A Phase II Study of Adjuvant Therapy Using a Regimen of Cyclophosphamide, Paclitaxel With Trastuzumab in Stage I-II HER2/Neu Positive Breast Cancer Patients
Phase: PHASE2
Conditions: HER2 Positive Breast Carcinoma, Stage I Breast Cancer AJCC v7, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7
Sponsor: University of Nebraska

Clinical Trials Office | Oncology and Hematology 
                                                                                                                                                        
STUDY PROTOCOL  
 
Official Study Title: A Phase II Study of Adjuvant Therapy Using a Regimen of Cyclophosphamide, 
Paclitaxel with Trastuzumab in Stage I-II HER2/neu Positive Breast Cancer Patients 
 
ClinicalTrails.gov Identifier (NCT number): 
 NCT02654119 
 
Protocol ID: 
0318-15-FB 
 
Sponsor/Institution: 
University of Nebraska Medical Center 
 
Document Version Type : 
Study Protocol Version 5.2 
 
Document Date : 03-02-2023 
 

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IRB#318-15 
A Phase II Study of Adjuvant Therapy Using a Regimen of Cyclophosphamide, Paclitaxel 
with Trastuzumab in Stage I-II HER2/neu Positive Breast Cancer Patients 
 
*Principal Investigator:  
Amulya Yellala, MBBS  
University of Nebraska Medical Center 
Phone: 402-559-5388 
Fax: 402-559-8895 
Email: amulya.yellala@unmc.edu 
 
Secondary Investigators: 
Elizabeth Reed, MD 402-559-5388  ereed@unmc.edu  
Kenneth Cowan, MD, PhD 
 
Participating Investigators: 
Rabih C Fahed, MD - Faith Regional Carson Cancer Center, Norfolk 
Irina E. Popa, MD - Faith Regional Carson Cancer Center, Norfolk 
 
 
 
Participating Sites:  
UNMC/Nebraska Medicine/Village Pointe CC/Bellevue Medical Center 
Faith Regional Carson Cancer Center, Norfolk 
 
Statistician: 
 
 
 
 
 
 
Jane Meza, PhD 
 
 
 
 
 
984375 Nebraska Medical Center, 
 
 
 
Omaha, NE 68198-4375 
 
 
 
 
Phone: 402-559-8407   
 
 
 
 
Fax: 402-559-7259  
 
 
 
 
 
Email: Jmeza@unmc.edu 
 
 
 
  
 
 
 
IRB# 318-15  Version 1.0 dated 04-22-2015 
Version 2.0 dated: 10-15-2015 
VERSION 3.0 Dated: 3-8-2016  
 
 
Version 4.0 dated: 01-03-2018 
 
 
Version 5.0 dated: 08-03-2018 
 
 
Version 5.1 dated: 11-06-2019 
 
 
Version 5.2 dated: 03-02-2023 
 
 
 
 
 
 
 
 
UNMC Investigator Initiated Project (No Sponsor) IND EXEMPT Per IND regulations [21 CFR 312.2(b)] this study meets all of the requirements for exemption from 
the IND regulations and, therefore, an IND is not required to conduct the investigation. In accordance with 21 CFR 312.2(b)(4) of the regulations, the FDA will not 
accept the application 
This protocol is being conducted as a translational clinical research project as part of the UNMC Fred & Pamela Buffett (NCI) Cancer Center Support Grant # P30 
CA036727. 

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Index 
Abstract/Schema 
 
 
 
 
 
 
Page  3 
Section  1.0 
Objectives 
 
 
 
 
 
Page  5 
Section  2.0 
Background   
 
 
 
 
Page  5 
Section  3.0 
Eligibility Criteria 
 
 
 
 
Page 12 
Section  4.0 
Registration Procedures 
 
 
 
Page 14 
Section  5.0 
Research Design 
 
 
 
 
Page 16 
Section  6.0 
Measurement of Effect 
 
 
 
Page 23 
Section  7.0  Study Parameters 
 
 
 
 
Page 25  
Section  8.0 
Drug Formulation and Procurement  
 
Page 26 
Section  9.0 
Toxicity Reporting Guidelines 
 
 
Page 31 
Section 10.0 Statistical Considerations 
 
 
 
Page 37 
Section 11.0 Records to Be Kept 
 
 
 
 
Page 40 
Section 12.0 Patient Consent Form Statement 
 
 
Page 40 
Section 13.0  References 
 
 
 
 
 
Page 42 
Section 14.0  Data Forms 
 
 
 
 
 
Page 45 
Appendix A (NYHA Criteria) 
 
 
 
 
Page 46 
Appendix B 
(Eligibility Checklist)  
 
 
 
Page 47 
Appendix C (Blood Sample Processing and Shipping)  
 
Page 49 
Appendix D 
(MedWatch)   
 
 
 
 
Page 50  
 
 
 
 
 
 

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IRB#318-15 
 
A Phase II Study of Adjuvant Therapy Using a Regimen of Cyclophosphamide, Paclitaxel with 
Trastuzumab in Stage I-II HER2/neu Positive Breast Cancer Patients 
 
Abstract: This is a Phase II study of adjuvant therapy using a dose-dense regimen of cyclophosphamide and 
paclitaxel with trastuzumab in patients with newly diagnosed stage I-II HER2/neu positive breast cancer. This 
will be a non-randomized study; all subjects will receive the combination chemotherapy.  
Objectives:  
1. To determine the toxicities and ability to complete the planned treatment of a dose-dense regimen of 
cyclophosphamide and paclitaxel with trastuzumab in subjects with newly diagnosed stage I-II HER2/neu 
positive breast cancer. 
2. To estimate recurrence free survival of a dose-dense regimen of cyclophosphamide and paclitaxel with 
trastuzumab in subjects with newly diagnosed stage I-II HER2/neu positive breast cancer.   
Eligibility: Histologically confirmed newly diagnosed Stage I-II HER2/neu positive breast cancer, women with 
no evidence of metastatic cancer and normal cardiac function as defined by an ejection fraction of >50% by 
echocardiogram. 
Intervention:  
Adjuvant (post surgery) treatment naïve subjects with newly diagnosed stage I-II HER2/neu positive breast 
cancer will receive therapy with growth factor support as follows: 
Systemic Therapy:  
• Cyclophosphamide 600mg/m2 in normal saline IV over 1 hour Day 1 cycled every 14 days (2 weeks) 
for 6 cycles 
• Paclitaxel 175mg/m2 in normal saline IV over 3 hours Day 1 cycled every 14 days (2 weeks) for 6 
cycles 
• All cycles are with pegfilgrastim support, 1-6 mg SQ on day 1 after PC dose adjust as medically 
indicated or hold for ANC >12,000 or bone pain (SOC).  (Pegfilgrastim support is optional 
following cycle 6) 
• Loading dose trastuzumab 6mg/kg in normal saline IV over 30 to 90 minutes per institutional 
protocol Day 1, Cycle 1. 
THEN  
• Subsequent cycles (Cycles 2-5) trastuzumab 4mg/kg in normal saline IV over 30 to 60 minutes per 
institutional protocol Day 1 every 14 days (2 weeks), Cycles 2-5.  
THEN  
• Maintenance therapy beginning with Cycle 6 trastuzumab 6mg/kg in normal saline IV over 30 to 60 
minutes per institutional protocol Day 1 every 21 days (3 weeks) to complete a total of 52 weeks, 
Cycles 6- 19. 
Radiation Therapy: 
Radiation will be given by the radiation oncologist and timing determined by the radiation and medical 
oncologist as per standard NCCN guidelines, either concurrent with chemotherapy or following chemotherapy 
unless the patient has received radiation to the area in the past.  
Hormonal Therapy: 
Subjects with estrogen/progesterone receptor positive tumors will receive hormonal therapy following adjuvant 
chemotherapy, and hormonal therapy will be determined by the medical oncologist as per standard NCCN 
guidelines. 
Evaluation: Subjects will have standard hematological and cardiac evaluations. Subjects will be clinically 
evaluated by an oncologist for toxicities every 2 weeks during chemotherapy,  then at least every 12 weeks after 
completing chemotherapy (until they complete 52 weeks of trastuzumab), and then every 3 months for 2 years. 
Subjects will have a repeat echocardiogram every 12 weeks until completion of trastuzumab to monitor their 
cardiac function.  

 
 
Clinical Trials Office | Oncology and Hematology 
                                                                                                                                                        
ADJUVANT SCHEMA  
(HER2/neu Positive Breast Cancer) 
Post-SURGERY (SOC)          
    
                                          C1       C2       C3       C4        C5        C6   Clinical Endpoint    RADIATION -**Maintenance Trastuzumab - End of Treatment   
Stage I-II HER2/neu +                                                                                   Serum Sample (Res) 
     Serum Sample (Res)    *PCH *PCH  *PCH  *PCH  *PCH  *PCH           
 
 
 
                                                     Serum Sample (Res) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F/U (SOC) 
*PCH  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 1-6 mg SQ on day 1 after PC dose adjust as medically indicated or hold for ANC >12,000 or bone pain (SOC).  
(Pegfilgrastim support is optional following cycle 6) 
Herceptin® (Trastuzumab) loading dose 6mg/kg Day 1, Cycle 1THEN subsequent dosing 4mg/kg Day 1 Q2wks Cycles 2-5, (SOC)  
Research Serum Samples collected at baseline Clinical Endpoint and End of treatment (Res) 
**Maintenance Herceptin® 6mg/kg Day 1 Q21 Days for a total of 52 weeks Cycles 6-19. (SOC) 
RADIATION Clinical Decision per standard NCCN guidelines, following surgery and chemotherapy. (SOC) 
SUBJECTS WITH ER/PR + TUMOR = HORMONAL THERAPY Subjects with estrogen/progesterone receptor positive tumors will also receive 
Hormonal Therapy to be determined by the medical oncologist as per standard NCCN guidelines. (SOC) 

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End of Treatment Follow-up (F/U)  
Echocardiogram at completion of CT and then every 12 weeks until completion of trastuzumab. 
Subjects will be monitored Q3 months until 2 years from date of treatment. (SOC) 

 
Clinical Trials Office | Oncology and Hematology 
                                                                                                                                                        
1.0 Objective(s)  
 
1. To determine the toxicities and ability to complete the planned treatment of a dose-dense 
regimen of cyclophosphamide and paclitaxel with trastuzumab in subjects with newly diagnosed 
stage I-II HER2/neu positive breast cancer. 
 
2. To estimate recurrence free survival of a dose-dense regimen of cyclophosphamide and 
paclitaxel with trastuzumab in subjects with newly diagnosed stage I-II HER2/neu positive breast 
cancer.   
 
2.0 Background  
 
Breast cancer is the most common cancer diagnosed in American women and the second most 
common cause of death. It is estimated that 232,670 women will be diagnosed with breast cancer 
and 40,000 would die of the disease in 20141. The mainstay of treatment for early breast cancer 
(EBC) is surgical removal of the tumor followed by adjuvant systemic treatment (chemotherapy 
+/- hormonal therapy) and/or radiation therapy to reduce the recurrence. SEER Summary Stage 
2000 shows the stage of distribution at diagnosis for localized breast cancers (those diagnosed 
while the cancer is still confined to the primary site) is 60% (Stage I); while 33% are diagnosed 
after the cancer has spread to regional lymph nodes or directly beyond the primary site (Stage II). 
The overall survival rates are 98.3% for localized stage I and 83.5% for regional stage II 
disease2. The relative overall survival, as well as, the risk of recurrence is improved after 
adjuvant therapy. It is estimated that the risk of recurrence for patients after adjuvant therapy 
with stage I breast cancer is 5% and patients with stage II disease is 11%3.  
 
Evolution of adjuvant chemotherapy in EBC: 
 
Until 1998, the regimen of cyclophosphamide, methotrexate and 5-fluorouracil (5-FU) (CMF) 
remained the standard adjuvant therapy of choice for women with node positive EBC4. CMF is a 
six month long regimen in which chemotherapy is administered intravenously twice every four 
weeks along with a daily oral chemotherapy, two of every four weeks. A newer and simpler 
regimen, adriamycin and cyclophosphamide (AC), given every three weeks for four cycles (total 
duration-12 weeks) has been compared to the CMF regimen with the goal to shorten the 
treatment duration. Two National Surgical Adjuvant Breast and Bowel Project (NSABP) trials 
(NSABP B15 in node positive and B23 in node negative patients) did demonstrate that four 
cycles of AC are equivalent to six cycles of CMF in the disease free and overall survival of 
EBC5.  
 
Later on, a meta-analysis reported on by the Early Breast Cancer Trialists Collaborative Group 
(EBCTCG) showed that the doublet regimen of AC was also associated with a small but 

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significant decrease in the recurrence and mortality rates of  breast cancer when compared to the 
triplet CMF regimen6. Based on this observation, the National Institutes of Health Consensus 
Development Conference on Adjuvant Therapy for Breast Cancer recommended anthracycline-
based regimens in the adjuvant treatment of breast cancer.  
 
With the evolution of taxanes in 1998 and studies demonstrating or documenting taxanes 
excellent activity in the treatment of metastatic breast cancer (MBC)7, the addition of a taxane to 
the conventional adjuvant therapy regimen for node positive and high risk node negative EBC 
was studied.  The results of these trials showed an improvement of the recurrence free and 
overall survival rates of EBC’s. A systematic review of taxane versus non-taxane containing 
chemotherapy regimens for adjuvant and neoadjuvant (before surgery) treatment of operable 
breast cancer was published by the EBCTCG in 20048. The review included data on more than 
12,000 women and strongly supported the addition of four cycles of the taxane paclitaxel to the 
standard four cycles of the AC regimen (PAC), or the substitution of the six cycle regimen of 5-
FU, adriamycin and cyclophosphamide (FAC) with a six cycle regimen of the taxane docetaxel 
in combination with adriamycin and cyclophosphamide (TAC). 
 
The largest study in the 2004 EBCTCG systematic review was the CALGB 9344 trial, which 
showed that the sequential addition of 4 cycles of every 3 weeks paclitaxel to the  4 cycles of 
every 3 week AC in the adjuvant setting is beneficial in achieving better disease free and overall 
survival in node positive breast cancer9.  
 
Single agent paclitaxel has been compared to FAC in the neo adjuvant setting in a small study by 
Buzdar etal. In this study, 174 patients were randomized to receive, pre-operatively, either 4 
cycles of FAC or paclitaxel. In this setting, paclitaxel was as effective as FAC, as shown in this 
table 10. 
FAC vs paclitaxel as neo adjuvant therapy in pts 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 
 
Since the FAC regimen has been considered an acceptable standard adjuvant chemotherapy 
regimen, it raised the question of the possibility of the equivalent efficacy of the single agent 
paclitaxel in the adjuvant setting. This hypothesis led to the inception of an Alliance trial, 
CALGB 40101in the adjuvant setting .  The objective was to evaluate four cycles of single agent 
paclitaxel given every two weeks compared to four cycles of AC given every two weeks with 
growth factor support. The trial comparison did not show non inferiority (means equivalence) of 
the single agent paclitaxel to AC however, paclitaxel was shown to be less toxic than AC11. 
 
Paclitaxel alone has been compared with the CMF plus prednisone (CMFP) regimen as a first-
line therapy for MBC and was found to have similar response rates and also significantly 

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improved overall survival as shown below12. Paclitaxel alone has also been compared with single 
agent adriamycin in MBC and was found to have equivalent efficacy and disease free survival7. 
 
Cardiotoxicity of anthracyclines: 
 
Significant cardiac toxicity has been observed with anthracyclines when used in the adjuvant 
setting for breast cancer patients. This observation rendered the evaluation of non-anthracycline 
based regimen particularly interesting.  
 
In order to get the same efficacy but less cardio toxicity, docetaxel was combined with 
cyclophosphamide (TC regimen) and was compared with standard regimen AC. Stage I – III 
breast cancer patients were randomized to receive TC every 3 weeks for 4 cycles vs AC every 3 
weeks for 4 cycles. At 5 years TC had comparable efficacy with slightly better disease free 
survival and less cardiac toxicity13. In an update of the above trial, at a median follow up of 
7years,TC was shown to be significantly better than AC in terms of disease free survival (81% 
Vs 75%) and overall survival (87% Vs 82%)14. 
 
Docetaxel has been compared to paclitaxel in a large randomized trial (ECOG 1199) involving 
4,950 women with EBC. This study consisted of 4 arms that compared weekly and every 3week 
docetaxel vs weekly and every 3 week paclitaxel in a 2 × 2 factorial design. These regimens were 
given sequentially after standard AC (AC every 3 weeks).  Similar efficacy and disease free 
survival was noticed when paclitaxel was given weekly and docetaxel was given every 3 weeks 
compared to the other arms15. 
Considering the high level of anti-neoplastic activity of paclitaxel in metastatic and locally 
advanced breast cancer (given pre-operatively), it is suggested that there is a high likelihood of 
the paclitaxel and cyclophosphamide regimen (PC) being at least as effective as other standard 
adjuvant regimens for breast cancer. We hypothesize that this regimen would have a comparable 

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efficacy and adverse event profile to standard adjuvant adriamycin based regimens. The reason 
to choose paclitaxel instead of docetaxel in our study will be explained later in this discussion.  
Dose dense hypothesis & reasons to choose paclitaxel instead of docetaxel: 
Based on tumor growth, shortening the interval between treatment cycles from every 3 weeks to 
every 2 weeks(in a dose-dense fashion) improved the outcome for patients with node-positive 
EBC16.  Dose-dense regimens limit the opportunity of re-growth of cancer cells between the 
chemotherapy cycles and improve overall and disease free survival.  
 
Using anthracyclines and taxanes in a dose dense schedule has been shown to be more beneficial 
than the conventional every 3 week chemotherapy. The CALGB 9741 trial tested both sequential 
versus concurrent chemotherapy administration and a conventional dosing interval versus a dose-
dense interval. In this trial, 2,005 women were randomly assigned to one of four arms in a 2 × 2 
factorial design. 
• Arm 1: Ax4→Tx4→Cx4 q 3 weeks (conventional interval, sequential administration) 
• Arm 2: Ax4→Tx4→Cx4 q 2 weeks with filgrastim (dose-dense interval, sequential 
administration) 
• Arm 3: ACx4→Tx4 q 3 weeks (conventional interval, concurrent administration) 
• Arm 4: ACx4→Tx4 q 2 weeks with filgrastim (dose-dense interval, sequential 
administration). 
A = adriamycin 60mg/m2, T = paclitaxel 175 mg/m2 over 3 hours, and C = cyclophosphamide 
600mg/m2. Tamoxifen was given after chemotherapy for hormone receptor positive (about 70 %) 
patients. 
 
The dose-dense treatment improved both disease free and overall survival. There was no 
difference between concurrent and sequential scheduling of taxanes. Surprisingly there was less 
frequent severe neutropenia in the patients receiving dose-dense regimens. Grade 3 and 4 
neutropenia was 11%, but this did not translate to significantly increased febrile episodes (<5%). 
 
Based on the above study, dose-dense AC followed by dose-dense paclitaxel is now one of the 
standard treatment options for node-positive women as defined by the National Comprehensive 
Cancer Network (NCCN).  
 
Also, paclitaxel given in a dose-dense fashion (every 2 weeks) was proven superior to once 
weekly paclitaxel in a SWOG (S0221) trial published last year17. The study design was an open-
label 2 × 2 factorial design with equal probability of receiving each treatment combination. The 
first factor compared dose-dense AC  for six cycles (total 12 weeks) versus a novel continuous 
schedule of adriamycin 24 mg/m2 IV once per week, cyclophosphamide 60 mg/m2 orally once 
per day, and filgrastim 5 micrograms/kg subcutaneously daily for 15 weeks. The second factor 
was subsequent dose-dense paclitaxel 175 mg/m2 IV day 1 once every 2 weeks for six cycles 
versus paclitaxel 80 mg/m2 IV once per week for 12 weeks. After October 2005, patients with 
human epidermal growth factor receptor 2 (HER2) positive tumors were allowed to receive 
trastuzumab concurrently with or after treatment with paclitaxel for a total of 1 year. It should be 
noted that the paclitaxel once a week was proven superior to paclitaxel given every 3 weeks in 
the ECOG 1199 trial discussed previously. This was the reason paclitaxel once per week (rather 
than paclitaxel given every three weeks) was taken as the control arm in the S0221 study.   
 

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Trial S0221 also showed that the patients achieved a similar DFS with any of these regimens. 
However, examination of relevant biologic subsets revealed that the advantage for dose-dense 
schedule observed only in patients with hormone receptor negative/HER2-negative disease. This 
observation is the result of a subset analysis that was not protocol specified and should be 
regarded as hypothesis generating only.  
 
Based on the above discussion, we can conclude that the paclitaxel weekly and every two week 
schedules has equal efficacy and better than paclitaxel given every 3 weeks. Docetaxel given 
every 3 weeks has equal efficacy to paclitaxel given weekly (as per ECOG 1199) but it was 
never tested in a phase III trial in a dose-dense (ever 2 week) setting. 
 
Of the taxanes, paclitaxel and docetaxel, paclitaxel has less hematological toxicity and has been 
used full dose every 2 weeks (dose-dense) with growth factor support in the CALGB 9741 and 
S0221 studies as discussed above. No similar dose-dense dosing has been established for 
docetaxel in phase III clinical trials.  
 
Both paclitaxel and docetaxel include hair loss, peripheral neuropathy, myopathy (mainly muscle 
pains), nausea, vomiting, diarrhea, mucositis and generalized weakness as their main non-
hematological toxicities. 
  
Docetaxel, unlike paclitaxel, is associated with significant nail changes in up to 40 % of patients 
which include nail loosening or separation from the nail bed, nail discoloration, hyper-
pigmentation and dislodgement. Also it was associated with lacrimal canal (tear canal) stenosis 
causing overflow of tears. These side effects were dose dependent and were reported in up to 75 
% of patients with weekly administration and in less than 1% with every 3 week administrations. 
 
For many young women with breast cancer, these toxicities were associated with psychological 
distress, pain and functional impairment. There is no curative treatment for nail toxicity 
associated with docetaxel and it takes up to 6 months for finger nails and up to a year for toe 
nails to become normal after treatment discontinuation18.  
 
As docetaxel was not studied in a dose-dense fashion in a phase III clinical trial and due to its 
significant non-hematological and hematological side effects as described above, we chose 
paclitaxel as our taxane of choice in combination with cyclophosphamide. 
 
In our protocol, patients will have the opportunity to receive chemotherapy in a dose-dense 
fashion with growth factor support and will be able to complete their treatment earlier than the 
conventional standard regimens without exposure to anthracyclines and the associated cardiac 
risks. 
 
Evolution of adjuvant therapy in Her 2 positive EBC: 
 
Her2 receptor (protein) overexpression or Her2 gene amplification occurs in 20-30% of breast 
cancers and is considered as one of the poor prognostic markers in EBC. In 1996, Baselga et al at 
Memorial Sloan Kettering Cancer Center showed an overall response rate of 11.6% with weekly 
trastuzumab in a small phase II study of extensively treated Her2 positive women19.In the pivotal 

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phase III trial for trastuzumab in MBC, the addition of trastuzumab to chemotherapy was 
associated with a significantly longer time to disease progression (median 7.4 Vs 4.6 months), 
higher objective response rate (50 vs 32 %) and longer survival (25.1 Vs 20.3 months). Based on 
this phase III trial, FDA approved trastuzumab in combination with paclitaxel for the first line 
treatment of women with Her2 positive MBC in 1998. This success motivated investigators to 
evaluate its role in the adjuvant setting. 
 
Two trials NSABP-B31 and NCCTG (North Central Cancer Treatment Group) N 9831 were 
analyzed jointly in view of their similarities between the control arms. Patients with Her-2 
positive tumors were treated with four cycles of AC every 3 weeks followed by 12 weekly doses 
of paclitaxel given concurrently or sequentially with 52 weeks of trastuzumab. The updated data 
(median follow up of 8 years) showed that the addition of adjuvant trastuzumab to chemotherapy 
increased the ten year overall survival from 75% to 84%20.  
 
Cardiac safety from these joint analyses, reviewed by an independent board of cardiologists and 
oncologists, concluded that the rate of symptomatic congestive heart failure was 0.5% with 
chemotherapy alone and 2.0% with AC followed by paclitaxel and trastuzumab. Moreover, 86% 
of patients in the trastuzumab arms had either complete or partial resolution of the cardiac 
events.  
 
The concern over cardio toxicity associated with adjuvant trastuzumab and anthracycline 
treatment emphasizes more to evaluate non-anthracycline based regimens in Her2 positive 
disease. This has led to the Breast Cancer International Research Group, BCIRG 006 trial. 
 
The docetaxel, carboplatin and trastuzumab (TCH) combination was compared with standard 
anthracycline based chemotherapy in the BCIRG 006 trial21. In this three arm study, TCH every 
3 weeks for 6 cycles was compared to AC every 3 weeks for 4 cycles followed by docetaxel 
every 3 weeks for 4 cycles (AC->T) and the same ( AC -> T ) with trastuzumab (AC-TH). After 
a median follow-up of 65 months, risk of recurrence was reduced to nearly 50% in both the 
trastuzumab containing arms. The rates of CHF were significantly higher in the group receiving 
AC-TH than in the TCH (2.0% Vs 0.4%). Eight cases of leukemia were reported and out of 
which seven were in anthracycline based regimens. This study established TCH ever 3 weeks for 
6 cycles (total duration 18 weeks) as the standard non anthracycline regimen for the Her 2 
positive disease in the adjuvant setting. 
 
Duration of Adjuvant Trastuzumab ( 6 months Vs 12 months Vs 24 months)  
 
The Finland Herceptin (Fin Her) study randomized 3 cycles of either every 3 weeks docetaxel or 
weekly vinorelbine followed by 3 cycles of FEC (5FU, epirubicin and cyclophosphamide). The 
subset of Her2 positive patients were further randomized to either observation or weekly 
trastuzumab for nine treatments given concurrently with docetaxel or vinorelbine22. The final 
analysis of this trial showed that the docetaxel arm had a better distant disease free survival than 
the vinorelbine arm. In the Her 2 positive subgroup, adjuvant trastuzumab for 9 weeks in 
combination with docetaxel improved the distant disease free survival. 
 

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The HERA trial allowed the use of any chemotherapy regimen prior to trastuzumab, and patients 
received either one or two years of trastuzumab. The study reported 50% reduction in relapse in 
patients receiving at least one year of trastuzumab. In this trial 94% patients received 
anthracyclines and 26% had a taxane. Clinical cardiac toxicity was a major side effect and was 
reported in 5% of patients and trastuzumab was discontinued23.  It also showed that two years of 
adjuvant trastuzumab was not more effective than one year of trastuzumab. 
 
The PHARE study showed that the adjuvant trastuzumab for a shorter duration for 6 months was 
not non inferior (means equivalence) to standard 12 months of adjuvant trastuzumab24. 
 
The above three trials established one year of trastuzumab as the standard of care in the adjuvant 
setting. Based on these resuls, the NCCN recommends one year of adjuvant trastuzumab as the 
standard of care for Her 2 positive breast cancer.  
 
The evidence from the above large randomized controlled trials in the adjuvant setting, along 
with some smaller trials in the neoadjuvant setting (NOAH), firmly established trastuzumab (for 
one year) in combination with various anthracycline and non anthracycline based chemotherapy 
regimens as the standard of care for the Her 2 positive EBC25. However, the TCH (where “C” 
stands for carboplatin and not cyclophosphamide) regimen was the only non anthracycline based 
combination chemotherapy regimen tested in a phase III clinical setting and it was administered 
every 3 weeks. So far, no dose-dense (every 2 weeks) non anthracycline regimens were studied 
in the Her2 positive EBC. 
 
We were hoping to test the feasibility of giving trastuzumab with the above mentioned PC 
regimen [The “PC-H” regimen] in a dose dense fashion (every 2 weeks) with growth factor 
support for 6 cycles.  This non anthracycline based regimen, if maintains efficacy, will not only 
reduce the cardio-toxicity but also shorten the duration of chemotherapy for Her 2 positive 
patients by 6 weeks compared to the now standard non anthracycline regimen TCH.  
 

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3.0: Eligibility Criteria 
3.1 Inclusion 
 
1. Histologically confirmed newly diagnosed Stage I-II HER2/neu positive breast cancer.  
2. Women above 19 years of age will be included. 
3. 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.  
4. 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). 
5. ECOG performance status of 0 or 1. 
6. 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 
• Hemoglobin >11gm/dl 
• 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 
• Able to give informed consent. 
7. All included subjects must have normal cardiac function as defined by an ejection fraction of 
>50% by echocardiogram.  
8. Able to return for treatment and follow-up on the specified days. 
 
3.2 Exclusion 
1. Prior malignancy; except for adequately treated basal cell or squamous cell skin cancer or 
noninvasive carcinomas. 
2. Subjects with pre-existing Grade II peripheral neuropathy. 
3. History of previous chemotherapy.  
4. Stage IV or metastatic breast cancer. 
5. Pregnant or nursing women. 
6. Inability to cooperate with treatment protocol. 
7. No active serious infections or other conditions precluding chemotherapy 
8. Any comorbidity or condition which, in the opinion of the investigator, may interfere with the 
assessments and procedures of this protocol e.g. unstable angina, myocardial infarction within 
6 months, severe infection, etc. 
9. Known hypersensitivity to any component of required drugs in the study. 
10. Known positive for HIV or infectious hepatitis, type A,B or C or active hepatitis. 
11.Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form. 
12.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 

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IRB#318-15 
conduction system abnormalities. (Appendix A)  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 UNMC potential subjects should be directed to 
the UNMC Coordinator .  
 
All questions regarding eligibility for Participating/Collaborating Site potential subjects 
should be directed to the Sponsor Principal Investigator by contacting the UNMC Fred & Pamela 
Buffett Cancer Center Multi-site Project Manager at 402-559-4596. 
 
NOTE: UNMC and Participating/Collaborating Sites may use the Eligibility Checklist 
(Appendix B) as source documentation if it has been reviewed, signed, and dated prior to 
registration by the treating physician. The eligibility checklist must be accompanied by all other 
source documents that evidence the subject’s eligibility (i.e., dictation, pathology, radiology, 
laboratory, etc.)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.0: Registration Procedures 
 
4.1 Recruitment 
 
Subjects who are referred to the Nebraska Medicine (NM) / UNMC; Faith Regional Carson 
Cancer Center (FRCCC); or other IRB approved participating/collaborating sites, with newly 
diagnosed Stage I-II HER2/neu positive breast cancer 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, assessment of Performance Status, and 
echocardiogram. Radiologic/Imaging evaluations for staging will be performed as clinically 
indicated and is at the discretion of the treating physician. Any pathologic specimens 
obtained at referring Institutions will be reviewed for accuracy.  
 
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. (Section 3.0) 
 
If the patient is screened as potentially eligible, she will then be offered the option to 
participate. An informed consent will be signed by the patient after thorough review of the 
study is completed by the physician and his/her designee.  
 
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.   
 
NOTE: Problems related to insurance coverage for UNMC potential subjects or enrolled 
subjects will be reported to the IRB as they are encountered. 
 
4.2 Eligibility Verification/Registration  
 
Before Subjects are registered to the study, an Eligibility Checklist (Appendix B) must be 
completed to verify the subject meets the eligibility criteria. Informed consent must be 
obtained by following procedures defined in section 12.6 entitled Process of Informed 
Consent.   
 
Subjects will be registered through the Sponsor Principal Investigator by contacting the 
UNMC Fred & Pamela Buffett Cancer Center Research Multi-site Project Manager.   
 
All Study personnel from UNMC and non-UNMC IRB approved sites will contact the 
UNMC Multi-site Project Manager if a subject appears to meet the eligibility criteria. They 
will submit the completed Eligibility Checklist (Appendix B) and relevant de-identified 
source documents to email to the UNMC Multi-site Project Manager to verify the subject 
meets the eligibility criteria. The Eligibility Check list will be maintained in a study file. If 
the UNMC Multi-site Project Manager confirms that the subject meets criteria and target 

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accrual has not been met, approval for the subject will be given. A confirmation of 
Registration will be forwarded by the UNMC Multi-site Project Manager. 
 
For UNMC subjects: 
Study personnel will provide the UNMC Fred & Pamela Buffett Cancer Center PRMS office  
and the UNMC Multi-site project manager a copy of the signed and dated consent form for 
each UNMC subject registered to the protocol within one (1) week that includes the 
following information:  
• Protocol Number 
• Subject Identification: Subject’s name/initials, Study ID number 
• Subject Demographics: gender, birth date (mm/dd/yyyy), race, ethnicity (See Subject 
Registration Request Form located in the Study Manual) 
• Additional CTRP reporting requirements: Subject zip code/country (if not USA) and 
primary method of payment information 
 
Participating/Collaborating Sites: 
Participating/Collaborating sites must have both local and UNMC IRB approval, and have 
met all other UNMC criteria to enroll. Study personnel from non-UNMC IRB approved sites 
will provide the UNMC Multi-site Project Manager with the following information: 
• Demographics cover sheet (located in the Study Manual) 
• Copy of the signed and dated consent form (subject signature obliterated with 
signature line and subject  initials visible)  
• Signed Eligibility Checklist 
• De-identified source documents with assigned subject I.D. (if known on each page or 
subject identification) to support eligibility (i.e., H&P, Medical/Surgical Hx, Lab, 
Pathology, scans, etc.). 
 
Registration Date: eligibility verification and notification of assigned subject number (by 
UNMC) will be known as the Registration date.  
 
 Date of enrollment: is defined as the date of the start of study treatment / first protocol 
related intervention. 
 
The listed documents/ information for subjects enrolled will be provided to the PRMS office 
within one (1) week of enrollment as applicable: 
o UNMC and Participating Site Protocol Numbers  
o Investigator/Participating Site Identifier (ID)  
o Subject ID: Assigned by UNMC [Site ID followed by subject number (##-###)]  
o Consent Date: Date subject signed consent  
o Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity 
o Re-consent Date: (If applicable)  
o Ineligibility Status: (If known)  

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o Off Study Date: (If applicable)  
 
4.3 Instructions for Subjects Who Do Not Start Assigned Protocol Treatment 
 
If a subject does not receive any assigned protocol treatment after consenting, baseline and 
follow-up data will still need to be collected and must be submitted according to the 
instructions in the protocol.  The reason he/she did not receive any treatment and the date and 
type of the first non-protocol treatment that the subject receives must also be reported.  
 
4.4 Requirements for Non-UNMC Sites/Participating/Collaborating Institutions 
Submitting Regulatory Documents 
 
Before an Institution may enroll Subjects, all site activation criteria must be met by submitting 
required protocol specific regulatory documents to the UNMC Multi-site Project Manager via 
email.  
 
 
4.5 Required Protocol Specific Regulatory Documents 
 
1. Confirmation that the UNMC Team Designee(s) conducted an Initial Site Teleconference 
prior to opening the protocol to accrual at each participating/collaborating site.  
 
 
 
 
5.0: Research Design 
This is a Phase II study of adjuvant therapy using a dose-dense regimen of cyclophosphamide 
and paclitaxel with trastuzumab in subjects with newly diagnosed stage I-II breast cancer. This 
will be a non-randomized study; all subjects will receive the combination chemotherapy. All 
subjects will receive the same doses of the active compound.  
 
5.1 Standard of Care (SOC) Pre-treatment Evaluations within 30 days prior to the Date of  
Enrollment (unless otherwise specified below). No tests or procedures are conducted solely for 
the purposes of research to determine subject eligibility.  

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• History and physical 
• Current medications 
• Documentation of baseline events (adverse events) if applicable  
• CBC, diff, Platelet count   
• Comprehensive Metabolic Panel (CMET) – electrolytes (sodium, potassium, chloride, 
bicarbonate, creatinine, BUN, AST, ALT, T. protein, albumin, bilirubin, alkaline 
phosphatase, calcium, glucose) 
• Serum or urine pregnancy test (if applicable) within 7 days of first study-related 
treatment date. 
• Height and weight 
• Vital signs, including blood pressure  
• ECOG Performance Status Assessment 
• Echocardiogram  
• The need for further radiologic evaluations for staging as clinically indicated and is at the 
discretion of the treating physician. 
• Any pathologic specimens obtained at referring institutions will be reviewed for 
accuracy.  
 
Research Blood Samples will be drawn at baseline, at the clinical endpoint (after cycle 6) and at 
the end of treatment (after year one or end of therapy). At each time point a blood collection of 
30 ml including two – 10ml EDTA lavender top tubes and one – 10ml red top tube will be drawn 
to store for future research purposes including DNA sequencing.  
 
Specimens submitted, by patients who consent to the additional specimen collection, will be 
processed to maximize their utility for future research projects and may include, but not limited 
to, extraction of plasma, serum, DNA and RNA.   
 
The appropriate materials will be distributed to investigators for the diagnostic reviews and 
research studies.   
 
Specimens from patients who consented to allow their specimens to be used for future approved 
research studies, including residuals from the currently defined reviews and research studies, will 
be retained in an UNMC-designated central repository.  
 
If the patient agrees to let the samples be kept for future research, the samples will be kept until 
they are used up or destroyed. Most future research studies will focus on cancer, some research 
projects may also include other diseases, such as heart disease, diabetes or Alzheimer's disease. 
This may also include research on inherited traits. 
 
 
5.2 Administration Schedule   
 
Premedication: All subjects will receive premedication for nausea and vomiting with appropriate 
anti-emetic regimens based on recommendations made by the NCCN Guidelines (SOC), pre and 
post medications as prescribed by the treating physician. 
 

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IRB#318-15 
(See http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf ) 
 
Subjects will receive diphenhydramine, ranitidine (or Pepcid if ranitidine is not on formulary) 
and dexamethasone prior to paclitaxel (SOC). 
 
Systemic Therapy (Medicare Qualifying research related combination chemotherapy): 
  
• Cyclophosphamide 600mg/m2 in normal saline IV over 1 hour Day 1 cycled every 14 
days (2 weeks) for 6 cycles 
 
• Paclitaxel 175mg/m2 in normal saline IV over 3 hrs  Day 1 cycled every 14 days (2 
weeks) for 6 cycles 
 
• All cycles are with pegfilgrastim support, 1-6 mg SQ on day 1 after PC dose adjust as 
medically indicated or hold for ANC >12,000 or bone pain (SOC).  (Pegfilgrastim 
support is optional following cycle 6) 
**NOTE: May use Neulasta On Body Injector per MD discretion. 
• Loading Dose trastuzumab 6mg/kg in normal saline IV over 30 to 90  minutes per 
institutional protocol Day 1, Cycle 1  
 
• THEN for Subsequent Cycles (Cycles 2-5), trastuzumab 4mg/kg in normal saline IV over 
30 to 60 minutes per institutional protocol  Day 1 every 14 days (2 weeks) Cycles 2-5. 
 
• THEN for  Maintenance Therapy beginning with Cycle 6, trastuzumab 6mg/kg in normal 
saline IV over 30 to 60 minutes per institutional protocol Day 1 every 21 days (3 weeks) 
to complete a total of 52 weeks after completing chemotherapy (Cycles 6- 19). 
 
All subjects will receive a maximum of 6 cycles of chemotherapy and a maximum of 52 weeks 
of trastuzumab. 
 
Radiation Therapy will be given by the radiation oncologist and timing determined by the 
radiation and medical oncologist as per standard NCCN guidelines, either concurrent with 
chemotherapy or following chemotherapy.  
See NCCN guidelines. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf   
 
Hormonal Therapy will be determined by the medical oncologist as per standard NCCN 
guidelines. See NCCN guidelines. Subjects with estrogen/progesterone receptor positive tumors 
will receive Hormonal Therapy following adjuvant chemotherapy.  
See NCCN guidelines.http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. 
 
 
5.3 
Evaluations during therapy (SOC):  
 
• Subjects will have standard hematological and cardiac evaluations. 

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• Subjects will be clinically evaluated by an oncologist during chemotherapy every 2 
weeks for toxicities, then at least every 12 weeks after completing chemotherapy until 
they complete 52 weeks of trastuzumab and then every 3 months for 2 years with the 
following at each visit:  
 
• 
CBC, platelet count  
• 
Comprehensive metabolic panel (CMET) – electrolytes (sodium, 
potassium, chloride, bicarbonate, creatinine, BUN, AST, ALT, T. protein, 
albumin, bilirubin, alkaline phosphatase, calcium, glucose) 
• 
Weight 
• 
Performance Status Assessment 
• 
Vital signs, including blood pressure 
 
• Subjects will have repeat echocardiogram every 12 weeks until completion of 
trastuzumab to monitor their cardiac function. Normal cardiac function as defined by an 
ejection fraction of >50% by echocardiogram. 
 
• The need for further radiologic evaluations for staging as clinically indicated and is at the 
discretion of the treating physician 
 
• Research Blood Samples will be drawn at the clinical endpoint (after cycle 6) and at the 
end of treatment (after year one or end of therapy). At each time point a blood collection 
of 30 ml including two – 10ml EDTA lavender top tubes and one – 10ml red top tube will 
be drawn to store for future research purposes including DNA sequencing. 
  
• Data will be collected on dose delays/reductions, hospitalizations, treatment 
discontinuation, deaths, and hematologic and cardiac toxicity. 
 
 
 5.4 Criteria for holding and resuming treatment  
 
Treatment should be held until any non-hematologic grade 3-4 toxicities resolve to less than or 
equal to a grade 1 with dose modifications as per instructions below. 
 
 
5.5 Dose Modifications 
 
5.5.1 General instructions for dose modifications and delays 
•    Adverse events (AEs) will be graded according to the National Cancer Institute  
Common Terminology, Criteria for Adverse Events (NCI-CTCAE), version 4.03 
June 
14, 
2010which 
can 
be 
accessed 
at 
the 
following 
URL.  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
•     All doses should be based on the AE requiring the greatest modification. 
 

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IRB#318-15 
•   Chemotherapy should be held for at least 1 week until any AE requiring dose 
modification returns to ≤ grade 1. The exceptions are neutropenia and bilirubin 
elevation (see Tables 3 and 4). If recovery to ≤ grade 1 has not occurred after 3 
weeks of delay, chemotherapy must be discontinued. 
 
•     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. 
 
5.5.2 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) 
Dose Level-2 
(mg/m2) 
Dose Level-3 
(mg/m2) 
Dose Level-4 
(mg/m2) 
paclitaxel  
175 
175 
135 
135 
100 
 
 
 
Instructions for all other toxicities are listed on Table 3. 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. 
 
TABLE 3. Dose modifications & delays for cyclophosphamide & paclitaxel 
NCI CTCAE v4.03 
Category/Grade 
Modifications for AEs that 
occurred during a cycle but 
DID NOT REQUIRE DELAY 
IN TREATMENT (a) 
Modifications for AEs that 
REQUIRED TREATMENT DELAY (b) 
Blood/bone marrow: 
Neutrophils/granulocytes 
Grades 3, 4 
 
 
 
 
Platelets 
Grades 2, 3 
Grade 4 
 
 
 
Maintain dose 
 
 
 
 
 
Maintain dose 
↓ one dose level 
 
 
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: Hold until ≥ 75,000/mm3 
If grade 2 or 3 and recovery takes: 
                  ≤ 1 week – maintain dose 
2 to 3 weeks - ↓ one dose level 
> 3 weeks – D/C study therapy 
If grade 4, ↓ one dose level  

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If recovery takes> 3 weeks, D/C study therapy. 
GI (if related to chemotherapy) 
Diarrhea 
Grade 2 
Grade 3 
Grade 4 
Mucositis/stomatitis 
Grade 2 
Grade 3 
Grade 4 
Vomiting (despite antiemetics) 
Grade 2 
Grades 3,4 
 
 
Maintain dose 
↓ one dose level 
↓ two dose levels or D/C 
 
Maintain dose 
↓ one dose level 
↓ two dose levels or D/C 
 
↓ one dose level (opt) 
↓ two dose levels or D/C 
 
 
↓ one dose level 
↓ one dose level 
↓ two dose levels or D/C 
 
↓ one dose level 
↓ one dose level 
↓ two dose levels or D/C 
 
↓ one dose level (opt) 
↓ two dose levels or D/C 
Hepatic function: 
 
Bilirubin or AST or alk phos 
Grade 2 
Grade 3 
Grade 4 
 
 
 
↓ one dose level 
↓ two dose levels 
D/C 
Hold until bilirubin returns to the baseline grade and 
AST and alk phos have returned to ≤ grade 1. 
 
↓ one dose level 
↓ two dose levels 
D/C 
Infection: 
Febrile neutropenia 
Grade 3 
Grade 4 
Infection with grade 3 or 4 ANC 
Grade 3 
Grade 4 
Infection with normal ANC 
Grade 3 
Grade 4 
 
 
↓ one dose level 
↓ two dose levels or D/C 
 
↓ one dose level 
↓ two dose levels or D/C 
 
Maintain dose 
↓ two dose levels or D/C 
 
 
↓ one dose level 
↓ two dose levels or D/C 
 
↓ one dose level 
↓ two dose levels or D/C 
 
Maintain dose 
↓ two dose levels or D/C 
Other clinically significant AEs (c): 
Grade 3 
Grade 4 
 
↓ one dose level 
↓ two dose levels or D/C 
 
↓ one dose level 
↓ 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. 
 
5.5.3 Management of paclitaxel-related hypersensitivity reactions 
Management of paclitaxel-related hypersensitivity reactions is at the investigator's 
discretion.  
 
5.5.4 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 the paclitaxel 
to the 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 the paclitaxel 
to the next lower dose 
 
 
 

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IRB#318-15 
 
(a),(c) 
 
Second episode: 
Stop the paclitaxel 
Stop the paclitaxel 
 
Grade 4  
Persistent paresthesias/dysesthesias that are 
disabling or life-threatening 
 
Stop the paclitaxel 
 
 
Stop the 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.) 
 
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 
the Next Cycle to be Delayed 
Grade 1 
Maintain dose 
Maintain dose 
Grade 2 
Maintain dose 
 
Maintain dose 
OR 
Decrease the paclitaxel 
to the next lower dose (b),(c) 
Grade 3 
 
First episode: 
Decrease the paclitaxel 
to the next dose (b),(c) 
 
 
Second episode: 
Stop the paclitaxel 
First episode: 
Decrease the paclitaxel 
to the next lower dose (b),(c) 
OR 
Stop the paclitaxel 
Second episode: 
Stop the paclitaxel 
Grade 4 
Stop the paclitaxel 
Stop the 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.) 
 
5.6 Correlative Studies Related to the Research -  
 
Research Blood Samples will be drawn at baseline, clinical endpoint (after cycle 6) and end of 
treatment (after year one or end of therapy)-30 ml including two – 10ml EDTA lavender top 
tubes and one – 10ml red top tube to store for future research purposes including DNA 
sequencing. SEE APPENDIX C for instructions.  
 
Send blood samples overnight at room temperature. Monday through Thursday only; do not send 
on Friday or the day before a holiday.  
 
Shipping Address: 
David L. Kelly PhD 
Assistant Professor 
Eppley Institute for Research in Cancer and Allied Diseases 
University of Nebraska Medical Center 
601 S. Saddle Creek Rd. 

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IRB#318-15 
F&PBCC Rm. 5.12.428 
Omaha, Nebraska 68106 
Tel: (402) 559-9157 
Cell: (402) 699-1132 
Fax: (402) 559-4651 
dkelly@unmc.edu 
 
And / Or 
 
Amy Wells, MS 
Research Technologist 
Eppley Institute for Research in Cancer and Allied Diseases 
University of Nebraska Medical Center 
601 S. Saddle Creek Rd. 
F&PBCC Rm. 5.12.428  
Omaha, Nebraska 68106 
Tel: (402) 559-6015 
awells@unmc.edu 
 
 
 
 
 
 
 
 
6.0: Measurement of Effect  
 
This trial will assess the safety and toxicity, particularly regarding cardiac function, of 
administering a dose dense regimen of cyclophosphamide, paclitaxel with trastuzumab for 6 
cycles with growth factor support in newly diagnosed Stage I-II HER2/neu breast cancer subjects 
by measuring adherence to the intended dosing schedule and accrual, as well as by documenting 
and reporting toxicities, and evaluating echocardiogram results from baseline, during and after 
trastuzumab.  Normal cardiac function as defined by an ejection fraction of >50% by 
echocardiogram.  
 
Toxicity Criteria: The NCI Common Toxicity Criteria Adverse Events version 4.03 June 14, 
2010 will be used to grade toxicity; it is available at the following internet 
sitehttp://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf .  
 
Survival: Subjects will be analyzed with respect to overall and recurrence free survival; however 
there will be no comparative group.   
 
Overall survival is defined as time from the first chemotherapy administered on the trial until 
death from any cause. For subjects who are still alive at the time of the study analysis or are lost 

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IRB#318-15 
to follow-up, survival will be censored at the last recorded date that the subject was known to be 
alive.   
 
Recurrence-free survival is defined as from the first date of therapy until the first notation of 
clinical progression, relapse or death from any cause. For subjects who are still recurrence-free at 
the time of the study analysis or are lost to follow-up, recurrence-free will be censored at the last 
recorded date that the subject was known to be recurrence-free.  Response will be determined by 
the principal investigator or the co-principal investigators. 

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IRB#318-15 
7.0: Study Parameters  
Table 6: 
Study 
Within 
30 days 
Rx start 
Cycle 1 
(Week 1-2, 
Cycles are 
Q2wks) 
Cycles 2-6 
(Week 3-12, 
Cycles are 
Q2wks) 
Maintenance Cycles 7-19 (52 
weeks)  
/Follow up 
 
Informed consent 
X 
 
 
 
History 
X 
 
 
 
Meds 
X 
X 
X 
X 
VS Wt &  ECOG PS 
X 
X 
X 
X c  
Ht 
X 
 
 
 
Serum or urine Pregnancy test (if 
applicable) 
X 
(within 7 
days of 
tx) 
 
 
 
CBC, diff, plt 
X 
X 
X 
X c  
CMET 
X 
X 
X 
X c  
Research Blood Sample 
X 
 
X g 
X g 
Echocardiogram a 
X a 
 
X a 
X a 
Adverse events 
X 
X 
X 
X e 
Radiologic evaluations f 
X f 
 
X f 
X f 
All SUBJECTS: 
 
 
 
 
N= pegfilgrastim 
 
Day1 d 
Day1d  
 
CT=cyclophosphamide paclitaxel 
 
Day 1  
Day 1 
Q Cycle 2-6 
 
Trastuzumab  
 
Loading dose  
6mg/kg Day 1 
Cycle 1 
Subsequent dose  
4mg/kg Day 1 
Cycles 2-5 
Maintenance dose  
6mg/kg/q 3 weeks (begin with 
cycle 6 & continue thru cycle 
19 ( 52 weeks) c. 
Radiation and hormone TRX b 
SOC (NCCN Guidelines) 
 
 
 
 
    
X = Prior to each cycle 
a- Repeat echocardiogram every 12 weeks until completion of trastuzumab to monitor cardiac function.  
b- Radiation Therapy will be given by the radiation oncologist and timing determined by the radiation and medical 
oncologist as per standard NCCN guidelines, either concurrent with chemotherapy or following chemotherapy 
unless the patient has received radiation to the area in the past. Subjects with estrogen/progesterone receptor 
positive tumors will receive Hormonal Therapy following adjuvant chemotherapy, and Hormonal Therapy will 
be determined by the medical oncologist as per standard NCCN guidelines.  
c-   Subjects will have standard hematological and cardiac evaluations. Subjects will be clinically evaluated by an 
oncologist during chemotherapy every 2 weeks for toxicities, then at least every 12 weeks after completing 
chemotherapy until they complete 52 weeks of trastuzumab and then every 3 months for 2 years.  
d- Administered 1-6 mg SQ on day 1 after PC dose adjust as medically indicated or hold for ANC >12,000 or bone 
pain (SOC).  (Pegfilgrastim support is optional following cycle 6)   
**Note: May use Neulasta On Body Injector per MD discretion.  
e- All AEs will be followed until resolution or a cause is identified. AEs judged by the investigator as not related or 
probably not related to the treatment will not be followed beyond the 4 weeks after the final chemotherapy 
(including trastuzumab). However, subjects will be monitored for neuro and cardio toxicities for up to 3 months 
after final chemotherapy treatment (including trastuzumab).  Concomitant medications will be collected up to 3 
months after final chemotherapy treatment (including trastuzumab) to facilitate AE attribution assessment.  
f- The need for further radiologic evaluations for staging as clinically indicated and is at the discretion of the treating 
physician 
g- Research Blood Samples collected at Baseline, Clinical Endpoint (after cycle 6 and End of treatment (after year 
one or end of therapy). (Res) 
 
 

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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. 
 
8.1.5 Method of Administration  
Loading dose: 6 mg/kg IV C1. Subsequent dose:  4 mg/kg IV C2-5. Maintenance dose: 
6mg/kg IV weekly C6-19. 
 
8.1.6 Precautions  
Benzyl alcohol hypersensitivity: use SWFI for reconstitution.  Extreme caution should 
be exercised in treating Subjects 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    
COMMON  
Hematologic: may exacerbate chemotherapy induced neutropenia or anemia 
Gastrointestinal: Diarrhea, nausea, and vomiting  
Other: May cause “flu-like symptoms” with generalized aches and pains, 
headache, fever, chills, nausea, vomiting and diarrhea  
 
SERIOUS  
Hypersensitivity reactions, including fatal anaphylaxis   
Infusion reactions, including some with a fatal outcome 
Respiratory: Acute respiratory distress syndrome (ARDS), bronchospasm, 
pneumonitis   
Other: cardiomyopathy, infusion associated symptoms, hypersensitivity reactions, 
changes in kidney function 
 
8.1.8 Commercial Availability  
This drug is commercially available. 
 
 

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8.2 Pegfilgrastim (per Micromedex®) 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 
1)  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). 
 
2)  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). 
 
3)  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 
 
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 
 
 
 
 
 
 

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8.3 Cyclophosphamide per Micromedex®) 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: Amenorrhea 
SERIOUS  
Cardiovascular: Cardiomyopathy  
Dermatologic: Stevens-Johnson syndrome, Toxic epidermal necrolysis (rare) 
Renal: Hemorrhagic cystitis 
Reproductive: Azoospermia, Oligozoospermia  
Respiratory: Interstitial pneumonia  
Other: Infectious disease 
 
8.3.5 Supplier 
Bristol-Myers Squibb 
 
8.3.6 Commercial Availability 

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This drug is commercially available 
8.4 Paclitaxel (per Micromedex®) 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 antimicrobial preservatives 
effectiveness test period demonstrating its low potential for contamination during 
long-term continuous infusion (Trissel et al, 1997a). 
 

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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 
 
 
 
 
 
 
 
 
 

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9.0:  Toxicity Reporting Guidelines 
The chemotherapeutic agents used in the protocol are commercially available agents with well-
characterized toxicity profiles. 
 
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, and FDA Guidelines for Toxicity Reporting.    
 
Adverse events (AEs) will be graded according to the National Cancer Institute Common 
Terminology, Criteria for Adverse Events (NCI-CTCAE), Version 4.03 June 14, 2010 which can 
be accessed at the following URL.   
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf   
 
All subjects will be closely followed for toxicity/adverse events (AEs). Adverse events will be 
assessed by reports from subjects to their physician/Investigator and by physical examinations. 
All AEs will be followed until resolution or a cause is identified.  
 
AEs considered by the Investigator as not related or probably not related to the treatment will not 
be followed beyond 4 weeks (30 days) after the final dose of study drug is administered 
(including trastuzumab). However, subjects will be monitored for neuro and cardio toxicities for 
a minimum of 3 months after final dose of study drug is administered (including trastuzumab).  
Concomitant medications will be collected up to 3 months after final dose of study drug is 
administered (including trastuzumab) to facilitate AE attribution assessment   
 
Deaths occurring within 30 days of study treatment regardless of relationship will be reported to 
the Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee (DSMC).  
 
 
Adverse Experiences Definitions 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not the event is considered causally 
related to the use of the product.  
 
An elective surgery or procedure that is scheduled to occur during a study will not be considered 
an adverse event if the surgery or procedure is being performed for a pre-existing condition and 
the surgery or procedure has been planned before study entry.  However, if the pre-existing 
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planned), then the deterioration of the condition for which the elective surgery or procedure is 
being done will be considered an adverse event.  
 
Any worsening of a pre-existing condition or illness is considered an adverse event.  Laboratory 
abnormalities and changes in vital signs are considered to be adverse events if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, meet protocol 
specific criteria (see Section 5.0, Treatment Plan) and/or if the Investigator considers them to be 
adverse events.  
 
Unexpected Adverse Event 
An unexpected adverse event is any adverse drug event that is not listed in the current 
labeling/Investigator’s Brochure.  “Unexpected,” as used in this definition, refers to an adverse 
drug experience that has not been previously observed (i.e., included in the labeling) rather than 
from the perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product. 
 
Serious Adverse Event 
UNMC IRB SAE DEFINITION: A serious adverse event is one that at any dose (including 
overdose) and regardless of causality that: 
 
Results in death 
 
Is a serious threat to life, health, safety or welfare-fare of subject 
1 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Required intervention to prevent permanent impairment or damage 
 
Persistent or significant disability or incapacity2 
 
Is a congenital anomaly or birth defect 
 
Another serious important medical event3 
 
Any medical event in an investigational drug study that requires treatment to 
prevent one of the outcomes listed above 
 
The rights, safety, or welfare of subjects is seriously jeopardized 
 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 subject 
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 subject 
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. 
 

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9.1 Adverse Event Reporting Per the University of Nebraska Medical Center, Institutional 
Review Board (IRB) and Fred & Pamela Buffett Cancer Center Data and Safety 
Monitoring Committee (DSMC) 
 
This protocol will adhere to all institutional guidelines for adverse event reporting.  
 
9.1.1 IRB REPORTING  
All internal serious adverse events (SAEs) must be reported to the local IRB promptly per 
Institutional Policy and in no case later than two (2) business days following PI notification 
that the event occurred. If the PI determines that conditions A, B, and C are met:  
 
A. The AE is unexpected, AND 
B. The AE is related to, or possibly related to, the drug, biologic, device, or 
other research intervention  
 
All unexpected, internal, fatal AEs must be reported promptly to the local IRB per 
Institutional Policy, but no later than 24 hours following PI notification that the event 
occurred. If documentation is still pending, the IRB office must be notified by a telephone 
call or e-mail.  
 
All expected, internal, fatal AEs (i.e., due to progressive disease or which reflect a risk 
currently found in the consent form) must be reported to the local IRB per Institutional 
Policy no later than ten (10) business days following PI notification that the event occurred.  
 
9.1.2  
FRED & PAMELA BUFFETT CANCER CENTER DATA AND SAFETY 
MONITORING COMMITTEE (DSMC) REPORTING  
 
All adverse events greater or equal to grade 3 (expected and unexpected, regardless of 
attribution) and any Internal AE that meets one or more of the definitions of SAE outlined in 
the DSMC SAE definition above regardless of whether or not it meets the UNMC IRB’s 
requirements for reporting, must be fully reported to the University of Nebraska Medical 
Center, Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee 
(DSMC) in accordance with DSMC guidelines (DSMC Policies and Procedures and DSMC 
Plan http://www.unmc.edu/cancercenter/clinical/prms.html).  
 
SAEs should be fully reported to the DSMC at the same time that they are reported to the 
UNMC IRB.  In general, reporting of SAEs to the DSMC is expected within seven (7) 
business days of the occurrence of the event. If additional information about the SAE is still 
being collected, a preliminary report should be filed within seven (7) business days with final 
reporting when additional information is available. Failure to fully report an SAE as required 
will be considered a study violation and may be reported to the Associate Director for 
Clinical Research. 
 
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:  

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Not related: The subject was not exposed to the study treatment or another cause is 
obvious (AE related to underlying or concurrent illness).  
 
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 (AE has no 
temporal relationship to the study drug and/or a more likely etiology exists). 
 
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 (AE has strong temporal relationship to study 
drug, alternative etiology is equal or less likely).  
 
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 (AE has strong temporal relationship to the study drug or recurs on re-
challenge, another etiology is unlikely or significantly less likely).  
 
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 4.03).  
 
AEs will be collected from the time the subject starts the study drugs 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 study drugs will 
NOT be followed beyond the 30 days after the final chemotherapy.  
 
 
ALL internal/external Adverse events (AEs) will be reported to the UNMC Fred & Pamela 
Buffett Cancer Center Data and Safety Monitoring Committee (DSMC). The DSMC will 
also review the protocol on at least a quarterly basis. 
 
Copies of the AE report will be submitted to the IRB as indicated in Section 9.1.1.  
 
A copy of the Policy and Procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html.  
 
9.1.3  
FOOD AND DRUG ADMINISTRATION (FDA) REPORTING  

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It is the responsibility of the UNMC Sponsor-Investigator, Amulya Yellala, MBBS, to 
submit to the FDA Post-marketing Safety Reports in accordance with 21 CFR 314.80.  
 
SAEs not meeting Post-marketing 15-day “Alert” will not be made available to FDA by the 
sponsor-investigator pursuant to 21 CFR 314.80 (c)(1)(i).  
 
All sites will utilize the FDA MedWatch Form (See Appendix D) for the reporting of serious 
adverse events (SAEs) and follow up information to those events. The form can be found at 
the following URL: http://www.fda.gov/Safety/MedWatch/default.htm  
 
It is the responsibility of ALL sites to submit the completed MedWatch Form, SAE PI 
Assessment Form and SAE fax cover sheet (located in your Study Manual) to the UNMC 
Multi-site Project Manager within 24 hours of his/her knowledge of the SAE.   
 
 
The SAE information will be routed to the UNMC PI who will further evaluate the SAE. The 
SAE will be submitted to FDA if the PI determines 21 CFR 314.80 (c) criteria are met.  
 
SAE reporting instructions are reiterated and further outlined in the Participating Site Study 
Manual. 
 
Additionally, serious adverse events will be reported to the IRB, SRC and the Data Safety 
Monitoring Committee by the Investigator. 
 
9.2 Auditing  
 
The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee (SRC) will 
review this protocol on at least an annual basis.  
 
This study will undergo audit on at least a quarterly basis by the UNMC Fred & Pamela Buffett 
Cancer Center Audit Committee.  
 
The UNMC Fred & Pamela Buffett Cancer Center Protocol Review & Monitoring System 
(PRMS) Office Audit Committee defines a Participating/Collaborating 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 of Nebraska Medical Center/The Nebraska 
Medical Center (UNMC/TNMC) Investigator and is Sponsored by UNMC. 
 
For participating/collaborating site(s) that are NCI Cancer Centers, the protocol specific finding 
of the 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 /collaborating 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. 
 
9.3 Monitoring  

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9.3.1 Various methods will be implemented by the Sponsor (UNMC) to exchange 
information with participating/collaborating sites. Methods of communication will include: 
  
• 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  
 
9.3.2 Ongoing safety monitoring for all the subjects in this study:  
 
All Participating/Collaborating 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. 
 
9.3.3 Data and Safety Monitoring Plan 
 
The UNMC Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Plan is 
designed to ensure the safety of participants in clinical trials conducted by the UNMC Fred & 
Pamela Buffett Cancer Center members and to comply with National Cancer Institute (NCI) 
and National Institutes of Health (NIH) requirements.  This protocol will comply with  all 
Monitoring Policies and Procedures outlined in the Monitoring Plan.   
 
 
 
A copy of the Policy and Procedures for this section may be reviewed at: 
 
http://www.unmc.edu/cancercenter/clinical/prms.html.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.0: Statistical considerations 
 
Statistical design 
This is a Phase II study of adjuvant therapy using a dose-dense regimen of cyclophosphamide 
and paclitaxel with trastuzumab in subjects with stage I-II HER2/neu positive breast cancer. This 
will be a non-randomized study; all subjects will receive the same doses of the active compound. 
Dose modifications for adverse events are described in Tables 1-5. 
 
Patient Accrual and Expected Duration of Trial 
We plan to accrue a total of 50 subjects.  For analysis, all subjects from this trial and Herceptin 
treated subjects from trial IRB#264-12 will be used.   
 
A total of 50 evaluable subjects are expected over a 6-year period. Evaluable patient defined as 
one that remains on study for 2 years. Target accrual is 50 to account for ineligible or withdrawn 
subjects.   
 
Definition of Analysis Sets 
Full analysis set:  All patients who received any dose of paclitaxel and cyclophosphamide with 
trastuzumab f. 
 
Safety analysis set:  All patients who received any dose of paclitaxel and cyclophosphamide with 
trastuzumab from the current study.   
Inability to complete treatment will be defined as a patient that a) requires a lower dose of 
therapy (defined as dose lowered by 50%) or b) a postponement of scheduled treatment of longer 
than 28 days, or c) discontinuation of treatment for any reason.  
 
Sample size justification 
This study is a non-randomized Phase II trial to estimate the toxicity profile for paclitaxel and 
cyclophosphamide with trastuzumab combination.  The primary toxicity for the sample size 
justification is neutropenia.  The secondary toxicities are paclitaxel-related neuropathy, grade 3/4 
cardiotoxicity and grade 3/4 nausea/vomiting.  A fixed expected toxicity rate of 10% will be used 
for grade 3/4 neutropenia and grade 3/4 paclitaxel-related neuropathy and a rate of 6% will be 
used for Grade 3/4 cardiotoxicity and grade 3/4 nausea/vomiting. 
 
Neutropenia and paclitaxel-related neuropathy:  10% of subjects experience neutropenia or 
paclitaxel-related neuropathy with standard treatment.  A sample size of 50 evaluable  subjects 
will produce a 97% confidence interval equal to the sample proportion plus or minus 0.09 when 
the estimated proportion is 0.10.   
 
Grade 3/4 cardiotoxicity and grade 3/4 nausea/vomiting:  < 6% of subjects should experience 
grade 3/4 cardiotoxicity or grade 3/4 nausea/vomiting with standard treatment, with herceptin 
addition, the cardiac toxicity should not be more than 6%.  We anticipate fewer grade 3/4 

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cardiotoxicity and grade 3/4 nausea/vomiting with this regimen when compared to standard 
regimens.  A sample size of 50 evaluable subjects will produce a 95% confidence interval equal 
to the sample proportion plus or minus 0.07 (precision) when the estimated proportion is 0.06.   
 
Recurrence free survival:   Under the null hypothesis, recurrence-free survival at three-years is 
85%.  Because outcome for these subjects is favorable, it is important to protect against the 
possibility of recurrence-free survival (RFS) inferior to 85%.  A reduction in RFS at 3 years to 
75% will be considered unacceptable.  Assuming accrual of 48 subjects over 6 years, with a 
minimum of 2 years of follow-up, the study will have 80% power at the 0.10 level of 
significance (one-sided) to detect a decrease in RFS at 3 years to 75%.  Two interim monitoring 
analyses will be conducted, at 33% and 66% of the expected information.  An Obrien and 
Fleming adjustment of 1.027 results in a sample size of 50 evaluable subjects.  Therefore, the 
sample size of 50 subjects is planned to allow for the two interim looks. 
 
Statistical analysis plan 
Descriptive statistics will be computed for all variables to examine data quality.  Variable 
distributions will be examined using stem-and-leaf plots, means, medians, standard deviations, 
ranges and frequencies and 90% confidence intervals.   
 
 Inability to complete treatment will be described using frequencies and proportions and 90% 
confidence intervals.   
 
Since this is a single arm study, the data analyses are descriptive.  The incidence rates of 
neutropenia and paclitaxel-related neuropathy, grade 3/4 cardiotoxicity and grade 3/4 
nausea/vomiting and adverse events will be summarized using frequencies, percentages and 90% 
confidence intervals.  Adverse events will be described by cycle.  The frequency of toxicity, 
categorized by toxicity grades, will be summarized. 
 
RFS and survival curves will be plotted following the method of Kaplan and Meier using the full 
analysis set. (11)   
 
Monitoring Plan 
The safety analysis set will be used for interim monitoring.  Therapy will be discontinued at any 
time if the data suggest this combination is found to be inferior to standard adjuvant therapy, 
regardless of whether the formal stopping rules are satisfied. 
 
Neutropenia and paclitaxel-related neuropathy:  One interim analysis will be performed after 25 
subjects have been off of their last cycle of chemotherapy for 2 weeks.  Follow up after the 
completion of therapy should be, as described earlier, every 3 months for 2 years and then every 
six months for total of 5 years. If 5 of 25 subjects develop grade 3/4 neutropenia or develop 
grade 3/4 paclitaxel-related neuropathy, accrual will be terminated.   If the true toxicity rate is 
10%, the probability of stopping accrual early is 10%.   If the true rate is 40%, the probability of 
stopping accrual early is 99%. 
 
Nausea/vomiting/cardiac toxicity for Her-2 neu negative subjects: One interim analysis will be 
performed after the accruals of 25 subjects have been off of their last cycle of chemotherapy for 

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2 weeks. Follow up after the completion of therapy should be as described earlier, every 3 
months for 2 years and then every six months for total of 5 years.  If 3 of 25 subjects develop 
grade 3/4 cardiotoxicity or develop grade 3/4 nausea/vomiting, accrual will be terminated.   If the 
true toxicity rate is 6%, the probability of stopping accrual early is 19%.   If the true rate is 20%, 
the probability of stopping accrual early is 90%. Cardiac toxicity will be monitored for Her-2 
positive subjects with an echocardiogram every 12 weeks until completion of trastuzumab. One 
interim analysis will be performed after 10 subjects have received trastuzumab for 26 weeks.  If 
1 of 10 Her-2 positive subjects develop grade 3/4, accrual will be terminated.    
 
Relapse-free survival:  Chemotherapy with cyclophosphamide and paclitaxel with trastuzumab is 
expected to produce recurrence free survival comparable to standard therapy.  Because the 
outcome for these subjects is favorable, it is important to protect against the possibility that 
cyclophosphamide and paclitaxel with trastuzumab will produce a RFS result inferior to 75%.  A 
one sample one-sided test will be conducted to compare RFS against a fixed expected null 
hypothesis of 0.85. Two interim monitoring analyses will be conducted at 33% and 66% of the 
expected information.  The monitoring p-values to be used for the 2 interim looks are p=0.003 
and p=0.036 with the final analysis at p=0.087.  Separate analyses will also be conducted for 
subjects with Stage 1 and Stage 2 disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 for centralized compliance monitoring. Serious adverse events, 
when noted, will be recorded on site via the standard Serious Adverse Event (SAE) form.  
 
11.1.1 Quality assurance:  
Complete records must be maintained in a research chart on each patient treated on the 
protocol. These records should include primary documentation (i.e., 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 (i.e., dated notes about doses given 
and reasons for any dose modifications). 
- Toxicity was assessed according to protocol (i.e., laboratory report slips, etc.). 
- Response was assessed according to protocol (i.e., x-ray, scan, lab reports, dated 
notes on measurements and clinical assessment, as appropriate). 
 
11.1.2 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 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 
and correlative research included in this application will have approval by the institutional 
review board.  
 
12.2 Study Population 

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Subjects 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 will be reviewed, and the diagnosis confirmed by the University 
Nebraska Medical Center Pathology Department as outlined in the protocol. 
 
12.4 Recruitment and Informed Consent 
Subjects with an initial diagnosis of cancer seen and evaluated at TNMC/UNMC and 
participating IRB approved sites will be available for recruitment. These Subjects 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 (NCT02654119) 
National Cancer Institute – http://www.cancer.gov (NCI-2015-01879) 
 
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 are any indications 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 the protocol chemotherapy in this patient population 
represents a reasonable treatment option. There are risks associated with chemotherapy, but 
the risk to benefit ratio is considered acceptable for patients with cancer. 

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IRB#318-15 
 
12.10 Potential Benefits to Society. 
Information obtained from this study may help other patients by contributing to the 
knowledge of the biology of cancers, and to understand the potential clinical benefit of this 
regimen. 
 
12.11 Potential Risks 
The use of cytototoxic chemotherapy are associated with numerous potential risks. Combined 
chemotherapy is considered a valid treatment option for patients with cancer. It is believed 
the treatment option outlined in the study will not pose significant additional risks compared 
to conventional treatment. 
 
12.12 Therapeutic Alternatives 
If  Subjects choose not to participate in this study they may elect to receive standard therapy 
as per their primary oncologist, which may include other chemotherapy drugs, radiation, 
surgery, or a combination of these approaches. The treatment recommendations may or may 
not be similar to treatment as described in this protocol. 
 
12.13 Risk/Benefit Relationship 
Although there are inherent risks involved because of the use of chemotherapy, we anticipate 
that Subjects 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 
The consent document used in this study will include the adult consent document.  
 
 
 
 
 
 
 
 
 
 
 
13.0: References 
1. Siegel, R., ma, J., zou, Z. and jemal, A. (2014), cancer statistics, 2014. CA: A cancer journal 
for clinicians, 64: 9–29. doi: 10.3322/caac.21208. .  
 
2. Young JL jr, roffers SD, ries LAG, fritz AG, hurlbut AA (eds).SEER summary staging manual - 
2000: Codes and coding instructions, national cancer institute, NIH pub. no. 01-4969, bethesda, 
MD, 2001. .  
 

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IRB#318-15 
3. Brewster AM, Hortobagyi GN, Broglio KR, et al. Residual risk of breast cancer recurrence 5 
years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179-1183. 
 
4. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant 
cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 
20 years of follow-up. N Engl J Med. 1995;332(14):901-906. 
 
5. Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide 
with and without interval reinduction therapy compared with 6 months of cyclophosphamide, 
methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-
nonresponsive tumors: Results from the national surgical adjuvant breast and bowel project B-
15. J Clin Oncol. 1990;8(9):1483-1496. 
 
6. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and 
hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the 
randomised trials. Lancet. 2005;365(9472):1687-1717. 
 
7. Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and the 
combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast 
cancer: An intergroup trial (E1193). J Clin Oncol. 2003;21(4):588-592. 
 
8. Nowak AK, Wilcken NR, Stockler MR, Hamilton A, Ghersi D. Systematic review of taxane-
containing versus non-taxane-containing regimens for adjuvant and neoadjuvant treatment of 
early breast cancer. Lancet Oncol. 2004;5(6):372-380. 
 
9. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential 
paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for 
patients with node-positive primary breast cancer. J Clin Oncol. 2003;21(6):976-983. 
 
10. Buzdar AU, Singletary SE, Theriault RL, et al. Prospective evaluation of paclitaxel versus 
combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as 
neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol. 1999;17(11):3412-
3417. 
 
11. Shulman LN, Berry DA, Cirrincione CT, et al. Comparison of doxorubicin and 
cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women 
with 0 to 3 positive axillary nodes: CALGB 40101 (alliance). J Clin Oncol. 2014;32(22):2311-
2317. 
 
12. Bishop JF, Dewar J, Toner GC, et al. Initial paclitaxel improves outcome compared with 
CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J 
Clin Oncol. 1999;17(8):2355-2364. 
 
13. Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus 
cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable 
breast cancer. J Clin Oncol. 2006;24(34):5381-5387. 

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IRB#318-15 
 
14. Jones S, Holmes FA, O'Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated 
with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year 
follow-up of US oncology research trial 9735. J Clin Oncol. 2009;27(8):1177-1183. 
 
15. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast 
cancer. N Engl J Med. 2008;358(16):1663-1671. 
 
16. 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;21(8):1431-
1439. 
 
17. Budd GT, Barlow WE, Moore HC, et al. SWOG S0221: A phase III trial comparing 
chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015;33(1):58-64. 
 
18. Baker J, Ajani J, Scotté F, et al. Docetaxel-related side effects and their management. 
European Journal of Oncology Nursing. 2009;13(1):49-59. 
 
19. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous 
recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-
overexpressing metastatic breast cancer. J Clin Oncol. 1996;14(3):737-744. 
 
20. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for 
human epidermal growth factor receptor 2-positive breast cancer: Planned joint analysis of 
overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014. 
 
21. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast 
cancer. N Engl J Med. 2011;365(14):1273-1283. 
 
22. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cyclophosphamide with 
either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast 
cancer: Final results of the FinHer trial. J Clin Oncol. 2009;27(34):5685-5692. 
 
23. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant 
chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672. 
 
24. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for 
patients with HER2-positive early breast cancer (PHARE): A randomised phase 3 trial. The 
Lancet Oncology. 2013;14(8):741-748. 
 
25. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab 
followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with 
HER2-positive locally advanced breast cancer (the NOAH trial): A randomised controlled 
superiority trial with a parallel HER2-negative cohort. The Lancet. ;375(9712):377-384. 

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IRB#318-15 
  
14.0 Data Collection Forms 
Attached 

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APPENDIX A 
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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IRB#318-15 
Appendix B –   ELIGIBILITY CHECKLIST 
IRB# 318-15   Title: A Phase II Study of Adjuvant Therapy Using a Regimen of 
Cyclophosphamide, Paclitaxel with Trastuzumab in Stage I-II HER2/neu Positive Breast 
Cancer Patients 
Date Completed: 
 
Institution:  
Subject ID:  
Checklist #: V4.0 
dated  01-03-2018 
PI: Amulya Yellala, MBBS 
Last Name:                                
First Name: 
Date of Birth:  
 
(MM/DD/YYYY) 
Gender:  [  ] M  [  ] F 
Race:  
[  ] White 
[  ] Black   
 [  ] Hispanic     [  ] Asian  
 
[  ] Native American 
 
[  ] Other            [  ] Unknown 
MRN: 
Zip Code/Country (if not 
USA):  
Primary 
method 
of 
payment 
information:  
 
 
Inclusion Criteria:                  
1. Histologically confirmed newly diagnosed Stage I-II HER2/neu positive breast cancer. 
2. Women above 19 years of age. Enter Age:___ 
3. 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. 
4. 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). Enter date: __/___/____ and  Result ________   
5. ECOG Performance Status of 0 or 1.  Enter PS: ________ 
6. Adequate laboratory parameters within 30 days prior to enrollment defined as:  
       Enter date: __/___/____ 
• 
Absolute neutrophil count greater than or equal to 1,500/mcl  
        Enter ANC: _____  
• 
Platelet count equal to or greater than 150,000/mcl  
               Enter Platelet count: ________ 
• 
Hemoglobin >11gm/dl                
        Enter Hgb count: ________ 
• 
Alkaline phosphatase equal or less than 1.5 times the ULN 
        Enter Alk Phos: ____  
• 
Total bilirubin equal to or less than 1.5 times the ULN  
        Enter Total Bili:____ 
• 
AST and ALT no greater than  1.5 times the ULN                 
        Enter AST: ____  Enter ALT: ____   
• 
Creatinine less than 1.5 times the ULN 
        Enter creatinine: ________   
7. Able to give informed consent. 
8. Normal cardiac function as defined by an ejection fraction of >50% by 
echocardiogram. 
9. Able to return for treatment and follow-up on the specified days. 
 
All of the above must be yes to be eligible 
 
Yes   No  N/A 
[   ]    [   ]1. 
[   ]    [   ]2. 
 
 
[   ]    [   ] [   ]3. 
 
 
 
[   ]    [   ] [   ]4. 
[   ]    [   ]5. 
 
 
 
 
 
[   ]    [   ]6. 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ]7. 
 
[   ]    [   ]8. 
[   ]    [   ]9. 
 
 
Exclusion Criteria: 
 

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IRB#318-15 
1. Prior malignancy; except for adequately treated basal cell or squamous cell skin cancer 
or noninvasive carcinomas. 
2. Pre-existing Grade II peripheral neuropathy. 
3. History of previous chemotherapy. 
4. Stage IV or metastatic breast cancer. 
5. Pregnant or nursing women. 
6. Inability to cooperate with treatment protocol. 
7. Active serious infections or other conditions precluding chemotherapy. 
8. Any comorbidity or condition which, in the opinion of the investigator, may interfere 
with the assessments and procedures of this protocol e.g. unstable angina, myocardial 
infarction within 6 months, severe infection, etc. 
9. Known hypersensitivity to any component of required drugs in the study. 
10. Known positive for HIV or infectious hepatitis, type A,B or C or active hepatitis. 
11. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
12. 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 A)  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. 
 
 
[   ]    [   ]1. 
[   ]    [   ]2. 
[   ]    [   ]3. 
[   ]    [   ]4. 
[   ]    [   ]5. 
[   ]    [   ]6. 
[   ]    [   ]7. 
 
 
[   ]    [   ]8. 
[   ]    [   ]9. 
[   ]    [   ]10.  
 
[   ]    [   ]11. 
 
 
 
 
 
[   ]    [   ]12.  
 
 
NOTE: All questions regarding eligibility for UNMC potential subjects should be directed to the UNMC Coordinator 
at 402-559-5582  or  UNMC Research Support Nurse Manager at 402-559-5286.  
 
All questions regarding eligibility for Participating/Collaborating Site potential subjects should be directed to the 
Sponsor PI by contacting the UNMC Fred & Pamela Buffett Cancer Center Multi-site Project Manager at 402-559-4596 
or the Research Support Nurse Manager at 402-559-5286. 
 
 
Patient Initials:  ______________MRN or Study ID#______________DOB ______________ 
Eligibility:    [   ]   Subject satisfies all criteria.  
                     [    ]  Subject not formally eligible, but admitted to study because (state reason);  
 
ELIGIBILITY reviewed and confirmed  
Site Investigator Signature _______________________Date_____________   
_____________________________________________________________________________________________ 
 
ELIGIBILITY reviewed and confirmed.  
 
Sponsor Investigator Signature _____________________________     Date_______________        
 
Printed Name of Sponsor Investigator:  __________________________________________________ 
        

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Appendix C: 
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 to store for future 
research purposes including DNA sequencing. (See protocol section 5.6 for details) No therapeutic 
intervention will be undertaken and the results of these studies will not have any influence on the medical 
management of the subjects.  
Sample 
Contact Person(s) 
Date and Time Points 
Blood: (30 ml total) two-
10ml EDTA (lavender top) 
and one- 10ml red top 
blood collection deliver or 
ship same day at room 
temperature 
Facility:  
Laboratory of David L. Kelly, PhD 
Fred & Pamela Buffett Cancer Center 
986805 Nebraska Medical Center 
Omaha, Nebraska 68198-6805 
 
Personnel:  
David L. Kelly PhD 
Tel: (402) 559-9157 
Cell: (402) 699-1132 
Fax: (402) 559-4651 
dkelly@unmc.edu 
 
Amy Wells, MS 
Research Technologist 
Tel: (402) 559-6015 
awells@unmc.edu  
 
Shipping Address: 
Attn:  Amy Wells, MS 
University of Nebraska Medical Center 
601 S. Saddle Creek Rd. 
F&PBCC 4.12.428 
 
Omaha, Nebraska 68106  
 
 
 Baseline, Blood Sample  
 
Date: ___/___/____ 
 
  Clinical endpoint (after cycle 6), Blood Sample 
 
Date: ___/___/____ 
 
  End of study (one year or end of tx) Blood Sample 
 
Date: ___/___/____ 
 
Please contact Amy Wells above to advise of planned shipments, and to discuss appropriate procedures 
and/or the UNMC Fred & Pamela Buffett Cancer Center Multi-site Project Manager at 402-559-4596. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D 
FDA 3500A MEDWATCH Form 
 
Available on-line at http://www.fda.gov/medwatch/SAFETY/3500.pdf