A Phase II Study of Neoadjuvant Chemotherapy With and Without Trastuzumab in Patients With Breast Cancer
Phase: PHASE2
Conditions: Estrogen Receptor Negative, Estrogen Receptor Positive, HER2/Neu Negative, HER2/Neu Positive, Invasive Breast Carcinoma, Progesterone Receptor Negative, Progesterone Receptor Positive, Stage IA Breast Cancer, Stage II Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage III Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Triple-Negative Breast Carcinoma
Sponsor: University of Nebraska

 
 
 
 
- i - 
 
 
IRB #:  264-12 
 
 
A Phase II Study of Neoadjuvant Chemotherapy with and without Trastuzumab 
in Patients with Breast Cancer 
 
 
*Principal Investigator: 
Pavankumar Tandra, MD  
986840 Nebraska Medical Center,  
Omaha, NE 68198-6840 
Phone: 402-559-3234 
Fax: 402-559-8895 
Email: pav.tandra@unmc.edu 
 
 
Secondary Investigators: 
Elizabeth Reed, MD 
Jairam Krishnamurthy, MD 
Kenneth Cowan, MD, PhD 
Ryan Ramaekers, MD  
CHI Health St. Francis 
 
Multi-site Participation:  
 
 
UNMC 
TNMC 
Village Pointe Cancer Center 
Bellevue Medical Center                           
CHI Health St. Francis, Grand Island 
 
 
 
Statistician: 
 
 
 
 
 
 
Lynette Smith, PhD 
 
 
 
 
 
 
984375 Nebraska Medical Center, 
 
 
 
Omaha, NE 68198-4375 
 
 
 
 
Phone: 402-559-8407 
 
 
 
 
 
Fax: 402-559-7259 
 
 
 
 
 
Email: lmsmith@unmc.edu 
 
 
 
 
 
                           
 
Version/Version Date  
V2.1 Dated 01-18-13 
 
V2.2 Dated 03-19-13 
 
V2.3 Dated 10-16-14 
 
V2.4 Dated 04-01-15 
 
V2.5 Dated 07-27-15 
 
V2.6 Dated 04-06-16 
 
V2.7 Dated 07-07-16 
 
V2.8 Dated 09-30-16 
 
V2.9 Dated 06-14-18  
 
V3.0 Dated 10-03-19 
 
V3.1 Dated 03-10-20 
 
V3.2 Dated 11-30-21 
 

 
 
 
 
- ii - 
 
 
 
 
NEO-ADJUVANT SCHEMA  
(Breast Cancer) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RADIATION 
**Maintenance Trastuzumab 
 
 
 
 
 
 
 
 
 
               
                                                                                               
 
 
 
 
 
                             
 
 
 
   
 
 
 
 
All HER2 + 
 
           
 
 
 
 
  
        
    
                     
 
C1       C2       C3       C4        C5        C6 
   Clinical Endpoint 
Stage T1cN0 & All Stage II-III 
 
 
           
 
Pre-op MRI&/or US for staging (SOC) StageT1cN0      RADIATION                      End of Treatment   
Diagnostic BIOPSY (SOC)                                                              
Pre-op Serum Sample (Res)       
 Triple Neg                                                        Serum Sample (Res)       
Baseline Mammo MRI&US^ 
 
                                                     SURGERY (SOC)  
 
 
 
 
           & F/U (SOC) 
   for staging (SOC)           PC       PC        PC     PC       PC       PC             
 
                         Only Stage II-III 
Serum ,Plasma,                 *PCH *PCH  *PCH  *PCH  *PCH  *PCH         
 
 
 
      Triple Neg  
WBC DNA (Res)   
    
 
 
 
 
 
                             
     C7  C8  C9   C10 
 
 
 
 
 
 
 
 
 
 
 
 
  
                  RADIATION 
 
 
 
 
 
 
 
 
 
 
 
 
      A    A    A    A 
 
 
^Mammogram MRI&US of Breast and Axilla (pre-op MRIand/or US may be omitted in the case of planned mastectomy)  
 
 
ALL PATIENTS = PC  Paclitaxel 175mg/m2 in normal saline IV over 3 hrs  / Cyclophosphamide 600mg/m2 in normal saline IV over 1 hr  REPEAT Day 1 Q 2wks x 6 cycles 
(Cycles 1-6), Pegfilgrastim support 1-4 mg SQ after PC dose adjust down or hold for ANC >12,000 or bone pain (SOC),  (Pegfilgrastim support is optional folloing cycle 6) 
 
PATIENTS WITH HER-2 NEU POSITIVE TUMOR = *PCH -  Paclitaxel/Cyclophosphamide REPEAT Day 1 Q 2wks x 6 cycles (Cycles 1-6), Pegfilgrastim SQ after PC , 
H - Herceptin® (Trastuzumab) loading dose 6mg/kg Day 1, Cycle 1THEN subsequent dosing 4mg/kg Day 1 Q2wks Cycles 2-6, (SOC) **Maintenance Herceptin® 6mg/kg 
Day 1 Q21 Days for a total of 52 weeks. (SOC) 
 
ALL PATIENTS = RADIATION Clinical Decision per standard NCCN guidelines, following chemotherapyand surgery. (SOC) 
 
Only STAGE II-III, TRIPLE NEGATIVE PATIENTS (HER2 - ER- PR-) = Adriamycin 60mg/m2 in normal saline IV Q2wks x 4 cycles (Cycles 7-10), Pegfilgrastim 
support 1-6mg, (Pegfilgrastim support is optional following cycle 4) 
   
PATIENTS WITH ER/PR + TUMOR = HORMONAL THERAPY Patients with estrogen/progesterone receptor positive tumors will also receive Hormonal Therapy to be 
determined by the medical oncologist as per standard NCCN guidelines. (SOC) 
 
End of Treatment Follow-up (F/U) (All subjects) 
Research Serum Samples collected at end of treatment (Res) 
Patients will be monitored Q3 months until 2 years from date of treatment for safety. (SOC) 
Patients will be followed annually for disease recurrence and overall survival to stop at 5 years from diagnosis.

 
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IRB#264-12:      V3.2 Dated 11-30-21 
 
 
 
 
TABLE OF CONTENTS 
 
Page 
 
SCHEMA ......................................................................................................................................... ii/iii 
 
1. OBJECTIVES 
...........................................................................................................................4 
 
2. BACKGROUND ...........................................................................................................................4 
 
3. ELIGIBILITY CRITERIA .........................................................................................................10 
 
4. REGISTRATION PROCEDURES……………………………………………...……………..13 
 
5. TREATMENT PLAN ..................................................................................................................15 
 
6. MEASUREMENT OF EFFECT .................................................................................................24 
 
 
7. STUDY PARAMETERS .............................................................................................................26 
 
8. DRUG FORMULATION AND PROCUREMENT ..................................................................28 
 
9. TOXICITY REPORTING GUIDELINES ................................................................................34 
 
10. STATISTICAL CONSIDERATIONS ........................................................................................38 
 
11. RECORDS TO BE KEPT............................................................................................................42 
 
12. PATIENT CONSENT FORM STATEMENT……...………………………………………….44  
 
13. REFERENCES .............................................................................................................................46 
 
14. DATA FORMS Attached …………………………………………………...…………………...50 
APPENDICE 
APPENDIX A 
ECOG Performance Status Criteria ....................................................................................... .50 
APPENDIX B 
NYHA Criteria ................................................................................................................. .51 
APPENDIX C 
            Eligibility Criteria CRF ............................................................................................................52 
      APPENDIX D 
HBM Sample Processing and Shipping (for research purposes only)…...……………...……55 
     APPENDIX E 
            Neuropathy Assessment Worksheet .........................................................................................56 
      APPENDIX F 
            NCI Common Toxicity Criteria Version 4.0 ............................................................................56 
APPENDIX  
           MEDWATCH ……………………………………………………………………...…………56 
 

 
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1.0   OBJECTIVES 
1.1  Primary Objective 
1.1.1 To evaluate the toxicities and tolerability of a neoadjuvant dose-dense regimen 
cyclophosphamide and paclitaxel with or without trastuzumab/radiation therapy (as 
clinically indicated) in patients with newly diagnosed stage T1cN0 and II-III breast cancer; 
followed by maintenance trastuzumab in HER2 positive OR adriamycin followed by RT 
in Stage II-III triple negative HER2 (-), ER (-), PR(-) Stage T1cN0 and II-III breast cancer 
patients.  
1.1.2 To determine the pathological complete response rate (pCR) of this treatment regimen.   
1.1.3 To   identify   possible gene   expression   profile signatures   from whole genome array 
analysis that correlate with clinical response/resistance to chemotherapy as measured by 
pathologic complete response rate (pCR). 
 
2.0  BACKGROUND 
Breast cancer is the most common cancer diagnosed in American women and the second most common 
cause of cancer death.  It is estimated that 226,870 women will be diagnosed with breast cancer while 
39,920 women will die of their disease in 2012. (1) The mainstay of the treatment for early stage disease 
is surgical removal of the tumor followed by adjuvant systemic treatment (chemotherapy and/or 
hormonal therapy) with or without radiation therapy to reduce the recurrence.  SEER Summary Stage 
2000 indicates that 60% of patients with breast cancer were diagnosed in Stage I, while 33% were 
diagnosed as Stage II.  The overall survival rates were 98.3% for localized Stage I and 83.5% for 
regional Stage II disease. (1)  Adjuvant systemic therapy has been associated with increased disease-free 
and overall survival in breast cancer patients.   Stage I and II breast cancer patients have an estimated 
5%, and 11% risk of recurrence risk respectively even after adjuvant systemic therapy. (2) 
 
In early stage breast cancer patients multiple combination chemotherapy regimens have been evaluated 
as adjuvant therapy.   A meta-analysis of adjuvant chemotherapy regimens reported by the Early Breast 
Cancer Trialists' Collaborative Group showed that combination chemotherapy regimens containing 
anthracyclines (e.g. adriamycin) was associated with a small but significant decrease in recurrence and 
mortality compared to regimens that did not contain anthracyclines. (3) Based on this observation, the 

 
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National Institutes of Health Consensus Development Conference on Adjuvant Therapy for Breast 
Cancer recommended anthracycline-containing regimens for the adjuvant treatment of breast cancer. (4) 
 
The development of taxanes and demonstration of their excellent clinical activity in metastatic breast 
cancer (5), lead to the clinical studies demonstrating improvement of recurrence free and overall survival 
with the addition of taxanes to adjuvant chemotherapy regimens in node positive breast cancer.  Results 
of CALGB 9344 showed that the sequential addition of paclitaxel to 4 cycles of adriamycin and 
cyclophosphamide (AC) as adjuvant therapy was associated with improved disease free and overall 
survival in node positive breast cancer. (6)  
 
Neoadjuvant chemotherapy has become one of the standards of care for both locally advanced breast 
cancer and for patients who desire breast-conserving therapy but are not candidates based on the initial 
size of the tumor in relation to the breast.(7) Neoadjuvant chemotherapy regimens that are considered 
“acceptable” include FAC(5FU, adriamycin, cyclophosphamide) ,CAF(cyclophosphamide, adriamycin, 
5FU), CEF(cyclophopshamide, epirubicine, 5FU) and FEC(5FU, epirubicine, cyclophosphamide).(8) 
Taxanes have been compared to treatment with FAC as neo- adjuvant treatment in breast cancer.   In one 
study breast cancer patients were randomized to receive either four cycles of FAC or paclitaxel as 
neoadjuvant treatment prior to surgery. As shown in Table I, there was no difference in the clinical 
response rates observed in breast cancer patients treated with paclitaxel alone compared to treatment 
with combination chemotherapy with FAC. (9) 
 
Table I. FAC vs paclitaxel as neo adjuvant therapy in patients with operable breast cancer 
 
FAC 
Paclitaxel 
Clinical CR 
24% 
27% 
Clinical PR 
55% 
53% 
Path CR 
18% 
6% 
Path in situ 
5% 
8% 
Path min. (<1cm) 
12% 
27% 
* Results not statistically significant. 
Buzdar et al. JCO 1999; 17:3412 
 

 
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Adriamycin containing chemotherapy regimens are effective as adjuvant therapy for early stage breast 
cancer but associated with increased cardiotoxicity. This has led to the evaluation of other effective but 
less toxic adjuvant chemotherapy regimens for breast cancer. In one recent study, Stage I – III breast 
cancer patients were randomized to receive four cycles of either Taxotere® (docetaxel) in combination 
with cyclophosphamide (TC) every 3 weeks or adriamycin and cyclophosphamide (AC) every three 
weeks.  Both treatment groups were balanced with respect to major prognostic factors. At five years, 
patients treated with TC had a slightly better disease-free survival and less cardiac toxicity than patients 
treated with AC. (10)  
 
Docetaxel has also been compared to Taxol® (paclitaxel) in a large randomized trial involving 4,950 
women with early stage breast cancer.  In this study, early stage breast cancer patients were treated with 
four cycles of AC every three weeks followed by treatment with either docetaxel or paclitaxel given either 
every week or every three weeks. This study demonstrated no difference in disease-free survival in patients 
treated with docetaxel or paclitaxel following treatment with four cycles of AC.  
 
Based on the hypothesis that dose-dense schedules would limit the opportunity for re-growth of cancer 
cells following cytotoxic chemotherapy and improve anticancer efficacy,  the effects of shortening the 
interval between treatment cycles from every three weeks (standard schedule) to every two weeks (dose-
dense schedule) were evaluated. In a CALGB study, breast cancer patients were treated with four cycles 
of AC followed by four cycles of paclitaxel given either every three weeks (standard schedule) or every 
two weeks (dose-dense schedule).  In this study, patients treated on the dose-dense schedule had improved 
disease free survival (risk ratio (RR) 0.74 p =.01) and overall survival (RR = 0.69, p = .013) compared to 
patients treated on the standard treatment schedule. (11) Dose-dense AC followed by paclitaxel is now 
one of the treatment options for node-positive women as defined by the National Comprehensive Cancer 
Network (NCCN).  While the dose-dense schedule was associated with increased grade 3/4 neutropenia 
(11%), this was not associated with increased febrile episodes (<5%).   
 
Since Her-2 neu targeted therapy has been shown to be effective in the treatment of metastatic cancer, its 
benefits have also been evaluated in early stage breast cancer.   In two recent studies, patients with Her-2 
neu positive tumors were treated with four cycles of AC followed by treatment with paclitaxel and they 

 
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were randomized to receive Herceptin® (trastuzumab) for a total of 52 weeks either starting concomitantly 
with paclitaxel or after chemotherapy.  The results revealed an absolute difference in disease free survival 
of 12% at three years with a 33% reduction in risk of death (p = .015) in patients treated with trastuzumab.  
However, there was a 5% incidence of clinical cardiac failure in patients treated with trastuzumab 
following treatment with adriamycin (12).  In another clinical trial (HERA trial) Her-2 neu positive breast 
cancer patients could be treated with any standard adjuvant chemotherapy regimen prior to treatment with 
trastuzumab.  This study reported a 50% reduction in relapse free survival in patients receiving at least 
one year of trastuzumab.  Clinical cardiac toxicity was also a major side effect in the HERA trial and was 
reported in 5% of patients (13). 
 
The cardiotoxicity associated with adjuvant therapy with trastuzumab and adriamycin emphasizes the 
need to evaluate non-anthracycline based regimens.  In the BCIRG trial adjuvant chemotherapy with 
docetaxel, carboplatin and trastuzumab (TCH) given every three weeks for six cycles, was compared to 
treatment with four cycles of AC, followed by four cycles of paclitaxel given every three weeks, with 
trastuzumab (AC-TH) or without trastuzumab (AC-T).  While the risk of recurrence was reduced by nearly 
50% in both trastuzumab containing arms TCH and AC-TH, there was a lower risk of cardiotoxicity in 
the TCH arm compared to patients treated in the AC-TH arm, with fewer grade 3 or 4 changes in left 
ventricular ejection fraction (LVEF) and fewer patients with clinically symptomatic congestive heart 
failure (p <0.001) in patients treated with TCH. (14,15) 
 
A pilot study at UNMC/TNMC (IRB#371-09) is evaluating the toxicity of adjuvant therapy with six cycles 
of cyclophosphamide (600mg/m2) and Taxol® (paclitaxel) (175 mg/m2) given every two weeks (dose-
dense schedule) in Her-2 neu positive and negative breast cancer.  Thus far, 99 patients have been enrolled 
in the pilot study and 86 patients have completed all six cycles of chemotherapy with or without 
trastuzumab.  Tables II and III reports the first interim analysis of the pilot study. 
 
 
 
 
 
 

 
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Interim Analysis  
Table II: Serious, Related Grade III or IV Adverse Events 
n = 50 
Event 
 
Comment 
Infection 
 
 
     Febrile neutropenia 
 
Hosp. salmonella gastroenteritis  
 
 
Urinary tract infection 
     Line associated sepsis 
 
Hosp. port removed 
     Shingles 
 
Treated as outpatient C. #3 delayed one week 
     Cellulitis, wound infection  
Outpt. Surgery implant removed 
     Fever 
 
Hosp. URI 
Neuropathy 
 
Cycle 6 dose reduced 
 
 
Cycle 2 removed from study 
 
 
Cycle 1 removed from study 
 
 
Cycle 4 & 5 dose reduced 
Anaphylaxis 
 
Off study C-2 treated outpatient 
Perforated duodenum 
 
Surgery off study 4 cycles 
↓ ejection fraction with CHF 
 
Medical management, improvement. Stopped herceptin 
Leukemia 
 
Treatment associated 7 mos after last chemotherapy. See 
attachment A 
Arm DVT 
 
Associated with line sepsis 
 
Table III: Serious, Related Grade III or IV Adverse Events  
n = 50 
 
OFF STUDY 
#2– neuropathy 
#1 – perforated duodenum 
#1 – withdrew after first cycle 
#1 – withdrew before any treatment, screen failure 
 
CYCLE DELIVERY 
Expected cycles   49 pts = 294 
Delivered cycles  279 (92%) 
Dose reduced cycle or delayed  4 
Full dose on time   275 (90%) 
 
 Based on these results, we plan to evaluate the overall clinical response rate and toxicities of neoadjuvant 
therapy offering six cycles of paclitaxel and cyclophosphamide (TC) given in a dose dense schedule in 
patients with clinical stage I-III breast cancer.  
 
Treatment of breast cancer patients with neoadjuvant chemotherapy allows the assessment of in vivo 
response to systemic chemotherapy (16) as well as the long-term clinical outcomes (17-19) associated 

 
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with in vivo clinical and pathological responses.  Neoadjuvant chemotherapy also affords the opportunity 
for some patients with locally advanced breast cancer (LABC) to undergo breast conservation therapy 
(BCT) as a result of therapeutic down staging of the tumor (20-22). 
 
Patients with LABC receive neoadjuvant therapy followed by surgical treatment which usually consists 
of a modified radical mastectomy combined with radiation therapy.  However, patients who are down 
staged by the neoadjuvant chemotherapy may be treated with BCT. Recent studies have demonstrated 
that patients with breast cancer that has metastasized to the regional axillae (T1-2) can also be treated 
with neoadjuvant chemotherapy prior to definitive surgery and can achieve a complete pathologic 
response in the breast and/or in the axillae (22-25). Sentinel node staging before treatment can optimize 
post treatment prognostic in clinically node negative patients (26). 
 
As noted above, in an effort to avoid anthracycline use, recent work using a combination of paclitaxel and 
carboplatin has also demonstrated this combination to be “effective and well tolerated” (27). Additional 
efforts are underway such as the XeNA-trial (Xeloda in Neoadjuvant), in which non-anthracycline 
preoperative regimens are utilized in HER-2 neu positive breast cancer, as they offer less cardiotoxicity 
and thus can be used concomitantly with preoperative trastuzumab therapy (28). 
 
Microarray Genomic Testing in the Treatment of Breast Cancer 
While randomized clinical studies have demonstrated a benefit from adjuvant chemotherapy in early stage 
breast cancer, the toxicity associated with chemotherapy has encouraged studies that attempt to better define 
which breast cancer patients benefit most from chemotherapeutic strategies in the adjuvant setting.  A 
variety of clinical and pathological features of breast cancer including stage and histologic grade have 
been associated with increased risk of relapse in the absence of adjuvant therapy, however standard 
clinical and pathological evaluation has limited utility in defining breast cancer patients that benefit form 
adjuvant therapy.  
 
The development of microarray technology has allowed genomic data to be used to classify breast tumors 
along with standard clinical prognostic factors to help define which patients would benefit least or most 
from adjuvant chemotherapeutic treatment. Gene signatures have been developed and validated against 

 
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large retrospective databases and adopted by medical oncologists as a means to risk stratify patients and 
selectively recommend adjuvant treatments for breast cancer therapy. Another approach has used intrinsic 
subtyping and p53 mutations as a possible predictive test for response to therapy as in XeNA study (29). 
 
Development of new profiles for Neo-Adjuvant chemosensitivity 
One of the correlative objectives of the current study is to identify and/or cross validate a unique set of 
classifier genes that will accurately predict a complete Pathologic Response (pCR) to treatment with dose 
dense CT in the neoadjuvant setting. Studies to date have demonstrated a 25-27% complete pathologic 
response in both breast and axilla to a variety of neoadjuvant chemotherapy regimens.  Furthermore, 
neoadjuvant trials have indicated that the achievement of a pathological complete response affords the 
patients a survival advantage of 80% in five years, which is double the expected survival of the remaining 
patients without complete pathologic response. (30-31) If the subset of patients with complete pathologic 
response could be identified by a genomic signature then the remaining patients would best be suited to 
treatment with an alternative regimen.  
 
3.0  
ELIGIBILITY CRITERIA  
3.1 Inclusion Criteria  
3.1.1  
Women with histologically proven invasive breast cancer without distant 
metastases  A clinical tumor classification of tumor size must be at least 1 cm with 
or without clinical pathologic evidence of positive nodes.  
3.1.2  
Age: Patients must be 19 years of age or older. (This is the age of consent in 
Nebraska. Breast cancer does not occur in the pediatric age group.) 
3.1.3  
ECOG performance status of 0 or 1. (Appendix A) 
3.1.4  
At least one lesion that can be accurately measured in two dimensions utilizing 
mammogram, ultrasound, or MRI images to define specific size and validate 
complete clinical and pathologic response.  
3.1.5 
Patients who received radiation therapy > 5 years ago for malignancies other than 
breast cancer and whose radiation therapy field is not overlapping with the 20% 
isodose line of current radiation field are eligible, provided that radiation therapy 
was completed > 5 years ago and that there is no evidence of the second malignancy 
at the time of study entry. 

 
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3.1.6 
Patients must have adequate laboratory parameters within 30 days prior to 
enrollment defined as:  
• Absolute neutrophil count greater than or equal to 1,500/mcl 
• Platelet count equal to or greater than 150,000/mcl 
• Alkaline phosphatase equal or less than 1.5 times the ULN 
• Total bilirubin equal to or less than 1.5 times the ULN 
• AST and ALT no greater than  1.5 times the ULN 
• Creatinine less than 1.5 times the ULN  
3.1.7 
All included patients must have normal cardiac function as defined by an ejection 
fraction of ≥50% and no decrease in wall motion by echocardiogram. 
3.1.8 
The patient must be aware of the neoplastic nature of his/her disease and willingly 
provide written, informed consent after being informed of the procedure to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, 
side-effects, risks, and discomforts. 
3.1.9 
Women of reproductive potential must be non-pregnant and non-nursing and must 
agree to employ an effective barrier method of birth control throughout the study 
and for up to 6 months following treatment. 
3.1.10 
Women of child-bearing potential must have a negative pregnancy test within 7 
days of initiating study. (No childbearing potential is defined as age 55 years or 
older and no menses for two years or any age with surgical removal of the uterus 
and/or both ovaries).  
 
3.2 
Exclusion criteria 
3.2.1 
Any patient with inflammatory breast cancer or Stage IV or confirmed metastatic 
disease. 
3.2.2 
Patients who have had any prior chemotherapy, or endocrine therapy for the 
treatment of breast cancer or any other cancer. 
3.2.3 
Patients who cannot undergo surgery.  

 
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3.2.4 
Patients with a known or documented anaphylactic reaction or allergy to any of 
chemotherapy agents used in this protocol, or to antiemetic’s appropriate for 
administration in conjunction with protocol-directed therapy. 
3.2.5 
Uncontrolled inter-current illness including, but not limited to ongoing or active 
infection requiring intravenous antibiotics, symptomatic congestive heart failure, 
unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might 
jeopardize the ability of the patient to receive the therapy program outlined in this 
protocol with reasonable safety. 
3.2.6 
Patients with preexisting Grade II peripheral neuropathy. 
3.2.7 
Pregnant and nursing women are excluded from this study because the 
chemotherapy agents and radiation therapy all have the potential for teratogenic or 
abortifacient effects. 
3.2.8 
Patients with prior malignancy will be excluded except for adequately treated basal 
cell or squamous cell skin cancer, adequately treated noninvasive carcinomas. 
3.2.9 
Inability to cooperate with treatment protocol. 
3.2.10 
Patients with known HIV infection, infectious hepatitis, type A, B or C, active 
hepatitis, or hepatic insufficiency. 
3.2.11 
Patients may not be receiving or have received any other investigational agents 
during/or within 1 month prior. 
3.2.12 
Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
3.2.13 
Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. (Appendix B)  Prior to study 
entry, any ECG abnormality at screening has to be documented by the investigator 
as not medically relevant. 
NOTE: All questions regarding eligibility for potential subjects should be directed to the UNMC 
Coordinator at 402-559-5582 or 402-559-5286.   
 
 

 
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4.0 REGISTRATION PROCEDURES 
All patients with breast cancer or suspicious breast masses referred to the Nebraska Medical Center 
(NMC) / UNMC or other IRB approved participating sites may be eligible for this trial.  
 
Screening eligibility based on standard clinical care will be performed by the treating physician at the time 
of encounter.   On initial presentation, a history and physical examination are performed, laboratory data 
obtained, and performance status is assessed. Imaging studies obtained may include a high-resolution 
multi-detector computed tomography (CT) of the chest, abdomen and pelvis to evaluate as indicated for 
metastatic disease. Further imaging studies will be obtained as clinically indicated that may include but 
are not limited to MRI, Mammogram and Ultrasound. At least 1 lesion must be accurately measured bi-
dimensionally. Any pathologic specimens obtained at referring institutions are reviewed for accuracy 
except for IRB centers participating in the study. Patients with suspicious breast masses will require breast 
biopsy for confirmation of malignancy. Biopsy techniques available include percutaneous and 
CT/ultrasound guidance. The patient’s primary oncologist will make the decision as to screened eligibility 
of the candidate based on the eligibility criteria listed above, prior to offering consent. 
 
Patients with Stage T1cN0 and Stage II-III breast adenocarcinoma screened as potentially eligible, will 
then be offered the option to participate in the treatment portion of this trial. More subjects will participate 
in this pre-therapy evaluation phase than will ultimately be found to be suitable candidates for the 
chemotherapy/radiation therapy. An informed consent will be signed by the patient after thorough review 
of the study is completed by the physician and his/her designee. 
 
Patients with localized or locally advanced breast cancer will traditionally receive surgical treatment 
following neoadjuvant therapy. This treatment usually consists of a modified radical mastectomy 
combined with radiation therapy while patients who are down staged by the treatment may be treated with 
breast conserving surgery.   
 
Some insurance carrier’s may decline to cover the costs of usual medical care if the patient is participating 
in a clinical trial.  The patient will be provided assistance by the research nurse coordinator or designated 
staff in determining if the insurance carrier will decline coverage.  Insurance carriers may or may not pay 
for study related expenses. The patient can then decide if they wish to participate.   
 

 
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4.1 Eligibility Verification/Registration 
Before patients are enrolled into the study, an eligibility checklist (Appendix C) must be completed to 
verify the subject meets the eligibility criteria and may be used as source documentation if it has been 
reviewed, signed, and dated prior to registration by the treating physician. Study personnel from non-
UNMC IRB approved sites will contact the UNMC Research Project Coordinator if a non-UNMC patient 
appears to meet the eligibility criteria. They will scan and email the completed eligibility checklist 
(Appendix C) along with de-identified relevant source documents to the UNMC Research Coordinator to 
verify the subject meets the eligibility criteria. If the UNMC Research Coordinator confirms that the non-
UNMC patient meets criteria, and target accrual has not been met, approval for the non-UNMC patient 
will be given. A confirmation of registration will be forwarded by the UNMC Research Project 
Coordinator. 
 
Enrollment: Date of enrollment is defined as the date of the start of study treatment / first protocol related 
intervention. All eligibility criteria do not need to be met until the date of the first study related treatment. 
The eligibility check list will be maintained in the study file. 
 
Registration: Eligibility verification and notification of assigned subject number (by UNMC) to  
 
Participating Sites will be known as the registration date.    
 
UNMC:  
Study personnel from UNMC will provide the UNMC Fred & Pamela Buffett Cancer Center PRMS office 
an electronic copy of the signed and dated consent form for each UNMC subject enrolled in the protocol 
within one (1) week that includes the following information: 
• 
Protocol Number 
• 
Patient Identification: Patient’s name study subject number 
• 
Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity 
• 
Subject zip code/country (if not USA) and primary method of payment information 
 
Participating Sites:  
The UNMC Fred & Pamela Buffett Cancer Center Protocol Review & Monitoring System (PRMS) Office 
Audit Committee defines a Participating Site as:  a hospital clinic, or other provider of medical services 
who has agreed to participate in a therapeutic trial that has been designed and developed by a University 

 
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of Nebraska Medical Center/Nebraska Medical Center (UNMC/NMC) investigator and is sponsored by 
UNMC. 
 
Participating/Collaborating sites must have local and UNMC IRB approval, and have met all other criteria 
to enroll.   Study personnel from non-UNMC IRB approved sites will provide the UNMC Multi-site 
Project Manager with the following information: 
• Registration request with Demographics cover sheet (located in the Study site Manual) 
• Copy of the signed and dated consent form (subject signature obliterated with signature line and 
subject  initials visible)  
• 
Signed Eligibility Checklist 
 
5.0  TREATMENT PLAN  
This is a Phase II study of neo-adjuvant therapy using a dose-dense regimen of cyclophosphamide and 
paclitaxel with or without trastuzumab in patients with newly diagnosed stage T1cN0 or stage II-III breast 
cancer. This will be a non-randomized study; all patients will receive the combination chemotherapy. All 
subjects will receive the same doses of the active compound. Dose modifications for adverse events are 
described in Tables 1-5. 
5.1  Diagnostic Biopsy (SOC)  
• Pathology review 
• Determination of ER, PR, HER2 status 
 
5.2 Pre-treatment Evaluations  
Standard of Care (SOC) No tests or procedures are conducted solely for the purposes of research to 
determine subject eligibility. 
• History and physical 
• CBC, diff, plt, CMET,  
• Serum pregnancy test 
• Height and weight 
• Vital signs, including blood pressure 
• ECOG Performance status 

 
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• Neuropathy Assessment worksheet NOTE: Coordinator to complete the neuropathy 
worksheet (Appendix E) with the subject.  
• Echocardiogram  
• Mammogram/MRI/US radiologic evaluations for staging (SOC)  
Biospecimen Samples (Mandatory) Solely for the purposes of research 
• A baseline Blood Draw of 30 ml including two – 10ml purple top tubes and one – 10ml 
red top tube for WBC DNA to identify possible gene expression profile signatures from 
whole genome array analysis that correlate with clinical response/resistance to 
chemotherapy as measured by pathologic complete response rate (pCR) will be obtained 
pre-chemotherapy.   
SEE APPENDIX D for instructions. Blood Samples to be sent overnight at room temp 
Monday through Thursday only; do not send the day before a holiday. 
 
5.3 Administration Schedule  
All Patients will receive: 
Premedication: All patients will receive premedication for nausea and vomiting with appropriate anti-
emetic regimens (SOC). Patients will receive diphenhydramine, ranitidine and dexamethasone prior to 
paclitaxel (SOC). Pre and post medications as prescribed by the treating physician. 
Systemic Therapy (Medicare Qualifying research related combination chemotherapy):  
• Paclitaxel 175mg/m2 in normal saline intravenously (IV) over 3 hours  Day 1 cycled every 14 
days (2 weeks) for 6 cycles  
• Cyclophosphamide 600mg/m2 in normal saline IV over 1 hour Day 1 cycled every 14 days (2 
weeks) for 6 cycles 
• All cycles are with pegfilgrastim support 1-4 mg (optional with cycle 6) given by subcutaneous 
injection after PC chemotherapy. Dose adjust down for ANC>12,000. (SOC) 
Patients with Her-2 neu positive tumor will also receive trastuzumab (SOC):  
Loading Dose trastuzumab 6mg/kg in normal saline IV over 30 minutes Day 1, Cycle 1  
THEN for Subsequent Cycles (Cycles 2-6), trastuzumab 4mg/kg in normal saline IV over 30 
 
minutes  Day 1 every 14 days (2 weeks) Cycles 2-6. 
 

 
Page 17  
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Clinical Endpoint/Restaging Assessments 
A dedicated Breast MRI and/or Ultrasound restaging assessment will be done following 6 cycles of 
treatment with paclitaxel and cytoxan and prior to surgery if deemed appropriate.  Restaging 
imaging may be omitted if the patient is having a planned mastectomy. 
Patients without metastasis will undergo definitive surgery.  
If no contraindication for surgical resection is identified, surgery will be performed 4-8 weeks after 
completing PC/PCH. All surgery will be performed with curative intent with resection of all gross tumor 
(i.e. R0 [negative margins]. Standardized histopathologic analysis of resected specimens will be 
performed. Examination of regional lymphatics will be performed according to standard pathology 
techniques.  
 
Pre-op Biospecimen Samples (Mandatory) Solely for the purposes of research 
• A pre-op Blood Draw of 30 ml including two – 10ml purple top tubes and one – 10ml red 
top tube for WBC DNA to identify possible gene expression profile signatures from whole 
genome array analysis that correlate with clinical response/resistance to chemotherapy as 
measured by pathologic complete response rate (pCR)will be obtained anytime post 
chemotherapy  but before surgery.  (San Ming Wang, MD) 
SEE APPENDIX D for instructions. Blood Samples to be sent overnight at room temp 
Monday through Thursday only; do not send the day before a holiday. 
 
 
Post-Surgery / Systemic Therapy (Medicare Qualifying research related combination 
chemotherapy): 
HER2 positive patients: 
Upon recovery from surgery HER-2 positive patients will receive Radiation Therapy given by the 
radiation oncologist and timing determined by the radiation and medical oncologist as per standard NCCN 
guidelines, following mastectomy or patients who are down staged by the treatment may be treated with 
breast 
conserving 
surgery. 
See 
attached 
NCCN 
guidelines. 
http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf  
 
Patients with Her-2 positive cancer will also receive maintenance therapy with trastuzumab 6mg/kg in 

 
Page 18  
IRB#264-12:      V3.2 Dated 11-30-21 
 
normal saline IV over 30 minutes Day 1 every 21 days (3 weeks) to complete a total of 52 weeks (Cycles 
7- 19) timing determined by the radiation and medical oncologist as per standard NCCN guidelines, 
following mastectomy or breast conserving surgery. 
 
Hormone Therapy in ER/PR positive patients: 
Patients with estrogen/progesterone receptor (ER/PR) positive tumors will receive adjuvant hormonal or 
endocrine therapy as determined by the medical oncologist per standard NCCN guidelines. See attached 
NCCN guidelines. Patients with estrogen/progesterone receptor positive tumors will receive Hormonal 
Therapy 
following 
adjuvant 
chemotherapy. 
http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. 
 
Stage T1cN0 Triple negative patients (HER2-, ER-, PR-) patients: 
Patients with Stage T1 cN0 Triple negative patients (HER2-, ER-, PR-) will receive Radiation Therapy 
given by the radiation oncologist and timing determined by the radiation and medical oncologist as per 
standard NCCN guidelines, following mastectomy or patients who are down staged by the treatment 
may be treated with breast conserving surgery. See attached NCCN guidelines. 
http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf  
 
Stage II-III Triple negative (HER2-, ER-, PR-) patients: 
Upon recovery from surgery, only Stage II-III triple negative patients (HER2-, ER-, PR-) will receive 
four cycles of chemotherapy with adriamycin 60mg/m2 in normal saline IVP over 15 minutes on Day 1 
cycled every 14 days (2 weeks) for 4 cycles (cycles 7-10).  All cycles are with pegfilgrastim support 1-6 
mg (optional with cycle 4) given by subcutaneous injection Patients will also receive Radiation Therapy 
given by the radiation oncologist and timing determined by the radiation and medical oncologist as per 
standard NCCN guidelines; following mastectomy or patients who are down staged by the treatment 
may be treated with breast conserving surgery. See attached NCCN guidelines. 
http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf  
 
 
 

 
Page 19  
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End of Treatment/Post-Trial Assessments all patients: 
Biospecimen Samples (Mandatory) Solely for the purposes of research 
• A Blood Draw of 30 ml including two -10ml purple top tubes and one -10ml red top tube 
for WBC DNA to identify possible gene expression profile signatures from whole genome 
array analysis that correlate with clinical response/resistance to chemotherapy as measured 
by pathologic complete response rate (pCR)will be obtained.   
SEE APPENDIX D for instructions. Blood Samples to be sent overnight at room temp 
Monday through Thursday only; do not send the day before a holiday. 
 
 
Follow-up (SOC): All patients will then be followed at three month intervals for two years for safety and 
annually thereafter for disease recurrence and overall survival to end at 5 years from diagnosis. During 
the first two years of follow up, physical exam and other tests may be done as requested by the physician.   
 
Patients who go off study treatment at any time during the trial will be followed for 30 days after the last 
day of treatment or until other disease-related treatment begins. For all patients, drug-related SAEs and 
AEs will be followed until baseline or ≤ grade 1 levels. 
 
5.4 Evaluations during therapy (SOC):  
• Patients will have standard hematological and cardiac evaluations.  
• Patients will be clinically evaluated by an oncologist during chemotherapy every 2 weeks for 
toxicities, vital signs, performance status, and neuropathy assessment worksheet. Her-2 neu 
positive patients will be monitored at least every 12 weeks after completing chemotherapy until 
they complete 52 weeks of trastuzumab and then every 3 months for 2 years. Her-2 neu negative 
patients will be monitored every 3 months after completing chemotherapy for 2 years.  
• Her-2 neu positive patients will have a repeat echocardiogram every 12 weeks to monitor their 
cardiac function. Normal cardiac function is defined by an ejection fraction of ≥50% and no 
decrease in wall motion by echocardiogram. 
• Her-2 neu negative patients will have a repeat echocardiogram at the end of chemotherapy to 
evaluate their cardiac function. Normal cardiac function is defined by an ejection fraction of≥50% 
and no decrease in wall motion by echocardiogram.  

 
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• Data will be collected on dose delays/reductions, hospitalizations, treatment discontinuation, 
deaths, and hematologic and cardiac toxicity. 
 
5.5 Criteria for holding and resuming treatment 
Treatment should be held until any non-hematologic grade 3-4 toxicities resolve to less than a grade 
1 with dose modifications as per instructions below. 
 
5.6 Dose Modifications 
 
5.6.1 General instructions for dose modifications and delays 
• The Common Terminology Criteria for Adverse Events Version 4.0 (Appendix F) must be used to grade 
the severity of adverse events (AEs). 
• All doses should be based on the AE requiring the greatest modification. 
• Doses that have been reduced may not be escalated. 
• Proceeding with study therapy after grade 4 events, other than neutropenia/granulocytopenia and 
thrombocytopenia, is at the discretion of the physician. 
 
 
 
5.6.2 Dose modifications and delays for cyclophosphamide and paclitaxel  
 
All dose modifications for cyclophosphamide are based on the dose level changes in Table1.  
 
TABLE 1. Dose level changes for cyclophosphamide 
 
Dose 
Level-0 
Starting 
Dose 
(mg/m2) 
Dose 
Level-1 
(mg/m2) 
 
Dose 
Level-2 
(mg/m2) 
 
Dose 
Level-3 
cyclophosphamide 
600 
500 
400 
Discontinue 
 
All dose modifications and delays for paclitaxel are based on the dose level changes in Table 2 
 
 
TABLE 2. Dose level changes for paclitaxel  
 
Dose Level-0 
Starting Dose 
(mg/m2) 
Dose Level-1 
(mg/m2) 
DoseLevel-2 
(mg/m2) 
Dose Level-3 
(mg/m2) 
Dose Level-4 
(mg/m2) 
paclitaxel 
175 
175 
135 
135 
100 

 
Page 21  
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Table 3 revised to align more clearly 7/17/12 
Instructions for all other toxicities are listed on Table 3.  
 
TABLE 3. Dose modifications and delays for cyclophosphamide and paclitaxel 
Note: Dose modifications must be based on AE requiring the greatest modification; AEs observed during 
the cycle; and AEs present on the scheduled Cycle Day 1.  
 
NCI CTCAE v4.0   
Category/Grade (Gd) 
Modifications for AEs that 
occurred during a cycle but 
DID NOT REQUIRE 
TREATMENT DELAY a 
Modifications for AEs that 
REQUIRED TREATMENT 
DELAY b 
Blood/bone marrow: 
 
 
Neutrophils/granulocytes 
Grades 3 or 4 
 
 
Gd 3/4 -Maintain dose 
 
ANC: Hold until ≥ 1000/mm3 
If recovery takes: 
1 week – maintain dose 
2 to 3 weeks – ↓ one dose level 
> 3 weeks – D/C study therapy 
Platelets 
Grades 2 or 3 
 
 
 
 
Grade 4 
 
 
Gd 2/3 -Maintain dose 
 
 
 
 
Gd 4 -↓ one dose level 
 
Platelets: Hold until ≥ 75,000/mm3 
If Gd 2 or 3 recovery takes: 
≤ 1 week – maintain dose 
2 to 3 weeks - ↓ one dose level 
> 3 weeks – D/C study therapy 
 
If Gd 4: ↓ one dose level  
If Gd 4 recovery takes: 
> 3 weeks, D/C study therapy 
GI (if related to chemotherapy) 
 
 
Diarrhea 
Grade 2 
Grade 3 
Grade 4 
 
Gd 2 -Maintain dose 
Gd 3 -↓ one dose level 
Gd 4 -↓ two dose levels or D/C 
 
Gd 2 -↓ one dose level 
Gd 3 -↓ one dose level 
Gd 4 -↓ two dose levels or D/C 
Mucositis/stomatitis 
Grade 2 
Grade 3 
Grade 4 
 
Gd 2 -Maintain dose 
Gd 3 -↓ one dose level 
Gd 4 -↓ two dose levels or D/C 
 
Gd 2 -↓ one dose level 
Gd 3 -↓ one dose level 
Gd 4 -↓ two dose levels or D/C 
Vomiting (despite antiemetics) 
Grade 2 
Grades 3 or 4 
 
Gd 2 -↓ one dose level (optional) 
Gd 3/4 -↓ two dose levels or D/C 
 
Gd 2 -↓ one dose level (optional) 
Gd3/4 -↓ two dose levels or D/C 
Hepatic function: 
 
 
Bilirubin 
AST 
alk phos 
Grade 2 
Grade 3 
 
 
 
Gd 2 -↓ one dose level 
Gd 3 -↓ two dose levels 
Hold until bilirubin returns to the 
baseline grade and AST / alk phos 
have returned to ≤ Gd 1 then: 
Gd 2 -↓ one dose level 
Gd 3 -↓ two dose levels 

 
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IRB#264-12:      V3.2 Dated 11-30-21 
 
Grade 4 
Gd 4 -D/C 
Gd 4 -D/C 
Infection: 
 
 
Febrile neutropenia 
Grade 3 
Grade 4 
 
Gd 3 -↓ one dose level 
Gd 4 -↓ two dose levels or D/C 
 
Gd 3 -↓ one dose level 
Gd4 -↓ two dose levels or D/C 
Infection with grade 3 or 4 ANC 
Grade 3 
Grade 4 
 
Gd 3 -↓ one dose level 
Gd 4 -↓ two dose levels or D/C 
 
Gd 3 -↓ one dose level 
Gd 4 -↓ two dose levels or D/C 
Infection with normal ANC 
Grade 3 
Grade 4 
 
Gd 3 -Maintain dose 
Gd 4 -↓ two dose levels or D/C 
 
Gd 3 -Maintain dose 
Gd 4 -↓ two dose levels or D/C 
Other clinically significant AEs c 
 
 
Grade 3 
Grade 4 
Gd 3 -↓ one dose level 
Gd4 -↓ two dose levels or D/C 
Gd 3 -↓ one dose level 
Gd 4 -↓ two dose levels or D/C 
a Treatment may not proceed until toxicity is ≤ grade 1, except for neutrophils/ granulocytes, which 
must be ≥ 1000/mm3 and bilirubin, which must be at or below the baseline grade. 
b Hold and check weekly. With exception of neutrophils and bilirubin, resume treatment when toxicity 
is ≤ grade 1. If toxicity has not resolved to ≤ grade 1 after 3 weeks of delay, discontinue chemotherapy. 
c Determination of "clinically significant" AEs is at the discretion of the investigator. 
 
 
 
5.6.3 Management of paclitaxel-related hypersensitivity reactions 
Management of paclitaxel-related hypersensitivity reactions is at the investigator's discretion.  
 
 
5.6.4 Management of paclitaxel-related Neurosensory Toxicity and  Musculoskeletal pain 
Dose modifications for paclitaxel related neurosensory toxicity are outlined on Table 4.  
Dose modifications for paclitaxel related musculoskeletal pain are outlined on Table 5. 
TABLE 4. Dose modifications for neurosensory toxicity related to the paclitaxel  
Paresthesias/Dysesthesias 
1-7 Day Duration 
Persistent for > 7 Days or 
Caused the Next Cycle to be 
Delayed 
Grade 1 Paresthesias/dysesthesias 
of short duration that resolve  
and do not interfere with function 
 
Maintain dose 
 
 
Maintain dose 
 
Grade 2 Paresthesias/dysesthesias 
interfering with function, but not 
activities of daily living 
 
Maintain dose a 
 
Decrease paclitaxel to next lower 
dose. b,c 
 
Grade 3 Paresthesias/dysesthesias 
with pain or with function 
impairment that also interfere with 
activities of daily living 
 
First episode: 
Decrease paclitaxel 
to next lower dose a,c 
 
Second episode: 
Stop paclitaxel 
     
 
 
Stop paclitaxel 
 
Grade 4  
Persistent paresthesias/dysesthesias 
 
Stop paclitaxel 
 
Stop paclitaxel 

 
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IRB#264-12:      V3.2 Dated 11-30-21 
 
that are disabling or life-threatening 
 
a Use of narcotics and NSAIDs is encouraged to maintain dose of paclitaxel if possible. 
b Consider modifying G-CSF. 
c Decrease the paclitaxel to the next lower dose, e.g., for paclitaxel, from 175 mg/m2 to 135 mg/m2 or 
from135 mg/m2 to 100 mg/m2. (Note that, the paclitaxel dose does not always decrease by one dose 
level; therefore, reducing the paclitaxel dose may mean adjusting by more than one dose level 
increment. Refer to Table 2.) 
 
TABLE 5. Dose modifications for musculoskeletal pain attributed to the paclitaxel and not 
controlled by analgesics (a) 
Musculoskeletal Pain 
1-7 Day Duration 
Persistent for > 7 Days        or  
Caused Next Cycle to be Delayed 
Grade 1 
Maintain dose 
Maintain dose 
Grade 2 
Maintain dose 
 
Maintain dose 
OR 
Decrease paclitaxel  to next lower dose b,c 
Grade 3 
 
 
 
 
 
First episode: 
Decrease the paclitaxel 
to next dose b,c 
 
 
Second episode: 
Stop the paclitaxel 
First episode: 
Decrease paclitaxel to next lower dose b,c 
          OR 
Stop paclitaxel 
 
Second episode: 
Stop paclitaxel 
 
Grade 4 
Stop the paclitaxel 
Stop paclitaxel 
a Use of narcotics and NSAIDs is encouraged to maintain dose of paclitaxel if possible. 
b Consider modifying G-CSF. 
c Decrease the paclitaxel to the next lower dose, e.g., for paclitaxel, from 175 mg/m2 to 135 mg/m2 or 
from135 mg/m2 to 100 mg/m2. (Note that, the paclitaxel dose does not always decrease by one dose 
level; therefore, reducing the paclitaxel dose may mean adjusting by more than one dose level 
increment. Refer to Table 2.) 
 
5.7 Criteria for Removal from Study 
5.7.1  Progression of Disease 
 
5.7.2 If at any time the constraints of this protocol are detrimental to the patient's wellbeing, or if 
the patient is unable to comply with the requirements of the protocol, the patient will be removed 
from protocol therapy. In this event, the reason(s) for withdrawal will be documented. 
 
5.7.3 If the patient experiences an adverse reaction that, in the opinion of the investigator, 
necessitates the removal of the patient from the study, including any unresolved serious adverse 
event.   
 

 
Page 24  
IRB#264-12:      V3.2 Dated 11-30-21 
 
5.7.4 Any patient who suffers a serious systemic allergic response or severe degree of intolerance 
to the study medication will be withdrawn from further study treatment but will be followed up 
for a period of two years following treatment. 
 
5.7.5 Development of intercurrent medical problems that would make continued protocol therapy 
detrimental to the patient’s safety. 
 
5.7.6 There is concurrent illness or other reasons that would, in the opinion of the investigator, 
affect assessment of clinical status or conduct of the study to a significant degree. 
 
5.7.7 The patient completes study treatment as per study schedule. 
 
5.7.8 The patient chooses to discontinue treatment or follow-up. In this event, the reason(s) for 
withdrawal will be documented. 
 
5.8  Removal of subject from Study Therapy 
The reason(s) for withdrawing the patient from the treatment portion of the study will be 
documented in the case report form. Where possible and feasible, patients who received at least 
one dose of study drugs should be subjected to the procedures scheduled at the end of the study 
and should be submitted to the follow up to assess disease progression. If available, the following 
information will be recorded in the case report form: date of disease relapse, date of death, cause 
of death, and autopsy report. 
 
6.0 
Measurement of Effect 
 
6.1 Tumor Response   
The primary endpoint is pathological complete response (pCR) which is defined as the absence 
of invasive carcinoma in both the breast and axilla at microscopic examination of the resection 
specimen, regardless of the presence of carcinoma in situ. Partial response is defined as decrease 
in longest tumor diameter or RCB1as defined using the online calculator at 
http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3., a secondary 
endpoint for neo-adjuvant chemotherapy patients. 
 
6.2 
 Response criteria 
The following parameters are required from pathologic examination in order to calculate 
Residual Cancer Burden (RCB) after neoadjuvant treatment: 
1. The largest two dimensions (mms) of the residual tumor bed in the breast (largest tumor 
bed if multicentric disease) 
2. Submission of the entire largest cross-sectional area of the residual tumor bed for 
histologic mapping, with specific identification of those slides in the pathology report 
(e.g. "the largest cross-sectional area of primary tumor bed was submitted in cassettes A5 
- A9") 

 
Page 25  
IRB#264-12:      V3.2 Dated 11-30-21 
 
• 
If the residual tumor is large (i.e. largest diameter > 5 cm), then at least 5 
representative cassettes from the largest cross-sectional area are sufficient, but 
should be identified in the original pathology report (e.g. "representative sections 
from the largest cross-sectional area of primary tumor bed were submitted in 
cassettes A5 - A9") 
3. Histologic assessment of the percentage of the tumor bed area that contains carcinoma 
(all carcinoma, i.e. invasive and in situ), select one of the following: 
o 0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% 
• 
To assess cellularity it is helpful to scan across the sections of tumor bed and then 
estimate the average cellularity from the different microscopic fields. 
• 
When estimating percentage cancer cellularity in any microscopic field, compare 
the involved area with obvious standards, e.g. more or less than half, one quarter, 
one fifth, one tenth, one twentieth, etc. 
• 
Expect there to be variable cellularity within the cross section of any tumor bed, 
but estimate the overall cellularity from the average of the estimates in different 
microscopic fields of the tumor bed. 
• 
e.g. if cellularity in different fields of the tumor bed were estimated as 20%, 10%, 
20%, 0%, 20%, 30%, then an average estimate of overall cellularity would be 
20%. 
4. Histologic estimate of the percentage of the carcinoma in the tumor bed that is in situ, 
select one of the following: 
o 0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% 
5. The number of positive (metastatic) lymph nodes 
6. The largest diameter (mm) of the largest nodal metastasis 
 
 
Residual Cancer Burden Calculator 
http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3: 
*Values must be entered into all fields for the calculation results to be 
accurate. 
(1) Primary Tumor Bed 
     Primary Tumor Bed Area: 
_____ (mm) X ____ (mm) 
   Overall Cancer Cellularity (as percentage of 
area): 
_____ (%) 
   Percentage of Cancer That Is in 
situ Disease: 
_____ (%) 
  
(2) Lymph Nodes 

 
Page 26  
IRB#264-12:      V3.2 Dated 11-30-21 
 
   Number of Positive Lymph Nodes: 
____ 
   Diameter of Largest Metastasis: 
____ (mm) 
    
Residual Cancer Burden:   ______ 
 
   Residual Cancer Burden Class: _______ 
 
 
6.3 
Toxicity criteria 
The NCI Common Toxicity Criteria Adverse Events Version 4.0 will be used to grade toxicity; it 
is available at the following internet site:  http://ctep.cancer.gov/forms/CTCAEv4.pdf. 
 
 
7.0 Study Parameters   
 
 
Screening 
Staging 
BASELINE 
Cycle1 
 
Cycle2 
 
Cycle3 
 
Cycle4 
 
Cycle5 
 
Cycle6 
 
C 
L 
I 
N 
Diagnostic BIOPSY 
Pathology review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
I
C 
ER/PR/HER2 status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
A 
Staging Mammogram, 
MRI, US as necessary (may 
be omitted after chemo prior 
to surgery  in the case of 
planned mastectomy) 
X 
 
 
 
 
 
 
 
 
 
 
 
X after 
chemo 
prior to 
surgery  
L 
 
Chemotherapy Regimen 
 
Day1 
 
Day1 
 
Day1 
 
Day1 
 
Day1 
 
Day1 
 
 
ALL PATIENTS = PC  
Paclitaxel, 
Cyclophosphamide 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
E
N
D 
Pegfilgrastim support 
(optional following cycle 6) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X P 
PATIENTS WITH HER-2 NEU 
POSITIVE TUMOR = *PCH,  
 
 
 
 
 
 
 
 
 
 
 
 
 
O
I 
H - Herceptin® 
(Trastuzumab) loading dose 
 
X 
 
 
 
 
 
 
 
 
 
 
 
N
T 
H - Herceptin® 
(Trastuzumab) maintenance 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Blood Draw for 
Research(Res) 2-10ml 
EDTA and 1-10ml Red 
X prior to 
chemo 
 
 
 
 
 
 
 
 
 
 
 
X after 
chemo
prior to 
surgery 
 
Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
History 
X 
 
 
Physical examination 
X 
Every 2 weeks 
 
Vital signs, including BP 
X 
Every 2 weeks 
 
Height 
X 
 
 

 
Page 27  
IRB#264-12:      V3.2 Dated 11-30-21 
 
Weight 
X 
Every 2 weeks 
 
Performance status 
(ECOG) 
X 
Every 2 weeks 
 
Neuropathy Assessment 
worksheet 
X 
Every 2 weeks 
 
CBC, diff, Plt  
X 
Every 2 weeks 
 
Comprehensive 
metabolic panel 
(including, alk phos) 
X 
Every 2 weeks 
 
Echocardiogram 
X 
End of Chemotherapy Cycle 6 
 
ALL PATIENTS = PC  Paclitaxel 175mg/m2 in normal saline IV over 3 hrs  / Cyclophosphamide 600mg/m2 in normal saline IV over 1 hr  
REPEAT Day 1 Q 2wks x 6 cycles (Cycles 1-6), Pegfilgrastim support 1-4 mg (optional with cycle 6) SQ after PC dose adjust down or 
hold for ANC >12,000 or bone pain (SOC) 
PATIENTS WITH HER-2 NEU POSITIVE TUMOR = *PCH -  Paclitaxel/Cyclophosphamide REPEAT Day 1 Q 2wks x 6 cycles (Cycles 1-6), 
Pegfilgrastim support 1-4mg (optional with cycle 6) SQ after PC , H - Herceptin® (Trastuzumab) loading dose 6mg/kg Day 1, Cycle 
1THEN subsequent dosing 4mg/kg Day 1 Q2wks Cycles 2-6, (SOC)  
 
**Post-operative RECOVERY / ** Post-restaging: 
Start when the clinician’s determine that the patient has recovered from surgery   
**Post-operative 
RECOVERY/**Post-
restaging  
SOC Cycle7  
Cycle8  
Cycle9  
Cycle10  
 
End of 
Treatment 
Follow-
Up 
Every 3 
months 
for 2 
years 
Survival 
and 
disease 
recurrence 
Follow-up 
to 5 years 
Triple NEG Stage II-III 
patients only 
Chemotherapy 
Regimen Adriamycin 
 
 
Day1 
 
X 
 
 
Day1 
 
X 
 
 
Day1 
 
X 
 
 
Day1 
 
X 
 
 
 
 
 
 
 
 
Pegfilgrastim support 
(optional following cycle 
4) 
 
 
X  
X 
 
X  
X  
 
 
 
ALL PATIENTS WITH 
HER-2 NEU POSITIVE 
TUMOR H - Herceptin® 
(Trastuzumab) 
maintenance every 21 
days for a total of 52 
weeks 
X  
 
 
 
 
 
 
 
 
 
 
 
 
PATIENTS WITH ER/PR 
+ TUMOR = 
HORMONAL THERAPY 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ALL Patients 
Radiotherapy (per 
clinical decision/NCCN 
guidelines) 
X 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 28  
IRB#264-12:      V3.2 Dated 11-30-21 
 
Blood Draw for 
Research(Res) 2-10ml 
EDTA and 1-10ml Red 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Physical examination 
X 
SOC  
 
X 
 
Weight 
X 
SOC 
 
X 
 
CBC, diff, Plt  
X 
SOC 
 
X 
 
Comprehensive 
metabolic panel 
(including,  alk phos) 
X 
SOC 
 
X 
 
Echocardiogram 
 
HER2 positive  echo every 12 weeks until complete 
52 weeks of trastuzumab 
 
 
 
Mammogram, MRI, US 
as necessary 
 
SOC 
 
 
 
CT 
Chest/abdomen/pelvis 
with oral/IV contrast 
 
SOC 
 
 
 
Survival and disease 
status assessment 
 
 
 
 
X 
 
 
 
TRIPLE NEGATIVE PATIENTS (HER2 - ER- PR-) = Adriamycin 60mg/m2 in normal saline IV Q2wks x 4 cycles (Cycles 7-10) , 
Pegfilgrastim support 1-6 mg SQ (optionial with cycle 4) 
 
ALL PATIENTS WITH HER-2 NEU POSITIVE TUMOR **Maintenance Herceptin® 6mg/kg Day 1 Q21 Days for a total of 52 weeks. 
(SOC) 
PATIENTS WITH ER/PR + TUMOR = HORMONAL THERAPY Patients with estrogen/progesterone receptor positive tumors will also 
receive Hormonal Therapy to be determined by the medical oncologist as per standard NCCN guidelines. (SOC) 
RADIATION Clinical Decision per standard NCCN guidelines, following chemotherapy. (SOC) 
End of Treatment Follow-up (F/U) (All subjects) 
Research Serum Samples collected at end of treatment (Res) 
Patients will be followed Q3 months until 2 years from end date of study treatment. (SOC). After 2 years follow up, patients will be 
followed annually for disease recurrence and overall survival to end after 5 years from diagnosis.   
 
 
 
8.0  
Drug Formulation and Procurement 
 
8.1 Trastuzumab (Herceptin) 
8.1.1 Form: herceptin for injection 
 
8.1.2 Preparation: Supplied as 440mg lyophilized Powder.  
 
8.1.3 Dilution: Reconstitute with 20ml SWFI (sterile water for injection) or BWFI (bacteriostatic 
water for injection); dilute with NS to a concentration of 21mg/ml.  DO NOT USE D5W. 
 
8.1.4 Storage and Stability:  Refrigerate vials, do not freeze. 

 
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8.1.5 Method of Administration:  Loading dose: 6 mg/kg IV over 30 minutes. Subsequent dose:  4 
mg/kg IV over 30 minutes. Maintenance dose: 2mg/kg IV over 30 minutes weekly. 
  
 8.1.6 Precautions: Benzyl alcohol hypersensitivity: use SWFI for reconstitution.  Extreme caution 
should be exercised in treating patients with pre-existing cardiac dysfunction, congestive heart 
failure/ventricular dysfunction. Treatment discontinuation should be considered.  Prior/concurrent 
AC or radiation to the chest may enhance the risk of cardiotoxicity. 
 
8.1.7 Clinical Toxicities:   Hypersensitivity reactions, including fatal anaphylaxis.  Infusion 
reactions, including some with a fatal outcome.  Trastuzumab may exacerbate chemotherapy 
induced neutropenia or anemia.  May also cause diarrhea, cardiomyopathy, infusion associated 
symptoms, hypersensitivity reactions, changes in kidney function, pulmonary events such as 
ARDS, bronchospasm, pneumonitis.  May cause “flu-like symptoms” with generalized aches and 
pains, headache, fever, chills, nausea, vomiting and diarrhea. 
 
8.1.8 Commercial Availability: This drug is commercially available. 
 
 
 
8.2 Pegfilgrastim (per Micromedex®) Other names: Neulasta 
 
8.2.1Classification 
Colony stimulating factor, hematopoietic 
 
8.2.2 Mode of Action 
Systemic: Pegfilgrastim is a Colony Stimulating Factor that acts on hematopoietic cells by binding 
to specific cell surface receptors thereby stimulating proliferation, differentiation, commitment, 
and end cell functional activation. 
 
8.2.3 Storage and Stability 
The manufacturer recommends storage of Neulasta(TM) syringes at 2 to 8 degrees C (36 to 46 
degrees F), avoidance of freezing or shaking, and leaving syringes in the carton provided until time 
of use to protect from light (Prod Info Neulasta(TM), 2000). 
 
Syringes of Neulasta(TM) can reach room temperature for up to 48 hours prior to use; during this 
time, they should be protected from light. Syringes left at room temperature for longer than 48 
hours should be discarded (Prod Info Neulasta(TM), 2000). 
 
If syringes are accidentally frozen, thawing under refrigeration is acceptable prior to use. However, 
syringes should be discarded if accidentally frozen a second time (Prod Info Neulasta(TM), 2000). 
 
8.2.4 Known Clinical Toxicities 
COMMON  Gastrointestinal: Nausea and vomiting  
Musculoskeletal: Bone pain  
Other: Influenza-like illness 

 
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SERIOUS  
Hematologic: Hemoglobin SS disease with crisis  
Respiratory: Acute respiratory distress syndrome  
Other: Rupture of spleen (rare) 
 
8.2.5 Supplier  
AMGEN 
 
8.2.6 Commercial Availability 
This drug is commercially available 
8.3 Cyclophosphamide per Micromedex®) Other names: Cytoxan, Cytoxan Lyophilized 
 
8.3.1 Classification 
Alkylating Agent, Antineoplastic Agent, Nitrogen Mustard 
 
8.3.2 Mode of Action 
Cyclophosphamide is classed as an alkylating agent of the nitrogen mustard type. An activated 
form of cyclophosphamide, phosphoramide mustard, alkylates or binds with many intracellular 
molecular structures, including nucleic acids. Its cytotoxic action is primarily due to cross-linking 
of strands of DNA and RNA, as well as to inhibition of protein synthesis. Cyclophosphamide is a 
potent immunosuppressant. It also causes marked and persistent inhibition of cholinesterase 
activity. 
 
8.3.3 Storage and Stability 
1)  Intravenous Powder for Solution: 1 GM, 2 GM, 100 MG, 200 MG, 500 MG) 
 
2)  Reconstituted solutions of lyophilized cyclophosphamide are chemically and physically stable 
for 24 hours at room temperature or for 6 days in the refrigerator. Specific temperatures are not 
provided by the manufacturer (Prod Info Cytoxan(R), 2000a; Brooke et al, 1973). 
 
3)  The rate of dissolution is occasionally slow (10 to 15 minutes) due to various crystal forms. 
Warming the solution to 50 or 60 degrees Celsius for 15 minutes may improve dissolution with 
negligible decomposition. However, heating to 70 to 80 degrees Celsius for 15 minutes has 
resulted in 10% to 23% loss of potency. Lyophilized cyclophosphamide for injection has a rapid 
dissolution rate with no warming needed (Brooke et al, 1975). 
 
4)  Reconstitution of cyclophosphamide with bacteriostatic water containing benzyl alcohol 
preservative may result in decomposition (Brooke et al, 1973 
 
8.3.4 Known Clinical Toxicities 
 
COMMON Dermatologic: Alopecia Gastrointestinal: Nausea and vomiting Hematologic: 
Leukopenia 
Reproductive: 
AmenorrheaSERIOUS 
Cardiovascular: 
Cardiomyopathy 
Dermatologic: Stevens-Johnson syndrome, Toxic epidermal necrolysis (rare) Renal: Hemorrhagic 
cystitis Reproductive: Azoospermia, Oligozoospermia Respiratory: Interstitial pneumonia Other: 
Infectious disease 

 
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8.3.5 Supplier 
Bristol-Myers Squibb 
 
8.3.6 Commercial Availability 
This drug is commercially available 
8.4 Paclitaxel (per Micromedex®) Other names: Taxol, Onxol, Nov-Onxol, Paclitaxel Novaplus 
 
8.4.1 Classification 
Antineoplastic Agent, Mitotic Inhibitor 
 
8.4.2 Mode of Action 
Paclitaxel belongs to the class of medications known as antimicrotubule agents. It promotes the 
assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. This stability results in the inhibition of the normal dynamic reorganization of 
the microtubule network that is essential for vital interphase and mitotic cellular functions. In 
addition, paclitaxel induces abnormal arrays or 'bundles' of microtubules throughout the cell cycle 
and multiple asters of microtubules during mitosis. Paclitaxel enhances the cytotoxic effects of 
ionizing radiation in vitro.  
 
8.4.3 Storage and Stability 
1)  Intravenous Solution: 6 MG/ML 
2)  Paclitaxel vials should be stored between 20 to 25 degrees Celsius (68 to 77 degrees 
Fahrenheit)) in the original containers protected from light. Refrigeration or freezing will not 
adversely affect the product. If a precipitate forms upon refrigeration, allow the vial to come to 
room temperature and the precipitate will dissolve with little or no agitation (Prod Info Taxol(R), 
2000c). 
 
3)  Paclitaxel solutions prepared in 5% dextrose or 0.9% sodium chloride in concentrations of 1.2 
mg/mL, leached diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags at 1, 2, 4, 
and 8 hours (DEHP range of 50 to 208 micrograms/mL). Leaching also occurred after simulated 
three-hour infusions. In all tested conditions, leaching was primarily due to the lipophilic vehicle. 
The highest amount of DEHP leached by the vehicle was 83 mcg/mL at 8 hours, with a 1.2 mg/mL 
0.9% sodium chloride solution, stored at 20 to 22 degrees Celsius. Leaching of DEHP, a commonly 
used plasticizer in PVC bags, increased with time and was independent of the brand of PVC 
infusion materials. When compared to docetaxel, paclitaxel leached two to eight times more DEHP 
from the PVC infusion materials (Mazzo et al, 1997). 
 
4)  Extended-stability paclitaxel admixtures containing 1 mg/mL paclitaxel in 5% dextrose 
injection with the addition of sterile, dehydrated alcohol injection to yield a 20% or 25% ethanol 
concentration was found to be physically stable for at least 7 days as compared to conventional 
paclitaxel admixtures. Extended-stability paclitaxel 1 mg/mL containing 25% ethanol was also 
able to maintain a low concentration of bacteria, yeast and molds throughout the 28-day 

 
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antimicrobial preservatives effectiveness test period demonstrating its low potential for 
contamination during long-term continuous infusion (Trissel et al, 1997a). 
 
5)  Stability studies have demonstrated that paclitaxel, in concentrations of 0.3 to 1.2 
milligrams/milliliter is stable for 24 hours at room temperature in Dextrose 5% in water or Sodium 
chloride 0.9% (Waugh et al, 1991). 
 
 
 
8.4.4 Black Box Warning 
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients 
receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite 
premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H(2) 
antagonists. Patients who experience severe hypersensitivity reactions to paclitaxel should not be 
rechallenged with the drug. 
 
Paclitaxel therapy should not be given to patients with solid tumors who have baseline neutrophil 
counts of less than 1,500 cells/mm(3). In order to monitor the occurrence of bone marrow 
suppression, primarily neutropenia, which may be severe and result in infection, it is recommended 
that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. 
 
8.4.5 Known Clinical Toxicities 
COMMON Dermatologic: Alopecia  
Gastrointestinal: Nausea and vomiting  
Hepatic: Liver function tests abnormal  
Musculoskeletal: Arthralgia, Myalgia 
Neurologic: Peripheral neuropathy 
SERIOUS Cardiovascular: Coronary artery stent thrombosis (late (> 1 year), 0.7%), Hypotension 
(12%) bradycardia 
Hematologic: Myelosuppression, Neutropenic disorder  
Immunologic: Anaphylaxis (2-4%), Immune hypersensitivity reaction 
 
8.4.6 Supplier 
Abbott Laboratories 
 
8.4.7 Commercial Availability 
This drug is commercially available 
 
8.5 Doxorubicin (per Micromedex®) Other names: Adriamycin 
8.5.1 Classification 
Anthracycline , Antineoplastic Agent 
 
8.5.2 Mode of Action 
Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic thought to act on malignant 
cells by intercalating the cell nucleotide base and binding the cell membrane lipid. Intercalation 

 
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blocks replication of nucleotide and action of DNA and RNA polymerases. It also interacts with 
topoisomerase II to form DNA-cleavable complexes, which is believed to be an important 
mechanism of its cytocidal activity . 
 
8.5.3 Storage and Stability 
1)  Intravenous Powder for Solution: 10 MG, 20 MG, 50 MG, 100 MG, 150 MG , Intravenous 
Solution: 2 MG/ML 
2) STABILITY IN ADMINISTRATION CONTAINERS 
a)  Doxorubicin 8 milligrams/500 milliliters glucose 5% was stable for 7 days when 
stored in PVC (polyvinyl chloride) bags at 4 degrees Celsius with light protection. There 
was also no loss of doxorubicin when infused via PVC infusion bags with PVC 
administration sets (Dine et al, 1992). 
b)  Doxorubicin 2 milligrams/milliliter was stable for up to 14 days at 3 or 23 degrees 
Celsius and for an additional 28 days at 30 degrees Celsius in portable pump reservoirs 
(Stiles & Allen, 1991). 
c)  Doxorubicin was stable (less than 10% loss of potency) for 24 days in 0.9% sodium 
chloride stored at 25 degrees Celsius in PVC (polyvinyl chloride) minibags and syringes 
at a pH of 6.47. Also, doxorubicin was stable for at least 43 days in 0.9% sodium chloride 
(pH, 6.47) and 5% dextrose (pH, 4.36) at 4 and -20 degrees Celsius (Wood et al, 1990). 
 
8.5.4 Black Box Warning 
Severe local tissue necrosis will occur if there is extravasation during administration. 
Doxorubicin must not be given by the intramuscular or subcutaneous route. 
Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart 
failure may occur either during therapy or months to years after termination of therapy. The 
probability of developing impaired myocardial function based on a combined index of signs, 
symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1% to 2% at 
a total cumulative dose of 300 mg/m(2) of doxorubicin, 3% to 5% at a dose of 400 mg/m(2), 5% 
to 8% at 450 mg/m(2) and 6% to 20% at 500 mg/m(2). The risk of developing congestive heart 
failure (CHF) increases rapidly with increasing total cumulative doses of doxorubicin in excess 
of 450 mg/m(2). Risk factors (active or dormant cardiovascular disease, prior or concomitant 
radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or 
anthracenediones, concomitant use of other cardiotoxic drugs) may increase the risk of cardiac 
toxicity. Cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or not 
cardiac risk factors are present. Pediatric patients are at increased risk for developing delayed 
cardiotoxicity. 
Secondary acute myelogenous leukemia (AML) has been reported in patients treated with 
anthracyclines, including doxorubicin. The occurrence of refractory secondary leukemia is more 
common when such drugs are given in combination with DNA-damaging anti-neoplastic agents, 
when patients have been heavily pretreated with cytotoxic drugs, or when doses of 
anthracyclines have been escalated. The rate of developing treatment-related leukemia was 
estimated in an analysis of 1474 breast cancer patients who received adjuvant treatment with 
doxorubicin-containing regimens (i.e., FAC) in clinical trials. The estimated risk of developing 
treatment-related leukemia at 10 years was 2.5% for the 810 patients receiving radiotherapy plus 

 
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chemotherapy and 0.5% for the 664 patients receiving chemotherapy alone. The overall risk was 
estimated at 1.5% at 10 years for the entire patient population. Pediatric patients are also at risk 
of developing secondary AML. 
8.5.5 Known Clinical Toxicities 
COMMON  
• 
Dermatologic: Alopecia  
• 
Gastrointestinal: Nausea, Vomiting 
• 
Expect urine discoloration (red) for 1 to 2 days after therapy 
 
SERIOUS  
• 
Cardiovascular: Cardiac dysrhythmia, Congestive heart failure  
• 
Hematologic: Myelosuppression 
8.5.6 Supplier 
Pharmacia & Upjohn 
 
8.5.7 Commercial Availability 
This drug is commercially available 
 
9.0  
Toxicity Reporting Guidelines 
 
Reporting only for PC/PCH Adriamycin – Herceptin “study medication” until 30 days after last 
administration of study medication.   
 
No surgery, hormonal or radiation related AE’s will be recorded or reported. 
 
This protocol will comply with monitoring and adverse event reporting requirements of the UNMC/ Fred 
& Pamela Buffett Cancer Center Data Monitoring plan. The protocol will adhere to the institutional IRB 
and FDA guidelines for the toxicity reporting.    
 
All patients will be closely followed for toxicity from the time of informed consent until 30 days after last 
administration of study medication.  
 
Per NCI guidelines, adverse event (AE) and serious adverse events (SAEs) will be graded. Toxicity will 
be assessed using the NCI CTCAE Version 4.0 (Appendix F). AEs and SAEs will be followed until 
resolution, baseline or ≤ grade 1 levels. 
 
Serious adverse events should be followed until resolution, death, or until no further improvement is 
reasonably expected. Deaths occurring within 30 days of study treatment regardless of relationship will 
be reported to the UNMC DSMC.  
 
 
9.1  Definitions 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation subject 

 
Pa ge 3 5   
I R B # 2 6 4-1 2:      V 3. 2 Date d 1 1 -3 0 -2 1  
 
a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t his 
treat me nt.  A n a d verse e v e nt ca n t her ef ore be a n y u nfa v ora bl e a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y  fi n di n g),  s y m pt o m,  or  disease  te m p orall y  ass ociate d  wit h  t he  use  of  a  me dici nal  
(i n vesti gati o nal) pr o d uct, w het her or n ot t he e ve nt is c o nsi dere d ca us all y rel ate d t o t he use of t he pr o d uct.  
 
A n electi ve s ur ger y or pr oce d ur e t hat is sc he d ule d t o occ ur d uri n g a st u d y will n ot be c o nsi dere d a n 
a d verse e v e nt if t he s ur g er y or pr o ce d ure is b ei n g perf or me d f or a pre -e xisti n g c o n diti o n a n d t he s ur ger y 
or pr oce d ure has b ee n pl a n ne d bef ore st u d y e ntr y.  H o we v er, if t he pre -e xisti n g c o n diti o n deteri orates 
u ne x pecte dl y d uri n g t he st u d y ( e. g., t he s ur g er y is perf or m e d earlier t ha n pl a n ne d), t he n t h e deteri orati o n 
of t he c o n diti o n f or w hic h t he electi ve s ur ger y or pr oce d ure is bei n g d o ne will be c o nsi dere d a n a d verse 
e ve nt.  
 
A n y  w orse ni n g  of  a  pr e -e xisti n g  c o n diti o n  or  ill ness  is  c o nsi dere d  a n  a d vers e  e v e nt.   L a b orat or y  
a b n or malities  a n d  c ha n ges  i n  vital  si g ns  are  c o nsi dere d  t o  be  a d v erse  e v e nts  if  t he y  res ult  i n  
disc o nti n uati o n  fr o m  t h e  st u d y,  necess itate  t hera pe utic  me di cal  i nter v e nti o n,  meet  pr ot oc ol  s p ecific  
criteria (s ee Secti o n 5. 0, Treat me nt Pla n ) a n d/ or if t he i n vesti gat or c o nsi ders t he m t o be a d verse e ve nts.  
 
  
 
U ne x pecte d A d verse E v e nt  
A n  u ne x pect e d  a d vers e  e ve nt  is  a n y  a d v erse  dr u g  e ve nt  t h at  is  n ot  liste d  i n  t he  c urre nt  
la beli n g/I n v esti gat or’s  Br oc h ure.  T his  i ncl u des  e ve nts  t hat  ma y  be  s y m pt o maticall y  a n d  
pat h o p h ysi ol o gicall y relate d t o a n e ve nt liste d i n t he la beli n g, b ut differ fr o m t he la bele d e ve nt beca use of 
greater se verit y or s pecifi cit y. F or e xa m ple, u n d er t his defi niti o n, he patic necr osis w o ul d be u ne x p ecte d 
( b y virt ue of greater se verit y) if t he la beli n g o nl y referre d t o ele vate d he patic e nz y mes or h e p atitis. 
Si milarl y, cere br al t hr o m b oe m b olis m a n d cere bral vasc ulitis w o ul d be u n e x pecte d ( b y virt ue of greater 
s pecificit y) if t he la beli n g o nl y liste d cere bral vasc ular acci d e nts. “ U ne x pecte d,” as use d i n t his defi niti o n, 
refers t o a n a d verse dr u g e x perie n ce t hat has n ot b ee n pre vi o usl y o bser ve d (i.e., i ncl u de d i n t he la beli n g) 
rat her t ha n fr o m t he pers pecti ve of s uc h e x perie nce n ot b ei n g a ntici p ate d fr o m t he p har mac ol o gical 
pr o perties of t he p h ar mace utical pr o d u ct. 
 
Seri o us A d verse E ve nt  
A seri o us a d verse e v e nt is o ne t hat at a n y d ose (i n cl u di n g o ver d ose) a n d re gar dless of ca usalit y t h at: 
 
Res ults i n deat h  
 
Is a seri o us t hreat t o life, healt h, safet y or welfare of s u bject  1  
  
Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
  
Persiste nt or si g nifica nt disa bilit y or i nca pacit y 2  
 
Is a c o n ge nital a n o mal y or birt h defect 
  
A n ot her seri o us i m p orta nt me dical e ve nt3  
 
 A n y me dical e ve nt i n a n i n vesti gati o nal dr u g st u d y t hat re q uires treat me nt t o pre ve nt o ne 
of t he o utc o mes liste d a b o ve 
  
T he ri g hts, safet y, or welfare of s u bjects is seri o usl y je o par dize d 

 
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 1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse event; it does not 
refer to a serious adverse event that hypothetically might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to carry out 
normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in situations where 
none of the outcomes listed above occurred.  Important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above should also usually be considered serious.  Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  A new diagnosis of cancer during the course of a 
treatment should be considered as medically important. 
 
9.2 Adverse Event Reporting and Definitions Per University of Nebraska Medical Center, IRB 
and FRED & PAMELA BUFFETT CANCER CENTER Data and Safety Monitoring Committee 
(DSMC)  
 
9.2.1 IRB REPORTING 
All internal adverse events (AE) will be reported to the local IRB promptly per institutional human 
research protection program policies.  
 
 
9.2.2 Fred & Pamela Buffett Cancer Center DATA AND SAFETY MONITORING 
COMMITTEE (DSMC) REPORTING 
 
In its initial review, the DSMC will make a recommendation for the frequency of monitoring 
based on an assessment of risk associated with study-associated therapy, per the DSMC policy.  
Reporting of the following will be done in accordance with DSMC guidelines: 
 
• All serious adverse events (expected or unexpected, regardless of attribution) and toxicities 
will be reported to the DSMC 
• All adverse events (AE) > grade 3 will be reported to the DSMC.  
 
Attribution of AE: The likelihood of relationship of the AE to the study drugs will be determined 
by the investigator based on the following definitions: 
 
Not related:  The subject was not exposed to the study treatment or another cause is 
obvious. 
 
Probably not related: The AE is most likely explained by another cause, and the time of 
occurrence of the AE is not reasonably related to the study treatment. 
 
Possibly related:  Study treatment administration and AE occurrence reasonably related 
in time, and the AE is explained equally well by causes other than study treatment, or 
treatment administration and AE occurrence are not reasonably related in time, but the AE 
is not obviously a result of other causes. 
 

 
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Probably related:  Study treatment administration and AE occurrence are reasonably 
related in time, and the AE is more likely explained by study treatment than by other 
mechanisms. 
 
Definitely related: There occurrence and timing of the AE are clearly attributable to the 
study treatment.  
 
Severity Grade of AE. The severity of events reported on the AE case report form will be 
determined by the principal investigator according the NCI Common Toxicity Criteria (CTC 
version 4.0).  
 
AEs will be collected from the time the subject signs the consent form and ending 30 days 
following the final chemotherapy. All AEs will be followed until resolution or a cause is 
identified. Prescription medication taken to relieve symptoms of the AE will be recorded in 
addition to the outcome.  
 
AEs judged by the investigator as not related or probably not related to the treatment will NOT 
be followed beyond the 30 days after the final chemotherapy.  
 
Surgical, hormonal, and radiation related Adverse Experiences (AE’s) or Serious Adverse 
Experiences (SAE’s) will NOT be collected. However, per the UNMC DSMC, any grade 4 and 
above non-hematologic toxicities (expected or unexpected, regardless of attribution) will be 
collected and reported to the UNMC DSMC. 
 
 
All SAE and AE reporting will be completed using DSMC approved forms.  Detailed policy and 
procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html 
 
9.2.3 Food and Drug Administration (FDA) Reporting 
It is the responsibility of the sponsor-investigator to submit to the FDA IND Safety Reports in 
accordance with 21 CFR 312.32. In addition the sponsor-investigator must notify the Ethics 
Review Committee/Institutional Review Board (EC/IRB) of a serious adverse event in writing in 
accordance with international and local laws and regulations. SAEs not meeting expedited criteria 
will be made available to FDA by the sponsor-investigator via the annual report. The Investigator 
will utilize the FDA MedWatch Form (Appendix G) for the reporting of adverse events and follow up 
information to those events. The form can be found at the following URL: 
http://www.fda.gov/medwatch 
 
 
9.3 Auditing   
The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee will review this 
protocol on at least an annual basis.  
 
This study will undergo audit on at least a semi-annual basis by the UNMC Fred & Pamela Buffett 
Cancer Center Audit Committee.  

 
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For participating site(s) that are NCI Cancer Centers, the protocol specific finding of the 
participating site’s Audit Committee will be submitted to the UNMC Audit Committee for 
review on a schedule to be determined by the UNMC Audit Committee.  For participating site(s) 
that are not NCI Cancer Centers, the audit process will be established by the UNMC Audit 
Committee on a site-by-site basis. 
 
Adverse events will be reported to the UNMC Fred & Pamela Buffett Cancer Center Data and 
Safety Monitoring Committee (DSMC). The DSMC will also monitor the protocol on at least a 
quarterly basis and as per the DSMC request via the regularly scheduled DSMC review process. 
 
Detailed policy and procedures for this section may be reviewed at: http://www.unmc.edu/ccto.  
 
 
9.4 Monitoring 
9.3.1 Various methods will be implemented by the sponsor to exchange information with 
participating sites: 
 
• Site Initiation/Orientation 
• Regular Teleconferences including group wide progress within the agenda 
• Investigator meetings as feasible (remote or TBA, possibly in conjunction with larger 
meetings) 
• Email distributions/reports as needed 
 
9.4.2 Ongoing safety monitoring for all the subjects in this study: 
 
All participating sites are required to execute a data compliance policy agreement.   UNMC will 
monitor the data of participating sites in adherence to applicable research regulations, the 
protocol, and the policy agreement. De-identified source documents which support data entered 
must be provided to the sponsor by mail, fax, or electronic means for centralized compliance 
monitoring. 
 
 
 
10.0 STATISTICAL CONSIDERATIONS  
 
Study Design:  This is an open-label, single arm trial in subjects with histologically proven invasive breast 
cancer and a clinical tumor classification of T1cN0 or Stage II-III. 
 
10.1 Primary End Point 
The primary endpoint is pathological complete response (pCR) after the first six cycles of PC or PCH.  
Pathological complete response is determined form the surgical specimen and is defined as the absence 
of invasive carcinoma in both the breast and axilla at microscopic examination of the resection 
specimen, regardless of the presence of carcinoma in situ. 
 
10.2 Safety Endpoints 
Overall incidence and severity of toxicities. 

 
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10.3 Secondary End Points 
• Failure –free survival 
• Overall survival 
• Research blood specimens, to   identify   possible gene   expression   profile signatures   
from whole genome array analysis that correlate with clinical response/resistance to 
chemotherapy as measured by pathologic complete response rate (pCR) 
 
10.4 Sample Size – 125 subjects 
The pathological complete response rate is expected to be 13%.  Under the null hypothesis, the pCR 
rate is 13%.  It is important to protect against the possibility that neoadjuvant chemotherapy with and 
without Trastuzumab will produce a pCR rate greater than 13%.  A reduction in the pCR rate to 7% 
will be considered unacceptable.  With accrual of 112 subjects, the study will have 90% power at the 
0.20 level of significance (one-sided) to detect a decrease in the pCR rate to 7% using a one-sample 
Binomial test.  Assuming a 10% withdrawal rate, the sample size will be increased to 125.   
 
10.5 Planned Analyses for Primary Endpoint 
The primary endpoint is the pCR rate after the first six cycles of PC or PCH.  The pCR rates and 
exact one-sided 80% confidence intervals will be calculated.  The primary analysis is based on the 
full analysis set (all treated patients).  The pCR rates will be summarized overall and for HER+ and 
HER- subsets. 
 
10.6 Planned Analysis for Safety Endpoints 
Adverse events will be tallied for overall frequency (number and percentage of subjects), worst 
reported severity, and relationship to study drugs.  Serious adverse events will be summarized 
similarly.  Listings of deaths, SAEs and AEs leading to early termination of study treatment or 
premature withdrawal from study will also be provided.  Analyses will be reported overall and for 
HER+ and HER- subsets. 
 
10.7 Planned Analysis for Endpoints   
• Failure –free survival (FFS) will be defined as the date of administration of study drug to the 
date of first appearance of tumor lesions by imaging, or death.  Patients who are lost to 
follow-up will be censored at the date they were last known to be alive.   The analysis will be 
based on Kaplan-Meier estimates.  FFS will be summarized overall and for HER+ and HER- 
subsets. 
• Overall survival will be measured from the date of the date of administration of study drug to 
the date of death from any cause.  Patients who are lost to follow-up will be censored at the 
date they were last known to be alive.  The analysis will be based on Kaplan-Meier estimates.  
OAS will be summarized overall and for HER+ and HER- subsets. 
• This study will carry out whole genome exome sequencing at depth to uncover mutations in 
the protein coding region in the genome, followed by rapid testing of the functional 
significance of genes using a unique human in vitro culture model. These studies are aimed 
to identify and/or cross validate a unique set of classifier genes that will accurately predict a 
complete Pathologic Response (pCR) to treatment with dose dense CT in the neoadjuvant 
setting. We hypothesize that if the subset of patients with complete pathologic response could 

 
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be identified by a genomic signature then the remaining patients would best be suited to 
treatment with an alternative regimen, allowing development of a new stratification 
methodology to guide therapeutic interventions. 
 
Tests to be performed with HBM:  
Exome sequencing through Illumina Genome Analyzer GAIIx as 2x 76-bp paired-end 
reads, following Illumina sequencing protocol. 
 
DNA sequences will be aligned to the human reference genome sequences hg19 using Bowtie 
or MAQ. Potential single-nucleotide variants, deletions and insertions will be identified using 
BMA tool of MAQ or SAMtools. RNA will be used for validation for the mutated genes by 
using targeted, RT-PCR/Sanger sequencing methods. 
 
The data of this study will be used for a NIH application for a validation study. There are no 
plans for disclosure of the marker results since this is a pilot/ discovery study. 
 
Lymphocytes from the sample provides a source of DNA.  This DNA will be extracted by  the 
UNMC Dept. Genetics, Cell Biology & Anatomy laboratory personnel.  The specimen is sent 
to the genetics laboratory without any personal identifying information such as name or date 
of birth; it is identified by an ID number assigned for the study.  This ID number is linkable to 
personal identifying information and individual clinical findings.  Summaries of this 
information, stripped of personal identifiers, are provided to the genetics laboratory. 
 
The following clinical data will be collected: 
• Patient demographics (age, sex,) 
• Clinical and pathologic information 
• Staging and other prognostic indicators 
• Family history of cancers. Information about cancer family history is generally 
available in the patient’s medical records and will be recorded as First Degree 
(father, mother, brothers, sisters, children) or Second Degree (aunts, uncles, 
grandfathers, grandmothers, grandchildren, nieces, nephews, half-brothers, half-
sisters). 
 
The proposed study is conducted to identify potential mutated genes. The number of the 
identified mutated genes, the frequency of each gene being validated by RT-PCR/Sanger 
sequencing method, and the functions of these identified genes will be descriptively 
summarized. Up to 125 subjects/samples will be enrolled/collected.  
 
10.8 Interim Analysis 
pCR:  Two interim monitoring analyses for the pCR rate, using a one-sample Binomial test against a 
fixed null hypothesis of p=0.13,  will be conducted after 42, and 84 patients have completed after the 
first six cycles of PC or PCH.   The monitoring p-values to be used for the 2 interim analyses are 
p=.02644 and p=0.10871, with the final analyses at p=0.16592.  These results assume that 3 
sequential tests are made using the O'Brien-Fleming spending function truncated at 3 standard 

 
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deviations to determine the test boundaries.  These p-values define the following interim stopping 
rules:   
• After testing the regimen on 42 patients, the trial will be terminated if 1 or fewer achieve 
pCR. If 2 or more patients have achieved pCR, the trial will continue. 
• After testing the regimen on 84 patients, the trial will be terminated if 7 or fewer achieve 
pCR. If 8 or more patients have achieved pCR, the trial will continue. 
• At the final analysis, after testing the regimen on 125 patients, the regimen will be rejected if 
12 or fewer patients have achieved pCR. 
 
Neutropenic fever:  Two interim analyses will be performed after 42, and 84 patients have patients 
have been off of their last cycle of chemotherapy for 2 weeks.  It is important to protect against the 
possibility that neoadjuvant chemotherapy with and without Trastuzumab will produce a proportion 
with neutropenic fever greater than 11%.  The proportion with neutropenic fever will be tested 
against a fixed null hypothesis of 11% at the one-sided 0.10 level of significance using a one-sample 
Binomial test.  The monitoring p-values to be used for the 2 interim analyses are p=.00439 and 
p=0.04256, with the final analyses at p=0.08701.  These results assume that 3 sequential tests are 
made using the O'Brien-Fleming spending function truncated at 3 standard deviations to determine 
the test boundaries.  These p-values define the following interim stopping rules:   
• After testing the regimen on 42 patients, the trial will be terminated if 10 or more patients 
experience neutropenic fever. If 9 or fewer patients experience neutropenic fever, the trial 
will continue. 
• After testing the regimen on 84 patients, the trial will be terminated if 15 or more patients 
experience neutropenic fever. If 14 or fewer patients experience neutropenic fever, the trial 
will continue. 
• At the final analysis, after testing the regimen on 125 patients, the regimen will be rejected if 
19 or more patients experience neutropenic fever. 
 
Neurotoxicity:  Two interim analyses will be performed after 42, and 84 patients have patients have 
been off of their last cycle of chemotherapy for 2 weeks.  It is important to protect against the 
possibility that neoadjuvant chemotherapy with and without Trastuzumab will produce a proportion 
with > Grade III neurotoxicity greater than 11%.  The proportion with neurotoxicity will be tested 
against a fixed null hypothesis of 11% at the one-sided 0.10 level of significance using a one-sample 
Binomial test.  The monitoring p-values to be used for the 2 interim analyses are p=.00439 and 
p=0.04256, with the final analyses at p=0.08701.  These results assume that 3 sequential tests are 
made using the O'Brien-Fleming spending function truncated at 3 standard deviations to determine 
the test boundaries.  These p-values define the following interim stopping rules:   
• After testing the regimen on 42 patients, the trial will be terminated if 10 or more patients 
experience > Grade III neurotoxicity. If 9 or fewer patients experience neurotoxicity, the trial 
will continue. 
• After testing the regimen on 84 patients, the trial will be terminated if 15 or more patients 
experience > Grade III neurotoxicity. If 14 or fewer patients experience neurotoxicity, the 
trial will continue. 
• At the final analysis, after testing the regimen on 125 patients, the regimen will be rejected if 
19 or more patients experience > Grade III neurotoxicity. 
 

 
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Cardiotoxicity:  Two interim analyses will be performed after 42, and 84 patients have patients have 
been off of their last cycle of chemotherapy for 2 weeks.  It is important to protect against the 
possibility that neoadjuvant chemotherapy with and without Trastuzumab will produce a proportion 
with a 10% reduction in ejection fraction from baseline and/or > Grade III  cardiotoxicity greater 
than 10%.  The proportion with cardiotoxicity will be tested against a fixed null hypothesis of 10% 
at the one-sided 0.10 level of significance using a one-sample Binomial test.  The monitoring p-
values to be used for the 2 interim analyses are p=.00439 and p=0.04256, with the final analyses at 
p=0.08701.  These results assume that 3 sequential tests are made using the O'Brien-Fleming 
spending function truncated at 3 standard deviations to determine the test boundaries.  These p-
values define the following interim stopping rules:   
• After testing the regimen on 42 patients, the trial will be terminated if 10 or more patients 
experience a 10% reduction in ejection fraction from baseline and/or > Grade III  
cardiotoxicity. If 9 or fewer patients experience cardiotoxicity, the trial will continue. 
• After testing the regimen on 84 patients, the trial will be terminated if 14 or more patients 
experience a 10% reduction in ejection fraction from baseline and/or > Grade III 
cardiotoxicity. If 13 or fewer patients experience cardiotoxicity, the trial will continue. 
• At the final analysis, after testing the regimen on 125 patients, the regimen will be rejected if 
18 or more patients experience a 10% reduction in ejection fraction from baseline and/or > 
Grade III  cardiotoxicity. 
 
 
 
10.9 Definition of Analysis Sets 
The analyses will be based on the full analysis set, consisting of all patients who received the study 
medication. 
 
10.10 Missing Data 
Only non-missing data will be analyzed, missing clinical data will not be replaced.  
 
10.11 Stopping Rules for HBM 
Subjects will be informed verbally and in the consent they sign, that they may withdrawal from the 
original study and/or revoke the authorization to use and share their HBM and all associated 
information at any time by contacting the principal investigator of the original study in writing.  
 
Subjects may withdrawal from the original study and/or revoke the authorization to use and share 
their HBM and all associated information at any time. They will be informed in the consent of the 
original study that if they revoke this authorization, they may no longer participate in this research, 
that the use HBM and all associated information will be stopped immediately, and that the HBM and 
all associated information, which has already been collected, will be destroyed immediately.  
 
11.0 
RECORDS TO BE KEPT 
Information regarding the actual treatments, adverse effects, radiographic and laboratory information, and 
pathology are to be recorded on appropriate forms. See attached Data forms.  De-identified source 
documents which support data entered must be provided to the sponsor by mail, fax, or electronic means 

 
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for centralized compliance monitoring.  Serious adverse events, when noted, will be recorded on site via 
the standard serious adverse effects form. 
 
11.1 Quality assurance 
Complete records must be maintained on each patient treated on the protocol. These records should 
include primary documentation (e.g., lab, report slips, X-ray reports, scan reports, pathology 
reports, physician notes, etc.) which confirm that: 
 
- The patient met the eligibility criteria. 
- Signed informed consent was obtained prior to treatment. 
- Treatment was given according to protocol (dated notes about doses given & reasons for any 
dose modifications). 
- Toxicity was assessed according to protocol (laboratory report slips, etc.). 
- Response was assessed according to protocol (x-ray, scan, lab reports, dated notes on 
measurements & clinical assessment, as appropriate) 
 
11.2 Forte Electronic Data Capturing (EDC) System 
Data will be stored electronically for this study in the Forte EDC system contained on the Forte 
secure server. Data forms will not differ from the paper versions with the exception of an 
electronic format containing the UNMC Fred & Pamela Buffett Cancer Center and Forte logo.  
 
Forte EDC provides for remote data collection that meets FDA 21 CFR Part 11 requirements as 
well as HIPAA and other regulatory requirements designed to enhance data security and protect 
patient confidentiality. Authorized users log into Forte through a secure connection and must 
provide a valid username, password, and database ID. This data may be made available to the 
public at large. 
 
 
12.0 
PATIENT CONSENT 
12.1 Human Subjects Research Protection Training 
All personnel involved in this research project will have completed the OHRP-approved computer 
based training course on the Protection of Human Research Subjects. All clinical research included 
in this application will have approval by the institutional review board. 
12.2 Study Population 
Patients are from all socio-economic groups and will be entered into the study without bias with 
respect to gender or race. Attempts will be made to recruit minorities. No vulnerable subjects will 
be included in the study. 
12.3 Sources of Material 
Pathology material must be reviewed, and the diagnosis confirmed by University Nebraska 
Medical Center pathology department as outlined in the protocol.   
 
12.4 Recruitment and Informed Consent 
Patients with an initial diagnosis of locally advanced breast carcinoma will be available for 

 
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recruitment. These patients will be informed of the nature of this study, and will be asked to 
participate on a voluntary basis after informing them of the possible risks and benefits of the study. 
A number of public registries may be accessible to health care providers and prospective subjects 
as listed below. 
 
National Library of Medicine - http://clinicaltrials.gov (NCT01336933) 
National Cancer Institute - http://www.cancer.gov (NCI-2011-00254) 
12.5 Subject Competency 
Subjects will be eligible to participate in the study only if they are competent to give informed 
consent. A subject that the investigators judges to be incompetent will not be enrolled. 
12.6 Process of Informed Consent 
If the patient chooses to be a participant in this study, informed consent will be obtained by the 
investigators. The study and procedures involved including the risks will be explained in detail to 
each subject. It will be clearly explained to the subject that this is a research study and that 
participation is entirely on a voluntary basis. Subjects will be given the option to discuss the study 
with a family member, friend, counselor or, another physician. The participating investigators will 
be available to discuss the study with them. 
12.7 Subject/Representative Comprehension 
When the process of informed consent is completed, the subject will be asked to state in his/her 
own words, the purpose of the study, the procedures that will be carried out, potential risk, potential 
benefits to the subject, the alternatives and the right to withdraw from the study. If there is any 
indication that a given subject's comprehension is anything less than accurate, the points of 
confusion will be discussed and clarified. 
12.8 Information Purposely Withheld 
The results of the tests done solely for research purposes will not be disclosed to the subject. No 
other information will be purposely withheld from the subject. 
12.9 Potential Benefits of the Proposed Research to the Subjects 
It is anticipated that the use of neoadjuvant therapy in this patient population would result in greater 
tumor response and possibly prolong survival.   
12.10 Potential Benefits to Society 
Information obtained from this study may help other patients by contributing to the knowledge of 
the biology of breast cancer, and whether this treatment offers potential advantages over other 
treatments currently available.  
12.11 Potential Risks 
The use of cytototoxic chemotherapy, external beam radiotherapy, and surgical resection are 
associated with numerous potential risks. Combined chemotherapy/radiation is considered a valid 
treatment option for patients with breast cancer. Adjuvant therapy following surgical resection for 
breast cancer is considered a valid treatment option. It is believed the treatment option outlined in 

 
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the study will not pose significant additional risks compared to conventional treatment. 
12.12 Therapeutic Alternatives 
If patients choose not to participate in this study they may elect to receive standard therapy as per 
their primary oncologist, which may include surgery, chemotherapy, or radiation, or a combination 
of these approaches. The treatment recommendations may or may not be similar to treatment as 
described in this protocol (pre-operative chemotherapy, followed by external beam radiotherapy), 
followed by tumor resection and additional chemotherapy).  
12.13 Risk/Benefit Relationship 
Although there are inherent risks involved because of the use of chemotherapy, radiotherapy in 
combination with surgical resection, we anticipate that patients who receive the treatment phase 
of the protocol will do no worse than expected with standard therapy, and may experience an 
improved outcome. The risk is considered to be acceptable in the setting of cancer. 
12.14 Consent Form Documents 
No information will be purposely withheld from the patients.  The consent document used in this 
study will include the adult consent document. See attached consent form 
 
 
13.0 REFERENCES: 
 
1. 
Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, et al. SEER Cancer Statistics 
Review, 1975-2006, National Cancer Institute. Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2006/ 
2. 
Abena M. Brewster, Gabriel N. Hortobagyi; Residual risk of breast cancer recurrence 5 
years after adjuvant therapy. J Natl Cancer Inst2008;100:1179-1183.  
3.  Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, 
Taylor C, Wang YC, Bergh J, Di Leo A, Albain K, Swain S, Piccart M, Pritchard K   
Comparisons between different polychemotherapy regimens for early breast cancer: meta-
analyses of     long-term outcome among 100,000 women in 123 randomised trials.Early Breast 
Cancer Trialists' Collaborative Group (EBCTCG), Lancet. 2012 Feb 4;379(9814):432-44. Epub 
2011 Dec 5. 
4. Adjuvant chemotherapy for breast cancer. National Institutes of Health Consensus 
Development Conference Statement. Natl Inst Health Consens Dev Conf Consens Statement. 
1985;5(12):5 p.  
5. Sledge, G. et al;., Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of 
Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An 

 
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Intergroup Trial (E1193) Journal of Clinical Oncology, Vol 21, Issue 4 (February), 2003: 588-
592) 
6. Henderson, I. Berry D, et al., Improved outcomes disease free survival and overall survival 
from adding the addition of sequential paclitaxel but not from escalating Doxorubicin dose in an 
the escalation of doxorubicin dose level in adjuvant chemotherapy regimen for of patients with 
node- positive primary breast cancer. JIn Pro Am Soc Clin Oncol 2003 Mar 15;21(6):976-83. 
1998. 
7. Liu SV, Melstrom L, Yao K et al. Neoadjuvant therapy for breast cancer. J Surg Oncol. 
2010;15:283-291  
 8. Shenkier T, Weir L, Levine, M et al. Clinical Practice guidelines for the care and treatment of 
breast cancer: 15. Treatment for women with Stage III or locally advanced breast cancer. CMAJ. 
2004;170:983-994. 
9. Buzdar, A.U et al., Prospective evaluation of paclitaxel vs combination chemotherapy with 
fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with 
operable breast cancer. J Clin Oncol 21:141, 2002 (abstr 141), 1999. 17(11): p. 3412-7. 
10. Jones SE; Savin MA; Holmes FA; Phase III trial comparing doxorubicin plus 
cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable 
breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. 
11. Citron ML; Berry DA; Cirrincione C et al; Randomized trial of dose-dense versus 
conventionally scheduled and sequential versus concurrent combination chemotherapy as 
postoperative adjuvant treatment of node-positive primary breast cancer: first report of 
Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003 Apr 
15;21(8):1431-9. Epub 2003 Feb 13  
12. Martine J. Piccart-Gebhart Trastuzumab after Adjuvant Chemotherapy in HER2-Positive 
Breast Cancer N Engl J Med 2005;353:1659-72  
13. Romd, EH, et. al., Trastuzumab plus adjuvant chemotherapy for operable Her2-positive 
breast cancer. NEJM 353:16,1673-1684, 2005.) 
14. Slamon, D, Eiermann, W, Robert, N, et al. BCIRG 006: 2nd interim analysis phase III 
randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) 
with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with 
docetaxel, carboplatin and trastuzumab (TCH) in HER2neu positive early breast cancer patients 

 
Page 47  
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(abstract). Data presented at the 29th annual San Antonio Breast Cancer Symposium, San 
Antonio, TX, December 15th, 2006. 
15. Slamon, D. et. al., Adjuvant trastuzumab in Her2 positive Breast Cancer. NEJM 365:1273-
83, 2011. 
16. Smith IC, Heys SD, Hutcheon AW, et al. Neoadjuvant chemotherapy in breast cancer: 
significantly enhanced response with docetaxel. J Clin Oncol. 2002;20(6):1456-1466. 
 
17. Kuerer HM, Singletary SE, Buzdar AU, et al. Surgical conservation planning after 
neoadjuvant chemotherapy for stage II and operable stage III breast carcinoma. Am J Surg. 
2001;182(6):601-608.  
18. Cohen LF, Breslin TM, Kuerer HM, Ross MI, Hunt KK, Sahin AA. Identification and 
evaluation of  axillary sentinel lymph nodes in patients with breast carcinoma treated with 
neoadjuvant chemotherapy. Am J Surg Pathol. 2000;24(9):1266-1272. 
19. Kuerer HM, Sahin A, Hunt KK, et al. Incidence and Impact of documented eradication of 
breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant 
chemotherapy. Ann Surg Oncol. 1999;230(1):72-78.  
20. Cance WG, Carey LA, Calvo BF, et al. Long-term outcome of neoadjuvant therapy for 
locally advanced breast carcinoma: effective clinical downstaging allows breast preservation and 
predicts outstanding local control and survival. Ann Surg. 2002;236(3):295-302; discussion 302-
293.  
22. Bear HD, Anderson S, Brown A, et. al. The effect on tumor response of adding sequential 
preoperative docetaxel to preopertive doxorubicin and cyclophosphamide: Preliminary results 
from national surgical adjuvant breast and bowel project protocol B-27. J Clin Oncol. 2003;21:1-
10.  
23. Merajver SD, Weber BL, Cody R, et al. Breast conservation and prolonged chemotherapy for 
locally advanced breast cancer: the University of Michigan experience. J Clin Oncol. 
1997;15(8):2873-2881.  
24. Chung MH, Ye W, Giuliano AE. Role for sentinel lymph node dissection in the management 
of large (> or = 5 cm) invasive breast cancer. Ann Surg Oncol. 2001;8(9):688-692. 
25. Bedrosian I, Reynolds C, Mick R, et al. Accuracy of sentinel lymph node biopsy in patients 
with large primary breast tumors. Cancer. 2000;88(11):2540-2545. 

 
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IRB#264-12:      V3.2 Dated 11-30-21 
 
26. Schrenk P, Hochreiner G, Fridrik M, Wayand W. Sentinel node biopsy performed before 
preoperative  chemotherapy for axillary lymph node staging in breast cancer. Breast J. 
2003;9(4):282-287.  
 27. Cox CE, Cox JM, White LB et al. Sentinel node biopsy before neoadjuvant chemotherapy 
for determining axillary status and treatment prognosis in locally advanced breast cancer. Ann 
Surg Oncol.  2006;13(4):483-90.  
 28. Gogas H, Pectasides D, Kostopoulos I et al. Paclitaxel and carboplatin as neoadjuvant 
chemotherapy  in patients with locally advanced breast cancer: A Phase II Trial of the Hellenic 
Cooperative Oncology Group. Clin Breast Cancer. 2010;10:230-237. 
29. Glück S, McKenna EF Jr, Royce M et al. XeNA: capecitabine plus docetaxel, with or 
without trastuzumab, as preoperative therapy for early breast cancer. Int J Med Sci. 
2008;5(6):341-346.  
30. van 't Veer LJ, Dai H, van de Vijver MJ et al. Gene expression profiling predicts clinical 
outcome of  breast cancer. Nature. 2002;415(6871):530-536. 
 31. van de Vijver MJ, He YD, van't Veer LJ et al. A gene-expression signature as a predictor of 
survival in breast cancer. N Engl J Med. 2002;347:1999-2009. 
 
 
 

 
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14.0 DATA FORMS  Attached 
 
 
 
 
 
 
 
APPENDIX A 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX B 
NYHA Classification 
Excerpted from Oxford Textbook of Medicine. Vol 2, p.2228. Oxford Press.1997. 
Class 
Description 
I 
Subjects with cardiac disease but without resulting 
limitations of physical activity.  Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
II 
Subjects with cardiac disease resulting in slight 
limitation of physical activity.  They are comfortable 
at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
III 
Subjects with cardiac disease resulting in marked 
limitation of physical activity.  They are comfortable 
at rest.  Less than ordinary physical activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Subjects with cardiac disease resulting in inability to 
carry on physical activity without discomfort.  
Symptoms of cardiac insufficiency or of the anginal 
syndrome may be present event at rest.  If any 
physical activity is undertaken, discomfort is 
increased. 
 
 
 
 
 
 
 

 
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APPENDIX C 
Eligibility Criteria Checklist CRF 
Date Completed: 
(dy/mth/yr) 
 
 
Protocol #:  
Institution: 
Patient ID: 
 
Checklist #:2.3 
 
 
Effective Date (dy/mth/yr) 
 
 
 
Waiver #: 
Eligibility Checklist                                
1  
Women with histologically proven invasive breast cancer without distant metastases 
A clinical tumor classification of tumor size must be at least 1 cm with or without 
clinical pathologic evidence of positive nodes.  
2  
Age: Patients must be 19 years of age or older. (This is the age of consent in Nebraska. 
Breast cancer does not occur in the pediatric age group.) 
3  
ECOG performance status of 0 or 1. (Appendix A) 
4  
At least one lesion that can be accurately measured in two dimensions utilizing 
mammogram, ultrasound, or MRI images to define specific size and validate complete 
clinical and pathologic response. 
 
5 
Patients who received radiation therapy > 5 years ago for malignancies other than 
breast cancer and whose radiation therapy field is not overlapping with the 20% isodose 
line of current radiation field are eligible, provided that radiation therapy was 
completed > 5 years ago and that there is no evidence of the second malignancy at the 
time of study entry. 
6 
Patients must have adequate laboratory parameters within 30 days prior to enrollment 
defined as:  
• 
Absolute neutrophil count greater than or equal to 1,500/mcl 
• 
Platelet count equal to or greater than 150,000/mcl 
• 
Alkaline phosphatase equal or less than 1.5 times the ULN 
• 
Total bilirubin equal to or less than 1.5 times the ULN 
• 
AST and ALT no greater than  1.5 times the ULN 
• 
Creatinine less than 1.5 times the ULN  
7 
All included patients must have normal cardiac function as defined by an ejection 
fraction of ≥50% and no decrease in wall motion by echocardiogram. 
Yes   No  N/A 
 
[   ]     [   ]    [   ]1. 
 
 
 
[   ]     [   ]    [   ]2. 
 
[   ]     [   ]    [   ]3. 
 
 
 
 
[   ]     [   ]    [   ]4. 
 
 
 
 
 
 
 
 
[   ]     [   ]    [   ]5. 
 
 
 
[   ]     [   ]    [   ]6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[   ]     [   ]    [   ]7. 
 

 
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8 
The patient must be aware of the neoplastic nature of his/her disease and willingly 
provide written, informed consent after being informed of the procedure to be followed, 
the experimental nature of the therapy, alternatives, potential benefits, side-effects, 
risks, and discomforts. 
9 
Women of reproductive potential must be non-pregnant and non-nursing and must 
agree to employ an effective barrier method of birth control throughout the study and 
for up to 6 months following treatment. 
10 
Women of child-bearing potential must have a negative pregnancy test within 7 days 
of initiating study. (No childbearing potential is defined as age 55 years or older and 
no menses for two years or any age with surgical removal of the uterus and/or both 
ovaries).  
All of the above must be yes to be eligible.  
 
1 Any patient with inflammatory breast cancer or Stage IV or confirmed metastatic disease. 
2 Patients who have had any prior chemotherapy, or endocrine therapy for the treatment of 
breast cancer or any other cancer. 
3 Patients who cannot undergo surgery.  
4 Patients with a known or documented anaphylactic reaction or allergy to any of 
chemotherapy agents used in this protocol, or to antiemetic’s appropriate for administration 
in conjunction with protocol-directed therapy. 
5 Uncontrolled inter-current illness including, but not limited to ongoing or active infection 
requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina 
pectoris, or serious, uncontrolled cardiac arrhythmia, that might jeopardize the ability of 
the patient to receive the therapy program outlined in this protocol with reasonable safety. 
6 Patients with preexisting Grade II peripheral neuropathy. 
7 Pregnant and nursing women are excluded from this study because the chemotherapy 
agents and radiation therapy all have the potential for teratogenic or abortifacient effects. 
8 Patients with prior malignancy will be excluded except for adequately treated basal cell or 
squamous cell skin cancer, adequately treated noninvasive carcinomas. 
9 Inability to cooperate with treatment protocol. 
 
 
 
[   ]     [   ]    [   ]8. 
 
 
 
 
 
 
[   ]     [   ]    [   ]9. 
 
 
 
 
[   ]     [   ]    [   ]10. 
 
 
 
 
 
 
[   ]     [   ]    [   ]11. 
 
 
 
 
[   ]     [   ]    [   ]1.  
 
 
[   ]     [   ]    [   ]2. 
 
[   ]     [   ]    [   ]3. 
 
 
 
 
[   ]     [   ]    [   ]4. 
 
 
 
 
 
 
 
 
[   ]     [   ]    [   ]5. 
 
[   ]     [   ]    [   ]6. 
 
 
 
[   ]     [   ]    [   ]7. 
 
 

 
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10 Patients with known HIV infection, infectious hepatitis, type A, B or C, active hepatitis, or 
hepatic insufficiency. 
11 Patients may not be receiving or have received any other investigational agents during/or 
within 1 month prior. 
12 Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form. 
13 Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure uncontrolled angina, severe uncontrolled 
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities. (Appendix B)  Prior to study entry, any ECG 
abnormality at screening has to be documented by the investigator as not medically 
relevant. 
All of the above must be no to be eligible.  
NOTE: All questions regarding eligibility for potential subjects should be directed to 
the UNMC Coordinator at 402-559-5582 or 402-559-5286.   
 
 
 
[   ]     [   ]    [   ]8. 
 
[   ]     [   ]    [   ]9. 
 
 
 
[   ]     [   ]    [   ]10. 
 
 
[   ]     [   ]    [   ]11. 
 
 
 
[   ]     [   ]    [   ]12. 
 
 
 
 
 
 
 
 
 
 
[   ]     [   ]    [   ]13. 
 
Eligibility:      [    ]  Patient satisfies all criteria.  
                     [    ]  Patient not formally eligible, but admitted to study because (state reason);  
 
 
             __________________________________________________________________________________________________ 
 
 
   
             __________________________________________________________________________________________________ 
 
Patient Initials:  ______________MR #______________DOB ______________ 
   
ELIGIBILITY reviewed and confirmed  
Site Investigator Signature _______________________Date_____________        
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX D 
HBM Sample Processing and Shipping (for research purposes only) 
 
Sample Collection: Source and human biologic material (HBM) to be used: We will use two 10 ml EDTA 
(lavender top tubes) and one- 10ml red top tube blood sample from the patient for DNA sequencing.  
 
Tests performed with HBM:  
DNA sequencing through Illumina Genome Analyzer GAIIx as 2x 76-bp paired-end reads, following 
Illumina sequencing protocol. 
 
DNA sequences of high quality will be aligned to the human reference genome sequences (hg19). 
Potential single-nucleotide variants, deletions and insertions will be identified. 
 
Facility 
Sample 
Contact Person(s) and 
Shipping Address 
Date and Time 
Points 
Laboratory of San Ming 
Wang 
UNMC Dept. of Genetics, 
Cell Biology and Anatomy 
Blood: (30 ml total) 
two-10ml EDTA 
(lavender top) and 
one- 10ml red top 
blood collection 
deliver or ship same 
day at room 
temperature 
 
David L. Kelly PhD  
Tel: (402) 559-9157 
Cell: (402) 699-1132 
Fax: (402) 559-4651 
dkelly@unmc.edu 
 
Amy Wells 
Tel: (402) 559-6015 
awells@unmc.edu  
 
Shipping Address: 
University of Nebraska 
Medical Center 
601 S. Saddle Creek Rd. 
Amy Wells, MS,  
Fred & Pamela Buffett 
Cancer Center, Room # 
BCC 5.12.429 
Omaha, Nebraska  68106 
Baseline date: 
___/___/____ 
Pre-Chemo 
 
 
Blood: (30 ml total) 
two-10ml EDTA 
(lavender top) and 
one- 10ml red top 
blood collection 
deliver or ship same 
day at room 
temperature 
Same as above 
Sample Date:  
___/___/____ 
Post-Chemo/ 
Pre-Surgery 
 
Blood: (30 ml total) 
two-10ml EDTA 
(lavender top) and 
one- 10ml red top 
blood collection 
deliver or ship same 
day at room 
temperature 
Same as above. 
 
Sample Date:  
___/___/____ 
End of treatment Post-
Chemo, Radiation 
 

 
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APPENDIX E 
 
 
Neuropathy Assessment Worksheet 
 
 
 
(1 page See Attached) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX F 
 
NCI Common Toxicity Criteria Version 4.0 (CTCAE) 
 
 
 
 
 
Active Date: May 29, 2009 
 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event reporting.  A copy of the NCI 
CTC Version 4.0 can be downloaded from the CTEP homepage: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).   
All appropriate treatment areas have access to a copy of the CTC Version 4.0.  
 
Minor editorial updates have been made to CTCAE v4.0, which are represented in v4.03.  These edits do 
not change the meaning of v4.0 content and all previous versions (CTCAE v4.0, v4.01, v4.02) are still 
valid and referred to as CTCAE v4.0.  V4.03 includes clarifications for a select few grading scales and 
adverse event term definitions.  Most of the revisions are associated with grading scales that include a 
quantitative component.  A list of changes is located at http://evs.nci.nih.gov/ftp1/CTCAE/About.html.  
 
An updated version (4.03) is now in use as of June 14, 2010. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX G 
 
 
 
 
 
 
 
 
 
 
 
 
FDA MEDWATCH form 
 
Available on-line at http://www.fda.gov/medwatch/SAFETY/3500.pdf 
 
 
 
 
 
NOTE: Attached NCCN guidelines. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf