 0.9% NS or 
5% D5W over 30-60 minutes or per institutional standards on day 1, every 14 days. 
6.2  Concomitant Pre-Medication and Supportive Care Guidelines 
6.2.1 Suggested Usage of Concomitant Pre-Medications for Paclitaxel 
 
1. Dexamethasone 
• 20 mg administer intravenously over 10-15 minutes, 30-60 minutes before 
Paclitaxel on day 1, 8, and 15.  May reduce to 10mg iv after cycle 1, day 1, or 
• Dexamethasone 20mg oral 12 and 6 hours prior to first dose of paclitaxel and 
then may reduce over time to 8mg doses, or   

 
 
 
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• Other institutional standard of care.   
 
2. Diphenhydramine 25-50 mg; administer by intravenous injection 30-60 minutes 
before Paclitaxel on day 1, 8, and 15. 
 
3. Famotidine  
• 20 mg; administer intravenously over 10-15 minutes, 30-60 minutes before 
Paclitaxel on day 1, 8, and 15, or 
• Ranitidine 50 mg; administer intravenously over 10-15 minutes, 30-60 minutes 
before Paclitaxel on day 1, 8, and 15. 
 
6.2.2 Usage of Concomitant Antiemetics 
 
• Ondansetron 16 mg; administer intravenously over 10-15 minutes, 30-60 minutes 
before Carboplatin on day 1, 8, and 15, or 
• Granisetron 1 mg; administer intravenously over 10-15 minutes, 30-60 minutes 
before Carboplatin on day 1, 8, and 15, or 
• Fosaprepitant 150 mg and Ondansetron 16 mg; administer intravenously over 
10-15 minutes, 30-60 minutes before Doxorubicin/Cyclophosphamide on day 1, 
or 
• Other institutional standard of care 
 
6.2.3 Usage of Concomitant Supportive Care 
 
1. Growth Factor Support: 
a. During Carboplatin/Paclitaxel: 
• Prophylactic filgrastim (or biosimilar such as tbo-filgrastim) is 
allowed during the weekly Carboplatin/Paclitaxel if clinically 
indicated.  
• Filgrastim (or biosimilar such as tbo-filgrastim) given during 
neutropenia period is also allowed as per treating physician’s 
discretion. 
• Pegfilgrastim should not be used during these cycles 
 
b. During Doxorubicin/Cyclophosphamide: 
• Pegfilgrastim 6 mg/0.6 ml by subcutaneous injection for 1 dose 
begin 24- 48 hrs after chemotherapy of Doxorubicin/ 
Cyclophosphamide is completed, or  
• 
Filgrastim 5 mcg/kg per day rounded to 300 or 480mcg dose by 
subcutaneous injection for 7-10 days with dose to begin on day 3 
after chemotherapy of Doxorubicin/Cyclophosphamide is 
completed.  Biosimilar to filgrastim also allowed. 
 
2. Post-treatment antiemetics to be given per institutional standard of care.During 
paclitaxel and carboplatin, treating physicians should try to limit additional steroid 
use.  

 
 
 
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3. Packed red blood cell or platelet transfusion is allowed for chemotherapy induced 
anemia or thrombocytopenia as clinically indicated per institutional guideline or 
individual physician discretion.  
 
6.3  Follow-Up Period 
After completion of chemotherapy, subjects will be seen within 30 days after the surgery 
for the primary endpoint determination. After that, subjects will be followed according to 
the standard of care recommended by NCCN guidelines up to 2 years.  
AEs will be followed  for 30 days after the last dose of chemotherapy. SAEs will be 
followed until resolution or until considered permanent by the treating physician.  All 
subjects, including these, will be followed for two years post final study treatment 
(chemotherapy or surgery) per SOC..   
7. DOSING DELAYS/DOSE MODIFICATIONS 
7.1  Monitoring and Toxicity Management 
Each subject receiving cytotoxic chemotherapy will be evaluable for safety. The safety 
parameters include all laboratory tests and hematological abnormalities, physical 
findings, subjective symptoms and spontaneous reports of adverse events reported to 
the investigator by subjects. 
Toxicity will be assessed according to the NCI CTCAE v5.0. Dose adjustments will be 
made according to the degree of toxicity. Treatment-related toxicities are those at least 
possibly related to the study therapy.   
During the administration of chemotherapy, subjects will be evaluated on day 1 (+/- 1 
day) of each cycle (except cycle 1 may be seen up to 3 days prior to C1D1).  
Subjects will also be monitored for delayed or prolonged toxicities after completion of 
chemotherapy. This will be monitored by physician in charge of the subjects during the 
follow up according to standard of care.  
If protocol therapy is discontinued during Regimen A due to toxicity, the subject may 
receive Regimen B per physician discretion. If no further chemotherapy is administered 
and subject proceeds next to breast surgery, then they should be entered in the follow 
up stage of the study.  If protocol therapy is discontinued during Regimen B due to 
toxicity and the subject proceeds next to breast surgery, then they should be entered in 
the follow up stage of the study.  If the treating physician decides that it is in the 
subject’s best interest to receive non-protocol therapy prior to surgery, the subject 
should be withdrawn from the study and no further follow-up is required. 
7.2 Toxicity Management Table 
 
Toxicity 
Management 

 
 
 
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Hematologic Toxicity on day of treatment (Regimen A: Cycle 1-4)* For Regimen B (Cycle 
5-8), please refer to footnote c 
• 
Platelet count < 100 x 109/L 
and/or 
• 
ANC grade 3 (< 1.00 x 
109/L) 
 
 
• 
Hold Treatment, repeat CBC w/diff within 7 days.  
• 
If repeat platelet count is ≥ 100 x 109/L and ANC ≤ grade 
2, then resume the delayed chemotherapy (both 
agents) as full dose. 
• 
If not recovered in 7 days, continue to hold and repeat 
CBC w/diff at least weekly until platelet count is ≥ 100 x 
109/L and ANC ≤ grade 2. 
• 
If delayed ≤ 14 days, resume at full dose. 
• 
If delayed > 14 days up to 28 days, resume 
chemotherapy with 20% dose reduction. 
• 
If delayed > 28 days, discontinue regimen A protocol 
therapy and proceed to regimen B.   
• 
Platelet count decreased < 
25 x 109/L 
and/or 
• 
ANC grade 4 (<0.5 x 109/L) 
• 
Hold Treatment, repeat CBC w/diff within 7 days.  
• 
If repeat platelet count is ≥ 100 x 109/L and ANC ≤ grade 
2, then resume the delayed chemotherapy (both 
agents) with 20% reduction.  
• 
If not recovered in 7 days, continue to hold and repeat 
CBC w/diff at least weekly until platelet count is ≥ 100 x 
109/L and ANC ≤ grade 2. 
• 
If delayed ≤ 14 days, resume with 20% dose reduction. 
• 
If delayed > 14 days, discontinue regimen A therapy 
and proceed to regimen B.  
 
*There will be no dose modifications/delays for WBC or other components of the differential 
(i.e. lymphocytes, monocytes, eosinophils and basophils). Only hematology labs resulted on 
treatment days will be used to determine dose modifications. 
Anemia (Regimens A and B: Cycle 1-8) 
PRBC transfusions are recommended for symptomatic or clinically significant anemia.  
Cardiac Toxicity (Regimen B: Cycle 5-8) 
• 
Cardiomyopathy  
• 
Discontinue 
doxorubicin. 
Cardiomyopathy 
to 
be 
managed per institutional standard of care.  
Neuropathy (Regimen A: Cycle 1-4) 
• 
Grade 1a 
• 
Consider symptomatic management (not required).  
• 
No dose modifications to carboplatin or paclitaxel.  
• 
Grade 2 
• 
Symptomatic management required.  
• 
Continue carboplatin at full dose.  
• 
Continue paclitaxel with 20% dose reduction for all 
subsequent doses as long as the neuropathy does not 
progress to grade 3 or 4.   
• 
Grade 3 (first occurrence) 
• 
Symptomatic management required.  
• 
Hold study drug. If recovers to ≤ grade 2 in less than 3 
weeks, resume both carboplatin & paclitaxel with 20% 
dose reduction for all subsequent doses, as long as the 
neuropathy does not progress to grade 3 or 4.  
• 
If neuropathy does not recover to ≤ grade 2 within 3 
weeks discontinue carboplatin & paclitaxel. Proceed to 
regimen B.  

 
 
 
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• 
Skipped doses are made up. 
• 
Grade 3 (recurrence) 
• 
If grade 3 neuropathy recurs after previously recovering 
to ≤ grade 2, discontinue carboplatin & paclitaxel. 
Proceed to regimen B.  
• 
Grade 4 
• 
Discontinue carboplatin & paclitaxel. Proceed to 
regimen B. 
All Other Non-Hematologic Toxicities (Cycle 1-4)c 
• 
Grade ≤ 2 
• 
Continue study therapy at full dose.  SOC management 
required. 
• 
Grade 3b 
• 
Hold until ≤ grade 2. SOC management is required.  
Resume at full dose if toxicity resolves to ≤ grade 2 in ≤ 
14 days. If toxicity resolves to ≤ grade 2 in 14 to ≤ 28 
days, resume therapy with 20% dose reduction.  
• 
If delayed > 28 days, discontinue regimen A therapy 
and proceed to regimen B.   
• 
Grade 4  
• 
Discontinue regimen A therapy, proceed to regimen B.  
a This includes grade 1 paresthesia (mild symptoms) 
bException will be for Grade 3 nausea, or any electrolyte abnormalities.  These should be 
promptly maximally medically managed and only will result in treatment delay if grade 3 event 
is lasting longer than 24 hours despite maximal medical treatment. 
cDuring AC chemotherapy (cycle 5-8), dose modifications or holds for hematologic or non-
hematologic toxicity (except cardiomyopathy) should be per SOC and treating physician’s 
discretion. 

 
 
 
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8. ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS 
8.1 Adverse Event Attribution 
Attribution is an assessment of the relationship between the AE and the medical 
intervention. 
 
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to 
the intervention 
Unlikely 
The AE is doubtfully related to 
the intervention 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the 
intervention 
Probable 
The AE is likely related to the 
intervention 
Definite 
The AE is clearly related to the 
intervention 
 
Relationship Assessment:  In-Depth Definitions 
For all collected AEs, the clinician who examines and evaluates the subject will 
determine the adverse event’s causality based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the 
categories below: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response 
to withdrawal of the drug (de-challenge) should be clinically plausible. The event must 
be pharmacologically or phenomenologically definitive, with use of a satisfactory re-
challenge procedure if necessary.  
Probably Related: There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal laboratory 
test result, occurs within a reasonable time sequence to administration of the drug, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (de-challenge). Re-challenge information 
is not required to fulfill this definition.  
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, the influence of other factors may have contributed to the event (e.g., the 
subject’s clinical condition, other concomitant events). Although an adverse drug event 

 
 
 
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may rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely related”, as 
appropriate. 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) 
and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the subject’s clinical condition, other concomitant treatments).  
Unrelated: The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.  
8.2  Known Adverse Events List 
Refer to the potential side effects of each chemotherapeutic agent listed in section 10. 
8.3  Time Period and Grade of Adverse Event Capture 
Any AEs and the grade of the AEs will be captured from the beginning of the 
chemotherapy until it is completed.  
8.4  Monitoring and Recording an Adverse Event  
Definition.  Any clinically relevant deterioration in laboratory assessments or other 
clinical finding is considered an AE.   
Reporting source.  AEs may be spontaneously reported by the Subject and/or in 
response to an open question from study personnel or revealed by observation, 
physical examination or other diagnostic procedures.   
Prior to the trial.  Planned hospital admissions or surgical procedures for an illness or 
disease that existed before the subject was enrolled in the trial are not to be considered 
AEs unless the condition deteriorated in an unexpected manner during the trial (e.g., 
surgery was performed earlier or later than planned).   
Pretreatment events following signed informed consent. For serious pretreatment 
events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.  
Treatment events. For serious AEs, the investigator must determine both the intensity 
of the event and the relationship of the event to study drug administration.  
Not serious AEs.  For non-serious AEs, the investigator must determine both the 
intensity of the event and the relationship of the event to study drug administration. 
 

 
 
 
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Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management 30 days 
following the last dose of the study drug or treatment. SAEs will be followed until 
resolution or until considered permanent by the treating physician.  
8.4.1 Procedure for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant, or suspects that she is pregnant, while participating in 
this study, she must inform the investigator immediately and permanently discontinue 
the study drug. The sponsor-investigator must notify the DSMC by email. The 
pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male subject becomes pregnant during the male subject’s 
participation in this study, the sponsor-investigator must also immediately notify the 
DSMC by email. Every effort should be made to follow the pregnancy for the final 
pregnancy outcome. 
9. DATA AND SAFETY MONITORING PLAN (DSMP) 
9.1  Oversight and Monitoring Plan 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the 
regular review and monitoring of all ongoing clinical research in the UWCCC. A 
summary of DSMC activities are as follows:  
• Reviews all clinical trials conducted at the UWCCC for subject safety, protocol 
compliance, and data integrity.  
• Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as 
defined in the protocol, for all clinical trials conducted at the UWCCC, and studies 
conducted at external sites for which the UWCCC acts as an oversight body.  
• Reviews all reports generated through the UWCCC DSMS elements (Internal 
Audits, Quality Assurance Reviews, Response Reviews, Compliance Reviews, 
and Protocol Summary Reports) described in Section II of this document.  
• Notifies the protocol Principal Investigator of DSMC decisions and, if applicable, 
any requirements for corrective action related to data or safety issues.  
• Notifies the CRC of DSMC decisions and any correspondence from the DSMC to 
the protocol Principal Investigator.  
• Works in conjunction with the UW Health Sciences IRB in the review of relevant 
safety information as well as protocol deviations, non-compliance, and 
unanticipated problems reported by the UWCCC research staff.  
• Ensures that notification of SAEs requiring expedited reporting is provided to 
external sites participating in multi-institutional clinical trials coordinated by the 
UWCCC. 
 
 

 
 
 
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9.2  Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study 
sponsorship and risk level of the protocol as determined by the PRMC. All protocols 
(including Intervention Trials, Non-Intervention Trials, Behavioral and Nutritional 
Studies, and trials conducted under a Training Grant) are evaluated by the PRMC at the 
time of committee review. UWCC monitoring requirements for trials without an 
acceptable external DSMB are as follows: 
Protocols subject to intermediate monitoring generally include UW Institutional Phase 
I/II and Phase II Trials. These protocols undergo review of subject safety at regularly 
scheduled DOT meetings where the results of each subject’s treatment are discussed 
and the discussion is documented in the DOT meeting minutes. The discussion includes 
the number of subjects enrolled, significant toxicities, dose adjustments, and responses 
observed. Protocol Summary Reports are submitted on a semi-annual basis by the 
study team for review by the DSMC. 
9.3  Review and Oversight Requirements 
9.3.1 Serious Adverse Events – Reported Within 24 Hours 
Serious Adverse Events requiring reporting within 24 hours (as described in the 
protocol) must also be reported to the Data and Safety Monitoring Committee (DSMC) 
Chair via an email to saenotify@uwcarbone.wisc.edu within one business day. The 
OnCore SAE Details Report must be submitted along with other report materials as 
appropriate (NCI AdEERS form or FDA Medwatch Form #3500 and/or any other 
documentation available at that time of initial reporting). The DSMC Chair will review the 
information and determine if immediate action is required. Within 10 working days, all 
available subsequent SAE documentation must be submitted electronically along with a 
24-hour follow-up SAE Details Report and a completed UWCCC SAE Routing Form to 
saenotify@uwcarbone.wisc.edu. All information is entered and tracked in the UWCCC 
database. 
The Principal Investigator notifies all investigators involved with the study at the 
UWCCC, the IRB, the sponsor, and the funding agency and provides documentation of 
these notifications to the DSMC.  
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor 
investigator, the PI reviews the event to determine whether the SAE requires reporting 
to the FDA and other participating investigators.  
For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are 
reported to the FDA as well as to all participating investigators.  
See Section 9.3.5 for detailed instructions on SAE reporting. 
 

 
 
 
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9.3.2 Serious Adverse Events – Reported within 10 Days 
Serious Adverse Events requiring reporting within 10 days (as described in the protocol) 
must also be reported to the Data and Safety Monitoring Committee (DSMC) Chair via 
an email to saenotify@uwcarbone.wisc.edu. The OnCore SAE Details Report must be 
submitted along with other report materials as appropriate (NCI AdEERS form or FDA 
Medwatch Form #3500 and/or any other documentation available at the time of initial 
reporting). The DSMC Chair will review the information and determine if further action is 
required. All information is entered and tracked in the UWCCC database.  
The Principal Investigator notifies all investigators involved with the study at the 
UWCCC, the IRB, the sponsor, and the funding agency and provides documentation of 
these notifications to the DSMC.  
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-
investigator, the PI reviews the event to determine whether the SAE requires reporting 
to the FDA and other participating investigators.  
For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are 
reported to the FDA as well as to all participating investigators.  
See Section 9.3.5 for detailed instructions on SAE reporting. 
9.3.3 Sponsor-Investigator Responsibilities for SAE Review 
In the event the UWCCC Principal Investigator is acting as the Sponsor-Investigator 
(i.e., the PI holds the IND), the PI assumes responsibilities of the study sponsor in 
accordance with FDA 21 CFR 312.32. In this capacity, the UWCCC PI reviews all 
reports of serious adverse events occurring on the study at the UWCCC and 
participating external sites and makes a determination of 1) suspectedness (i.e., 
whether there is a reasonable possibility that the drug caused the AE); and 2) 
unexpectedness (the event is not listed in the Investigator’s Brochure or is not listed at 
the specificity or severity that has been observed) in the context of this study. SAE with 
suspected causality to study drug and deemed unexpected are reported as IND Safety 
Reports by the UWCCC PI to the FDA, all participating investigators on the study, and 
the external global sponsor (if applicable) within 15 calendar days. All fatal or life-
threatening SAE that are unexpected and have suspected causality to the study drug 
will be reported by the UWCCC PI to the FDA, all participating investigators on the 
study, and the external global sponsor (if applicable) within 7 calendar days. 
Refer to Section 9.3.5.5 for UWCCC PI instructions for reporting to the FDA 
9.3.4 Study Progress Review 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC in the 
timeframe determined by the risk level of the study (quarterly; semi-annually; or 
annually). The PSR provides a cumulative report of SAEs, as well as instances of 
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responses that have occurred on the protocol in the timeframe specified. PSRs for 
those protocols scheduled for review are reviewed at each DSMC meeting. 
Protocol Summary Reports enable DSMC committee members to assess whether 
significant benefits or risks are occurring that would warrant study suspension or 
closure. This information is evaluated by the DSMC in conjunction with other reports of 
quality assurance activities (e.g., reports from Internal Audits, Quality Assurance 
Reviews) occurring since the prior review of the protocol by the DSMC. Additionally, the 
DSMC requires the study team to submit external DSMB or DSMC reports, external 
monitoring findings for industry-sponsored studies, and any other pertinent study-related 
information. 
In the event that there is significant risk warranting study suspension or closure, the 
DSMC will notify the PI of the DSMC findings and ensure the appropriate action is taken 
for the protocol (e.g., suspension or closure). The DSMC ensures that the PI reports 
any temporary or permanent suspension of a clinical trial to the sponsor (e.g., NCI 
Program Director, Industry Sponsor Medical Monitor, Cooperative Group Study Chair) 
and other appropriate agencies. DSMC findings and requirements for follow-up action 
are submitted to the CRC. 
9.4  Expedited Reporting of Serious Adverse Events 
Depending on the nature, severity, and attribution of the serious adverse event an SAE 
report will be phoned in, submitted in writing, or both according to the table below. All 
serious adverse events must also be reported to the UWCCC Data and Safety 
Monitoring Committee Chair. All serious adverse events must also be reported to the 
UW IRB (if applicable), and any sponsor/funding agency not already included in the list. 
Determine the reporting time line for the SAE in question by using the following table. 
Then refer to sections 9.3.5.1 and 9.3.5.2 below if the SAE occurred at the UWCCC or 
sections 9.3.5.3 and 9.3.5.4 if the SAE occurred at 1 South Park, Johnson Creek, or a 
WON Site. 
Expedited Reporting Requirements for Adverse Events that occur on Studies 
within 30 Days of the Last Administration of the investigational 
Agent/Intervention 
 
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the UWCCC and any other parties 
outlined in the protocol ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event. 
3) An adverse event that results in inpatient hospitalization or prolongation of 
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4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered serious when, based 
upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria* MUST be 
immediately reported to the UWCCC within the timeframes detailed in the table 
below: 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour; 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar 
Days 
Expedited AE reporting timelines are defined as: 
• 24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours 
of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
• 10 Calendar Days – A complete expedited report on the AE must be submitted 
within 10 calendar days of learning of the AE 
1 Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or 
definite require reporting as follows: 
 
Expedited 24-hour notification followed by complete report within 5 calendar 
days for: 
• All Grade 4 and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of 
hospitalization 
• Grade 3 events 
 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the 
agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period.  
 
9.4.1 SAE Requiring [24] Hour Reporting Occurs at UWCCC 

 
 
 
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1. Report to the UWCCC:  
Reference the SAE SOP (Standard Operating Procedure) and the SAE 
Reporting Workflow for DOTs on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and 
what to report to the UWCCC for [24] hour initial and follow-up reports. A follow-
up report is required to be submitted within 10 days of the initial [24] hour 
report.  
For this protocol, the following UWCCC entities are required to be notified:  
a) saenotify@uwcarbone.wisc.edu  
b) Kari Wisinski, MD: kbwisinski@medicine.wisc.edu 
c) Tamara Koehn: tmkoehn@medicine.wisc.edu  
d) Any other appropriate parties listed on the SAE Routing Form (for follow-up 
reports only)  
 
2. Report to the IRB:  
Consult the UW Health Sciences IRBs website for reporting guidelines. 
9.4.2 SAE Reporting [10] Day Reporting Occurs at UWCCC: 
1. Report to the UWCCC:  
Reference the SAE SOP (Standard Operating Procedure) and the SAE 
Reporting Workflow for DOTs on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and 
what to report to the UWCCC for [10] day reports. 
For this protocol, the following UWCCC entities are required to be notified:  
a) saenotify@uwcarbone.wisc.edu  
b) Kari Wisinski, MD: kbwisinski@medicine.wisc.edu 
c) Tamara Koehn: tmkoehn@medicine.wisc.edu 
d) Any other appropriate parties listed on the SAE Routing Form (for follow-up 
reports only)  
 
2. Report to the IRB:  
Consult the UW Health Sciences IRBs website for reporting guidelines. 
9.4.3 SAE Requiring [24] Hour Reporting Occurs at 1 South Park (1SP), Johnson 
Creek (JC), or a WON Site: 
1. Report to the UWCCC:  

 
 
 
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Reference the SAE SOP and the SAE Reporting Workflow for 1SP, JC, and 
other Affiliates on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and 
what to report to the UWCCC for [24] hour initial and follow-up reports. A follow-
up report is required to be submitted within 10 days of the initial [24] hour 
report. 
Send the OnCore SAE details report and any supporting, applicable 
documentation to: saenotify@uwcarbone.wisc.edu 
NOTE: After 1SP, JC, or a WON site has submitted the [24] hour SAE follow-up 
report, the report is triaged initially to the UW Principal Investigator or Study 
Chair, the DOT Program Manager, the Affiliate Coordinator, and the DSMC Chair 
for review. The Principal Investigator or Study Chair is then responsible for 
ensuring the SAE is reported to the FDA, the global sponsor (if applicable), 
the UW IRB, and any other entity requiring notification, in accordance each 
entities’ reporting requirements. 
 
2. Report to the IRB:  
WON sites should follow their local IRB reporting guidelines for SAE submission. 
The UW PI/Study Chair is responsible for the submission of the SAE to the UW 
Health Sciences IRBs for any sites for which the UW serves as the IRB of record. 
9.4.4 SAE Requiring [10] Day Reporting Occurs at 1 South Park (1SP), 
Johnson Creek (JC), or a WON site:  
1. Report to the UWCCC: 
Reference the SAE SOP and the SAE Reporting Workflow for 1SP, JC, and 
other Affiliates on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and 
what to report to the UWCCC for [10] day reports.  
Send the OnCore SAE details report and any supporting, applicable 
documentation to: saenotify@uwcarbone.wisc.edu 
NOTE: After 1SP, JC, or a WON site has submitted the [24] hour SAE follow-up 
report, the report is triaged initially to the UW Principal Investigator or Study 
Chair, the DOT Program Manager, the Affiliate Coordinator, and the DSMC Chair 
for review. The Principal Investigator or Study Chair is then responsible for 
ensuring the SAE is reported to the FDA, the global sponsor (if applicable), 
the UW IRB, and any other entity requiring notification, and in accordance 
each entities’ reporting requirements. 
2. Report to the IRB: 

 
 
 
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The UW PI/Study Chair is responsible for the submission of the SAE to the UW 
Health Sciences IRBs. WON sites should follow their local IRB reporting 
guidelines for SAE submission. 
9.4.5 Other Reporting Requirements 
Reporting to the FDA  
Serious Adverse Events occurring on studies on which a UW PI is acting as 
sponsor/investigator must be reported to the FDA within the appropriate time frame. 
Mandatory and voluntary reporting guidelines and instructions are outlined on the FDA 
website: http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
10. PHARMACEUTICAL INFORMATION 
10.1 Carboplatin  
10.1.1 Product Description 
Classification: Antineoplastic Agent, Alkylating Agent;  
                          Antineoplastic Agent, Platinum Analog 
Mechanism of Action: Carboplatin is a platinum compound alkylating agent which 
covalently binds to DNA; interferes with the function of DNA by producing interstrand 
DNA cross-links. 
Metabolism: Carboplatin does not undergo significant metabolism. It undergoes 
aquation reaction in the presence of low concentrations of chloride. Carboplatin is 
extensively cleared by the kidneys, with about 60-70% of drug excreted in the urine 
within 4 hours.  
Contraindications: History of severe allergic reaction to carboplatin, cisplatin, other 
platinum-containing formulations, mannitol, or any component of the formulation; should 
not be used in subjects with severe bone marrow depression or significant bleeding 
Side Effects:  Complete and updated adverse event information is available in the 
Investigational Drug Brochure and/or product package insert. 
Common side effects include myelosuppression, nausea, vomiting, renal toxicity, 
peripheral neuropathy, elevation of liver enzymes, allergic reaction, amenorrhea, sterility 
and alopecia.  
 
10.1.2 Solution Preparation  
Carboplatin is available in solution of 50 mg/5 mL (5 mL); 150 mg/15 mL (15 mL); 450 
mg/45 mL (45 mL); and 600 mg/60 mL (60 mL) for intravenous administration.  
10.1.3 Storage Requirements 

 
 
 
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Store intact vials at room temperature at 25°C (77°F); excursions permitted to 15°C to 
30°C (59°F to 86°F). Protect from light. 
10.1.4 Stability 
Further dilution to a concentration as low as 0.5 mg/mL is stable at room temperature 
(25°C) for 8 hours in NS or D5W. Stability has also been demonstrated for dilutions in 
D5W in PVC bags at room temperature for 9 days; however, the manufacturer 
recommends use within 8 hours due to lack of preservative. Multidose vials are stable 
for up to 14 days after opening when stored at 25°C (77°F) following multiple needle 
entries. 
10.1.5 Route of Administration  
Intravenous. 
10.1.6 Nursing Implications 
Assess subject allergy history prior to therapy and note specific use cautions (e.g., bone 
marrow suppression and renal function). Assess other drugs subject may be taking for 
potential interactions (especially products that may be ototoxic or nephrotoxic and need 
for sequencing with taxane derivatives). Assess hematology, electrolytes, and renal and 
hepatic function tests prior to treatment and on a regular basis during therapy. Monitor 
for nausea and vomiting (pretreatment with antiemetic may be required), ototoxicity 
(audiometry may be advisable), bone marrow depression, anemia, bleeding, and 
peripheral neuropathy. 
10.2 Cyclophosphamide  
10.2.1 Product Description 
Classification: Antineoplastic Agent, Alkylating Agent;  
                    
Mechanism of Action: Cyclophosphamide is an alkylating agent that prevents cell 
division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle 
phase nonspecific agent. Cyclophosphamide also possesses potent 
immunosuppressive activity. Cyclophosphamide is a prodrug that must be metabolized 
to active metabolites in the liver. 
Metabolism: Extensively metabolized in the liver by the cytochrome P450 system to 
both active and inactive form. Parent drug and its metabolites are eliminated exclusively 
in urine. The elimination half-life ranges from 4 to 6 hours.  
Contraindications: Hypersensitivity to cyclophosphamide or any component of the 
formulation; urinary outflow obstruction. 
Side Effects:  Complete and updated adverse event information is available in the 
Investigational Drug Brochure and/or product package insert. 

 
 
 
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Common side effects include myelosuppression, bladder toxicity, nausea, vomiting, 
alopecia, amenorrhea with ovarian failure, sterility, cardiotoxicity in high dose, risk of 
second malignancies, immunosuppression with increased risk of infection, SIADH and 
hypersensitivity reaction.  
 
10.2.2 Solution Preparation  
Cyclophosphamide is available in reconstituted solution of 500 mg, 1 gm and 2 gm for 
intravenous administration. It also is available in 25 mg and 50 mg in capsule and tablet 
form for oral administration.  
10.2.3 Storage Requirements 
Injection powder for reconstitution: Store intact vials of powder at ≤25°C (77°F). 
Exposure to excessive temperatures during transport or storage may cause active 
ingredient to melt (vials with melting may have a clear to yellow viscous liquid which 
may appear as droplets); do not use vials with signs of melting. Solutions reconstituted 
in sterile water for injection should be further diluted immediately; do not inject SWFI 
reconstituted solution directly. 
10.2.4 Stability 
Reconstituted solutions in normal saline (NS) are stable for 24 hours at room 
temperature and for 6 days refrigerated at 2°C to 8°C (36°F to 46°F). Solutions diluted 
for infusion in 1/2NS or NS are stable for 24 hours at room temperature and for 6 days 
refrigerated; solutions diluted in D5W or D5NS are stable for 24 hours at room 
temperature and for 36 hours refrigerated. 
10.2.5 Route of Administration  
Intravenous or oral 
10.2.6 Nursing Implications 
Adjust dose for renal or hepatic dysfunction. Assess other drugs subject may be taking 
that may increase or prolong nephrotoxicity and cardiotoxicity. Note infusion specifics in 
administration. Adequate hydration is required for all uses, but protocol and method of 
administration may be indication-specific. Monitor IV site for signs of extravasation. 
Assess results of urinalysis, BUN, and serum creatinine to evaluate for nephrotoxicity. 
Monitor CBC with differential and platelet count to identify myelosuppression. Monitor 
for hemorrhagic cystitis and renal tubular necrosis, especially in high doses. Teach 
subject importance of adequate hydration, especially for subjects who are taking oral 
tablets. Teach subject the importance of follow-up to monitor for secondary 
malignancies. 
10.3 Doxorubicin  
10.3.1  Product Description 

 
 
 
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Classification: Antineoplastic Agent, Anthracycline; Antineoplastic Agent, Topoisomerase 
II Inhibitor 
 
Mechanism of Action: Inhibition of DNA and RNA synthesis by intercalation between 
DNA base pairs by inhibition of topoisomerase II and by steric obstruction. Doxorubicin 
intercalates at points of local uncoiling of the double helix. Although the exact 
mechanism is unclear, it appears that direct binding to DNA (intercalation) and inhibition 
of DNA repair (topoisomerase II inhibition) result in blockade of DNA and RNA synthesis 
and fragmentation of DNA. Doxorubicin is also a powerful iron chelator; the iron-
doxorubicin complex can bind DNA and cell membranes and produce free radicals that 
immediately cleave the DNA and cell membranes. 
Metabolism: Metabolized extensively in the liver in the active hydroxylated metabolite, 
doxorubicinol. About 40-50% of drug is eliminated via biliary excretion in feces. Less 
than 10% of drug is cleared by the kidneys. Prolonged terminal half-life of 20-48 hours.   
Contraindications: Hypersensitivity (including anaphylaxis) to doxorubicin, any 
component of the formulation, or to other anthracyclines or anthracenediones; recent MI 
(within past 4 to 6 weeks), severe myocardial insufficiency, severe arrhythmia; previous 
therapy with high cumulative doses of doxorubicin, daunorubicin, idarubicin, or other 
anthracycline and anthracenediones; severe persistent drug-induced myelosuppression 
or baseline neutrophil count <1500/mm3; severe hepatic impairment (Child-Pugh class 
C or bilirubin >5 mg/dL) 
Side Effects:  Complete and updated adverse event information is available in the 
Investigational Drug Brochure and/or product package insert. 
Common side effects include myelosuppression, nausea, vomiting, mucositis, diarrhea, 
cardiotoxicity, hyperpigmentation of nails, alopecia, discoloration of urine, allergic 
reaction. 
 
10.3.2  Solution Preparation  
Doxorubicin is available in reconstituted solution of 10 mg; 20 mg; and 50 mg for 
intravenous administration.  
10.3.3  Storage Requirements 
Lyophilized powder: Store powder at 20°C to 25°C (68°F to 77°F). Protect from light. 
Retain in carton until time of use. Discard unused portion from single-dose vials.  
Solution: Store refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. Retain in 
carton until time of use. Discard unused portion. Storage of vials of solution under 
refrigeration may result in formation of a gelled product; if gelling occurs, place vials at 
room temperature for 2 to 4 hours to return the product to a slightly viscous, mobile 
solution. 
 

 
 
 
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10.3.4  Stability 
Reconstituted doxorubicin is stable for 7 days at room temperature under normal room 
lighting and for 15 days when refrigerated at 2°C to 8°C (36°F to 46°F). Protect 
reconstituted solution from light. 
10.3.5  Route of Administration  
Intravenous. 
10.3.6  Nursing Implications 
Use with caution in subjects with history of heart failure, kidney or liver disease, prior 
treatment with same drug class, or past radiation to the chest. Assess cardiac function 
prior to beginning therapy with this drug and periodically during therapy. Initiate routine 
surveillance for risk of secondary malignancies. Subjects should not receive live 
vaccines while undergoing treatment. Antiemetics should be given to help prevent 
nausea and vomiting. Infusion site must be closely monitored; extravasation can cause 
sloughing or tissue necrosis (use dexrazoxane or DMSO). 
10.4 Paclitaxel  
10.4.1  Product Description 
Classification: Antineoplastic Agent, Antimicrotubular;  
                          Antineoplastic Agent, taxane derivative 
Mechanism of Action: Paclitaxel promotes microtubule assembly by enhancing the 
action of tubulin dimers, stabilizing existing microtubules, and inhibiting their 
disassembly, interfering with the late G2 mitotic phase, and inhibiting cell replication. In 
addition, the drug can distort mitotic spindles, resulting in the breakage of 
chromosomes. Paclitaxel may also suppress cell proliferation and modulate immune 
response. 
Metabolism: Metabolized extensively by the hepatic P450 microsomal system. About 
70-80% of drug is excreted via fecal elimination. Less than 10% is eliminated as the 
parent form with the majority being eliminated as metabolites. Renal clearance is 
relatively minor with less than 10% of drug cleared via the kidneys. Terminal elimination 
half-life ranges from 9 to 50 hours depending on the schedule of administration.   
Contraindications: Hypersensitivity to paclitaxel, polyoxyl 35/polyoxyethylated castor 
oil (Cremophor EL), or any component of the formulation; treatment of solid tumors in 
subjects with baseline neutrophil counts <1,500/mm3; treatment of Kaposi sarcoma in 
subjects with baseline neutrophil counts <1,000/mm3. 
Side Effects:  Complete and updated adverse event information is available in the 
Investigational Drug Brochure and/or product package insert. 

 
 
 
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Common side effects include myelosuppression, hypersensitivity reaction, neurotoxicity, 
transient asymptomatic sinus bradycardia, alopecia, mucositis, diarrhea, transient 
elevation in liver enzymes, onycholysis.  
 
10.4.2  Solution Preparation  
Paclitaxel is available in concentrate of 100 mg/16.7 mL (16.7 mL); 30 mg/5 mL (5 mL); 
150 mg/25 mL (25 mL); and 300 mg/50 mL (50 mL) for intravenous administration. 
10.4.3  Storage Requirements 
Store intact vials at room temperature of 20°C to 25°C (68°F to 77°F). Protect from 
light.  
10.4.4  Stability 
Solutions diluted for infusion in D5W and NS are stable for up to 27 hours at ambient 
temperature (~25°C). 
10.4.5  Route of Administration  
Intravenous. 
10.4.6  Nursing Implications 
Paclitaxel (protein bound) is not interchangeable with paclitaxel (conventional). Assess 
subject carefully for cautious use indications and contraindications. Infusion site must be 
monitored closely to avoid extravasation. Monitor for hypersensitivity reaction, 
cardiovascular abnormalities, sensory neuropathy, myelosuppression, and GI irritation 
prior to, during, and between each infusion. 
11. REPORTING AND DOCUMENTING RESULTS 
11.1 Evaluation of Efficacy during Chemotherapy 
This evaluation is recommended as SOC but not mandatory for the study. The 
evaluation is determined by the physician in charge of the subjects through the physical 
examination during the regular follow up visit while on chemotherapy (from cycle 2 to 8). 
Objective radiographic response using MRI, ultrasound or mammogram if clinically 
indicated could also be obtained before the final surgery. 
11.2  Evaluation of Final Objective Pathologic Response 
 
Pathologic complete response (pCR) 
This is defined as the absence of residual invasive cancer on hematoxylin and eosin 
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nodes following completion of neoadjuvant systemic therapy (i.e., ypT0/T is ypN0 in the 
current AJCC staging system). 
11.3  Evaluation of Survivals 
Recurrence-free survival 
Duration for which the subject is without evidence for local-regional or distant relapse, 
second primary, or death. 
Overall survival 
This is defined as the time from initiation of study until death from any cause. 
11.4  Evaluation of Safety 
Analyses will be performed for all subjects having received at least one dose of study 
drug. The study will use the CTCAE v5.0 for reporting of nonhematologic adverse 
events and modified criteria for hematologic adverse events.  
12 STATISTICAL CONSIDERATIONS 
12.1 Study Endpoints 
The primary endpoint is pathologic complete response rate (pCR) and the secondary 
endpoints are the number of cycles, doses and delays of chemotherapy administered, 
treatment-related toxicity, 2-year recurrence-free survival (RFS) and overall survival 
(OS). 
 
12.2 Study Design 
The hypothesis is that the use of low dose weekly Carboplatin/Paclitaxel followed by 
dose-dense Doxorubicin/Cyclophosphamide in subjects with TNBC in neoadjuvant 
setting will result in less dose reductions or delays and similar pCR rate seen with the 
every 3 week carboplatin schedule.  This is a Phase II, open- label, single-arm, 
multicenter, prospective study.  This is the first study to evaluate the addition of low 
dose weekly Carboplatin to standard anthracyclines/taxane regimen in subjects with 
triple-negative breast cancer. 
 
12.3 Stratification Factors 
 
None 
 

 
 
 
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12.4 Determination of Sample Size and Power Estimate 
 
A sample size of 48 achieves 80% power to detect a 20% difference using a one-sided 
binomial test at an alpha significance level of 0.025. These results assume that the 
population proportion under the null hypothesis is 0.34, which is the reported pCR with 
anthracyclines and taxane regimens in TNBC.  Allowing for drop-out rate of 5%, a total 
of 50 subjects is planned.   
 
12.5 Accrual Estimates 
 
Approximately 50 subjects are planned for accrual and it is estimated that enrollment 
will be completed in 24 months.  On average, subjects will be on the study for 6 months. 
 
12.6 Interim Analyses and Stopping Rules 
 
No interim analyses are planned for this study 
12.7 Analyses Plans 
 
The analysis of the primary and secondary endpoints will be performed on all subjects 
according to the intention to treat (ITT) principle.  All efficacy analyses will be performed 
on all subjects who receive at least 1 dose of study drug.   
12.7.1 Primary Analysis (or Analysis of Primary Endpoints) 
The primary endpoint of pCR will be assessed according to the RECIST 1.1 criteria by 
the investigator.  The point estimate of the primary efficacy endpoint pCR and its exact 
95% confidence intervals (CI) will be calculated.  In evaluating pCR, subjects with 
missing data will be considered non-responders. 
12.7.2  Secondary Analysis (or Analysis of Secondary Endpoints) 
Simple descriptive statistics will be used to describe the number of cycles, doses and 
delays of chemotherapy administered.  This would enhance the assessment of the 
chemotherapy regimen. 
For the secondary endpoints of RFS and OS, the median RFS and OS will be obtained 
by the Kaplan-Meier technique.  The 95% CI will be calculated.  Also, estimates of the 
recurrence-free rate at fixed time point will be obtained using the Kaplan-Meier 
technique and 95% CI will be calculated using the Greenwood’s formula for standard 
deviation.  In addition, estimates of hazard ratios and their 95% CI will be obtained by 
Cox regression. All failure time variables would be measured by the time interval from 
the date of registration to the date of the first failure. 
12.7.3  Demographic and Baseline Characteristics 
Descriptive statistics will be provided to summarize demographics and baseline 
characteristics parameters.  Categorical data will be summarized as frequency and its 

 
 
 
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corresponding percentage.  For continuous data, frequency (n), mean, standard 
deviation, median (as appropriate), minimum, and maximum will be provided for each of 
the parameters. 
 
12.8 Evaluation of Safety 
 
Analyses will be performed for all subjects having received at least one dose of study 
drug. The study will use the NCI CTCAE v5.0. 
12.9 Study Results 
The statistical analysis will be reported using summary tables, figures, and data listings. 
Continuous variables will be summarized by standard descriptive statistics in terms of 
means, standard deviations, medians, minimums, and maximums. Categorical variables 
will be summarized by counts and by percentage of subjects in corresponding 
categories. All raw data obtained from the case report forms as well as any derived data 
will be included in data listings. Data analysis will be performed using SAS® version 9.4 
or greater. 
 
A formal statistical analysis plan (SAP) will be developed before the database lock. It 
will include detailed descriptions of summaries and mock-ups of tables, listings, and 
figures to be included in the clinical study report.  
13 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
13.1 Ethical Standard 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with 
GCP and all applicable regulatory requirements. 
13.2 Regulatory Compliance 
This study will be conducted in compliance with: 
 The protocol 
 Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common 
Rule), B (Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and 
D (Children), GCP/ICH guidelines, and all applicable regulatory requirements. 
The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 

 
 
 
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13.3 Prestudy Documentation  
Prior to implementing this protocol, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by 
the UW Health Sciences IRB. Prior to implementing this protocol at the participating 
sites, approval for the UW Health Sciences IRB-approved protocol must be obtained 
from the participating site’s IRB.  
The following documents must be provided to UWCCC before the participating site can 
be initiated and begin enrolling participants:  
 
 Participating Site IRB approval(s) for the protocol, appendices, informed consent 
form and HIPAA authorization  
 Participating Site IRB approved consent form  
 Participating Site IRB membership list  
 Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number  
 Curriculum vitae and medical license for each investigator and consenting 
professional  
 Documentation of Human Subject Research Certification training for investigators 
and key staff members at the Participating Site  
 Participating site laboratory certifications and normals  
 
Upon receipt of the required documents, UWCCC will formally contact the site and grant 
permission to proceed with enrollment. 
13.4 Institutional Review Board 
The protocol, the proposed informed consent form and all forms of participant 
information related to the study (e.g. advertisements used to recruit participants) will be 
reviewed and approved by the UW Health Sciences IRB. Prior to obtaining UWCCC 
approval, the protocol must be approved by the UWCCC Protocol Review and 
Monitoring Committee. The initial protocol and all protocol amendments must be 
approved by the IRB prior to implementation.  
After the UW Health Sciences Institutional Review Board (HS-IRB) grants initial 
approval for a WON study, the Affiliate Coordinator provides the WON sites with the 
approved documents. Sites use the UW HS IRB-approved consent document as a 
template. WON sites may make minor changes to the consent form to reflect their 
institutional standards. No substantial changes, including changes to the risk language, 
are allowed (sites can always clarify existing risk information or add risk language if they 
wish to do so).  
Each WON site must receive local IRB approval of both the UW-IRB approved protocol 
and informed consent/HIPAA documents (with minor revisions allowed). The local IRB 
approval notice and informed consent documents are forwarded to the Affiliate 
Coordinator at the address listed below. Once all of UWCCC administrative 

 
 
 
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requirements are completed and local IRB approval is verified, the Affiliate Coordinator 
issues an activation notice for the site. Study activities can begin at the local site only 
once this activation notice is issued.  
Any site under the UW HS-IRB’s purview must receive UW HS-IRB approval for their 
participation prior to study activation at the site. UWCCC-Johnson Creek uses the same 
UW HS-IRB approval process and consent form as the UW. Of note, member sites of 
the Wisconsin IRB Consortium (WIC), may be approved for participation through IRB 
deferral agreements made possible by the WIC mechanism. Both UWCC-Johnson 
Creek and WIC institutions must also be issued activation notices prior to enrolling 
subjects.  
The Affiliate Coordinator is responsible for continued oversight of regulatory 
documentation for each WON site. The Affiliate Coordinator distributes all additional UW 
HS-IRB-approved amendments and consents to participating WON sites. The Affiliate 
Coordinator uses OnCore and additional spreadsheets to track local IRB approvals of 
all amendments and consents for participating WON sites. All local IRB approvals and 
informed consent documents should be forwarded to the Affiliate Coordinators at the 
UWCCC by email (affiliatecoordinators@uwcarbone.wisc.edu) or regular mail:  
Affiliate Coordinators  
University of Wisconsin Carbone Cancer Center  
600 Highland Avenue, CSC, K4/6  
Madison, WI 53792-6164  
 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this therapy will be provided to the 
subjects and their families. Consent forms describing in detail the study interventions/
products, study procedures, and risks are given to the subject and written 
documentation of informed consent is required prior to starting 
intervention/administering study product. 
Potential subjects will be told and a statement will be included that this study is 
designed to determine both safety and effectiveness. The consent forms will include the 
approved UW Health Sciences IRB template language. 
Consent forms will be IRB-approved and the subject will be asked to read and review 
the document. Upon reviewing the document, the investigator will explain the research 
study to the subject and answer any questions that may arise. In accordance with 46 
CR 46.111, the subject will sign and date the informed consent document prior to any 
procedures being done specifically for the study.  

 
 
 
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The subjects will have the opportunity to discuss the study with their surrogates or think 
about it prior to agreeing to participate. The subjects may withdraw consent at any time 
throughout the course of the trial.  
A copy of the informed consent document will be given to the subjects for their records. 
The rights and welfare of the subjects will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in 
this study. If there are changes to the consent form, all revisions will be reviewed with 
study subject at the next appropriate opportunity. Subjects that require reconsenting will 
be defined in the IRB approved amendment submission. The process for obtaining 
informed consent will again be performed. Study subjects will not be reconsented for 
continuing reviews. Sites should follow their IRB’s policy for subjects who demonstrate 
limited English proficiency or limited literacy.  
After the subject’s visit in which the consent is signed, it is documented in the clinic 
chart that the consent has been signed and that all questions have been answered to 
the subject’s satisfaction after adequate time for review of the consent. It is also 
documented that a copy of the consent is given to the subject. The original consent is 
kept with the subject’s study file, and a copy of the consent is sent for inclusion in the 
legal medical record. 
All WON sites under the purview of their local IRBs follow recruitment and consent 
processes approved by the local IRB of record. 
Documentation of both the informed consent process and that the process occurred 
prior to a subject’s entry into a WON study is recorded in the subject’s source 
documents. The original consent form, signed and dated by the subject and by the 
person consenting the subject, must be maintained in the investigator’s study files at 
each site. All current FDA, NCI, state, federal and institutional regulations concerning 
informed consent will be followed. 
13.5 Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the principal investigator and all 
research staff.  This confidentiality includes the clinical information relating to 
participating subjects, as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence.  No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the principal 
investigator/study chair  
The conditions for maintaining confidentiality of the subjects’ records are required for 
the life of the data. Identifiable subject information will be maintained at the enrolling 
site.  All source documentation will be maintained within the subject’s research chart 
which will be accessible only to authorized study personnel. Subject research charts will 
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Study data will be collected via the UWCCC Oncore database.  Each enrolling site is 
responsible for entering data into study specific eCRFs.  Subject data used for analysis 
will be coded.   Databases in which the study subject information is stored and 
accessed are password protected, allowing for limited access by authorized personnel 
only. Data/PHI kept in the electronic Case Report Forms contains the study identifiers, 
subject initials, date of birth and date of service.  
Personal identifiers such as name and medical record number will be removed from 
accompanying lab reports and test results. Any Data/PHI that is not stored for the 
purposes of the study are shredded in the Clinical Trials Office. 
After all study queries and analyses are completed, the Data/PHI will not be destroyed 
but will be archived in a secure long-term storage site in order to keep an accurate 
record of screened and enrolled subjects for the sponsor and potential audit purposes 
only specific for this study. Data/PHI would not be destroyed until permission is granted 
by the sponsor to destroy the records.  
The principal investigator/study chair will allow access to all source data and documents 
for the purposes of monitoring, audits, IRB review, and regulatory inspections.  
The study monitor or other authorized representatives of the principal investigator/study 
chair may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the subjects in this study. Each clinical study site will permit 
access to such records. 
13.6 Protection of Human Subjects 
13.6.1 Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human 
experimentation. This is accomplished through the IRB mechanism and the informed 
consent process. The IRB reviews all proposed studies involving human 
experimentation and ensures that the subject’s rights and welfare are protected and that 
the potential benefits and/or the importance of the knowledge to be gained outweigh the 
risks to the individual. The IRB also reviews the informed consent document associated 
with each study in order to ensure that the consent document accurately and clearly 
communicates the nature of the research to be done and its associated risks and 
benefits. 
13.6.2 Protection of Privacy 
As noted, subjects will be informed of the extent to which their confidential health 
information generated from this study may be used for research purposes. Following 
this discussion, they will be invited to sign informed consent documents. The original 
signed document will become part of the subject’s medical records, and each subject 
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13.7 Investigator Compliance  
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority(ies).  
Onsite Audits 
WON sites will be audited in accordance with the WON auditing and monitoring plan. 
Regulatory authorities, the IRB and/or sponsor may request access to all source 
documents, data capture records and other study documentation for on-site audit or 
inspection. Direct access to these documents must be guaranteed by the investigator, 
who must provide support at all times for these activities. 
14 DATA HANDLING AND RECORD KEEPING 
14.1 Overview 
Every effort is made to uphold the integrity of the project, the research, the institution, 
and the researchers involved. Data collection guidelines and methodologies are 
carefully developed before the research begins. Investigators focus on the following to 
ensure data integrity:  well-trained data collectors/recorders to ensure consistency and 
quality, well-designed data collection protocols and ongoing monitoring. In this way, 
study rigor and validity are maintained. Data is protected from physical damage as well 
as from tampering, loss or theft. This project’s data management is a multidisciplinary 
activity that includes investigators, research coordinators and nurses, data mangers, 
support personnel, biostatisticians and database programmers. Quality control will be 
applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly.  
14.2 Data Management Responsibilities 
14.2.1 Principal Investigator 
The principal investigator oversees the management of subject records/case report 
forms and ensures that a) complete and accurate data will be obtained and provided to 
the sponsor; b) subject records are maintained to include history, prescribed medication 
and investigational product(s), measurements, exams, evaluations and adverse events; 
c) corrections are applied to clinical research data according to principles of good 
research practice (i.e., single-line delete, date and initial). He or she will ensure that 
there is correlation between the Case Report Forms and the source documents. The 
Principal Investigator will have additional oversight responsibilities as applies to subjects 
enrolled trough Wisconsin Oncology Network affiliate sites: 
• Verify that weekly summaries are obtained and verified. 
• Review all SAE’s submitted by WON sites. 
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14.2.2 Research Coordinator  
A research coordinator creates, collects and organizes Clinical Trial 
Documentation. He or she ensures that source documentation and data 
abstraction and entry are being done at protocol specified time points. 
 
14.2.3 Research Nurse/Medical Staff 
The research nurse and medical staff documents protocol required care or assessment 
of the subject’s outcomes, adverse events and compliance to study procedures. 
14.2.4 Biostatistician 
The biostatistician may assist in CRF development (content and design), dataset 
specifications (annotation of CRFs and record layout) and validation. 
14.3 Handling and Documentation of Clinical Supplies 
The Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational 
drugs. The date, quantity and batch or code number of the drug, and the identification of 
subjects to whom study drug has been dispensed by subject number and initials will be 
included. The sponsor-investigator will maintain written records of any disposition of the 
study drug. 
The Principal Investigator shall not make the investigational drug available to any 
individuals other than to qualified study subjects. Furthermore, the Principal Investigator 
will not allow the investigational drug to be used in any manner other than that specified 
in this protocol. 
14.4 Source Documents 
Source documents for clinical information (subject history, diagnosis, clinical and 
diagnostic test reports, etc.) are maintained in the subject’s clinical file. Source 
documents for the correlative studies are maintained in the laboratory conducting the 
study.  
The source documents for this protocol are as follows:   
Original documents, data and records (e.g., hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, X-rays, subject files and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical trial). 
All source documents will be written following ALCOA standards:  
 

 
 
 
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ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of 
events. If a clinical observation cannot be entered when 
made, chronology should be recorded. Acceptable amount 
of delay should be defined and justified. 
Original  
Original, if not original should be exact copy; the first record 
made by the appropriate person. The investigator should 
have the original source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 
Available and 
accessible 
Easily available for review by treating physicians and during 
audits/inspections. The documents should be retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 
 
14.5 Case Report Forms  
The Principal Investigator and/or his/her designee will prepare and maintain adequate 
and accurate participant case histories with observations and data pertinent to the 
study. Study-specific Case Report Forms (CRFs) will document safety and treatment 
outcomes for safety monitoring and data analysis. All study data will be entered into 
OnCore® via standardized CRFs in accordance with the study calendar, using single 
data entry with a secure access account.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the subject’s medical records 
maintained by each site’s personnel. All source documentation should be kept in 
separate research folders for each subject. 
In accordance with federal regulations, the Investigator is responsible for the accuracy 
and authenticity of all clinical and laboratory data entered onto CRFs.  
All source documentation and data will be available for review/monitoring by the 
UWCCC DSMC and regulatory agencies. 
14.6 Study Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of 
the drug, including dates, quantity and use by subjects, as well as written records of the 
disposition of the drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate 
case histories that record all observations and other data pertinent to the investigation 
on each individual administered the investigational drug or employed as a control in the 

 
 
 
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investigation. Case histories include the case report forms and supporting data 
including, for example, signed and dated consent forms and medical records including, 
for example, progress notes of the physician, the individual's hospital chart(s), and the 
nurses' notes. The case history for each individual shall document that informed 
consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed subject consent forms). 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 
two years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until two years after the investigation is 
discontinued and FDA is notified. 
14.7 WON Site Oversight  
The UWCCC Affiliate Office serves as the coordinating center for WON. Coordinating 
center responsibilities are shared between the Affiliate Coordinator and UWCCC 
Breast/Melanoma DOT. A detailed description of coordinating center responsibilities, as 
well as other WON processes and procedures, is provided in the WON Manual 
available on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal/page.php?id=42878). 
Regular communication between the UWCCC Affiliate Office and WON sites ensures 
that all participating parties are notified of protocol changes, informed consent 
document revisions, action letters, study status changes, reportable events/Serious 
Adverse Events (as necessary), and any other applicable information. This 
communication is accomplished through regular email updates and conference calls. 
 
15 CORRELATIVE STUDIES 
See Study Operations Manual for sample processing and shipping instructions. Testing 
will be completed to meet the exploratory endpoint of this study.  Testing may be 
performed at UWCCC, MCW or an outside laboratory.  Samples will be coded with 
subject number and date/time of acquisition.  No subject health information will be 
provided with the samples.  Results from the research testing will be provided to the 
investigators to be used for the purposes of this study.  Samples will be stored until 
depleted or until subject withdraws consent for optional research testing. 
Tissue samples will be stored at the UWCCC or MCW until the time of correlative 
research testing.  Samples will be stored with study number, subject number, date and 
time of sample acquisition.  Upon direction from the Principal Investigator, samples will 
be distributed by the staff at the designated laboratory to the facility performing the 
requested testing. Testing will be completed to meet the exploratory endpoint of this 
study.  Testing may be performed at UWCCC, MCW or an outside laboratory.  Samples 
will be coded with subject number and date/time of acquisition.  No subject health 

 
 
 
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information will be provided with the samples.  Results from the research testing will be 
provided to the investigators to be used for the purposes of this study.  Samples will be 
kept indefinitely unless asked to be returned or subject withdraws consent for optional 
research testing. 
All future projects using the banked data or samples from this study will be submitted to 
the Institutional Review Board (IRB) for review and approval or exemption. Distribution 
of the banked samples will be limited to researchers within UW-Madison or MCW. 
Request for samples would be directed to the study PI or the study chair who will 
determine if the banked samples would be suitable for use in that study. Prior to 
distribution, scientific and IRB approval of the research study would need to be provided 
to the PI and study chair. Additionally, the PI and study chair will be responsible for 
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doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to 
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17. Hartman ZC, Poage GM, den Hollander P, et al. Growth of triple-negative breast cancer 
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18. Salgado R, Junius S, Benoy I, et al. Circulating interleukin-6 predicts survival in patients with 
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19.  Fasching, P, Jackish, C, Rhiem, K et al.  A Randomized Phase II Trial to Assess the 
Efficacy of Paclitaxel and Olaparib in Comparison to Paclitaxel and Carboplatin Followed by 
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Negative Early Breast Cancer and Homologous Recombination Deficiency.  ASCO Annual 
Meeting 2019.   
 
 
 
 
 
 

 
 
 
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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on 
all pre-disease performance 
without restriction 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease 
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) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active 
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 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs 
50 
Requires considerable 
assistance and frequent medical 
care 
3 
In bed > 50% of the time 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours 
40 
Disabled, requires special care 
and assistance 
30 
Severely disabled, 
hospitalization indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or 
chair 
20 
Very sick, hospitalization 
indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 

 
 
 
Protocol No:  UW16112 
59 
Version No.8  
 
 
Version Date: 011.26.2019 
APPENDIX 2. SPECIMEN COLLECTION 
Sampling and shipping information 
 
• Research blood: two 10 ml EDTA tubes of blood will be collected at 2 time points 
(first sample prior to initiation of study chemotherapy; second sample between last 
chemotherapy treatment and prior to surgery). Samples can be frozen and stored 
at the research site for later batch shipping. If sites do not have room to store 
samples they may be shipped to MCW for storage. Please refer to the study 
operations manual for processing and shipping instructions.  
 
• Tumor tissue 
 
o A formalin-fixed paraffin embedded tumor block (preferred) or 5-10 
unstained slides from the biopsy of the primary tumor and the surgical 
specimen (if residual tumor identified) are requested if subject consents 
o Samples will be coded with the study ID and labeled as biopsy or surgical 
specimen.   
o At completion of analysis, all tumor blocks will be returned if requested by 
the originating institution and any remaining tumor blocks will be 
destroyed. 
o Please refer to the study operations manual for shipping instructions. 
 
Sample shipment instructions 
For all shipments, an inventory of the samples should accompany the shipment. This 
inventory should include the study ID, subject ID, sample number, visit number and time 
of collection. 
A copy of the inventory will be retained at the site in the subject’s binder along with any 
shipping documents.  
All samples will be kept at the temperature specified up to and during the shipment and 
packed according to IATA shipping regulations.  
If shipping samples off campus, shipment will be sent via overnight courier (i.e. Fedex) 
and shipped Monday through Thursday. Samples will not be shipped on Fridays.

 
 
Protocol No:  UW16112 
60 
Version No.6  
 
 
Version Date: 10.26.2018 
APPENDIX 3. STUDY CALENDAR 
Procedure 
Screening 
Regimen 
A: Cycle 
1,2,3,4 
 
 
Regimen 
B: Cycle 
514,6,7,8 
 
Follow 
up visit 
Long 
term 
follow 
up 
Study Day/Visit 
Day 
-30 to 
Registration 
1 
(+/- 1) 
8 
(+/- 
1) 
15 
(+/- 
1) 
1 
(+/- 1) 
Regimen 
C: 
Surgery6 
Within 
30 days 
after 
surgery 
 
Informed consent 
X 
 
 
 
 
 
 
 
Treatment/Drug 
Administration 
 
 
 
 
 
 
 
 
Carboplatin 
 
X 
X 
X 
 
 
 
 
Paclitaxel 
 
X 
X 
X 
 
 
 
 
Doxorubicin 
 
 
 
 
X 
 
 
 
Cyclophosphamide 
 
 
 
 
X 
 
 
 
Clinical 
procedures 
 
 
 
 
 
 
 
 
Physical exam 
X 
   X12, 17 
 
 
X 
 
X 
 
Vital signs (weight, 
temperature, blood 
pressure, heart rate) 
X 
X17 
 
 
X 
 
X 
 
Medical history 
X 
 
 
 
 
 
 
 
Height 
X15 
X15 
 
 
 
 
 
 
Disease 
assessment 3 
X 
 
 
 
 
 
X 
 
 
ECOG Performance 
status 
X 
X12, 17 
 
 
X 
 
X 
 
Measurable disease 
(clinical) 
X 
X12 
 
 
X 
 
 
 
Breast biopsy (SOC)  
X 
 
 
 
 
 
 
 
AE assessment 
X 
X12 
 
 
X 
 
X18 
 
Laboratory 
procedures 
 
 
 
 
 
 
 
 
CBC w/ Diff  
X 
X9 
X1 
X1 
X 
 
X16 
 
Blood chemistry 4 
X 
X9 
 
 
X 
 
X16 
 
Pregnancy test 
(HCG) 
X 
X7 
 
 
 
 
 
 
Archived tumor 
tissue (optional) 
 
X11 
 
 
 
 
X 
 
Research blood 
(optional)  
 
X10 
 
 
X10 
X10 
 
 
Imaging 
procedures 
 
 
 
 
 
 
 
 
Systemic Imaging 
(CT, bone scan, 
PET or MRI) 5 
X 
 
 
 
 
 
 
 
Cardiac Assessment 
(ECHO, MUGA)13 
X 
 
 
 
 
 
 
 

 
 
Protocol No:  UW16112 
61 
Version No.6  
 
 
Version Date: 10.26.2018 
Procedure 
Screening 
Regimen 
A: Cycle 
1,2,3,4 
 
 
Regimen 
B: Cycle 
514,6,7,8 
 
Follow 
up visit 
Long 
term 
follow 
up 
Study Day/Visit 
Day 
-30 to 
Registration 
1 
(+/- 1) 
8 
(+/- 
1) 
15 
(+/- 
1) 
1 
(+/- 1) 
Regimen 
C: 
Surgery6 
Within 
30 days 
after 
surgery 
 
MRI/ultrasound/ 
Mammogram2 
X 
 
 
 
X 
 
 
 
Long term follow up8  
 
 
 
 
 
 
 
X  
 
1. CBC, Plts and differential (ANC can also be done instead of full differential on these dates).   
2. Disease assessment with MRI breast and/or ultrasound and/or mammogram is per standard of care for 
diagnosis, but at least one modality of imaging must be completed within 45 days of registration. Breast 
MRI, US or mammogram (if clinically indicated) within 45 days prior to surgery.   
3. Disease specific staging (clinical staging and/ or pathologic staging)  
4. Including alkaline phosphatase, ALT/AST, total bilirubin, calcium, (BUN), creatinine, total protein, albumin, 
glucose, potassium, sodium, chloride, bicarbonate.  
5. If clinically indicated (not required for study eligibility)  
6. Surgical intervention for management of breast cancer diagnosis; procedure and timing as determined by 
surgical team  
7. For women who are not postmenopausal.  Serum or urine pregnancy test to be done at screening. To be 
repeated if not done within 7 days of starting chemotherapy (cycle 1 day 1).  
8. Disease status, survival status and any interval systemic anti-cancer treatment will be collected every 6 
months (+/- 30 days) for 2 years after date of surgery.  Actual SOC follow up may be more frequent, data 
to be reported every 6 months. This includes all subjects who do not complete all cycles of the study 
treatment unless they are withdrawn from study.  
9. Screening labs to be repeated if complete more than 14 days prior to C1D1 treatment.  
10. Research sample to be drawn as follows: prior to starting chemotherapy on C1D1, prior to treatment on 
C8D1, and within 3 days prior to surgery. If the subject is taken off protocol therapy before C8D1, a blood 
sample should be drawn as close to the subject’s last chemotherapy treatment as possible.  
11. Cycle 1 Day 1 only (if subject agrees to archival tissue collection, it should be collected and submitted 
within 8 weeks of C1D1)    
12. For Cycle 1 only; H&P, disease assessment, ECOG performance status and AE assessment do not need 
to be repeated if done up to 3 days prior to Cycle1 Day 1 
13. ECHO or MUGA to be completed during screening period. During the study subjects should be monitored 
for changes to their left ventricular ejection fraction according to institutional standard of care.  
14. There is one week break between the end of cycle 4 and the beginning of cycle 5. 
15. Height can be obtained at screening or Cycle 1 Day  
16. Perform if clinically indicated 
17. For C2D1+; H&P, vitals and ECOG Performance Status do not need to be repeated if treatment is held for 
7 days due to ANC and platelet counts per Table 7.2. If treatment is held for longer than 7 days, these 
procedures need to be repeated. 
18. AEs will be followed for 30 days after the last dose of study drug or treatment. SAEs will be followed until 
resolution or until considered permanent by the treating physician.