Conditions: Breast Cancer Carcinoma of the Breast
Keywords: node-negative breast cancer HER-2 positive
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 406
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out what effect the postoperative combination of therapies: trastuzumab (herceptin) and paclitaxel (taxol) will have on breast cancer recurrence. A combination of trastuzuamb and chemotherapy has been used in women with node positive and high risk node negative disease. This tests utilizes a well tolerated regimen of weekly paclitaxel and trastuzumab in women with T1, node negative tumors that are HER2 positive. We would like to determine how effective this drug combination is when used in women with early stage breast cancer, as well as to better define the side effects of this treatment.

Detailed description:
* Participants will enroll in this study at the time they are starting their adjuvant therapy for breast cancer. Participants will receive chemotherapy with paclitaxel every week for 12 weeks. They will begin to receive trastuzumab at the same time they begin paclitaxel. Once they have completed the 12 weeks of paclitaxel and trastuzumab, they will receive trastuzumab every 3 weeks or weekly for 40 weeks.
* Participants will be followed with routine assessments such as physical exam and vital signs every 3 months for the first year, and then every 6 months for years 2-5. Then we would like to keep track of the participants medical condition by calling them on the telephone once per year.

Arms:
arm 1: 80 mg of paclitaxel per square meter of body-surface area weekly for 12 weeks and a loading dose of 4 mg of intravenous trastuzumab per kilogram of body weight on day 1, followed by 2 mg per kilogram weekly, for a total of 12 doses. After the completion of 12 weeks of treatment with Trastuzumab, the dosing of Trastuzumab could be continued on a weekly basis, or the regimen could be changed to 6 mg per kilogram every 3 weeks for 40 weeks to complete a full year of intravenous treatment with trastuzumab.

Interventions: intervention 1: Paclitaxel intervention 2: Trastuzumab
Intervention descriptions: intervention 1: Every week for 12 weeks intervention 2: Once a week for twelve weeks Then once a week or once every three weeks for 40 weeks

Protocol document:
Prot_SAP_000.pdf: 


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TABLE OF CONTENTS
                                                                                                      
1.0
SCHEMA
 
2.0
OBJECTIVES 
2.1
Primary Objectives
    
2.2
Secondary Objectives
    
3.0
BACKGROUND 
3.1
Rationale
    
3.2
HER2 Overexpression and Breast Cancer
    
3.3
Testing for HER2 Overexpression
    
3.4
Trastuzumab in the Adjuvant Setting
    
3.5
Node-negative HER2-positive patients
    
3.6
Interactions between HER2 expression and chemotherapy                               
3.7
Paclitaxel as a Single-Agent in Adjuvant Therapy of Breast Cancer                
3.8
Scheduling of Paclitaxel  
3.9
Amenorrhea During and After Treatment with Paclitaxel and Trastuzumab
3.9.1
Research Design and Methods                                                                                  
3.10
Correlative Studies Background                                                                        
3.10.1 Molecular Alterations of Small HER2+ cancer cMYC                                                          
3.10.2 Predictors of Paclitaxel-induced neuropathy   
                        
3.11
Rationale for banking tissue and serum
3.11.1 Tissue and Serum Bank Summary
3.11.2   Patient Withdrawal of Consent to Use Research Samples
    
                  
                  
4.0
STUDY DESIGN
4.1
Description of the study                                                                                      
4.2
Demographic and Baseline Assessment                                                             
4.2.1
Screening Assessments                                                                           
4.3
Outcome Measures                                                                                              
4.3.1
Primary Outcome Measures                                                                    
4.4
Outcome Assessment Schedule                                                                           
4.5
Biomarkers                                                                                                          
4.5.1
Tumor Tissue                                                                                          
4.5.2
Serum                                                                                                      
4.6
Ancillary Safety Outcomes                                                                                 
4.6.1
Safety Plan                                                                                              
4.6.2
Pregnancy                                                                                                
4.6.3
Cardiac Dysfunction                                                                                
4.6.4
Management of Cardiac Safety
                                                
                                                                                       
5.0
PATIENT SELECTION
5.1
Eligibility Criteria
5.2
Ineligibility Criteria


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5.3
Patient Registration
5.3.1
Patient Registration Guidelines for DF/HCC and DF/PCC Institutions
5.3.2
Registration Process for DF/HCC and DF/PCC Institutions
5.3.3
Registration Process for Other Participating Institutions
6.0
STUDY CALENDAR
7.0
INCLUSION OF WOMEN AND MINORITIES                                                                 
8.0
TREATMENT PLAN
8.1
Chemotherapy Administration and Supportive Measures
                
    
8.1.1
Trastuzumab                                                                                           
8.1.2
Paclitaxel
                
8.2
Radiation Therapy   
8.3
Endocrine Therapy                                                                                           
9.0
DOSE MODIFICATIONS
9.1
Paclitaxel
9.1.1
Anaphylaxis/Hypersensitivity                                                             
9.1.2
Cardiac Arrhythmias                                                                      
9.1.3
Hematologic Toxicity
9.1.4
Neurologic Toxicity                                                                             
9.1.5
Gastrointestinal Toxicity                                                                      
9.1.6
Febrile Neutropenia                                                                             
9.1.7
Infection with/without neutropenia                                                     
9.1.8
Other Grade 3 or 4 Toxicities                                                              
9.1.9
Dose Modifications for Obese Patients                                               
9.2
Trastuzumab
9.2.1
Infusion-associated symptoms                                                             
9.2.2
Trastuzumab when paclitaxel is delayed or discontinued                    
9.2.3
Cardiac Dysfunction                                                                  
9.2.4
Ischemia                                                                                               
9.2.5
Arrhythmia                                                                                           
9.2.6
Myocardial Infarction                                                                           
9.2.7
Fever
9.2.8
Chills                                                                                                    
9.2.9
Gastrointestinal                                                                                    
9.2.10 Allergy/Immunology                                                                            
9.2.11 Pulmonary                                                                                            
10.0
DRUG FORMULATION, AVAILABILITY, AND PREPARATION
10.1
Trastuzumab                                                                                                    
10.1.1 Availability                                                                                          
10.1.2 Preparation                                                                                           
10.1.3 Storage and Stability                                                                            


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10.1.4 Administration                                                                                     
10.1.5 Toxicities                                                                                             
10.2
Paclitaxel                                                                                                         
10.2.1 Availability                                                                                          
10.2.2 Preparation                                                                                           
10.2.3 Storage and Stability                                                                        
10.2.4 Administration                                                                                 
10.2.5 Toxicities                                                                                         
10.3
Ancillary Therapy                                                                                        
11.0
DEFINITION OF PRIMARY ENDPOINT AND REMOVAL OF PATIENTS FROM 
THERAPY
11.1
Primary Endpoint                                                                                        
11.2
Removal of Patients from Protocol Therapy                                              
12.0
STATISTICAL CONSIDERATIONS                                                                   
12.1
Study Design                                                                                               
12.2
End Points                                                                                                   
12.3
Sample Size Justification                                                                                                
12.4
Statistical Analysis                                                                                      
13.0
STUDY CONDUCT CONSIDERATIONS                                                          
13.1
Institutional Review Board or Ethics Committee Approval                      
13.2
Data Safety Monitoring Committee                                                 
13.3
Study Monitoring Requirements                                                                
13.4
Disclosure of Data                                                                                      
13.5
Retention of Records                                                                                  
14.0
ADVERSE EVENTS: REPORTING AND MONITORING
14.1
Adverse Event and Reporting Definitions                                                  
15.0
STUDY ORGANIZATION                                                                                   
16.0
REFERENCES                                                                                                       
APPENDICES
APPENDIX 1: Baseline Assessment of Menses        
     
APPENDIX 2: Follow-up Menses Assessment
APPENDIX 3: National Cancer Institute Common Toxicity Criteria
APPENDIX 4: ECOG Performance Status
APPENDIX 5: Treatment Completion/Off-Study Form
APPENDIX 6: Blood Collection Requisition Form
APPENDIX 7: Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety 
Monitoring Plan


APT, page 4
1.0
SCHEMA
HER2+ Breast Cancer:
Tumor 3cm
Lymph node negative*  Surgery**  Registration  Paclitaxel qwk + Trastuzumab qwk x 12  Trastuzumab qwk or q3wks x 40 wks†
HER2-positive***
*Patients with a micrometastasis are eligible
**Surgery with either lumpectomy or mastectomy, as clinically indicated, with sentinel lymph node biopsy or axillary node dissection.  
*** HER2 3+ by IHC or FISH 2
†Trastuzumab may be given 6 mg/kg every 3 weeks or 2 mg/kg weekly for 40 weeks after completion of paclitaxel 
(Total of 13 doses if given every 3 weeks)
Adjuvant endocrine therapy as per institutional standard.  Tamoxifen should not be given during treatment with paclitaxel


APT, page 5
2.0
OBJECTIVES
2.1
Primary Objective
2.1.1
Evaluate disease free survival (DFS) in patients with node-negative HER2-
positive breast cancer with tumors  3cm treated with adjuvant trastuzumab 
and paclitaxel
2.2
Secondary Objectives
2.2.1
Describe DFS in patient groups defined by tumor size  (≤1 cm or > 1 cm) 
and hormone receptor status
2.2.2
Evaluate the incidence of grade III/IV cardiac left ventricular dysfunction 
from adjuvant trastuzumab and paclitaxel
2.2.3
Evaluate the incidence of grade III/IV neurotoxicity associated with 
adjuvant paclitaxel
2.2.4
Characterize molecular alterations within tumors from patients with HER2-
positive breast cancer with tumors measuring  ≤ 3cm and no nodal 
involvement
2.2.5
Investigate the percentage of patients with amenorrhea at various times after 
start of treatment in premenopausal women treatment with paclitaxel and 
trastuzumab for early stage breast cancer
2.2.6
Explore predictors of amenorrhea that persist to the time period 6 to 12 
months after the start of treatment with paclitaxel and trastuzumab for early 
stage breast cancer. 


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3.0
BACKGROUND 
3.1
Rationale 
Five randomized trials have established trastuzumab-based therapy as standard of care for 
patients with HER2-positive, early stage breast cancer.  Despite these compelling results, 
there remains little data on outcomes for patients with lower-risk, stage1 breast cancers 
which are HER2-positive.  Most of the clinical trials excluded patients with small lymph 
node negative, while others accrued few patients with node-negative disease (see Table 
below).   
Trial
Eligibility Requirements
NSABP B-31
Node-positive disease
N-9831
Node-positive disease OR
High-risk node-negative disease: tumor 2 cm and ER- or PR-positive, or 
tumor 1cm and ER- and PR-negative
HERA
Node-positive disease OR
Node-negative disease with tumor 1cm
BCIRG 006
Node-positive disease OR
Node-negative disease AND one of the following risk factors: tumor 
>2cm, ER- and PR-negative, grade 2-3, or age <35
FinHER
Node-positive disease OR
Node-negative disease with tumor 2 cm and PR-negative
To date, none of the reported data for adjuvant trastuzumab has reported outcomes for 
node-negative patients in direct, absolute terms, though subset analyses suggest similar 
relative risk reduction for these tumors (approximately 50%) as seen in the overall study 
population.  Because the absolute benefit of trastuzumab for low-risk HER2-positive 
tumors remains unknown, the role of trastuzumab in patients with small, node-negative 
tumors remains controversial.  Current consensus guidelines from the NCCN do not 
recommend adjuvant trastuzumab for tumors <1 cm in size, owing to the lack of data for 
safety and efficacy in this patient population (see www.nccn.org).  Based on historical 
experience, it is reasonable to expect that the absolute benefit of chemotherapy and 
trastuzumab is more modest in node-negative breast cancer, as these tumors have in 
general a better prognosis and thus lower gains with adjuvant therapy.  Thus, the decisions 
to use adjuvant chemotherapy with agents such as anthracyclines and taxanes, and the use 
of adjuvant trastuzumab, may be informed by different considerations of risk and benefit 
for this lower risk group than for higher risk early stage breast cancer.  In clinical practice, 
oncologists have taken many different approaches in this group of women.  While some 
have held back on treatment entirely, others have given chemotherapy alone, adriamycin 
and cytoxan (AC) followed by trastuzumab (H), AC followed by paclitaxel and 
trastuzumab (AC-TH), docetaxel, carboplatin, and trastuzumab (T2CH), or paclitaxel and 
trastuzumab (TH).
This trial is designed to characterize the clinical course of women with small, node 
negative breast cancer who are treated with a uniform trastuzumab-containing regimen. 
The inclusion criteria specifically target women who were generally not eligible for 


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previous trials with HER2-directed therapy.   Ideally, a randomized controlled trial would 
be conducted in this population to compare the utility of treatment with trastuzumab in 
combination with paclitaxel compared to paclitaxel alone, but such a trial would require 
many thousands of patients, and it is not believed feasible to enroll a sufficient number of 
patients in a reasonable time period in order to accomplish such a trial.  For that matter, 
based on discussions with oncologists and breast cancer advocates, it seems unlikely that 
physicians and patients would be comfortable with the randomization.
Most adjuvant trastuzumab trials administered trastuzumab for 52 weeks of treatment.  The 
small but provocative FinHER trial included only 232 patients, but administered only 9 
weeks of trastuzumab paired with taxane therapy.  This study demonstrated relative risk 
reduction of >50% for the use of trastuzumab, suggesting indirectly that concurrent taxane-
trastuzumab therapy can be effective treatment for early stage breast cancer and is superior 
to taxane-anthracycline chemotherapy given in the absence of trastuzumab. Preliminary 
analyses of NCCTG N9831 suggest that concurrent use of taxane-trastuzumab therapy is 
superior to sequential use, further justifying a combination treatment program.
The most worrisome toxicity of adjuvant trastuzumab is congestive heart failure and 
cardiomyopathy, which arises in 2-4% of patients receiving adjuvant trastuzumab and 
anthracyclines (see Table below).  Limited clinical experience suggests a substantially 
lower risk of cardiomyopathy (on the order of 1%) for patients receiving non-anthracycline 
chemotherapy and trastuzumab.  In an attempt to potentially reduce toxicity, while 
maintaining efficacy, weekly paclitaxel therapy was selected as the agent of choice to be 
administered with trastuzumab therapy.  Paclitaxel has been shown to be efficacious in 
standard combination chemotherapy regimens in the neoadjuvant and metastatic settings.  
While anthracyclines have been shown to be effective in the treatment of HER2-positive 
breast cancer, we believe that the potential cardiac toxicity that may result from 
administration of both an anthracycline and trastuzumab would outweigh the benefits in 
this lower-risk population.


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Trial
Class III or IV CHF
NSABP B-31
ACT
ACTH
0.8%
4.1%
N-9831
ACT
ACTH
0.3%
2.5%
HERA
Chemotherapy
Chemotherapy + Trastuzumab x 1 year
0.06%
1.7%
BCIRG 006
ACT
ACTH
TCH
0.29%
1.59%
0.38%
FinHER
Docetaxel or Vinorelbine + FEC
Docetaxel or Vinorelbine + FEC + Trastuzumab
2.59%
0.27%
AC, adriamycin/cytoxan; TH, paclitaxel/trastuzumab; TCH, 
docetaxel/carboplatin/trastuzumab
For these reasons, we have developed an exploratory study to evaluate the safety and 
efficacy of paclitaxel and trastuzumab therapy as adjuvant treatment for patients with 
small, node-negative HER2-positive breast cancer. 
3.2
HER2 Overexpression and Breast Cancer
Overexpression of HER2 is observed in 20-25% of all breast cancers.1 HER2-positive 
breast cancers are associated with earlier recurrence and shorter overall survival and are 
associated with other adverse prognostic markers, such as high tumor grade, high rates of 
cell proliferation, increased nodal metastases, and relative resistance to certain types of 
chemotherapy.2,3 Based on retrospective studies, anthracycline-based chemotherapy is 
particularly beneficial in HER2-positive tumors.4 In addition, recent evidence suggests that 
paclitaxel may also be a particularly active agent in the adjuvant treatment of HER2 
positive disease.5 While about half of HER2-positive breast cancers express hormone 
receptors for estrogen and/or progesterone, they may be relatively resistant to tamoxifen.6 
Trastuzumab is a recombinant humanized monoclonal antibody that targets the 
extracellular domain of HER2.  While trastuzumab has been shown to improve outcomes 
in women with node-positive HER2-positive breast cancer, its mechanism of action is not 
clear.  It is thought that trastuzumab binds to the HER2 protein, resulting in apoptosis, 
down-regulation of surface HER2 expression, and alteration of downstream signaling.


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3.3
Testing for HER2 Overexpression
Initial clinical trials were performed using immunohistochemistry (IHC) to determine 
which patients had HER2-positive breast cancer.  This test measures HER2 protein levels 
on the cell surface, to determine HER2-positivity in breast cancer specimens.  IHC scoring 
is performed by a pathologist on a subjective basis.  HER2 immunostaining is graded as 0, 
1+, 2+, or 3+ based on the percentage of malignant cells stained and the degree of 
membrane staining present in these malignant cells.7 Two types of IHC tests are approved 
by the FDA: HerceptTest (Dako, Carpinteria, CA) and PATHWAY (Ventana Medical 
Systems, Inc, Tucson, AZ).
More recently, fluorescence in situ hybridization (FISH) has been developed to identify 
patients with HER2-positive tumors.  This test directly measures HER2 gene amplification.  
Three types of FISH tests are approved by the FDA: PathyVysion (Vysis Inc, Downers 
Grove, IL; 2.0 ratio HER2:CEP17 considered amplified), INFORM (Ventana Medical 
Systems Inc; ; 5.0 gene copies of HER2 considered amplified), and HER2 FISH pharmDx 
(Dako; 2.0 ratio HER2:CEN-17 considered amplified).
A strongly HER2-positive tumor is associated with the most clinical benefit from 
trastuzumab.  Subgroup analysis in a large phase III trial showed that patients with IHC 3+ 
tumors experienced significant improvement in all clinical outcomes with trastuzumab 
therapy, however, the benefit in patients with IHC 2+ tumors was minimal.8  Because 
patients with false-positive HER2 results may receive little benefit from trastuzumab, 
excluding them from clinical trials will better help evaluate the true effect of trastuzumab 
therapy.  When local and central evaluation used the same methodology, concordance was 
88.1% for FISH and 81.6% for IHC.7 Furthermore, the IHC 2+ category is the most likely 
to be discordant with FISH HER2 status.  In comparing FISH with HercepTest in central 
laboratories, agreement rates between FISH and IHC were 97% for IHC 0, 93% for IHC 
1+, 24% for IHC 2+, and 89% for IHC3+.9  
3.4
Trastuzumab in the Adjuvant Setting
Five important trials validate the use of trastuzumab in the adjuvant treatment of breast 
cancer.  
The NSABP B-31 and N-9831 trials compared adjuvant chemotherapy with or without 
concurrent trastuzumab in women with surgically resected HER2-positive breast cancer.10 
Both trials enrolled patients with node-positive disease.  N-9831 also enrolled patients with 
high-risk node-negative disease, defined as ER- or PR-positive with tumor size >2cm or 
ER- and PR-negative with tumor size >1cm.  Node-negative patients represented 0.1% of 
all patients on this study.  Due to similar eligibility and treatment protocols, the decision 
was made to perform a combined analysis.  The NSABP B-31 compared doxorubicin 60 
mg/m2, cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles followed by paclitaxel 
175 mg/m2 every 3 weeks for 4 cycles with the same regimen plus 52 weeks of weekly 
trastuzumab (loading dose 4 mg/m2 followed by 2 mg/m2 thereafter).  The N-9831 
compared 3 arms: doxorubin and cyclophosphamide every 3 weeks for 4 cycles followed 
by weekly paclitaxel 80 mg/m2 for 12 cycles, the same regimen followed by 52 weeks of 


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trastuzumab, and the same regimen plus 52 weeks of trastuzumab initiated concomitantly 
with paclitaxel.  Because trastuzumab was not given concurrently in the second arm, this 
arm was not included in the overall analysis.  Overall, there were 1,736 patients in the B-31 
trial and 1,615 patients in N-9831, and at the time of the combined analysis, the median 
follow-up was 2.0 years.  Compared with the control arm, the trastuzumab arm showed a 
statistically signficant increase in 3-year disease-free survival (DFS), 75.4% vs 87.1% 
respectively, p<0.0001; and a significant increase in overall survival (OS), 91.7% vs 
94.3%.   The cumulative incidence of class III or IV heart failure was 0.8% in the control 
group and 4.1% in the trastuzumab group.  
The HERA (Herceptin Adjuvant) trial focused on determining the optimal duration of 
trastuzumab for early-stage breast cancer.11 Patients were randomized to one of three arms: 
observation, trastuzumab every 3 weeks for 1 year, or trastuzumab every 3 weeks for 2 
years.  Trastuzumab was dosed with 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks 
thereafter.  Patients had either node-negative disease if tumor size >1cm (32.1%) or node-
positive disease, and all patients had HER2-positive tumors.  At a median follow-up of 2 
years, the addition of trastuzumab to neoadjuvant and adjuvant chemotherapy resulted in a 
statistically signficant improvement in DFS (86.1% vs 78%) and overall survival (96.9% vs 
93.6%).  Further analysis is expected to determine if 2 years is superior to a year of 
treatment.  
The BCIRG 006 trial aimed at maximizing the efficacy of trastuzumab while minimizing 
cardiac toxicity.12 The trial enrolled 3,222 patients with node-positive or high-risk lymph 
node-negative HER2-positive tumors to 1 of 3 arms: doxorubicin-cyclophosphamide every 
3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (ACT); or the same 
regimen plus 52 weeks of trastuzumab,weekly during chemotherapy then every 3 weeks 
during follow-up (ACTH); or docetaxel-carboplatin every 3 weeks for 6 cycles plus 52 
weeks of trastuzumab with the same schedule as given in arm 2 (TCH). At a 36 month 
follow-up, presented at the 2006 San Antonio Breast Conference, the 2 trastuzumab arms 
showed a statistically significant improvement in DFS compared with the control arm. 
Symptomatic cardiac events and an LVEF decline >15% were statistically significantly 
greater in the ACTH group compared with the ACT.  There was no statistically significant 
difference between the ACT and TCH groups in terms of cardiac side-effects.  This trial 
shows that fewer cardiac events are observed when trastuzumab is administered without 
prior anthracycline-based therapy. There was no statistically significant difference in terms 
of disease free survival across the two trastuzumab-containing arms.  A recent trial in the 
metastatic setting revealed that carboplatin does not improve response rates, time to 
progression, or overall response rate when added to docetaxel and trastuzumab.13  
Indirectly, this study suggests that a taxane-trastuzumab adjuvant regimen may be almost 
as effective as a regimen that contains both an anthracycline and a taxane and is almost 
certainly associated with less cardiotoxicity.  In patients at lower risk of recurrence, 
toxicity associated with adjuvant therapy becomes a major concern.
The FinHer trial involved 1,010 patients randomized to docetaxel every 3 weeks for three 
doses versus 9 weeks of vinorelbine followed, in both groups, by three weeks of 
cyclophosphamide, epirubicin, and fluoruracil (CEF).14   The 232 patients found to be 
HER2 positive were randomized to receive weekly trastuzumab for 9 weeks with docetaxel 


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or vinorelbine.  This trial enrolled women with axillary node-positive disease or women 
with node-negative breast cancer with tumors >2cm and progesterone-receptor negative. 
After a median follow-up of 3 years, they found that recurrence was less frequent amongst 
women receiving docetaxel/CEF with 42/502 recurrences compared with 71/507 
recurrences in the vinorelbine/CEF arm at 3 years.  They also found that trastuzumab for 9 
weeks was effective in preventing breast cancer recurrence, with 12/115 events in the 
trastuzumab arm compared with 27/116 events in the arm without trastuzumab (p=  0.01).  
In November 2006 the FDA approved trastuzumab for use as part of a treatment regimen 
containing doxrubicin, cyclophosphamide and paclitaxel for the treatment of patients with 
HER2 overexpressing, node positive breast cancer.
3.5
Node-negative HER2-positive patients
There have been a few studies done to look at the prognosis of node-negative breast 
cancers.  Andrulis et al found that a patients with a HER2-positive tumor had a two-fold 
increase in the risk of recurrence compared to those with HER2-negative tumors.15 The 3-
year DFS was 80% for those with HER2-positive tumors, and 90% for HER2-negative 
tumors. Press et al also found a two-fold increase risk of recurrence for HER-positive 
tumors relative to HER-negative tumors.16 The 4-year DFS was approximately 90% for 
HER-2 negative tumors, and 70% for HER-2 positive tumors.  They also found that 
patients with breast cancers ≤1cm in diameter who had evidence of HER2-amplification 
had a 5.7 times higher risk of recurrence compared to HER2-negative patients with small 
tumors.   A recent retrospective study reviewed records of 164 patients with node-negative 
HER2-positive breast cancer, and found a 19% risk of recurrence in T1a tumors, 15% in 
T1c, and 23% in T2 tumors at 5 years.  This reveals that small node-negative HER2-
positive breast cancer have a moderate risk of locoregional and distant recurrence.17  
3.6
Interactions between HER2 expression and chemotherapy
Among node-negative patients, HER2-overexpressing tumors have been found to be 
relatively refractory to benefit from CMF (cyclophosphamide, methotrexate, fluorouracil)-
based chemotherapy, and studies suggest that dose-intensification with an anthracycline-
containing chemotherapy such as CAF (cyclophosphamide, adriamycin, and fluorouracil) 
may be beneficial to patients with HER2-positive, lymph-node positive early breast 
cancers.18   
The combination of paclitaxel and trastuzumab has shown good efficacy, and favorable 
toxicity in the metastatic setting.  In a phase II study in women with metastatic breast 
cancer, weekly paclitaxel and trastuzumab resulted in a 67-81% response rate in HER2-
positive patients, with a 6% incidence of grade 3/4 neutropenia.19 Similarly, docetaxel and 
trastuzumab have had high response rates and favorable toxicity in metastatic HER2-
positive patients.20,21 


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3.7
Paclitaxel as a Single-Agent in Adjuvant Therapy of Breast Cancer
Paclitaxel has been compared to FAC (5-FU, doxorubicin, cyclophosphamide) in the 
neoadjuvant setting.22 Patients with T1-3, N0-1 disease were randomized to receive either 
paclitaxel (250 mg/m2) as a 24-hour infusion or FAC every 3 weeks.  Each patient 
received 4 cycles of preoperative therapy, and the extent of residual disease at the time of 
surgery was similar between the two arms.
A recent trial compared nonanthracycline adjuvant docetaxel and cyclophosphamide (TC) 
to doxorubicine and cyclophosphamide (AC) as adjuvant chemotherapy for women with 
operable breast cancer.23  In this study, 1016 patients were randomized to AC or TC given 
every 3 weeks for 4 cycles.  At a median follow-up of 66 months, patients treated with TC 
had significantly improved disease-free survival compared with AC-treated patients (86% 
vs 80%, p=0.015) and a favorable overall survival (90% vs 87%, =0.13).  There was 
significantly more grade 3 or 4 febrile neutropenia in the TC arm and more grade 3 or 4 
nausea and vomiting in the AC arm.  This study adds to the evidence that taxanes should be 
a part of adjuvant therapy, and suggests that omission of anthracycline therapy is possible.
When studied in the metastatic setting, paclitaxel resulted in similar response rates to 
patients receiving CMFP (cyclophosphamide, methotrexate, 5-FU, and prednisone).24  In 
addition, many aspects of quality of life were better in patients receiving paclitaxel 
compared to CMFP.  Paclitaxel resulted in significantly less bone marrow suppression, 
documented infection, mucositis, and nausea and vomiting.  Alopecia, peripheral 
neuropathy, and myalgias and arthralgias were greater with paclitaxel.  Overall quality of 
life appeared better for patients receiving paclitaxel.  
While it is difficult to extrapolate this information to the adjuvant setting, it appears that 
single agent paclitaxel is at least equivalent to FAC in the neoadjuvant setting, and to 
CMFP in the metastatic setting.  Also, CMF has been shown to be equivalent to AC as an 
adjuvant therapy in NSABP B-15, suggesting that paclitaxel will likely be equivalent to 
AC in the adjuvant setting.  There is an ongoing study, CALGB 40101 which is comparing 
4-6 cycles of AC to 4-6 cycles of paclitaxel, and this will help further compare paclitaxel to 
an anthracycline-based regimen. 
 
Based on the little that is known about the failure rate of the patients eligible for this study, 
we want a large chance of stopping accrual to the study early if the true 3 year failure 
percent is as large as 14%.  We want a small chance of declaring the regimen worthy of 
further research if the true 3 year failure percent is around 9%, and want a large chance of 
declaring the regimen worthy of further research if the true 3 year failure percent is as 
small as 5%.
 


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3.8
Scheduling of Paclitaxel
The optimal schedule for paclitaxel was studied in metastatic breast cancer in CALGB 
9840.  Patients were randomized to paclitaxel 80 mg/m2 over 1 hour weekly or a standard 
3-hour infusion of 175 mg/m2 every 3 weeks.  Patients with HER2 overexpression 
received trastuzumab.  Women in the weekly paclitaxel arm showed a significantly 
increased TTP (9 vs. 5 months) and a trend toward increased OS (24 vs. 16 months, 
p=0.17.25 Weekly paclitaxel caused less neutropenia (5% vs. 15%) but worsened 
neurosensory toxicity (23% vs. 12%).  
In the adjuvant setting, E1199 compared adriamcyin and cyclophosphamide (AC) followed 
by paclitaxel or docetaxel, given either weekly, or every 3 weeks.26 Disease-free survival 
(DFS) was not significantly different between docetaxel and paclitaxel or weekly and every 
3 weekly therapy.  However there was an important and unanticipated interaction between 
the taxane and dose.  DFS was significantly improved in the weekly paclitaxel and every 3 
week docetaxel arms compared with the every 3 week paclitaxel arm.
3.9
Amenorrhea During and After Treatment with Paclitaxel and Trastuzumab
Many premenopausal women undergoing adjuvant chemotherapy for breast cancer are 
concerned about the risk of ovarian damage due to the treatment.  Standard adjuvant breast 
cancer chemotherapy regimens are associated with chemotherapy-related amenorrhea 
(CRA) as well as with a risk of infertility.  Menses may cease temporarily or permanently 
during or shortly after chemotherapy.  Women may also continue menstruating normally (or 
resume menses after a period of amenorrhea) only to experience premature ovarian failure 
later on.  The risk of CRA with paclitaxel-trastuzumab therapy is unknown.   
Risk of CRA is known to increase with older age and when greater cumulative dose of 
alkylating agents are used.27  In the International Breast Cancer Study Group (IBCSG) Trial 
V, 31% of the 188 premenopausal women with node-positive disease who received only 
one cycle of perioperative cyclophosphamide-methotrexate-fluorouracil (CMF) reported at 
least three months of amenorrhea within the nine months after surgery, compared with 68% 
of the 387 similar patients who received 6-7 cycles of CMF.28  A recent retrospective 
evaluation of long-term follow-up data from IBCSG Trials V and VI (which also 
administered variable numbers of CMF cycles) showed that the 227 women who remained 
premenopausal after 6 cycles of adjuvant CMF had high probabilities of menopause at five 
years after start of CMF, even in younger age cohorts.29,30  In IBCSG V or VI, a woman 
who was 30 years old at time of diagnosis with continued menstruation after six cycles of 
CMF had a 37% risk of menopause at age 35 and an 84% risk at age 40.  Thus, alkylating 
agents can induce both immediate amenorrhea and eventual premature ovarian failure. 
However, the occurrence of not immediate, but nevertheless premature menopause 
following adjuvant chemotherapy is not well studied, as most studies of amenorrhea have 
focused on earlier endpoints.  
For example, a prospective study of 25-40 year old women with breast cancer undergoing 
either doxorubicin-cyclophosphamide (AC, 120 pts), doxorubicin-cyclophosphamide-


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paclitaxel (ACT, 168 pts), CMF (83 pts), 5-FU-doxorubicin-cyclophosphamide (FAC, 38 
pts), doxorubicin-cyclophosphamide-docetaxel (ACD, 19 pts), or another regimen (58 pts) 
found that menstrual cycles were more likely to persist after the regimens that contained a 
lower cumulative dose of cyclophosphamide (AC, ACT, or ACD rather than FAC or 
CMF).31  While women who were on CMF were more likely than those on AC, ACT, or 
ACD to bleed during the one month following chemotherapy (approx 50% vs. 20%, odds 
ratio 2.9, 95% CI 1.7-5), one year later the likelihood of menses was less in the CMF group 
(OR .37, 95% CI .37-.67).  
A meta-analysis of twelve studies confirmed that amenorrhea occurred after CMF 
chemotherapy in approximately 40% of women younger than 40, and in 76% of women 
older than 40.32  Anthracycline-containing regimens including cyclophosphamide-
epirubicin-5-FU (CEF) may be even more gonadotoxic than CMF.  In one study, 
premenopausal women who received CEF had a 51% risk of amenorrhea compared to a 
42.6% risk in women who received CMF at the 6 month follow-up (an 8% difference).33 
However, in this study, percents of amenorrhea were slightly closer in the two groups at 12 
months (76% in CEF group, 71% in CMF group, a 5% difference), highlighting the 
importance of longer term follow-up.
Because trastuzumab is a monoclonal antibody against Her2-expressing cells, it does not 
carry a risk of ovarian damage.  However, because paclitaxel is a mitotic inhibitor, it does 
carry at least a theoretical risk of amenorrhea, and the gonadotoxic effect of taxanes remains 
uncertain.  A small prospective evaluation of 50 premenopausal women revealed hormonal 
changes in follow-up suggesting that regimens containing a taxane were more gonadotoxic 
than those that did not.34  Another retrospective survey of 195 breast cancer patients under 
age 50 found that it was only among women aged 40 or younger that adding a taxane to AC 
increased the likelihood of six months of CRA beginning within a year of the start of 
chemotherapy (40% vs 61%, p=.04 in the <40 group; 81% vs 84%, p=.35 in the >40 
group).35  In this study, however, many resumed menses in the <40 group after this period 
of CRA (33% in the AC alone group, 43% in the ACT group).  In contrast, a 
retrospective evaluation of 235 premenopausal women younger than 40 treated with AC 
followed by a taxane showed only 17% had amenorrhea, which was no higher than historic 
controls treated with AC alone. 36  Similarly, a retrospective study of 403 patients evaluated 
after treatment with AC or AC followed by paclitaxel every 14 or 21 days revealed no 
significant increase in amenorrhea at six months or later with the addition of paclitaxel (OR 
1.45, 95% CI .78-2.69), when controlling for age and other variables.37  
Notably, none of these trials have evaluated percents of amenorrhea using paclitaxel 
without an anthracycline.  Study 07-199 will investigate the incidence of amenorrhea during 
and after therapy with paclitaxel-trastuzumab.  It is important that data on menstrual history 
is collected before start of treatment in order to establish a baseline, then again at the 
completion of chemotherapy to investigate how regular menses were during exposure to 
these agents, and then at each follow-up visit (every six months) in order to assess for 
duration of amenorrhea and also premature ovarian failure.  This information will be 
valuable to physicians and premenopausal patients making decisions regarding adjuvant 
therapy, as well as in their follow-up care and concerns.


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3.9.1
Research Design and Methods
In premenopausal patients (those with at least one menstrual period in the 6 months 
prior to registration) who are registered on 07-199 and who agree to take part in this 
sub-study on amenorrhea, this will be a prospective assessment of menstrual 
functioning and percents of amenorrhea over time in premenopausal women 
enrolled in 07-199.  A patient who was registered on 07-199 before the activation of 
the amenorrhea amendment will be assessed for eligibility at the time of her first 
study visit after the amendment is activated, and if she is deemed to have been 
premenopausal at the time of study registration and agrees to participate in this sub-
study, she will be asked to fill out the menstrual forms for past scheduled 
assessments retrospectively and the menstrual forms for future scheduled 
assessments prospectively.  Those who agree to participate in the sub-study 
(whether in a retrospective or prospective manner) will fill out a questionnaire 
regarding baseline menstrual status and date of last menstrual period at enrollment 
onto the trial (using the Baseline Menstrual Status Form, Appendix 1).  Prospective 
follow-up assessments will occur as close to the following specified timepoints as 
possible: on the final day of chemotherapy using the 12-week Menstrual Status 
Form (Appendix 2); at the office visit three months later using the Menstrual 
Follow-up Form (Appendix 3); and every six months to 4 years past enrollment, and 
annually at 5 and 6 years past enrollment, using the Menstrual Follow-Up Form 
(Appendix 3).   The surveys will be given to patients in clinic or mailed to them to 
complete at home.  If mailed, patients will both complete and mail back the survey 
or they will be contacted for collection of the information.  These surveys will ask 
about use of hormonal agents before diagnosis, at baseline, and during follow-up.  
Completion of the menses assessment survey by the patient is waived at the 
specified time points if the required information is documented in a physician’s 
note.
Outcomes: The primary endpoint of this sub-study will be to estimate the proportion 
of women who have menstruated at least once in the period of 6 to 12 months after 
enrollment on 07-199 (Trastuzumab therapy ends at the 12 month point.)   Although 
some women may lose or recover menses soon after this time point, the one-year 
mark should allow time for most women who will resume ovarian cycling to do so.  
The secondary endpoints will be to estimate the proportion of women who report at 
least one menstrual period over the six month period that encompasses the 12 weeks 
of chemotherapy (so including 3 months of menstrual history before starting 07-
199), and the proportion of women who report at least one period in the prior six 
months at each of the follow-up points (every six months to 4 years past enrollment, 
and annually at 5 and 6 years past enrollment).  An exploratory secondary endpoint 
will be to examine possible predictors of menstruating at least once in the period 6 
to 12 months after enrollment on 07-199.


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3.10
Correlative Studies Background
Identification of molecular markers that predict clinical outcome after trastuzumab based 
therapy will allow more optimal tailoring of therapy to a particular individual’s cancer. In 
addition, such markers may provide insight into the mechanisms of resistance to 
trastuzumab based therapy as well as provide potential approaches to overcoming this 
resistance.
 
3.10.1 Molecular Alterations of Small HER2+ cancer
Determining molecular alterations within cancer can help provide predictive and prognostic 
information.  Since there is currently no standard of care treatment for early stage HER2-
positive breast cancer, developing a better understanding of this subtype may provide 
deeper insights into therapeutic approaches for this disease.  
We propose performing sequencing on all archival tumor which yields adequate DNA from 
to better characterize molecular alterations within this subset of HER2-positive breast 
cancer.  We will also obtain tumor samples from biopsies performed at the time of relapse 
and perform next generation sequencing on these samples as well.
We anticipate that we will be able to get adequate DNA from approximately 50% of 
samples (n=200).  All slides will initially be reviewed to localize invasive cancer.  These 
areas will be extracted for DNA by the Center for Molecular Oncologic Pathology at Dana-
Farber Cancer Institute.  Nikhil Wagle at the Broad Institute will be responsible for 
performing generation sequencing, and for the analysis.
We will analyze all baseline samples paired with the recurrence samples for sequencing, 
assuming adequate DNA can be obtained from samples.  We will explore results to see if 
there are particular baseline molecular alterations that predict recurrence, and will explore 
how frequent of an alteration this is within this molecular subtype.  Additionally we will 
explore what alterations occur at time of recurrence to help define what escape mechanism 
may be responsible for development of recurrent disease.  Defining these molecular 
alterations may help us develop better therapies for this particular subgroup of breast 
cancer.


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3.10.2   Predictors of Paclitaxel-induced neuropathy
It is possible that inherited variation in the activity of drug-metabolizing enzymes can 
result in differences in the pharmacokinetics of paclitaxel between different patients.  Thus, 
some patients may be susceptible to a paclitaxel-induced neuropathy. The purpose of this 
investigation is to correlate genetic polymorphisms in enzymes involved in paclitaxel 
metabolism and elimination with paclitaxel-induced neuropathy. We plan to compare the 
genetic profiles of patients with paclitaxel-induced neuropathy to patients who do not 
manifest this side effect. The drug metabolizing enzymes that will be evaluated include the 
MDR1, CYP2C8, CYP3A4, CYP3A5, NR1I2. 
Allele
Frequency
CYP2C8*3
0.130
CYP2C9*2
0.125
CYP2C9*3
0.085
CYP3A4*1B
0.100
CYP3A5*3
0.900
MDR1 C3435T
0.539
PXR/NR1I2
0.620
Paclitaxel is a novel chemotherapy agent derived from the bark of the yew tree (Taxus 
Brevifolia) that promotes microtubule assembly and stabilizes tubulin formation.58 
Paclitaxel inhibits proliferation by inducing mitotic block.  However, this drug may have 
many other effects that have not been entirely elucidated.  Paclitaxel is metabolized to a 
minor metabolite by CYP3A4 and to a major but inactive metabolite 6-α-hydroxytaxol by 
CYP2C8. Recently a polymorphism in CYP2C8 has been discovered and characterized. In 
vitro studies have shown the polymorphic CYP2C8 has diminished catalytic activity for 
converting paclitaxel into 6-α-hydroxytaxol.59 The effects of this polymorphism on 
paclitaxel’s metabolism in vivo have not been determined and it is therefore a goal of this 
study to examine its correlation with increased paclitaxel’s toxicity. 
Methods:
DNA extraction and SNP analysis: The goal of this study is to identify SNPs that are 
associated with paclitaxel-induced neuropathy. SNPs can be isolated from DNA from 
multiple tissue sources including whole blood, buccal swabs and formalin-fixed, paraffin-
embedded tissue.60-62  DNA will be extracted from whole blood as described by previously 
using the DNeasy® Tissue kit.  DNA samples will be assayed for genetic polymorphisms as 
described previously using the Applied Biosystems’ Taqman® Allelic Discrimination Assay 
(Foster City, CA) according to the manufacturer’s instructions. Briefly, 10 ng DNA will be 
added to a 25 ul reaction containing forward and reverse primers along with 2 allele specific 
labeled probes (one wild-type and one variant allele specific). The PCR and fluorescence 
measurements will be performed using the ABI Prism 770 sequence detection system.  
We propose using the ABI Taqman assays for our SNP analysis because it has proven to be 
a robust and high-throughput approach. However, development of alternative assays will 
also be considered based on the anticipated need for future genotyping. If we encounter 
any SNPs that we cannot be reliably assayed from whole genome amplified DNA, we will 
use our expertise in other assays to design assays using alternative methods.  We currently 
run multiple different SNP assays for several other types of assays such as TaqMan 
OpenArray Genotyping System, restriction fragment length polymorphisms (RFLP), 


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SNPstream, and Illumina platforms. Baseline information will be collected to assess if 
patients have a known diagnosis of diabetes, an important risk factor for the development 
of neuropathy.
3.11
Rationale for banking tissue and serum
Banking of blood samples at the time of enrollment, every 6 months for two years, 
and upon disease recurrence will allow for future analyses that may identify 
predictors of recurrence.  
3.11.1 Tissue and Serum Bank Summary
Banking of tissue and serum will take place during this course of this study at the 
protocol specified timepoints.  Specimens will be banked for use in accordance with 
the research as outlined in this protocol.  
A tissue block or 15 uncharged slides will be stored and will become property of the 
DF/HCC SPORE Tissue and Pathology Core.  In addition, a de-identified copy of 
the associated pathology report will accompany the tissue specimen.  
Serum will be collected and analyzed for the biomarkers as outlined in the protocol.  
Any remaining serum will be stored in the DF/HCC Clinical Trials Core Laboratory 
until the supply has been exhausted. Only DF/HCC researchers as deemed 
appropriate by the PI and DF/HCC SPORE CORE Committee will have access to 
these specimens.  
Confidentiality of each patient will be maintained to the best of the study team’s 
ability.  All study participants will be assigned a unique subject number at study 
registration.  Once the specimen has been received at either the SPORE Tissue and 
Pathology Core or the DF/HCC Clinical Trials Core Laboratory, the specimens will 
be assigned a separate specimen ID number that will be tracked by the researchers 
associated at the specified laboratory.  Patient-derived material will be linked to 
patient clinical information using identifiers which will be coded using DFCI 
hospital number and internal banking identifying code numbers.  Any material 
shared with collaborators, in or outside of DFCI, will be supplied with code number 
identifiers only, and without patient name or other patient identifiers.  All study 
information will be stored in locked file cabinets and in password-protected 
computer files.  Only authorized study personnel will have access to these files.  
Any remaining specimens after these analyses are completed will be banked until 
the specimen has been fully exhausted.  Any research done on any remaining tissue 
or serum will be vetted by the PI and members of the SPORE CORE Committee in 
writing.  The committee will evaluate the proposed research for its scientific merit 
and need.  Patient information will not be disclosed for any non-protocol related 
research.  




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4.2
Demographic and Baseline Assessments
A signed, written, informed consent form must be obtained prior to screening assessments, 
and before any study-specific assessments are initiated, including obtaining archived tumor 
tissue for biomarker analysis.
The following will be obtained at screening:

Demographic data: date of birth, race, gender, height in centimeters, body 
weight in kilograms, and ECOG Performance Status.

Medical history including details of malignancy: date of diagnosis, primary 
tumor type, histology, ER and PR status, HER2 status, stage of cancer, 
relevant prior surgical procedures, and prior and concomitant medications 
within 2 weeks of first dose of investigational agents.
4.2.1
Screening Assessments
Assessments prior to registration

Subject to sign the informed consent form

Initiate completion of study eligibility form

Ascertain availability of archived tumor tissue for biomarker analysis 

Documentation of HER2 positivity (IHC 3+ or FISH  2)
Assessments within 21 days prior to first dose (unless otherwise noted)

Physical examination

Medical history, ECOG Performance Status

Electrocardiogram (12-lead ECG).  This test must be performed within 12 
weeks prior to first dose of investigational products.

Vital signs (blood pressure, pulse rate, body temperature, height, and body 
weight)

Hematology and blood chemistry

Serum pregnancy test for women of childbearing potential.  Test must be 
performed within 14 days prior to first dose of investigational products, but 
preferably as close to the first dose as possible.  The results must be 
reviewed prior to initiating treatment.

Echocardiogram (ECHO) or MUGA scan.  This test must be performed 
within 12 weeks prior to first dose of investigational products.

Baseline Assessment of Menses survey (Appendix 1) to women who have 
had a period in the past 6 months (deemed premenopausal at baseline)
Note: After all baseline and screening evaluations have been completed, and the 
data is obtained, determine if the subject is eligible for the study by reviewing 
the inclusion and exclusion criteria.


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Assessments for Weeks 2-12 

Hematology (CBC with differential) weekly

Blood chemistry (Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, 
SGOT(AST), SGPT(ALT)) every 3 weeks (+/- 1 week)  

Review all laboratory results.  

Physical examination to be done every 3 weeks (+/- 1 week)

Record any non-serious and serious adverse events (AE) and assign 
appropriate toxicity grade (NCI CTCAE version 3, published March 31, 
2003) weekly.

Echocardiogram (ECHO) or MUGA scan at 12 weeks (even if treatment has 
been delayed, cardiac evaluation should still occur at 12 weeks)
Assessments every 9 weeks (+/- 3 weeks) during trastuzumab monotherapy

Hematology (CBC with differential)

Blood chemistry (Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, 
SGOT(AST), SGPT(ALT)) 

Physical examination

Vital signs (blood pressure, pulse rate, body temperature, and body weight)

Record any non-serious and serious adverse events (AE) and assign 
appropriate toxicity grade (NCI CTCAE version 3, published March 31, 
2003)
Assessment after 12 weeks, 6 months, and at one year

Echocardiogram (ECHO) or MUGA scan (+/- 4 weeks)

Blood sample for translational research at 6 months and 1 year  (+/- 8 weeks)

Follow-up Menses Assessment survey (1 year: Appendix 2) to women 
deemed premenopausal at baseline  (+/- 4 weeks)
Assessment every 6 months for years 2, 3, and 4 or until endpoint reached (as 
defined by 4.3.1) (+/- 8 weeks)

Physical Follow-up Menses Assessment (Appendix 2) to women deemed 
premenopausal at baseline

Vital signs (blood pressure, pulse rate, body temperature, and body weight)

Blood sample for translational research at 18 months, 2 years, and at 
progression

Record any non-serious and serious adverse events (AE) and assign 
appropriate toxicity grade (NCI CTCAE version 3, published March 31, 
2003)


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
Appropriate screening of residual breast tissue performed at least yearly (+/- 
3 months)
Assessment annually for years 5, 6, 7, 8, 9, and 10or until endpoint reached (+/- 
3 months)

Physical examination

Follow-up Menses Assessment survey (Appendix 2) to women deemed 
premenopausal at baseline (+/- 3 months) only for years 5 and 6

Vital signs (blood pressure, pulse rate, body temperature, and body weight)

Blood sample for translational research at progression (+/- 3 months)

Record any non-serious and serious adverse events (AE) and assign 
appropriate toxicity grade (NCI CTCAE version 4).

Appropriate screening of residual breast tissue performed at least yearly (+/- 
3 months)

Patients may be contacted by phone after completion of annual follow-up 
visits in order to obtain long-term follow-up data. 

All patients will be followed for survival until withdrawal of consent or 
death, whichever occurs first.  
4.3
Outcome Measures
4.3.1
Primary Outcome Measure
The primary end-point of this study is disease-free survival (local invasive breast 
cancer recurrence, a new local invasive breast cancer, regional recurrence, distant 
recurrence, contralateral invasive breast cancer, and death before recurrence are all 
counted as “events that end disease-free survival).  The study is designed to have a 
large chance of declaring the regimen worthy of further research if the true 3 year 
failure percent is as small as 5% and a small chance of declaring the regimen worthy 
of further research if the true 3 year failure percent is as large as 9.2%.
4.4
Outcome Assessment Schedule
Assessment prior to the first dose

Documentation of tumor status: dimension of tumor, HER2 status (IHC 3+ or FISH 
 2), lymph node evaluation (sentinel node or axillary dissection)

Bone Scan only if clinically indicated

Blood samples for translational research
Assessment at 6 months

Blood sample for translational research


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Assessment at 12 months

Blood sample for translational research
Assessment at 18 months

Blood sample for translational research
Assessment at 24 months

Blood sample for translational research
Assessment at disease recurrence  

Blood sample for translational research

Biopsy of metastatic disease for ER, PR, HER2 and optional tissue collection for 
translational research
4.5
Biomarkers
4.5.1
Tumor Tissue
Paraffin-embedded tissue blocks (or 15 sections of paraffin-embedded tissue on 
uncharged slides) from archived tumor tissue samples (from time of biopsy or 
surgical resection) will be tested using gene sequencing to define molecular 
alterations that characterize these small tumors.  Fifteen (15) sections of paraffin-
embedded tissue on uncharged slides (or a tissue block of sufficient size to make 15 
slides) should be sent to DFCI for testing.  
4.5.2
Serum
We will use blood tests to examine the serum SNPs for predictors of neurotoxicity 
from paclitaxel. These research blood draws can be performed within +/- 8 weeks 
of the designated time points.  Sites will be sent a separate translational research 
specimen and tumor tissue procedures and shipping manual for further instructions 
concerning research blood and tumor tissue requirements. 


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4.6
Ancillary Safety Outcomes
4.6.1
Safety Plan
Patients will be evaluated at each study visit for the duration of their participation in 
the study.
Specific potential safety issues for this trial are outlined below.
4.6.2
Pregnancy
4.6.2.1 Pregnancy Testing
A screening -hCG (human chorionic gonadotrophin) pregnancy test is 
mandatory for all women of childbearing potential within 2 weeks prior to 
the first dose of investigational product.  Thereafter, the serum pregnancy 
test need only be repeated if clinically indicated or as required by local 
regulation.
4.6.2.2 Action to be taken if pregnancy occurs
The investigator will collect pregnancy information on any female subject 
who becomes pregnant while participating in this study.  Patients, who 
become pregnant on study, will be taken off study treatment.  The 
investigator will record information and submit it within 2 weeks of learning 
of a subject’s pregnancy.  The subject will also be followed to determine the 
outcome of the pregnancy. Generally, follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date.  Any premature termination 
of the pregnancy will be reported.   While pregnancy itself is not considered 
an AE or SAE, any pregnancy complication or elective termination of 
pregnancy for medical reasons will be recorded as an AE or SAE.  A 
spontaneous abortion is considered an SAE, and will be recorded as such.  
All pregnancies must be reported to Genentech, Inc.  
Genentech Drug Safety
Herceptin Safety Monitor
Tele: 1-888-835-2555
Fax:  (650) 225-4682
4.6.3
Cardiac Dysfunction
Signs and symptoms of cardiac dysfunction were observed in a number of women 
who received trastuzumab alone or in combination with chemotherapy, most often 
anthracycline-based treatment.  


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The nature of the observed cardiac dysfunction was similar to the syndrome of 
anthracycline-induced cardiomyopathy.  The signs and symptoms of cardiac 
dysfunction usually responded to treatment.  Complete and partial responses were 
observed among patients with cardiac dysfunction.  The risk appears to be 
independent of tumor response to therapy.  Analysis of the clinical database for 
predictors of cardiac dysfunction revealed only advanced age and exposure to an 
anthracycline as possible risk factors.  In the clinical trials, most patients with 
cardiac dysfunction responded to appropriate medical therapy, often including 
discontinuation of trastuzumab.  In many cases, patients were able to resume 
treatment with trastuzumab.  In a subsequent study using weekly paclitaxel and 
trastuzumab as first-line treatment for metastatic breast cancer, the observed 
incidence of serious cardiac dysfunction was 3% (N=95) (Seidmen et al. 2001).  
Since the occurrence of cardiac dysfunction in the trastuzumab plus chemotherapy 
trial was an unexpected observation, no information is available regarding the most 
appropriate method for monitoring cardiac function in patients receiving 
trastuzumab.  We will be using Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.0 to evaluate left ventricular systolic dysfunction.  Significant 
advances in the understanding and treatment of CHF have been made in the past 
several years, with many of the new drugs demonstrating the ability to normalize 
cardiac function.  
4.6.4
Management of Cardiac Safety
All patients must have a MUGA scan or echocardiogram (ECHO) at baseline, at 12 
weeks, 6 months, and at one year.  Investigators are strongly urged to schedule 
MUGA scans or ECHOs at the same radiology facility where the patient’s baseline 
scan was done whenever possible.  MUGA scans or ECHOs are required at 
protocol-specified time points and after any patient has any of the following: 
discontinuation of protocol therapy, congestive heart failure, or breast cancer 
recurrence.  When a cardiac event occurs, this should be reported in the electronic 
data capture system (eDC) as an adverse event.
5.0
PATENT SELECTION
5.1
Eligibility criteria
5.1.1
Patients must have histologically confirmed invasive carcinoma of the 
breast
5.1.2
Tumors must be  3 cm in greatest dimension
5.1.3
Patients must have node-negative breast cancer according to the AJCC 7th 
edition.  This includes:
Definition of node-negative disease: If the patient has had a negative 
sentinel node biopsy, then no further axillary dissection is required, and the 
patient is determined to be node-negative.  If an axillary dissection, without 
sentinel lymph node biopsy, is performed to determine nodal status, at least 


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6 axillary lymph nodes must be removed and analyzed and negative for the 
patient to be considered node-negative.  Axillary nodes with single cells or 
tumor clusters  0.2 mm by either H&E or immunohistochemistry (IHC) 
will be considered node-negative.  Any axillary lymph node with tumor 
clusters between 0.02 and 0.2cm is considered a micrometastasis.   Patients 
with a micrometastasis are eligible if an axillary dissection has been 
performed and no further lymph node involvement is seen.  In cases where 
the specific pathologic size of lymph node involvement is subject to 
interpretation, the principle investigator will make the final determination as 
to eligibility.  The investigator must document approval in the patient 
medical record.
5.1.4
ER/PR determination is required.  ER- and PR-assays should be performed 
by immunohistochemical methods according to the local institution standard 
protocol.
5.1.5
HER-2 positive: IHC 3+ or FISH 2
NOTE: DCIS components should not be counted in the determination of 
HER2 status
5.1.6
Bilateral breast cancers that individually meet eligibility criteria are 
allowed.
5.1.7
Patients should have tumor tissue available, and a tissue block of sufficient 
size to make 15 slides, which must be sent to DFCI for testing.  If a tissue 
block is unavailable, sites may send 15 sections of paraffin-embedded tissue 
on uncharged slides.  If tumor is not available, the investigator must 
document why tissue is not available in the patient medical record, and that 
efforts have been made to obtain tissue.
5.1.8
 90 days from the patient’s most recent breast surgery for this breast cancer 
5.1.9
All tumor should be removed by either a modified radical mastectomy or a 
segmental mastectomy (lumpectomy), with either a sentinel node biopsy or 
axillary dissection
5.1.9.1 All margins should be clear of invasive cancer or DCIS.  The local 
pathologist must document negative margins of resection in the 
pathology report.  If all other margins are clear, a positive posterior 
(deep) margin is permitted, provided the surgeon documents that the 
excision was performed down to the pectoral fascia and all tumor 
has been removed.  Likewise, if all other margins are clear, a 
positive anterior (superficial; abutting skin) margin is permitted 
provided the surgeon documents that all tumor has been removed.  
Radiation therapy to the conserved breast is required.
5.1.10 Endocrine Therapy
5.1.10.1
May have received up to 4 weeks of tamoxifen therapy, or 
other hormonal therapy, for adjuvant therapy for this malignancy but 
must temporarily stop such therapy at time of entry to study.
5.1.10.2
Prior oophorectomy for cancer prevention is allowed.
5.1.11  18 years of age with any menopausal status
5.1.12 ECOG Performance Status 0 or 1 (see Appendix 3)
5.1.13 Adequate bone marrow function: ANC  1000/mm3, hemoglobin  9 g/dl, 
and platelets  100,000/mm3


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5.1.14 Adequate hepatic function: Total bilirubin  1.5xULN, AST  1.5x ULN 
(Total bilirubin must be <2x ULN if it is determined to be a result of 
Gilbert’s syndrome)
5.1.15 Left ventricular ejection fraction (LVEF)  50%
5.1.16 Willingness to discontinue any hormonal agent prior to registration and 
while on study
5.1.17 Patients who have participated in a window study (treatment with an 
investigational agent prior to surgery for ≤2 weeks) are eligible.  Patients 
must have discontinued the investigational agent at least 14 days before 
participation
5.1.18 Willingness to discontinue sex hormonal therapy, e.g. birth control pills, 
prior to registration and while on study
5.1.19 Patients who have undergone partial breast radiation (duration ≤ 7 days) 
prior to registration are eligible
5.1.20 Patients with a history of ipsilateral DCIS are eligible if they were treated 
with wide-excision alone, without radiation therapy.
5.1.21 Patients undergoing breast conservation therapy (i.e. lumpectomy) must not 
have any contraindications to radiation therapy.
5.1.22 Willing and able to sign informed consent
5.1.23 Enrollment on Other Investigational Studies
5.1.23.1
Adjuvant Hormonal Studies: Patients may be enrolled on 
adjuvant hormonal studies, such as the SOFT and TEXT trials.  
Hormonal therapy will begin as outlined in the specific hormonal 
trial.  Specifically, patients enrolled on the TEXT trial should begin 
ovarian suppression concurrently with chemotherapy.  
5.1.23.2
Adjuvant Bisphosphonate Studies: Patients may be enrolled 
on adjuvant bisphosphonate studies, such as the adjuvant SWOG 
study (S0307).  Bisphosphonate therapy will begin as outlined in the 
specific trial.
5.1.23.3
Patients may be enrolled in any other investigational studies 
that do not use HER2-directed therapies or chemotherapy.
5.2
Ineligibility criteria
5.2.1
Any of the following due to teratogenic potential of chemotherapy:

Pregnant women

Nursing women

Women of childbearing potential who are unwilling to employ 
adequate contraception (condoms, diaphragms, IUDS, surgical 
sterilization, abstinence, etc).  Hormonal birth control methods are 
not permitted.
5.2.2
Locally advanced tumors at diagnosis, including tumors fixed to the chest 
wall, peau d’orange, skin ulcerations/nodules, or clinical inflammatory 
changes (diffuse brawny cutaneous induration with an erysipeloid edge)
5.2.3
Patients with a history of previous invasive breast cancer.
5.2.4
History of prior chemotherapy in the past 5 years.
5.2.5
History of prior trastuzumab therapy 


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5.2.6
Active, unresolved infection
5.2.7
Prior history of any other malignancy in the past 5 years, except for early 
stage tumors of the skin or cervix treated with curative intent
5.2.8
Sensitivity to benzyl alcohol
5.2.9
 grade 2 neuropathy per NCI’s Common Toxicity Criteria Version 3.0 
EXCEPTION: Any chronic neurologic disorder will be looked at on a case-
by-case basis by the study chair
5.2.10 Active cardiac disease

Any prior myocardial infarction  (asymptomatic changes on EKG 
suggestive of old MI is not an exclusion)

Documented congestive heart failure (CHF)

Current use of any therapy specifically for CHF

Current uncontrolled hypertension (diastolic >100 mmHg or systolic 
> 200 mmHg)

Clinically significant pericardial effusion
5.3
Patient Registration
Prior to the initiation of treatment, all protocol subjects must be registered in the Dana-
Farber/Harvard Cancer Center QACT Protocol Registration System.  The registration 
system is a computerized registry of all patients on DF/HCC oncology protocols.  When an 
investigator identifies a potential study candidate, he/she must confirm in detail if the 
candidate is appropriate to participate in the study.  The QACT eligibility checklist assures 
that all inclusion/exclusion criteria are met prior to protocol enrollment.  
5.3.1 Patient Registration Guidelines for DF/HCC and DF/PCC Institutions
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must 
occur prior to the initiation of treatment. Any participant not registered to the 
protocol before treatment begins will be considered ineligible and registration will 
be denied. 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
Following registration, participants may begin protocol treatment. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If 
a participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the QACT Registrar of participant status 
changes as soon as possible using the treatment completion/off-study form supplied 
in Appendix 6.
 5.3.2 Registration Process for DF/HCC and DF/PCC Institutions


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The QACT registration staff is accessible on Monday through Friday, from 8:00 AM 
to 5:00 PM Eastern Standard Time. If a participant must be registered during off-
hours or holidays, call the QACT registration line at 617-632-3761 and follow the 
instructions for registering participants after hours.  
The registration procedures are as follows:

Obtain written informed consent from the participant prior to the performance of 
any study related procedures or assessments.

Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each inclusion 
and exclusion criteria listed on the eligibility checklist. 

Fax the eligibility checklist and all pages of the consent form to the QACT at 
617-632-2295. 

The QACT Registrar will (a) validate eligibility, and (b) register the 
participant on the study. 

The QACT Registrar will send an email confirmation of the registration to the 
person initiating the registration immediately following the registration. 
If you have any questions regarding this process you can contact the study coordinator 
and/or a QACT registrar at 617-632-3761.
5.3.3   Registration Process for Other Participating Institutions
To register a participant, the following documents should be completed by the 
participating site’s research nurse or research coordinator and faxed to the DFCI 
study coordinator or designee at 617-632-3550: 

Copy of required laboratory tests, pathology report(s), EKG results, ECHO/MUGA 
results, and any other source documentation

Signed study consent form

HIPAA authorization form (if separate from the main informed consent document)

DF/HCC Eligibility Checklist (supplied by DFCI)
The research nurse or data manager at DFCI will then call or email the study coordinator 
at the participating site to verify eligibility. To complete the registration process, the 
research nurse or study coordinator will:

Register the participant on the study with QACT

Fax or e-mail the confirmation of registration including the participant subject 
number to the participating site
Once the participating site has received confirmation of registration, participants may 
begin protocol treatment. Issues that would cause treatment delays should be discussed 


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with the Principal Investigator. If a participant does not receive protocol therapy following 
registration, the participant’s protocol status must be changed. Notify the QACT Registrar 
of participant status changes as soon as possible using the treatment completion/off-study 
form supplied in Appendix 3.
If you have any questions regarding this process you can contact the study coordinator 
and/or a QACT registrar at 617-632-3761.


APT, page 31
6.0
STUDY CALENDAR
Tests and 
procedures
≤21 days 
prior to 
registration
Q6 months 
x 1 year, 
then 
q6months 
for year 2 
and at 
progressio
n
At 12 
weeks, 
6 
month
s and 
at 1 
year
Every 
week 
during 
weekly 
paclitaxel
Every 3 
weeks 
during 
weekly 
paclitaxel 
(+/- 1 
week)
Every 9 
weeks during 
trastuzumab 
monotherapy
(+/- 3 weeks)
Observat
ion years 
2-10 or 
until 
progressi
on14
Yearly
(+/- 3 
months)
History + exam, 
ECOG PS 
(ECOG at 
baseline only)
X
X
X
X
Vital signs, 
weight, height 
(height at 
baseline only)
X
X15
X
Pelvic Exam1
X
Hematology 
(CBC with diff)
X
X
X
Chemistry7 (Cr, 
T.bili, AST, 
ALT, Alk Phos)
X
X
X
Bone Scan2
X
Blood samples 
for translational 
research9
X7
X
EKG4
X
Mammogram or 
breast US
X6
X
MUGA or 
echocardiogram3
X
X
Pregnancy test5
X
Submission of 
tumor block8
X
Menses 
Assessment 
survey10
X11
X12
X13
Non-serious & 
serious AE + 
Toxicity grade
1 Pelvic exam within 12 months of study entry is recommended.  Yearly pelvic exams are recommended for those 
receiving tamoxifen, unless s/p hysterectomy.
2 If clinically indicated
3 Use the same method for each evaluation at the same facility where the baseline was done whenever possible.  
Baseline MUGA or ECHO must be within 12 weeks of beginning study treatment.  Cardiac evaluation should still 
occur at these time points even if there has been a treatment delay.
4 EKG should be performed within 12 weeks of beginning study treatment.
5 For women of childbearing potential only.  Must be done within 14 days of first dose of treatment.
6 Mammograms obtained as part of the initial diagnosis, biopsy, and surgery will suffice (do not need to be repeated).
7 Sodium, potassium, chloride, bicarbonate, BUN, creatinine, , total protein, albumin, total bilirubin, SGOT(AST), 
SGPT(ALT), Alkaline Phosphatase




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8.1.1 Trastuzumab
8.1.1.1 Concurrent Phase with Paclitaxel: Patients will receive a 4 mg/kg IV 
loading dose on day 1 followed by 2 mg/kg IV dose weekly (+/- 2 
days), for a total of 12 doses.  When trastuzumab is being 
administered concomitantly with paclitaxel, trastuzumab 
administration may occur prior to, or after, chemotherapy 
administration.  
8.1.1.2 Maintenance Phase after Paclitaxel: After completion of 12 weeks of 
trastuzumab, trastuzumab dosing may be on either of two schedules: 
Weekly schedule: 2 mg/kg IV weekly (+/- 2 days) (over 30 minutes) x 
40 weeks
Every 3 week schedule: 6 mg/kg IV every 3 weeks (+/- 7 days) (over 
30 minutes or per local standard operating procedures) x 40 weeks.  
A total of 13 doses should be administered, if there are no missed 
doses, or treatment delays during therapy.
Trastuzumab monotherapy should begin no sooner than 1 week after 
the completion of combination therapy and no later than 3 weeks 
after the completion of combination therapy.  It is permissible to 
switch from weekly to every 3 week dosing and vice versa.  When 
switching from weekly to every 3 weeks there is no need for the 8 
mg/kg loading dose.  When switching from every 3 week to weekly, 
there is no need for the 4 mg/kg loading dose.
Trastuzumab monotherapy may be administered at a non-
participating institution.  The referring site is responsible for 
initiating contact with the provider at the non-participating institution 
and ensuring the local provider has all protocol-related instructions 
regarding administration of trastuzumab per protocol.  The lead site 
is responsible for obtaining and reviewing all source documentation 
related to trastuzumab monotherapy administration.  This information 
should be placed in the participant’s research file.
8.1.1.3 The initial dose of trastuzumab will be administered over 90 minutes.  
If this first dose is well tolerated, subsequent infusion times may be 
shortened to 30 minutes or given per participating site’s institutional 
SOP for trastuzumab administration.  If the initial or a subsequent 
dose is not well tolerated (i.e. fevers, chills, or rigors), subsequent 
infusion times may be shortened only after a dose is well tolerated.
8.1.1.4 If during the 12 weeks of paclitaxel and trastuzumab a dose of 
paclitaxel is missed, this dose should be made up.  Trastuzumab 
should be administered if paclitaxel is being held.  Up to 3 doses of 
paclitaxel can be made up, and all paclitaxel must be completed 
within 16 weeks from starting therapy. 


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8.1.1.5 If during the maintenance phase with trastuzumab monotherapy a 
dose of trastuzumab is delayed due to patient scheduling, patients 
may continue on study, and 40 weeks of trastuzumab should be done, 
and the dose of trastuzumab is not made up.  Up to 9 missed doses of 
weekly trastuzumab or up to 3 missed doses of every 3 week 
trastuzumab can be missed. If greater than 9 missed doses of weekly 
trastuzumab or greater than 3 missed doses of every 3 week of 
trastuzumab are missed, permanently discontinue the patient from 
study treatment, and notify the study chair.  These patients 
permanently discontinued from the study treatment will still be 
followed for study endpoints.  If a patient has been without a dose of 
trastuzumab for  28 days, they will require a reloading dose.  The 
reloading dose is 8 mg/kg IV if given on the every 3 week schedule, 
or 4 mg/kg IV if given on the weekly schedule.  This reloading dose 
should be infused over 90 minutes.
8.1.1.6 During the maintenance phase, trastuzumab should be administered 
either every 3 weeks (+/- 7days), or weekly (+/- 2 days).  It is 
encouraged that patients stay on schedule +/- 1-2 days.  Patients can 
receive maintenance trastuzumab at non-participating sites in 
between their scheduled every 9 week evaluations.
8.1.1.7 Treatment is permitted in an asymptomatic patient if:

The LVEF increased or stayed the same OR

The LVEF decreased by 15 percentage points, but is still at or 
above the radiology facility’s lower limit of normal (LLN)
8.1.1.8 Treatment is prohibited in an asymptomatic patient if:

The LVEF decreased by 15 percentage points and is below the 
radiology facility’s lower limit of normal OR

The LVEF decreased by 16 percentage point or more, regardless 
of the radiology facility’s LLN

See Table below
Asymptomatic Decrease in LVEF: Percentage Points from Baseline
Relationship of 
LVEF to radiology 
facility’s LLN
Decrease of <10 
percentage points
Decrease of 10 to 15 
percentage points
Decrease of 16 
percentage points
Within normal 
limits
Continue
Continue
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
1-5 percentage 
points below LLN
Continue and repeat 
MUGA/echocardiogram 
after 4 weeks
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
 6 percentage 
points below LLN
Continue and repeat 
MUGA/echocardiogram 
after 4 weeks
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks


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8.1.2
Paclitaxel
8.1.2.1 Paclitaxel 80 mg/m2 will be administered over 30 – 180 minutes per 
local standard operating procedures.  It will be administered weekly 
(+/- 2 days) for 12 weeks.  
8.1.2.2 The following premedication regimen is recommended for the initial 
dose of paclitaxel.  If the patient does not experience an allergic 
reaction, the premedication regimen may be altered at the discretion 
of the treating physician.

Benadryl 12.5-50 mg IV, 30-60 minutes pre-paclitaxel

Ranitidine 50 mg IV, 30-60 minutes pre-paclitaxel  (can be 
replaced with cimetidine 300 mg, or famotidine 20 mg)

Dexamethasone 10 mg IV, <60 minutes pre-paclitaxel OR
Dexamethasone 20 mg po 6 hours and 12 hrs pre-paclitaxel.  
Methylprednisolone (60 mg IV) may be used instead of 
dexamethasone.


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8.1.2.3 In order to initiate each weekly treatment, the following is needed:
ANC  800/mm3 
Platelets  100,000/mm3
If these criteria are not met, delay treatment with paclitaxel until counts 
recover to this level.   Trastuzumab should be administered if paclitaxel is 
being held.  Paclitaxel should be held for all instances of febrile neutropenia.  
Please refer to section 9.1.6 for more information.  Missed doses of 
paclitaxel should be made-up.  If a delay of >21 days is required, 
permanently discontinue patient from study treatment, and notify study 
chair.  These patients permanently discontinued from the study treatment 
will still be followed for study endpoints.  
8.2 Radiation Therapy
8.2.1
Patients who undergo lumpectomy (breast conserving surgery) must receive 
breast radiation therapy.  This may be performed according to local 
institutional standards. Patients may be treated with conventional, post-
chemotherapy, whole breast radiation, or partial breast radiation, 
administered by external beam or brachytherapy.  
8.2.2
 Radiation therapy will begin after the conclusion of all study paclitaxel.
8.2.3
Patients undergoing mastectomy may receive chest wall and nodal radiation 
according to local institutional standards.  
8.2.4
Patients may receive adjuvant trastuzumab as per protocol during 
radiotherapy.
8.3 Endocrine Therapy
8.3.1
Patients may have received up to 4 weeks of tamoxifen therapy, or other 
hormonal therapy, for adjuvant therapy for this malignancy but must 
temporarily stop such therapy at time of entry to study. Patients may initiate 
adjuvant hormonal therapy per institutional standards after completion of 
treatment with paclitaxel. 
9
DOSE MODIFICATIONS
9.1 Paclitaxel

Dose modifications shall be considered optional when toxicities are deemed 
unrelated to treatment with Paclitaxel and do not adversely impact study drug 
administration.


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
These patients permanently discontinued from the study treatment will still be 
followed for study endpoints
9.1.1
Anaphylaxis/Hypersensitivity
9.1.1.1 Mild symptoms (Grade 1):  mild flushing, rash, pruritis
9.1.1.1.1
Complete infusion, observation in treatment area.  No 
treatment required.
9.1.1.2 Moderate symptoms (Grade 2): moderate rash, flushing, mild 
dyspnea, chest discomfort
9.1.1.2.1
Stop infusion.
9.1.1.2.2
Give intravenous diphenhydramine 25 mg and intravenous 
dexamethasone 10 mg. Methylprednisolone (60mg IV) 
may be used instead of dexamethasone.
9.1.1.2.3
Resume paclitaxel infusion after recovery of symptoms, at 
a slower rate.  10 ml/hour for 15 minutes, then 25 ml/hour 
for 15 minutes, then, if no further symptoms, at full dose 
rate until infusion is complete.
9.1.1.2.4
If moderate or severe symptoms recur after rechallenge, 
stop paclitaxel infusion, and report as an adverse event.  
9.1.1.2.5
Patient may be rechallenged after premedication with 
dexamethasone 8 mg po or IV q6hrs x 4 doses (moderate 
symptoms) or 20 mg po or IV q6hrs x 4 doses (severe 
symptoms) and diphenhydramine 25 mg po or IV q6hrs x 
4 doses (moderate or severe 
symptoms).Methylprednisolone (60mg IV) may be used 
instead of dexamethasone.
9.1.1.2.6
The paclitaxel should be administered at a slower rate.  10 
ml/hour for 15 minutes, then 25 ml/hour for 15 minutes, 
then, if no further symptoms, at full dose rate until 
infusion is complete.
9.1.1.3 Severe life-threatening symptoms (Grade 3): hypotension requiring 
pressor therapy, angioedema, respiratory distress requiring 
bronchodilation therapy, generalized urticaria.
9.1.1.3.1
Stop paclitaxel infusion.
9.1.1.3.2
Give intravenous diphenhydramine 25 mg and intravenous 
dexamethasone 10 mg. Methylprednisolone (60mg IV) 
may be used instead of dexamethasone.
9.1.1.3.3
Add epinephrine or bronchodilators if indicated.
9.1.13.4
Report episode as an adverse event.
9.1.1.3.5
Patient may be rechallenged after premedication with 
dexamethasone 20 mg po or IV q6hrs x 4 doses and 
diphenhydramine 25 mg po or IV q6hrs x4 doses. 
Methylprednisolone (60mg IV) may be used instead of 
dexamethasone.


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9.1.1.3.6
The paclitaxel should be administered at a slower rate, 10 
ml/hour for 15 minutes, then 25 ml/hr for 15 minutes, 
then, if no further symptoms, at full dose rate until 
infusion is complete.
9.1.2
Cardiac Arrhythmias
9.1.2.1 Asymptomatic, EKG-documented arrhythmias
9.1.2.1.1
Stop paclitaxel, and manage arrhythmia according to 
standard practice.  
9.1.2.1.2
Protocol treatment will be discontinued and the episode 
reported as an adverse event.  
9.1.2.2 Asymptomatic sinus bradycardia or tachycardia
9.1.2.2.1
No intervention is necessary.  
9.1.2.3 Sinus bradycardia or tachycardia associated with hypersensitivity 
reaction
9.1.2.3.1
Please see above.
9.1.3
Hematologic Toxicity
9.1.3.1 Requirements to initiate any cycle of paclitaxel:
9.1.3.1.1
ANC  800/mm3
9.1.3.1.2
Platelets  100,000/mm3
9.1.3.2 If ANC<800

Delay paclitaxel. Continue trastuzumab

Check counts weekly until ANC  800 mm3

If a delay of greater than 21 days is required, permanently 
discontinue protocol therapy and notify study chair.
9.1.3.3 If platelets <100,000
9.1.3.3.1
Delay paclitaxel.  Continue trastuzumab.
9.1.3.3.2
Check counts weekly until platelets  100,000/mm3
9.1.3.3.3
If a delay of >21 days is required, permanently 
discontinue protocol therapy and notify study chair.
9.1.3.4 There will be no dose reductions for hematologic toxicity.  Doses will 
not be reduced based on low nadir counts.  Nadir blood counts are not 
required.
9.1.4 Neurologic Toxicity: Neuropathy (motor and sensory)
9.1.4.1 Grade 1 or 2 Neurotoxicity


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9.1.4.1.1
There will be no dose modifications for grade 1 or 2 
neurotoxicity.
9.1.4.1.2
Treatment does not need to be delayed and previously 
administered doses can be continued.
9.1.4.1.3
If the patient is experiencing significant distress from 
grade 2 toxicity or the treating physician is uncomfortable 
with continuing the same doses, a dose reduction of 10 
mg/m2 in the paclitaxel dose is acceptable.  
9.1.4.2 Grade 3 Neurotoxicity
9.1.4.2.1
Patient should not receive additional treatment until the 
toxicity has resolved to  grade 2.  
9.1.4.2.2
The next infusion may be delayed up to 2 weeks to allow 
for neurologic toxicity to improve.
9.1.4.2.3
If it does not resolve to  grade 2 after 2 weeks, the patient 
will be permanently discontinued from protocol therapy.
9.1.4.2.4
Re-treatment should be initiated with a dose of paclitaxel 
10 mg/m2 below the previous dose level when the toxicity 
resolves to grade 2 or less.  All subsequent infusions will 
be administered using the reduced dose.  
9.1.4.2.5
If grade 3 neurotoxicity develops with additional 
infusions, further dose reductions may be made in 
increments of 10 mg/m2 to a maximum of 4 dose level 
reductions.
9.1.4.2.6
Patients whose toxicity does not improve after 4 dose level 
reductions will be permanently discontinued from protocol 
therapy.
9.1.4.2.7
Patients who develop worsening neurotoxicity with each 
infusion, even if it remains grade 2, should be carefully 
evaluated to determine if a dose reduction would be 
appropriate.
9.1.4.2.8
Dose reductions for neurotoxicity:
Full dose: 80 mg/m2
1st dose reduction: 70 mg/m2
2nd dose reduction: 60 mg/m2
3rd dose reduction: 50 mg/m2
4th dose reduction: 40 mg/m2
9.1.5
Gastrointestinal Toxicity
9.1.5.1 Nausea/Vomiting
9.1.5.1.1
Grade 0-2 Nausea/Vomiting: No change
9.1.5.1.2
 Grade 3 despite maximal anti-emetic therapy: Hold 
paclitaxel until  grade 2, then restart with 20% dose 
reduction in subsequent cycles.  Continue trastuzumab.
9.1.5.1.3
If nausea/vomiting toxicity causes a dosing delay of >21 
days, or if  Grade 3 nausea/vomiting recurs despite dose 


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reduction, permanently discontinue protocol therapy and 
notify study chair.
9.1.5.1.4
Prophylactic antiemetics should be used at the discretion 
of the investigator.  The specific regimen must be 
recorded in the patient’s medical record.
9.1.5.2 Mucositis
9.1.5.2.3
Grade 2 Mucositis
9.1.5.2.3.1 If grade 2 mucositis is present on the day of any 
treatment, the treatment should be delayed until the 
mucositis has resolved to a grade 1 or 0, and then 
resume paclitaxel at 80 mg/m2.
9.1.5.2.4
Grade 3 or 4 Mucositis
9.1.5.2.4.1 Delay treatment until mucositis has resolved to 
grade 1 or 0, then the dose of paclitaxel should be 
reduced to 70 mg/m2.
9.1.5.2.4.2 If grade 3 or 4 mucositis recurs, treatment should 
be delayed until mucositis has resolved to grade 1 
or 0, and the dose of paclitaxel should be reduced 
to 60 mg/m2.
9.1.5.2.4.3 If mucositis causes a delay of >21 days, the patient 
should be permanently discontinued from protocol 
therapy.  
9.1.5.2.4.4 Once the paclitaxel dose has been decreased, it 
should not be re-escalated.
9.1.5.3 Diarrhea
9.1.5.3.1
Grade 2
9.1.5.3.1.1 If grade 2 diarrhea is present on the day of any 
treatment, the treatment should be delayed until the 
diarrhea has resolved to grade 1 or 0, and then 
resume paclitaxel at 80 mg/m2
9.1.5.3.1.2 If diarrhea causes a delay of >21 days, the patient 
should be permanently discontinued from protocol 
therapy. 
9.1.5.3.1.3 Optimal use of anti-diarrheal agents is encouraged.
9.1.5.3.3
Grade 3 or 4
9.1.5.3.3.1 If grade 3 or 4 diarrhea occurs, delay treatment 
until the diarrhea has resolved to grade 1 or 0, then 
the dose of paclitaxel should be reduced to 70 
mg/m2.
9.1.5.3.3.2 If grade 3 or 4 diarrhea recurs, treatment should be 
delayed until diarrhea has resolved to grade 1 or 0, 


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and the dose of paclitaxel should be reduced to 60 
mg/m2.
9.1.5.3.3.3 If diarrhea causes a delay of >21 days, the patient 
should be permanently discontinued from protocol 
therapy. 
9.1.5.3.3.4 Once the paclitaxel dose has been decreased, it 
should not be re-escalated.
9.1.5.3.3.5 Optimal use of anti-diarrheal agents is encouraged.
9.1.5.4 Hepatic Dysfunction
Because the plasma clearance of paclitaxel is reduced in patients with 
hepatic impairment, careful evaluation of liver enzymes in necessary before 
the administration of each new cycle of paclitaxel (i.e. once every 3 weeks). 
For elevations in total bilirubin, SGOT(AST), SGPT(ALT), the following 
dose modifications will be applied:
9.1.5.4.1
Grade 1
9.1.5.4.1.1 No dose modifications
9.1.5.4.2
Grade 2  
9.1.5.4.2.1 Hold paclitaxel for one week.
9.1.5.4.2.2 If abnormal tests return to grade 0 or 1, paclitaxel 
should be continued at full dose.
9.1.5.4.2.3 If the abnormal test does not return to grade 0 or 1 
in one week, but remains at grade 2, continue 
paclitaxel at 70 mg/m2.  If the abnormal test result 
returns to grade 0 or 1, return to full dose, 80 
mg/m2.
9.1.5.4.3
Grade 3 or 4
9.1.5.4.3.1 Patient should be permanently discontinued from 
protocol therapy.
9.1.6
Febrile Neutropenia
9.1.6.1 Fever 38C (101.3F) in the presence of neutropenia (ANC <1000)
Paclitaxel should be held for all instances of febrile neutropenia.
9.1.6.1.1
First episode: G-CSF or GM-CSF may be used for 
subsequent cycles at the discretion of the treating 
physician, but it is not required.  There will be no dose 
reduction for the first episode of febrile neutropenia.
9.1.6.1.2
Second episode: Remaining doses will be reduced to 
paclitaxel 70 mg/m2 given with G-CSF or GM-CSF.   
9.1.6.1.3
Three episodes: Remaining doses will be reduced to 
paclitaxel 60 mg/m2 given with G-CSF or GM-CSF.  
9.1.6.1.4
More than three episodes: Discontinue protocol therapy.


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9.1.7
Infection with/without neutropenia
 
9.1.7.1 Grade 3
Paclitaxel should be held for all instances of Grade 3 infection 
with/without neutropenia.
9.1.7.1.1
First episode: G-CSF may be used for subsequent cycles at 
the discretion of the treating physician, but it is not 
required.  There will be no dose reduction for the first 
episode of febrile neutropenia.
9.1.7.1.2
Second episode: Remaining doses will be reduced to 
paclitaxel 70 mg/m2.  This should be given with G-CSF if 
infection occurred with neutropenia.
9.1.7.1.3
Three episodes: Remaining doses will be reduced to 
paclitaxel 60 mg/m2.  This should be given with G-CSF if 
infection occurred with neutropenia.
9.1.7.1.4
More than three episodes: Discontinue protocol therapy.
9.1.7.2 Grade 4
9.1.7.2.1
Discontinue protocol therapy.
9.1.8
Other Grade 3 or 4 Toxicities
9.1.8.1 Any patient experiencing grade 3 or 4 toxicity, other than those 
described above must be discussed with the study chair.
9.1.9
Dose Modifications for Obese Patients
9.1.9.1 There is no clearly documented adverse impact of treatment of obese 
patients when dosing is performed according to actual body weight.
9.1.9.2 All dosing is to be determined solely by the patient’s BSA as 
calculated from actual weight, OR actual weight without any 
modification unless explicitly described in the protocol.  
9.1.9.3 This will eliminate the risk of calculation error and the possible 
introduction of variability in dose administration.
9.1.9.4 Failure to use actual body weight in the calculation of drug dosages 
will be considered a major protocol deviation.


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9.1.9.5 Physicians who are uncomfortable with administering chemotherapy 
dose based on actual body weight should not enroll obese patients on 
this protocol.
9.2 Trastuzumab

No cardioprotective drugs are permitted. There are no data for the use of 
cardioprotective agents such as dexrazoxane (Zinecard)

No dose modifications are permitted. 

Must be discontinued if more than 8 weeks of therapy have been missed and 
permanently discontinue patient from study treatment, and notify study chair.  
These patients permanently discontinued from the study treatment will still be 
followed for study endpoints.

Trastuzumab may be administered at non-participating sites during the 
maintenance phase in between the required every 9 week visits.  The every 9 
week evaluations must be conducted at a participating site.
9.2.1
Infusion-associated symptoms
9.2.1.1 During the first infusion, a symptom complex of fever and/or chills 
may occur.  These are usually mild-to-moderate and may be 
accompanied by nausea, vomiting, headache, dizziness, rigors, pain, 
hypotension, rash, and asthenia.  These symptoms occur infrequently 
during subsequent infusions.  
9.2.2
Trastuzumab when paclitaxel is delayed or discontinued
9.2.2.1 If paclitaxel is delayed for any reason other than cardiotoxicity or 
severe hypersensitivity reactions that occurred when both paclitaxel 
and trastuzumab were administered, trastuzumab may be continued.
9.2.3
Cardiac Dysfunction
9.2.3.1 Initiation of trastuzumab will depend on review of the initial MUGA 
scan/echocardiogram results.
9.2.3.2 If trastuzumab is initiated, a decision about whether to continue or 
discontinue must occur after completion of all chemotherapy and 
while the patient is on trastuzumab alone.  
9.2.3.3 Individual patients should have their MUGA scans/echocardiograms 
performed at the same radiology facility to eliminate variability 
between facilities.
9.2.3.4 Asymptomatic decrease in LVEF:
9.2.3.4.1
Decision to continue or stop is based on the measured 
ejection fraction as it relates to the radiology facility’s 


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LLN and change in ejection fraction from baseline.  
Guidelines for performing MUGA scan/echocardiogram 
and management of patients who have an asymptomatic 
decrease in LVEF from baseline are in the table below:
Asymptomatic Decrease in LVEF: Percentage Points from Baseline
Relationship of 
LVEF to radiology 
facility’s LLN
Decrease of <10 
percentage points
Decrease of 10 to 15 
percentage points
Decrease of 16 
percentage points
Within normal 
limits
Continue
Continue
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
1-5 percentage 
points below LLN
Continue and repeat 
MUGA/echocardiogram 
after 4 weeks
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
 6 percentage 
points below LLN
Continue and repeat 
MUGA/echocardiogram 
after 4 weeks
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
Hold and repeat 
MUGA/echocardiogram 
after 4 weeks
9.2.3.4.2
If trastuzumab is held or discontinued during therapy with 
paclitaxel, paclitaxel may be continued at the discretion of 
the investigator.
9.2.3.4.3
If trastuzumab is not started or discontinued during 
therapy, MUGA scan/echocardiogram still needs to be 
done at 12 weeks and at 1 year.
9.2.3.4.4
Trastuzumab must be permanently discontinued when two 
consecutive “hold” categories occur.
9.2.7.1.1
Trastuzumab must be permanently discontinued when three intermittent 
“hold” categories occur.
9.2.3.4.6
At the discretion of the investigator, trastuzumab may also 
be permanently discontinued prior to the occurrence of 
three intermittent “hold” categories.
9.2.3.4.7
If LVEF is maintained at a “continue and repeat 
MUGA/echocardiogram” or improves from a “hold” to a 
“continue and repeat MUGA/echocardiogram” category, 
additional MUGA scans/echocardiogram prior to the next 
scheduled MUGA scan/echocardiogram will be at the 
discretion of the investigator.


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9.2.3.5 Symptomatic decrease in LVEF
9.2.3.5.1
Grade 3 CHF
9.2.3.5.1.1 Monitor for signs and symptoms of CHF (i.e. 
dyspnea, tachycardia, cough, neck vein distention, 
cardiomegaly, hepatomegaly, paroxysmal 
nocturnal dyspnea, orthopnea, peripheral edema, 
etc)
9.2.3.5.1.2 If patient develop these signs and symptoms, hold 
treatment.
9.2.3.5.1.3 If CHF occurs while on paclitaxel plus 
trastuzumab, resumption of paclitaxel is at the 
discretion of the investigator.
9.2.3.5.1.4 Confirm diagnosis of CHF with either a MUGA 
scan/echocardiogram.  A chest x-ray is also 
required.  Once a diagnosis of CHF is confirmed, 
trastuzumab must be permanently discontinued and 
reported as an adverse event.
9.2.3.5.1.5 Follow-up at 3, 6, and 12 months from time of 
CHF diagnosis with MUGA scan/echocardiogram.
9.2.3.5.2
Grade 4 CHF (severe refractory CHF or requiring 
intubation)
9.2.3.5.2.1 Discontinue treatment, and report as an adverse 
event.
9.2.3.5.2.2 Follow-up at 3, 6, and 12 months with 
MUGA/echocardiogram.
9.2.4
Ischemia
9.2.4.1 Grade 1
9.2.4.1.1
Continue treatment with frequent monitoring.
9.2.4.2 Grade 2
9.2.4.2.1
Hold treatment and conduct cardiac evaluation.
9.2.4.2.2
Based on this evaluation, treatment may be continued at 
the discretion of the investigator.
9.2.4.3 Grade 3 or 4
9.2.4.3.1
Discontinue treatment.
9.2.5
Arrhythmia
9.2.5.1 Grade 1
9.2.5.1.1
Continue treatment with careful monitoring OR hold 
treatment (and paclitaxel if patient is receiving paclitaxel) 
and conduct cardiac evaluation.


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9.2.5.1.2
Based on cardiac evaluation, treatment with trastuzumab 
and paclitaxel or trastuzumab alone may continue or 
discontinue at the discretion of the investigator.
9.2.5.1.3
If trastuzumab is discontinued, paclitaxel may also be 
discontinued at the discretion of the investigator, and 
patient removed from protocol therapy.
9.2.5.2 Grade 2
9.2.5.2.1
Hold treatment (and paclitaxel if patient is receiving 
paclitaxel) and conduct cardiac evaluation.
9.2.5.2.2
Based on cardiac evaluation, treatment with trastuzumab 
and paclitaxel or trastuzumab alone may continue or 
discontinue at the discretion of the investigator.
9.2.5.3 Grade 3 or 4
9.2.5.3.1
Discontinue trastuzumab.
9.2.5.3.2
Paclitaxel is not permitted.  
9.2.5.3.3
Patient should be removed from protocol therapy.
9.2.6
Myocardial Infarction

Discontinue Treatment
9.2.7
Fever
9.2.7.1 Grade 1 (38C - 39C [100.4 - 102.2F] OR Grade 2 (39.1C - 40C 
[102.3 - 104F]
9.2.7.1.1
Stop infusion and give antipyretics.  Once temperature is 
<38C, resume infusion at a slower rate.
9.2.7.2 Grade 3 (>40C [104]) 
9.2.7.2.1
Stop infusion immediately and give antipyretics
9.2.7.2.2
Monitor patient for a minimum of one hour
9.2.7.2.3
If temperature drops to <38C within 3 hours, resume 
infusion at a slower rate.
9.2.7.2.4
If fever does not resolve within 3 hours, inpatient 
monitoring is strongly recommended.
9.2.7.2.5
If temperature drops to <38C within 3 days, re-challenge 
at a slower rate.
9.2.7.2.6
If temperature remains >38C after 3 days, abandon this 
administration and subsequent administration is at the 
discretion of the investigator
9.2.7.3 Grade 4 (40C [104F] for 24 hours)
9.2.7.3.1
Stop infusion immediately and give antipyretics
9.2.7.3.2
Monitor patient for a minimum of one hour


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9.2.7.3.3
If fever does not resolve within 3 hours, inpatient 
monitoring is strongly recommended.
9.2.7.3.4
If temperature drops to <38C within 3 days, re-challenge 
at a slower rate.
9.2.7.3.5
If temperature remains >38C after 3 days, abandon this 
administration and subsequent administration is at the 
discretion of the investigator
9.2.8
Chills

Treat with acetaminophen and/or diphenhydramine hydrochloride.

Meperidine may be given at the investigator’s discretion.
9.2.9
Gastrointestinal
9.2.9.1 Diarrhea
9.2.9.1.1
Any grade
Any antidiarrheal medication may be given at the investigator’s 
discretion.
9.2.10 Allergy/Immunology
9.2.10.1
Allergic reaction/hypersensitivity (including drug fever)
9.2.10.1.1 Stop the infusion and give diphenhydramine 
hydrochloride
9.2.10.1.2   If toxicity resolves within 3 hours, treatment in next dose 
is allowed at a slower rate and under close observation.
9.2.10.1.3   If toxicity does not resolve in 3 hours, overnight 
observation is recommended and treatment in the next 
dose under close observation is at the discretion of the 
investigator.
9.2.11 Pulmonary
9.2.11.1
Any (e.g. Adult Respiratory Distress Syndrome[ARDS], 
pneumonitis/pulmonary infiltrates, etc)
9.2.11.1.1   Delay trastuzumab until case is known.
9.2.11.1.2   If pneumonitis/fibrosis, or pulmonary infiltrate is 
confirmed, and the relationship to trastuzumab cannot be 
excluded, trastuzumab must be permanently discontinued. 


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10
DRUG FORMULATION, AVAILABILITY, AND PREPARATION

Qualified personnel who are experienced with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handing, and safe 
disposal of chemotherapeutic agents in a self-contained, protective environment.

Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e. sterile water for injection 
USP or 0.9% sodium chloride for injection USP) within 8 hours of entry to minimize the 
risk of bacterial contamination

The total administered dose of chemotherapy may be rounded up or down within a range of 
5% of the actual calculated dose.
10.1 Trastuzumab (Trastuzumab)
10.1.1 Availability 
Trastuzumab is a commercially available sterile, white to pale yellow, 
preservative-free- lyophilized powder for intravenous (IV) administration.  Each vial 
of trastuzumab contains 440 mg of trastuzumab, 9.9 mg of L-histadine HCl, 6.4 mg 
of L-histadine, 400 mg of ,-trehalose dihydrate, and 1.8 mg of polysorbate 20, 
USP.  Reconstitution with 20 mL of the supplied Bacteriostatic Water for Injection 
(BWFI) USP, containing 1.1% benzyl alcohol as a preservative, yields 21 mL of a 
multidose solution containing 21 mg/mL trastuzumab, at a pH of ~6.
10.1.2 Preparation
10.1.2.1 Use appropriate aseptic technique.  Each vial of trastuzumab should 
be reconstituted with 20 mL of BWFI, USP, 1.1% benzyl alcohol 
preserved, as supplied, to yield a multidose solution containing 21 
mg/mL trastuzumab.  Immediately upon reconstitution with BWFI, 
the vial of trastuzumab must be labeled in the area marked “Do not 
use after” with the future date that is 28 days from the date of 
reconstitution.
10.1.2.2 If the patient has known hypersensitivity to benzyl alcohol, 
trastuzumab must be reconstituted with Sterile Water for Injection. 
Trastuzumab which has been reconstituted with SWFI must be used 
immediately and any unused portion discarded.  Use of other 
reconstitution diluents should be avoided.


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10.1.2.3
Determine the dose of trastuzumab needed, based on a 
loading dose of 4 mg trastuzumab/kg body weight for 
weekly dosing schedules or a maintenance dose of 2 mg/kg 
trastuzumab/kg body weight for weekly dosing schedules 
(OR 6 mg trastuzumab/kg body weight during q3wk 
dosing).  Calculate the correct dose using  21 mg/mL 
trastuzumab solution.  Withdraw this amount from the vial 
and add it to an infusion bag containing 250 mL of 0.9% 
sodium chloride, USP.  DEXTROSE (5%) SOLUTION 
SHOULD NOT BE USED.  Gently invert the bag to mix 
the solution.  The reconstituted preparation results in a 
colorless to pale yellow transparent solution.  Parenteral 
drug products should be inspected visually for particulates 
and discoloration prior to administration.
10.1.2.4
No incompatibilities between trastuzumab and 
polyvinylchloride or polyethylene bags have been 
observed.
10.1.3 Storage and Stability
Vials of trastuzumab are stable at 2C–8C (36F–46F) prior to 
reconstitution.  Do not use beyond the expiration date stamped on the vial.  
A vial of Trastuzumab reconstituted with BWFI, as supplied, is stable for 28 
days after reconstitution when stored refrigerated at 2C–8C (36F–46F), 
and the solution is preserved for multiple use.  Discard any remaining 
multi-dose reconstituted solution after 28 days.  If unpreserved SWFI (not 
supplied) is used, the reconstituted trastuzumab solution should be used 
immediately and any unused portion must be discarded.  DO NOT FREEZE 
TRASTUZUMAB THAT HAS BEEN RECONSTITUTED.
The solution of trastuzumab for infusion diluted in polyvinylchloride or 
polyethylene bags containing 0.9% sodium chloride for injection, USP, may 
be stored at 2C–8C (36F–46F) for up to 24 hours prior to use.  Diluted 
trastuzumab has been shown to be stable for up to 24 hours at room 
temperature 15C–25C; however, since diluted trastuzumab contains no 
effective preservative the reconstituted and diluted solution should be stored 
refrigerated (2C–8C).
10.1.4 Administration
Treatment may be administered in an outpatient setting by administration of 
a 4 mg/kg trastuzumab loading dose for weekly dosing schedules by 
intravenous (IV) infusion over 90 minutes.  DO NOT ADMINISTER AS 
AN IV PUSH OR BOLUS.  When trastuzumab is being administered 
concomitantly with paclitaxel, trastuzumab administration should precede 


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chemotherapy administration.  Patients should be observed for fever and 
chills or other infusion-associated symptoms.  If prior infusions are well 
tolerated subsequent doses of 2 mg/kg Trastuzumab weekly may be 
administered over 30 minutes. 
10.1.5 Toxicities
10.1.5.1
Cardiac Toxicity
Trastuzumab may result in clinically manageable left ventricular systolic 
dysfunction, and occasionally advanced congestive heart failure (CHF) in a 
small proportion of patients. The incidence and severity of cardiac 
dysfunction has been greatest in patients who received trastuzumab in 
combination with an anthracycline.  In the pooled NSABP/NCCTG 
experience, the risk of cardiac events was 4% among those treated with 
chemotherapy and trastuzumab, as compared with .6% for those given 
chemotherapy alone. There are data suggesting that the risk is lower when 
sequential chemotherapy followed by trastuzumab is given.  Furthermore, 
older patients and those patients with borderline normal LVEF at baseline 
may be at greater risk for cardiac events.  The incidence of class III or IV 
cardiac dysfunction was 2% for those receiving concurrent paclitaxel plus 
trastuzumab.66 The risk of cardiac toxicity is substantially lower in patients 
who received trastuzumab alone.  Cardiac dysfunction appears to improve in 
most patients who receive supportive medical treatment. 
10.1.5.2
Infusion-Associated symptoms
10.1.5.2.1 During the first infusion of trastuzumab, symptoms 
consisting of chills and/or fever are observed in about 
40% of patients.  Other symptoms may include nausea, 
vomiting, pain, rigors, headache, cough, dizziness, rash, 
and asthenia.  These symptoms are usually mild to 
moderate in severity, and occur infrequently with 
subsequent trastuzumab infusions. 
10.1.5.2.2 Serious adverse reactions to trastuzumab infusion include 
dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, and respiratory 
distress have been reported infrequently.  In rare cases (4 
per 10,000) these events were associated with a clinical 
course culminating in fatal outcome.  
10.1.5.3
Hematologic Toxicity
10.1.5.3.1 Anemia


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An increased incidence of anemia has been observed in patients 
receiving trastuzumab plus chemotherapy compared with patients 
receiving chemotherapy alone.  The majority of these anemia events 
were mild or moderate in intensity and reversible.  None resulted in 
discontinuation of trastuzumab.
10.1.5.3.2 Neutropenia
In randomized controlled clinical trials designed to assess the impact 
of the addition of trastuzumab to chemotherapy, the incidence of 
moderate to severe neutropenia and of febrile neutropenia were 
higher in patients receiving trastuzumab in combination with 
chemotherapy as compared to those who received chemotherapy 
alone.  The pathophysiologic basis for exacerbation of neutropenia 
has not been determined.
10.1.5.3.3 Secondary acute leukemia or myelodysplastic 
syndrome
Incidence of approximately 4 in 1200 patients who participated in 
trastuzumab clinical trials. Patients treated with chemotherapeutic 
agents are known to be at increased risk of secondary leukemia.  The 
observed incidence of leukemia among trastuzumab-treated patients 
appears to be consistent with the expected incidence of leukemia 
among patients treated with chemotherapy for metastatic breast 
cancer.67  The contribution of trastuzumab to the etiology of acute 
leukemia or myelodysplastic syndrome in these cases is unclear.
10.2
Paclitaxel
10.2.1 Availability
Paclitaxel is commercially available in 20 mg/5mL, 100 mg/16.7mL, and 300 mg/50 
mL multidose vials containing a clear colorless to slightly yellow viscous solution.  
Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of 
purified Cremophor EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated 
alcohol, USP.  Please refer to FDA-approved package insert for complete product 
information.
10.2.2 Preparation
Paclitaxel must be diluted prior to administration with 0.9% sodium chloride 
Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium 
Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to 1.2 mg/mL.  


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Paclitaxel should be prepared and stored in glass, polypropylene, or polyolefin 
containers due to leaching of DHEP [di-(2ethylhexyl)phthalate] plasticizer from 
polyvinyl chloride (PVC) containers.  Non-PVC containing tubing and connectors 
such as the IV administration sets (polyethylene or polyolefin) used to infuse 
parenteral nitroglycerin should be used.
In-line filtration should be accomplished by incorporating a hydrophilic, 
microporous filter of pore size not greater than 0.22 micron (e.g. IVEX-2) into the 
IV fluid pathway distal to the infusion pump.  The Chemo Dispensing Pin device 
or similar devices with spikes should not be used with vials of paclitaxel since they 
can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel 
solution.
10.2.3 Storage and Stability
Intact vials should be stored between 20 - 25 C (68 - 77 F) in the original 
package to protect from light, and remain stable until the expiration date on the 
label.  Neither freezing nor refrigeration adversely affects stability.  Upon 
refrigeration components in the paclitaxel vial may precipitate, but will redissolve 
upon reaching room temperature with little or no agitation.  There is no impact on 
product quality under these circumstances.  If the solution remains cloudy or if an 
insoluble precipitate is noted, the vial should be discarded.  Solutions for infusion 
prepared as recommended are stable at ambient temperature (approximately 25 C) 
and lighting conditions for up to 27 hours.
10.2.4 Administration
Paclitaxel will be administered as an IV infusion using an in-line 0.22 micron filter.  
10.2.5 Toxicities
Myelosuppression, liver function test abnormalities (elevated SGOT, SGPT, 
bilirubin, alkaline phosphatase), nausea, vomiting, diarrhea, mucositis, peripheral 
neuropathy, transient asymptomatic bradycardia, and with much less frequency, 
arrhythmias, hypotension, hypersensitivity/anaphylaxis reactions (dyspnea, 
tachycardia, rash, urticaria, hypotension, or hypertension), myalgias, arthralgias, and 
alopecia.
10.3
Ancillary Therapy
10.3.1 Patients should receive full supportive care, including transfusions of blood 
or blood products, antibiotics, antiemetics, etc., when appropriate.
10.3.2 Treatment with hormones or other chemotherapeutic agents or biologic 
agents may not be administered during therapy except for steroids given for 
adrenal failure: hormones administered for non-disease-related conditions 
(insulin for diabetes, synthroid for hypothyroidism); and intermittent use of 


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dexamethasone as an antiemetic and premedication for paclitaxel. Patients 
may have received up to 4 weeks of tamoxifen therapy, or other hormonal 
therapy, for adjuvant therapy for this malignancy but must temporarily stop 
such therapy at time of entry to study. Patients may initiate adjuvant 
hormonal therapy per institutional standards after completion of treatment 
with paclitaxel. 
10.3.3 Use of Growth Factors
10.3.3.1
Erythropoetin (EPO) and Related Agents
10.3.3.1.1 The use of EPO is permitted at the discretion of the 
treating physician.
10.3.3.2
Filgrastim (G-CSF) and Related Agents
10.3.3.2.1 The use of filgrastim is permitted during treatment with 
weekly paclitaxel.  Please see section 9.1.6 and 9.1.7for 
specific recommendations about the use of these agents. 
11.0
DEFINITION OF PRIMARY ENDPOINT AND REMOVAL OF 
PATIENTS FROM THERAPY 
11.1
Primary Endpoint: Disease-Free Survival (DFS)
Disease-free survival (DFS) is defined to end at the time of the first of the 
following events: local/regional ipsilateral invasive recurrence (or ipsilateral 
invasive new primary), contralateral invasive breast cancer, distant recurrence, 
or death from any cause.  Local/regional recurrence is defined as an invasive 
ipsilateral breast cancer invasive breast cancer in the axilla, regional lymph 
nodes, chest wall, or skin of the ipsilateral breast.   A distant recurrence is 
metastatic disease that has either been biopsy confirmed or clinically 
diagnosed as recurrent invasive breast cancer.   A single new lesion on a bone 
scan without evidence of lytic disease on x-ray and without symptoms does 
not in and of itself constitute distant recurrence, but multiple new bone 
lesions, or increased isotope uptake associated with new bone symptoms are 
more likely due to metastases.  Bone metastases must be documented with x-
rays and clinical description.  Contralateral invasive breast cancer will be 
included as an event.  Death attributable to any cause, including breast cancer, 
non-breast cancer, or unknown cause will be included as an event.  In situ 
cancer will not be included as an event that ends DFS.  If a patients has in situ 
breast cancer (on the ipsilateral or contralateral side) diagnosed during follow-
up before any of the events which are defined to end DFS, then the patient 
should continue to be followed for DFS on study (even if she is given 
hormonal therapy after the in situ diagnosis).  The primary endpoint is to 
estimate disease-free survival (DFS). Yearly mammograms will not be used to 
determine DFS. Any abnormality on imaging alone is not used towards the 
DFS endpoint. A disease recurrence, or a new primary breast cancer can only 


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be determined by a biopsy. There is therefore no need for central review of 
mammography.
11.1.1
If a patient is diagnosed with a cancer of another site (i.e. other than a 
new breast cancer, a breast cancer recurrence, or breast cancer 
metastases) that is NOT a non-melanoma skin cancer or a 
cervical/vaginal carcinoma in situ, then the patient will be removed 
from study treatment.  These patients will still be followed for 
survival.  If a patient is diagnosed with a non-melanoma skin cancer 
or a cervical/vaginal carcinoma in situ, she will continue on this 
study and continue to be followed for DFS. 
11.2
Removal of Patients from Protocol Therapy (patients should still 
be followed for study endpoints)
11.2.1 Patients will be removed from protocol therapy if they experience toxicities 
per the guidelines in section 9 of the protocol.  Patients should still be 
followed for study endpoints after removal from protocol therapy.
11.2.2 Disease Progression
11.2.2.1 If a patient has a DFS event (see section 11.1) treatment should be 
permanently discontinued.  
11.2.2.2 Extraordinary Medical Circumstances
11.2.2.3
If at any time the constraints of this protocol are 
detrimental to the patient’s health and/or the patient no 
longer wishes to continue on protocol therapy, protocol 
therapy shall be discontinued.  In this event:

Notify study chair

Document the reasons for discontinuation of therapy
At the time of removal of patients from protocol therapy, participating sites are responsible 
for completing the treatment ending part of the treatment completion/off-study form found 
in appendix 6 and faxing it to the QACT at 617-632-2295 and inputing this information in 
the eDC system.  This patient will continue in follow-up on study (for DFS and survival if 
the reason for discontinuing treatment is something other than a DFS event, and for survival 
if the reason for discontinuing treatment is a DFS event).  This form must be submitted 
again when the patient goes off study.  
12.0
STATISTICAL CONSIDERATIONS
12.1 Study Design
This is a single arm, three stage study evaluating the efficacy and toxicity of weekly 
paclitaxel chemotherapy x 12 with weekly trastuzumab x 12 followed by trastuzumab 
given every 3 weeks or weekly, for a total of 52 weeks in node-negative HER2-positive 
patients with tumors  3cm.
12.2
End Points


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12.2.1 The primary end point is duration of disease-free survival.  Events that 
determine the end of disease-free survival are listed in 11.1.
12.2.2  In the rest of this section (section 12), a patient with any one of these events 
is said to have a “failure”.  At any particular calendar time after the study 
opens for accrual, each patient who has entered the study and who has 
already had a failure has a time (from entry) to failure. Each patient who has 
entered the study and has not yet had a failure has a censored time (which is 
either the time between study entry and the diagnosis of a non-breast cancer 
other than those listed in section 11.1, or else the time between entry on 
study and the most recent date that patient is known to not have a failure, 
which may be zero for a patient who has recently entered and has no follow-
up yet).  The phrase “patient-years of follow-up” refers to the sum of failure 
times for all patients who have failed plus the sum of censored times for all 
patients who have not yet failed.
12.2.3 The secondary endpoints are listed in section 2.2 (describe DFS in patients 
grouped by tumor size and hormone status, evaluate the incidence of serious 
cardiac toxicity, evaluate the incidence of serious neurotoxicity, ,characterize 
molecular alterations in small HER2+ breast cancers,  investigate the 
percentage of patients with amenorrhea at various times after start of 
treatment in premenopausal  and explore predictors of amenorrhea). 
12.3 Sample Size Justification
The target accrual of this study is approximately 400 patients. 
This is a single arm, three stage study.  The study will terminate early if more than 7 
failures are observed by the time there has been 225 patient-years of follow-up or if more 
than 24 failures are observed by the time there has been 800 patient-years of follow-up.  If 
more than 40 failures are observed by the time there has been 1600 patient-years of follow-
up, then the regimen will be declared not worthy of further study.  If none of these 
boundaries are crossed, then the regimen will be declared worthy of further study.  
 
Based on the little that is known about the failure rate of the patients eligible for this study, 
the investigators want a large chance of stopping the study at the first look if the true 3 year 
failure percent is as large as 14%, want a small chance of declaring the regimen worthy of 
further research if the true 3 year failure percent is around 9%, and want a large chance of 
declaring the regimen worthy of further research if the true 3 year failure percent is as 
small as 5%.
 
Using the exact Poisson distribution and the stopping rule above, the probability of stopping 
the study at the first look (225 patient-years of follow-up) is 0.88 if the true 3 year failure 
percent is 14%, is 0.74 if the true 3 year failure percent is 12%, and is 0.53 if the true 3 year 
failure percent is 10%. Using the exact conditional Poisson distribution, the probability that 
the regimen is declared worthy of further research is 0.05 if the true 3 year failure percent is 
9.2% and is 0.95 if the true 3 year failure percent is 5%.  


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Among HER2-positive patients receiving bisphosphonate therapy, the 3 year failure percent 
is unknown. Given the lack of data in this population of patients, the investigators 
hypothesize that patients who do not receive bisphosphonate therapy may have a failure rate 
that is not much different from those who receive bisphosphonate therapy. In addition, it is 
expected that fewer than 20 (5%) of patients who are enrolled will be receiving adjuvant 
bisphosphonate therapy (such as in S0307). Therefore, it is hypothesized that the overall 3 
year failure percent (combining patients who do not receive bisphosphonates with those 
receving bisphosphonates) will be the same as that of the original cohort.
It is hypothesized that the failure rate is higher among patients with micrometasis, however 
little is known about the 3 year failure percent in this group. With the inclusion of patients 
with micrometastasis, the overall 3 year failure percent (taking both cohorts together) is 
anticipated to be higher and therefore the probability that the regimen will be declared not 
worthy of further study will be higher.  It is estimated that patients with micrometastasis 
will account for at most 10% of accrual.  If the 3 year failure percent remains 9.2% among 
patients without micrometastasis (original cohort) and it is up to 50% higher among patients 
with micrometastasis (13.8%), then approximately the overall 3 year failure percent is 
hypothesized to be 9.7% and the probability that the regimen is declared not worthy of 
further study will be at most 3% higher. In an extreme case where 20% of patients have 
micrometastasis, the overall 3 year failure percent will be 10.1% and the probability will be 
at most 4% higher.  These calculations are based on an overall 3 year percent that is a 
weighted average of the 3 year percents of the two cohorts.
The table below gives the probability of stopping the study at the first look and the 
probability of declaring the regimen worthy of further study for various true 3 year failure 
percents.
True 3 Year Failure 
Percent
Probability That Study 
Will Be Stopped At 
First Look
Probability That 
Regimen Will Be 
Declared 
NOT WORTHY Of 
Further Study
Probability That 
Regimen Will Be 
Declared 
WORTHY Of Further 
Study
10.1
0.55
0.99
0.01
9.7
0.50
0.98
0.02
9.2
0.44
0.95
0.05
8.7
0.37
0.90
0.10
8.2
0.31
0.81
0.19
6.1
0.11
0.20
0.80
5.5
0.07
0.10
0.90
5.3
0.06
0.07
0.93
5.0
0.04
0.05
0.95
12.4 Statistical Analysis


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12.4.1 The primary analysis will include all patients enrolled to the study. Kaplan-
Meier estimates of DFS will be plotted for the study as a whole and for 
subgroups of patients determined by tumor size (≤1 cm vs. >1 cm) and 
hormone receptor status (positive vs. negative).  If the regimen is deemed to 
be worthy of further research, there will be at most 40 failures at the time of 
final analysis, and if the hypothesis of a true 5% 3 year failure percent is 
correct, it is expected that there will be only 26 failures, or about 6.5% of the 
400 patients (at a median follow-up at about 4 years).  So analysis of DFS 
will not be much more powerful than the analysis of the percentage of 
patients who have failed.  If 25% of the patients entered have tumor size ≤ 1 
cm, this study will have adequate (85%) power to declare that the two size 
groups differ significantly if the true percents of patients with failures (at a 
median follow-up of 4 years) are 1% and 8.3%.  If 25% of the patients are 
ER positive, this study will have adequate (85%) power to declare the two 
hormone receptor status groups differ significantly if the true percents of 
patients with failures are 1% and 8.3%.  These calculations assume that one-
sided 0.05 Fisher exact tests are used and that there is no adjustment for 
multiple comparisons. 
12.4.2 The incidence of grade 3 or worse cardiac toxicity will be estimated, with a 
95% confidence interval.  If the study accrues 400 patients (i.e., the study is 
not terminated before accrual is complete), then the 95% Binomial 
confidence intervals for grade 3 or worse cardiac toxicity will be 0 to 0.7% if 
no cases of serious or worse cardiac toxicity are observed, 0.3 to 2.5% if 4 
cases are observed, 0.8 to 3.9% if 8 cases are observed, 1.5 to 5.2% if 12 
cases are observed, 2.3 to 6.4% if 16 cases are observed, and 3.1 to 7.6% if 
20 cases are observed.
12.4.3 The incidence of grade III/IV neurotoxicity will be estimated, with a 95% 
confidence interval.  If the study accrues 400 patients (i.e., the study is not 
terminated before accrual is complete), then the 95% Binomial confidence 
intervals for serious neurotoxicity will be 3.1 to 7.6% if 20 cases are 
observed, 5.5 to 11.1% if 32 cases are observed, and 7.2 to 13.4% if 40 cases 
are observed.  The incidence of grade 2-4 neuropathy reported for prior 
studies of 12 weeks of paclitaxel (ECOG 1199) is approximately 27%. 
Assuming there are 50 patients who have the CYP2C8*3 polymorphism and 350 
patients who do not have the polymorphism among the 400 patients, and the 
incidence of grade 2-4 neuropathy is 27% among those without the polymorphism, 
there is 80% power to detect an absolute difference of 20%  (27% versus 47%) in 
the grade 2-4 neuropathy.  This calculation assumes a 0.05 level 2-sided test for two 
binomial proportions.  An exploratory analysis will be conducted for other possible 
SNPs that may predict neurotoxicity from paclitaxel.
12.4.4 For the correlative objective to characterizes the molecular alterations by 
gene  sequencing on all archival tumor, descriptive statistics will be used to 
report the types and frequencies of molecular events seen using 95% 
Binomial exact confidence intervals for the observed proportions. Based on 
the few DFS events expected, no statistical inferences will be used to assess 
associations, and all point and interval estimates will be reported as 
exploratory and hypothesis generating.    


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12.4.4.1  Since approximately 25% of breast cancer patients 
are premenopausal, we expect there will be a 90% chance that 
there will be at least 89 premenopausal patients who agree to 
be on the amenorrhea sub-study and who will be available for 
the amenorrhea analysis. The primary endpoint will be the 
percent of patients who report at least one menstrual period in 
the time period 6 to 12 months after protocol entry (termed 
“percent still menstruating at 12 months” below).  12.4.4.1 
We will first explore whether the proportions of patients still 
menstruating at 12 months differ between the patients 
assessed for menstrual history at the time of registration to 
07-199 and patients assessed after registration (because the 
latter will be answering questions about menstruation further 
in the past).  If these proportions differ by less than 15%, then 
the results of all patients reporting they were premenopausal 
at the time of enrollment on 07-199 will be combined.  If 
these proportions differ by 15% or more, then the primary 
analysis will involve only those patients who were assessed 
for menstrual history at the time of enrollment on 07-199.
12.4.4.2
We will report the proportion of patients with at least 
one menstrual period in the past 6 months for the group as a 
whole (either all patients, or all patients who were assessed 
for menstrual history at the time of enrollment on 07-199) and 
also by age group (<40 years vs. >40 years) and by body mass 
index (BMI <30 or ≥30) at each time point.  Exact binomial 
two-sided 95% confidence intervals for the percent of patients 
will menstruating at 12 months overall and in these 4 
subgroups will be calculated; they will not be corrected for 
multiple comparisons.  If there are at least 10 patients still 
menstruating at 12 months and at least 10 patients not still 
menstruating at 12 months (in the overall group), then factors 
associated with the probability of still menstruating at 12 
months will also be evaluated in an exploratory manner using 
logistic regression, with one covariate at a time and using a 
step-up procedure with the logistic regression.  Covariates 
that will be considered include age, (<40 years vs. ≥40), body 
mass index (<30 or ≥30), and whether the patient had some 
grade 3 toxicity (other than amenorrhea) on study.  
Exploratory descriptive statistics regarding the approximate 
frequency of recent (within the last 6 months) menses (once 
monthly, every two months, twice a month, every 2-6 months, 
or less than every six months) will also be presented for each 
time point.
If at least 89 patients who are menstruating at study entry are accrued and 
one year menstrual data is gathered on all of them and the patients assessed 
for menstrual history at the time of study registration can be combined with 


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the patients assessed for menstrual history after study registration, and if no 
corrections for multiple comparisons are made, then the largest width of the 
95% confidence interval for the proportion still menstruating at 12 months 
will be 21% (i.e., 40% to 61% if 45 of the 89 are still menstruating).  If 
approximately 75% of the patients are observed to be menstruating at 12 
months, the 95% confidence interval will be 65%-84%.  
The number of premenopausal patients accrued will be small, which means 
that the confidence intervals on percent still menstruating at any time point 
will be large and also means that only exploratory analysis can be done on 
factors affecting the proportion still menstruating.  Also, if the study stops 
accrual early, there will be fewer patients available for estimating 
amenorrhea.  In addition, there may be a difference in recall between patients 
first questioned about their menstrual history at protocol entry (before 
treatment starts) and patients first questioned later. However, data resulting 
from this assessment will provide preliminary estimates of percents of 
amenorrhea in the population receiving this regimen.
13.0
STUDY CONDUCT CONSIDERATIONS
13.1
Institutional Review Board or Ethics Committee Approval
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated.  The 
study will be conducted in accordance with U.S. FDA, applicable national and local health 
authorities, and IRB requirements.
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case the 
IRB must be updated at least once a year.  The Principal Investigator must also keep the 
IRB informed of any significant adverse events.
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to serious adverse 
events that are not already identified in the Investigator Brochure and that are considered 
possibly or probably related to the molecule or study drug by the investigator.  Some IRBs 
may have other specific adverse event requirements that investigators are expected to 
adhere.  Investigators must immediately forward to their IRB any written safety report or 
update provided by Genentech (e.g., IND safety report, Investigator Brochure, safety 
amendments and updates, etc.).
13.2
Data Safety Monitoring Board (DSMB)
The Dana Farber DSMB will be utilized for this study.  Interim analyses are planned to 
take place when a total of 225 and 800 patient years of follow-up have been collected, with 
a final analysis when a total of 1600 patient years of follow-up have been collected.  If the 
assumptions of section 12.5 are correct, then these analyses will occur approximately at 
1.5, 3, and 5 years after accrual to the study starts.  The analyses will be done early if 8 


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failures are observed before 225 patient years of follow-up are collected, or if 25 failures 
are observed before 800 patients years of follow-up are collected, or if 41 failures are 
observed before 1600 patient years of follow-up are collected.  
13.3
Study Monitoring Requirements
The coordinating site will collect and review data on an on going basis via an internet 
application using the Electronic Data Capture (eDC) system provided by the Quality 
Assurance for Clinical Trials (QACT).  All appropriate participating site staff must 
complete the eDC system-training course prior to any data entry.  The lead institution will 
supply each participating site with the appropriate information to register for training and to 
access the eDC system.  
The coordinating site will conduct at least one visit at each participating site location within 
the first year of patient enrollment.  QACT auditors or their designee (s) will require access 
to all patient medical records to verify source and ensure appropriate review of the data 
submitted on the eCRFs. Additional site visits and source documentation may be conducted 
at the discretion of the principal investigators.  In addition, source documentation may be 
requested from participating sites periodically at the discretion of the principal 
investigators.  
13.4
Disclosure of Data
Subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited.
Upon the subject’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, Genentech, and the 
IRB for each study site, if appropriate.
13.5
Retention of Records
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining 
to the conduct of this study and the distribution of investigational drug, including CRFs, 
consent forms, laboratory test results, and medication inventory records, must be retained 
by the Principal Investigator for 2 years after marketing application approval.  If no 
application is filed, these records must be kept 2 years after the investigation is 
discontinued and the U.S. FDA and the applicable national and local health authorities are 
notified.  Genentech will notify the Principal Investigator of these events.
14.0
ADVERSE EVENTS: REPORTING AND MONITORING
14.1
Adverse Event and Reporting Definitions
With the occurrence of an adverse event, the first concern will be for the safety of the 
subject.  The investigator must report any serious adverse events, which occur during the 
clinical study or within 30 days of receiving the last dose of study medication, whether or 


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not related to the study drugs to the Principal Investigator, Genentech (if applicable per 
guidelines specified below), and per participating local IRB reporting requirements.  
DF/HCC and DF/PCC institutions must report all SAEs directly to the DFCI IRB using the 
DFCI IRB-Serious Adverse Event Reporting Form found on the Oncology Protocol System 
website in addition to notifying the Principal Investigator.  All other participating 
institutions SAE report notifications will be reviewed by the lead institution to determine if 
it meets DFCI IRB SAE reporting requirements.  If the event does meet the DFCI IRB SAE 
reporting requirements, the study coordinator or designee at the lead institution will submit 
the event information to the DFCI IRB using the DFCI IRB IND Safety Reporting Form.  
Investigators are required to report to Genentech Drug Safety any serious adverse event, 
whether expected or unexpected, and which is assessed by the investigator to be 
reasonably or possibly related to or caused by trastuzumab.  All events meeting these 
criteria will be reported for the time period beginning with any amount of exposure to 
trastuzumab through the protocol-defined follow-up period.  Serious criteria, definitions, 
and guidance for reporting follow.
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational study or protocol regardless of causality assessment.  An adverse event can 
be an unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, syndrome or disease associated with or occurring during the use of an 
investigational product whether or not considered related to the investigational product.  
During the course of this study, only grade 2 or higher adverse events will be followed and 
recorded in the electric data capture system (eDC). During the follow up period only Grade 
2 neurotoxicity and cardiac events need to be reported.
Serious adverse events (SAE) are adverse events occurring at any dose which meet one or 
more of the following serious criteria:
Results in death (i.e. the AE caused or led to death)
Is life-threatening (i.e. the AE placed the subject at immediate risk of death; it does not 
apply to an AE which hypothetically might have caused the death if it were more severe)
Requires or prolongs inpatient hospitalization (i.e. the AE required at least a 24-hour 
inpatient hospitalization or prolonged a hospitalization beyond the expected length of stay; 
hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion)
Is disabling (i.e. the AE resulted in a substantial disruption of the subject’s ability to carry 
out normal life functions)
Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed to the study drug prior to conception or during pregnancy)
Does not meet any of the above serious criteria but may jeopardize the subject and may 
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Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure. 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.).  This includes adverse events for which the specificity or 
severity is not consistent with the description in the P.I. or I.B.  For example, under this 
definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated 
hepatic enzymes or hepatitis.
 Reporting of Serious Adverse Events Associated with Trastuzumab
All SAEs that are serious and reasonably or probably related to the use of trastuzumab (this 
applies to both expected and unexpected events) should be recorded on a MedWatch 3500 
Form and faxed to:
Genentech Drug Safety Contact Line
Tele: 1-888-835-2555
Fax:  (650) 225-4682/ (650) 225-4683 
AND:
Study Coordination Center/Principal Investigator: Sara Tolaney
Contact Information: 
 
MedWatch 3500 Reporting Guidelines:
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500 form:

Protocol description (and number, if assigned)

Description of event, severity, treatment, and outcome if known

Supportive laboratory results and diagnostics


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
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication
Follow-up information:  
Additional information may be added to a previously submitted report by any of the 
following methods:

Adding to the original MedWatch 3500 report and submitting as follow-up

Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500 form 

Summarizing new information and faxing it with a cover letter including subject 
identifiers (i.e. D.O.B. initial, subject number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted). The patient identifiers are important so that the new 
information is added to the correct initial report)
Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the subject for whom and adverse event was reported.  For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative noted 
above.
Study Drug Relationship:
The investigator will determine which events are associated with the use of study drug.  For 
reporting purposes, an AE should be regarded as possibly related to the use of trastuzumab 
if the investigator believes:

There is a clinically plausible time sequence between onset of the AE and trastuzumab 
administration; and/or

There is a biologically plausible mechanism for trastuzumab to cause or contribute to 
the AE; and
The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures.
15.0
STUDY ORGANIZATION
This study will be run by the Dana-Farber Cancer Institute as part of the Dana Farber/Harvard 
Cancer Center.  


APT, page 64
16.0  REFERENCES
1.
Revillion F, Bonneterre J, Peyrat JP: ERBB2 oncogene in human breast cancer and its clinical 
significance. Eur J Cancer 34:791-808, 1998
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Esteva FJ, Cheli CD, Fritsche H, et al: Clinical utility of serum HER2/neu in monitoring and 
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Abusief ME MS, Ginsburg ES, Weeks JC, Winer EP, Partridge AH.: Chemotherapy-related 
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associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast 
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HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 24:2428-36, 2006
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Hicks DG, Yoder BJ, Pettay J, et al: The incidence of topoisomerase II-alpha genomic 
alterations in adenocarcinoma of the breast and their relationship to human epidermal growth factor receptor-2 
gene amplification: a fluorescence in situ hybridization study. Hum Pathol 36:348-56, 2005
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in primary breast carcinomas using immunohistochemistry and differential polymerase chain reaction. Int J 
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Mol Cell Biol 13:4125-36, 1993
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its occurrence and prognostic relevance. Br J Cancer 83:1688-95, 2000
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Kim C BJ, Horne Z, Geyer CE, Wicherham DL, Wolmark N, Paik S.: Trastuzumab sensitivity 
of breast cancer with co-amplification of HER2 and cMYC suggests pro-apoptotic function of dysregulated 
cMYC in vivo., 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texax, 2005
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the treatment of breast cancer: a review of the literature on HER-2, p53 and BCL-2. Ann Oncol 11:647-63, 2000
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Yamashita H, Nishio M, Toyama T, et al: Coexistence of HER2 over-expression and p53 protein 
accumulation is a strong prognostic molecular marker in breast cancer. Breast Cancer Res 6:R24-30, 2004
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Campbell IG, Russell SE, Choong DY, et al: Mutation of the PIK3CA gene in ovarian and 
breast cancer. Cancer Res 64:7678-81, 2004
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Saal LH, Holm K, Maurer M, et al: PIK3CA mutations correlate with hormone receptors, node 
metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 
65:2554-9, 2005
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Lee JW, Soung YH, Kim SY, et al: PIK3CA gene is frequently mutated in breast carcinomas 
and hepatocellular carcinomas. Oncogene 24:1477-80, 2005
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Bachman KE, Argani P, Samuels Y, et al: The PIK3CA gene is mutated with high frequency in 
human breast cancers. Cancer Biol Ther 3:772-5, 2004
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growth factor receptor mutation screening. Clin Cancer Res 12:751-8, 2006
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Nagata Y, Lan KH, Zhou X, et al: PTEN activation contributes to tumor inhibition by 
trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117-27, 2004
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Bose S, Crane A, Hibshoosh H, et al: Reduced expression of PTEN correlates with breast cancer 
progression. Hum Pathol 33:405-9, 2002
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Nahta R, Yuan LX, Zhang B, et al: Insulin-like growth factor-I receptor/human epidermal 
growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. 
Cancer Res 65:11118-28, 2005
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Laux I, Jain A, Singh S, et al: Epidermal growth factor receptor dimerization status determines 
skin toxicity to HER-kinase targeted therapies. Br J Cancer 94:85-92, 2006
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Goldstein JA DD: Genetic Polymorphisms of Human CYP2C8 and Their Effects on Metabolism 
of the Anticancer Drug Taxol. Proceedings of the 13th international symposium on Microsomes and drug 
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Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is 
associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-8, 2005
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Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen 
metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30-9, 2005
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Stearns V, Johnson MD, Rae JM, et al: Active tamoxifen metabolite plasma concentrations after 
coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 
95:1758-64, 2003
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Muller V, Thomssen C, Karakas C, et al: Quantitative assessment of HER-2/neu protein 
concentration in breast cancer by enzyme-linked immunosorbent assay. Int J Biol Markers 18:13-20, 2003
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Fornier MN, Seidman AD, Schwartz MK, et al: Serum HER2 extracellular domain in metastatic 
breast cancer patients treated with weekly trastuzumab and paclitaxel: association with HER2 status by 
immunohistochemistry and fluorescence in situ hybridization and with response rate. Ann Oncol 16:234-9, 2005
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Schwartz MK, Smith C, Schwartz DC, et al: Monitoring therapy by serum HER-2/neu. Int J 
Biol Markers 15:324-9, 2000
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Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials 
experience. J Clin Oncol 20:1215-21, 2002
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Cross M, Dexter TM: Growth factors in development, transformation, and tumorigenesis. Cell 
64:271-80, 1991


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APPENDICES
APPENDIX 1
Baseline Assessment of Menses
Patient Initials:
___________________________________Subject Number:
Date Today:______________
1)Have you menstruated in the past 6 months?
  Yes      
 No
2)When was the month and year of your last menstrual period (approximately)? 
____ / ______ (MM/YYYY)
3)Do you consider yourself pre-menopausal at this time?  
 Yes
 
  No       
 
 Unsure
4)Have you taken any hormonal agents (e.g. birth control pills or steroids or fertility drugs) in the past 6 months?  
 No
If yes, please explain: ________________________________________
5)
Approximately how often did you have a menstrual period in the 6 
months prior to diagnosis?
  once every month
     
 once every 2 months
    
  2 times per month 
              
 once every 2-6 months      
 less often than every 6 months  
   none
 


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Appendix 2 
Follow-Up Menses Assessment
Patient Initials:
___________________________________ Subject Number:______________
Date Today:______________ 
1)
Have you menstruated in the past 6 months? 
  Yes      
 No
2)
When was the month and year  of your last menstrual period (approximately)?
 _______ / ________ (MM/YYYY)
3)
Approximately how often have you had your menstrual period over the past six months?
  once every month
     
  once every 2 months
       
  2 times per month 
  
    
  once every 2-6 months     
  less often than every 6 months    
   none
4)
Are you currently taking any of the following?  
  Tamoxifen (date started :______________)
  Ovarian suppression (date started :______________)
  Birth control pill (date started :______________)
  Aromatase inhibitor (date started :_____________)
  Other hormonal agent (___________________date started :_____________)


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Appendix 3
National Cancer Institute Common Toxicity Criteria V4.0
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm


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Appendix 4
ECOG Performance Status*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., 
light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of 
waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
*obtained from: http://www.ecog.org/general/perf_stat.html 




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DATE TREATMENT ENDED
This is when protocol treatment for a subject (i.e. chemotherapy, radiation, 
surgery etc) is stopped due to the various reasons listed below (1-10).  
The date treatment ended is linked to Chemo-order entry as applicable.  
Therefore, it is critical that as subjects complete protocol therapy that this 
is documented in the QACT registration system.  
OFF STUDY
This is when the subject will no longer be followed on the protocol due to 
the reasons listed below (1-10).  Subjects can come off treatment before 
they come off study if they are still being followed on protocol or, they may 
come off treatment at the same time.  This often is protocol dependent.
1. Subject Canceled-
This is selected only when a subject never starts protocol treatment  (i.e. 
chemotherapy, radiation, surgery etc).  This should be selected for both off 
treatment and off study if the subject never started treatment.
2. Subject Ineligible-
This is selected when a subject has already begun treatment (i.e. 
chemotherapy, radiation, surgery etc) and has been deemed 
ineligible. Some protocols require follow-up for ineligible subjects so 
the subject may continue on follow-up.  This may be selected for off 
treatment or off study.
NOTE: The subject will be taken Off Treatment AND taken Off Study when 
selecting this number, unless ‘Yes’ is selected for Follow-up.
3. Subject Completed 
Protocol Requirements
This is selected when a subject has finished the protocol 
requirements.  (may mean treatment is finished or follow-up is 
finished).  This may be selected for off treatment or off study.
4. Unacceptable Toxicity
This is selected when a subject experiences toxicity that either the subject or 
physician find unacceptable. Please specify the toxicity and if a Phase I trial select 
Yes or No to indicate if the toxicity is a protocol DLT. This may be selected for off 
treatment or off study.
5. Progressive 
disease/Relapsed
This is selected when a subject’s disease worsens and meets the criteria in the 
protocol for progression; i.e. the tumor is measured and evaluated according to the 
tumor evaluation criteria written in the protocol (RECIST, WHO, etc) and it is 
deemed “progressive” (the tumor has grown larger or the disease has spread to 
other parts of the body).  This may be selected for off treatment or off study.
6. Subject Withdrawal of 
Consent and Follow-up
This is selected when a subject, at any time during the study, 
decides to no longer participate in either the treatment portion of the 
protocol or the follow-up portion.  Subject must be off treatment and 
off study.
7. Subject Died-
If the subject dies while still receiving protocol treatment this option can be chosen 
for off treatment.  If the subject has completed treatment but is in follow-up then 
this reason can be chosen for off-study but should not be selected for off-


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treatment.   Please indicate the date of death when selecting this number.
NOTE: The subject will be taken Off Treatment AND taken Off Study when 
selecting this number.
For DFCI only: PI or study staff designee must notify the Medical Record 
Department/Health Information Services, dfcideceasedpatients@partners.org
8. Lost to Follow-up 
This is selected when the subject cannot be located during the treatment or follow-
up portion of the protocol and all communication is lost.  Subject must be off 
treatment and off protocol.
9. Other
This is selected when the reason for stopping protocol treatment does not meet 
any of the other reasons listed on this form.  A description of the reason MUST be 
written in.  This may be selected for off treatment or off study.
10. Subject Withdrawal of 
Consent but Agrees to be 
Followed
This is selected when a subject, at any time during the study, decides to no longer 
participate in the treatment portion of the protocol BUT agrees to participate in the 
follow-up portion. Used for off treatment only.
11.  Subject unable to 
proceed to treatment
This is selected when a subject meets eligibility requirements, is registered, and 
has study specific procedures performed but is unable to proceed to the study 
treatment (for example: transplant). This could be due to progression prior to the 
study intervention, subject no longer medically fit to receive transplant, donor 
unavailable, or in the case of vaccine studies, vaccine cannot be made.  This 
should be selected for both off treatment and off study.


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Appendix 6   
Blood Collection Requisition Form
Blood Samples 
1. Complete this requisition form and deliver with sample.
2. Label ALL tubes
Sample information
Patient Name:  _____________________________________
Patient MRN:  ________________________________
Patient Case Number: _______________________________
Protocol Number: ______________________________________
Date of Collection: __________________________________
Comments: ________________________________________
Contact Information
Name: ________________________________
Telephone Number: _____________________
Address: _______________________________
  _______________________________
  _______________________________


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APPENDIX 7
Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan
1.0
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol. 
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center (DF/HCC) Multi-
center protocol will comply with Federal regulations (21 CFR Part 11); Good Clinical Practice (GCP) 
Guidelines; and Health Insurance Portability and Accountability Act (HIPAA) requirements in 
accordance with the CTEP Multi-center Guidelines.       
1.2 Multi-Center Data and Safety Monitoring Plan Components
The Multi-Center Data and Safety Monitoring Plan includes the following components:
DF/HCC Multi-center Protocol:  One or more outside institutions collaborating with Dana-
Farber/Harvard Cancer Center on a research protocol where DF/HCC is the Lead Institution. Dana-
Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates are not viewed as outside 
sites in this definition.
Lead Institution:  Dana-Farber Cancer Institute will be the Lead Institution and will be responsible 
for the coordination, development, submission, and approval of a protocol as well as its subsequent 
amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, FDA, OBA etc.). 
DF/HCC Contract Principal Investigator:  Investigator located at the Lead Institution who will be 
charged with the responsibility of the administration of the DF/HCC Project. This most often will be 
the Protocol Chair, but occasionally this may be the overall grant or contract holder, as applicable.
Protocol Chair:  Dr. Sara Tolaney is the Principal Investigator for the DF/HCC protocol submitted 
as the Lead Institution.  For applicable protocols, the Protocol Chair will be the single liaison with 
any regulatory agencies (ie.CTEP Protocol and Information Office (PIO), FDA, OBA etc.). 
Participating Institution:  A participating institution is an institution that desires to collaborate with 
DF/HCC and commits to accruing participants to a DF/HCC protocol.  The participating institution 
acknowledges the Protocol Chair as having the ultimate authority and responsibility for the overall 
conduct of the study.   
Coordinating Center: The Lead Institution is the Coordinating Center for the DF/HCC Multi-center 
Protocol. The Coordinating Center will provide the administrative support to the Protocol Chair in 
order that he/she may fulfill the responsibilities outlined in the DSMP and as specified in applicable 
regulatory guidelines (ie. CTEP Multi-Center Guidelines).  In addition to the Lead Institution, the 
Quality Assurance Office for Clinical Trials (QACT) provides support services to assist the Protocol 
Chair. 


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2.0
GENERAL ROLES AND RESPONSIBILITIES
In accordance with the CTEP Multi-center Guidelines, the Protocol Chair (DF/HCC Principal 
Investigator), Coordinating Center (Lead Institution or designee), and the Participating Institutions will 
all agree to the general responsibilities as follows (specific procedures for these general responsibilities 
are detailed in the DSMP):
2.1
Protocol Chair (DF/HCC Principal Investigator)
The Protocol Chair will accept responsibility for all aspects of the Multi-Center Data and Safety 
Monitoring Plan to:

Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments.   

Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the protocol.

Assure all participating institutions are using the correct version of the protocol.

Monitor progress and overall conduct of the study at all participating institutions. 

Ensure all DFCI IRB, DF/HCC and other applicable (i.e. CTEP, FDA, OBA) reporting 
requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with CTEP/PIO Office (CTEP trials) or FDA (sponsor-investigator 
IND trials) or OBA (gene therapy trials), as applicable.

Identify participating institutions and obtain accrual commitments. The Protocol Chair will also 
submit a protocol attachment labeled as “Participating Investigators” to the DFCI IRB and if 
applicable CTEP, FDA or OBA that provides the names and contact information for all 
participating institutions that perform the function of recruiting, enrolling, and treating 
participants for the protocol.  The Coordinating Center (Lead Institution or designee) must be 
designated on the title page. Revisions to the list will be submitted to the DFCI IRB and if 
applicable NCI/CTEP Protocol Information Office (PIO), FDA or OBA as an administrative 
protocol amendment to reflect changes in staff and assignment of responsibility as they occur.
    2.2   Coordinating Center (Lead Institution)
The Coordinating Center is the DF/HCC Lead Institution’s study team or designee (i.e Medical 
Monitor, Clinical Research Organization). The DF/HCC Lead Institution will ensure that all 
participating sites within the Multi-Center Protocol demonstrate their intent and capability of 
complying with Federal Regulations, GCPs and Health Insurance Portability and Accountability Act 
(HIPAA) requirements.   To assist the Protocol Chair in meeting his/her responsibilities as required 
by the DSMP, the DF/HCC Lead Institution’s study team or designee will assume the following 
general responsibilities:

Assist in protocol review.

Maintain copies of Institutional Review Board (IRB) approvals and Office for Human 
Research Protections (OHRP) form 310 from all participating institutions.

Maintain CTEP, FDA or OBA correspondence, as applicable.

Ensure all participating institutions’ OHRP forms 310 have been submitted to 
CTEP/PIO, if applicable.

Maintain updated roster of participants. 


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
Verify eligibility.

Verify response.

Collect data on protocol specific CRFs.

Prepare all submitted data for review by the Protocol Chair.

Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to Protocol Chair for timely review.  

Distribute external Serious Adverse Event safety reports. 

Monitor and audit Participating Institutions either by on-site inspection of selected 
participant records and/or with submitted source documents and research records 
submitted to the Lead Institution. 
   
In addition to the Lead Institution, the DF/HCC Quality Assurance Office for Clinical Trials provides 
the following support services to assist the Protocol Chair:

Develop protocol specific case report forms (CRF/eCRFS).

QA/QC data of protocol specific CRFs. 

Provide Central Participant Registration.

Confirm eligibility and consent. 

Provide auditing services.
    2.3   Participating Institution
The Participating Institution(s) will be identified on the title page for each protocol.   In addition, 
each participating institution will provide to the Lead Institution or designee a list of the key 
personnel assigned to the role for oversight of data management at their site. All sites must have 
office space, office equipment, and internet access that meet HIPAA standards.
The general responsibilities for each participating institution are as follows:

Commit to accrual to the Lead Institution’s (DF/HCC) protocol.

Submit protocol and/or amendments to their local IRB.

Update Coordinating Center (Lead Institution or designee) with research staff changes on        
a timely basis.

Register participants through the QACT. 

Submit source documents, research records, and CRFs per protocol specific                              
submission guidelines to the Coordinating Center (Lead Institution or designee). 

Submit Serious Adverse Event reports directly to the Coordinating Center (Lead                      
Institution or designee). For CTEP trials, submit SAE reports directly to CTEP                         
and provide copies to the Coordinating Center (Lead Institution or designee). 

Submit deviations and violations to the Coordinating Center (Lead Institution or    
            designee).

For protocols using investigational agents, the participating institution will               
            order their own investigational agents regardless of the supplier (i.e. NCI, 
            pharmaceutical company).
3.0
DF/HCC QUALITY ASSURANCE OFFICE FOR CLINICAL TRIALS
The DF/HCC QACT is a unit that has been developed to collect, manage, and monitor data for 
DF/HCC trials.  The DF/HCC QACT is located administratively in the office of the Senior Vice 


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President for Clinical Research, at Dana-Farber Cancer Institute.  The QACT uses DF/HCC 
computerized institutional databases for participant registrations and for the management of trial data as 
well as a set of quality assurance programs designed to monitor DF/HCC trials.  
3.1
Organizational Structure
The DF/HCC Quality Assurance Office for Clinical Trials administrative structure consists of:
DF/HCC Quality Assurance Officer for Clinical Trials: Oversees the functions of the DF/HCC 
QACT.
QACT Assistant Director for Data: Provides direct oversight to the QACT Data Analysts 
assigned to CRF design, data collection and computerization for DF/HCC trials. 
The DF/HCC QACT Data Analysts will be assigned on a protocol-by-protocol basis. Each protocol’s 
data analyst is responsible for database management, data entry, data quality assurance, and protocol 
specific correspondence related to the collection and quality assurance of data.
QACT Assistant Director for Monitoring: Provides direct oversight to the QACT Protocol 
Registrars and Clinical Research Auditors.
The DF/HCC Protocol Registrars are responsible for the confirmation of each participant’s 
eligibility and consent prior to protocol registration. 
If funded and QACT approved, the DF/HCC Clinical Research Auditors may assist the Lead 
Institution in their auditing responsibilities for multi-center trials. The QACT auditor is responsible 
for systematically evaluating participant safety, protocol compliance, institutional SOPs, ICH GCP 
and Federal regulation compliance, data accuracy and investigational drug handling to assure a high 
standard of quality for DF/HCC trials.
4.0 PROTOCOL DEVELOPMENT
4.1 Activation of a Protocol
The Protocol Chair is responsible for the coordination, development, and approval of the protocol as 
well as its subsequent amendments, and reporting SAEs, violations and deviations per DFCI IRB 
guidelines and if applicable CTEP Multi-center, FDA or OBA Guidelines.  Further, the Protocol 
Chair will be the single liaison with the CTEP/PIO, the FDA or OBA, as applicable.
To meet these requirements, the Protocol Chair will be responsible for the following minimum 
standards:

Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the protocol as 
an appendix.

Identify participating institutions and obtain accrual commitments. The Protocol Chair 
will also submit a protocol attachment labeled as “Participating Investigators” to the DFCI 
IRB and if applicable CTEP, FDA or OBA, that provides the names and contact 


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information for all participating institutions that perform the function of recruiting, 
enrolling, and treating participants for the protocol. The Coordinating Center (Lead 
Institution or designee) must be designated on the title page. 

Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the Protocol Chair.

Ensure that there is only one version of the Protocol and that all Participating Institutions 
use the correct version. 

Oversee the development of data collection forms (case report forms) that are of common 
format for use at all the Participating Institutions. 
4.2
Coordinating Center Support Function
The DF/HCC Lead Institution’s study staff or designee will provide administrative and clerical 
support to the Protocol Chair for the development and distribution of the protocol. 
The tasks to be performed by the DF/HCC Lead Institution’s study staff or designee include:

Review of the protocol and consent to check for logistics, spelling, and consistency.  
Provide the Protocol Chair a list of queries related to any inconsistencies.

Provide necessary administrative sections, including paragraphs related to registration 
logistics, data management schedules, and multi-center guidelines. 

Maintenance of contact list of all participating institutions in the DF/HCC Multi-center 
Protocol and the distribution of updates to the sites as needed. 

Derivation of the study calendar, if applicable.

Assistance in preparation and maintenance of case report forms. 

Maintain and document communication with all participating institutions. 
5.0 PROTOCOL MANAGEMENT
The Coordinating Center (Lead Institution of designee) is responsible for assuring that each Participating 
Institution in the DF/HCC Multi-center Protocol has the appropriate assurance on file with the Office of 
Human Research Protection (OHRP).   Additionally, the Lead Institution or designee must maintain 
copies of all IRB approvals, for each participating institution. 
5.1
Protocol Distribution
The Coordinating Center (Lead Institution or designee) will distribute the final approved protocol and 
any subsequent amended protocols to all Participating Institutions.   
5.2
Protocol Revisions and Closures
The participating institutions will receive phone, fax, mail or e-mail notification of protocol revisions 
from the Lead Institution or designee.  It is the individual participating institution’s responsibility to 
notify its IRB of these revisions.
Non life-threatening revisions: Participating institutions will receive written notification of protocol 
revisions regarding non life-threatening events from the Lead Institution or designee. Non-life-


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threatening protocol revisions should be implemented within 90 business days from receipt of the 
notification.
Revisions for life-threatening Causes: Participating institutions will receive telephone notification 
from the Lead Institution or designee concerning protocol revisions required to protect lives with 
follow-up by fax, mail or e-mail.  Life-threatening protocol revisions will be implemented 
immediately.
Protocol Closures and Temporary Holds: Participating institutions will receive fax, e-mail, or 
phone notification of protocol closures and temporary holds, with follow-up by mail from the Lead 
Institution or designee. Closures and holds will be effective immediately.  In addition, the Lead 
Institution or designee will update the Participating institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures.
5.3 NCI Physician Investigator Registration
All physicians registering participants on NCI funded investigational drug trials must have submitted 
a Form FDA 1572 to the NCI and possess an active investigator number.  Each institution shall 
submit their FDA 1572 forms to the NCI and a copy of FDA 1572 form, Curriculum Vitae (CV), and 
NCI investigator number to the Lead Institution or designee annually.  Physicians should not register 
participants to DF/HCC studies without an active FDA 1572, current CV, and NCI investigator 
number.  
5.4 IRB Documentation
The following must be on file with the DF/HCC Lead Institution or designee prior to participant 
registration:

Approval Letter of the institution's IRB (An Expedited IRB first approval is NOT 
acceptable)

IRB approval for all amendments
It is the individual institution's responsibility to notify its IRB of protocol revisions.  Participating 
institutions will have 90 days from receipt to provide the DH/HCC Lead Institution or designee their 
IRB approval for Major Amendments* to a protocol.   
* DF/HCC defines a Major Amendment as: A substantive change in the study which may increase 
or decrease the risk to study participants.  Major revisions require full IRB approval.  The following 
criteria are examples of revisions to a protocol that are considered to be major amendments:

Change of eligibility (inclusion/exclusion) criteria

Change in design of protocol

Change in statistical section

Change in sample size/accrual (e.g., doubling the sample size)

Change in informed consent

Change of estimated dropout rate

Change of treatment or intervention

Change of device


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
Change in primary objective evaluation process
5.5 IRB Re-Approval
         
Annual IRB re-approval from the Participating institution is required in order to register participants 
onto a protocol.  There is no grace period for annual re-approvals.
Protocol registrations will not be completed if a re-approval letter is not received by the DF/HCC 
Lead Institution or designee from the Participating Institutions on or before the anniversary of the 
previous approval date.  
5.6 Participant Confidentiality and Authorization Statement
The Health Insurance Portability and Accountability Act of 1996 contains, as one of its six major 
components, the requirement to create privacy standards for health care information that is used or 
disclosed in the course of treatment, payment or health care operations.  The original Privacy Rule, as 
it has come to be known, was published in December 2000.  The Final Rule was published on August 
14, 2002, which has modified the privacy rule in significant ways vis-à-vis research.
In order for covered entities to use or disclose protected health information during the course of a 
DF/HCC Multi-Center Protocol the study participant must sign an Authorization.  This Authorization 
may or may not be separate from the Informed Consent.  The DF/HCC Multi-Center Protocol, with 
the approval from the DFCI IRB and if applicable NCI/CTEP, will provide an Informed Consent 
template, which covered entities (DF/HCC Multi-Center Protocol participating institutions) must use. 
The DF/HCC Multi-Center Protocol will use all efforts to limit its use of protected health information 
in its trials.  However, because of the nature of these trials, certain protected health information must 
be collected per National Cancer Institute requirements. These are the primary reasons why DF/HCC 
has chosen to use Authorizations, signed by the participant in the trial, rather than limited data sets 
with data use agreements.  
5.7 DF/HCC Multi-center Protocol Case Number
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a five-digit protocol case number.  This number is unique to the participant on this trial and 
must be used for QACT CRF/eCRF completion and written on all data and QACT correspondence 
for the participant.
5.8
DF/HCC Multi-center Protocol Registration Policy
    5.8.1 Initiation of Therapy: Participants must be registered with the DF/HCC QACT before 
receiving treatment.  Treatment may not be initiated until the site receives a faxed or e-
mailed copy of the participant’s Registration Confirmation memo from the DF/HCC 
QACT. Therapy must be initiated per protocol guidelines.  The Protocol Chair and DFCI 
IRB must be notified of any exceptions to this policy. 


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5.8.2 Eligibility Exceptions: The DF/HCC QACT will make no exceptions to the eligibility 
requirements for a protocol.  In addition, the Cancer Therapy Evaluation Program (CTEP) 
specifically prohibits registration of a participant on any NCI Sponsored protocol that 
does not fully and completely meet all eligibility requirements. The DF/HCC QACT 
requires each institution to fully comply with this requirement.
5.8.3 Verification of Registration, Dose Levels, and Arm Designation: A registration 
confirmation memo for participants registered to DF/HCC Multi-Center Protocol will be 
faxed or emailed to the registering institution within one working day of the registration. 
Treatment may not be initiated until the site receives a faxed or e-mailed copy of the 
registration confirmation memo. 
5.8.4 Confidentiality: All documents, investigative reports, or information relating to the 
participant are strictly confidential. Any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Lead Institution or 
designee must have the participant’s full name & social security number “blacked out” 
and the assigned DF/HCC QACT case number and protocol number written in (with the 
exception of the signed informed consent document). Participant initials may only be 
included or retained for cross verification of identification.
5.9  Schedule of Data Submission
The DF/HCC QACT develops a set of either paper or electronic case report forms, (CRF/eCRFs) 
for use with the DF/HCC Multi-Center Protocol.  These forms are designed to collect data for each 
study. The schedule for submission of case report forms to the DF/HCC QACT is generally 
specified in each protocol. 
5.10. Eligibility Checklist
Purpose - Outlines protocol-specific eligibility criteria and includes the following:
             
Participant Demographics (address, zip code, sex, race, ethnicity, initials, date of birth)
1) Parameters for eligibility
2) Parameters for exclusion
3) Parameters for stratifications
If a time frame is not specified in the protocol, tests must be completed as follows:

Lab tests required for eligibility must be completed within 14 days prior to study 
enrollment by the QACT.

For protocols requiring measurable disease, lab baseline measurements must be completed 
within 14 days prior to study enrollment by the QACT. Examples: flow cytometry, HLA 
typing, fluid cytology, tumor markers and hormones (CEA, CA-27-29, CA-125).

Non-lab tests required for eligibility must be performed within 30 days prior to study 
entry. Example: radiological scans

Schedule for Submission - Completed prior to participant registration. The                       
Informed Consent/ Participant Authorization for the Release of Personal        


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            Health Information should be submitted with the Eligibility Checklist at the time                
of registration.
5.10.1 Off Treatment/Off Study Form
Purpose - The Off Treatment/Off Study Form is submitted when the participant is 
removed from the study or has completed all protocol treatment.  Note: If the participant 
dies while on protocol, the Off Study Form is the last form submitted.
Schedule of Submission – Submitted within 14 days after completing treatment or taken off 
study for any reason.
5.10.2   Follow up / Survival Form
Purpose - Summarizes participant status at a given point in time after being removed from 
treatment. 
Schedule of Submission – Submitted within 14 days after the protocol defined follow up visit 
date or call.   
5.11 Data Form Review
When data forms arrive at the DF/HCC QACT, they are reviewed for:
 
Timeliness: 
Did the form arrive on time as specified in the protocol?
Completeness: 
Is all the information provided as required per protocol?
Participant Eligibility: 
Does the participant meet the eligibility requirements for the study based on the demographic data, 
lab values and measurements provided?
Stratification: 
Are the stratification parameters consistent with what was given at the time of registration?
Protocol Treatment Compliance: 
Are the body surface area (BSA) and drug dosage calculations correct?  The dose must be within 
10% of the calculated protocol dose.
 
Adverse Events (Toxicities): 
Did the participant experience adverse events (toxicities or side effects) associated with the 
treatment? Was the treatment delayed due to the adverse event? What was the most severe degree 
of toxicity experienced by the participant?
Notations concerning adverse events will address relationship to protocol treatment for each 
adverse event grade.  All adverse events encountered during the study will be evaluated according 


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to the NCI Common Toxicity Criteria assigned to the protocol and all adverse events must be noted 
on the participant's Adverse Event (Toxicity) Forms.
5.12 Missing and Deficient Memorandum
Data submissions are monitored for timeliness and completeness of submission. Participating 
institutions are notified of their data submission delinquencies in accordance with the following 
policies and procedures:
Incomplete or Questionable Data
If study forms are received with missing or questionable data, the submitting institution will receive 
a written query from the DF/HCC QACT Data Analyst.  Responses to the query should be 
completed and returned within 14 days.  Responses may be returned on the written query or on an 
amended case report form. In both instances the query must be attached to the specific data being 
re-submitted in response.  
Missing Forms
If study forms are not submitted on schedule, the participating institution will receive a Missing 
Form Report from the DF/HCC QACT noting the missing forms.  These reports are compiled by 
the DF/HCC QACT and distributed a minimum of three times a year. 
6.0 REQUISUITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is generally specified in the protocol. 
Participating sites should order their own agent regardless of the supplier (i.e., NCI or a 
pharmaceutical company.) 
If the agent is commercially available, check with the local Director of Pharmacy and/or the Research 
Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the agent can be 
ordered once the protocol is approved by the local IRB. If the agent is investigational, ensure that the 
pharmacy will be able to receive and store the agent. The local IRB should be kept informed of who 
will supply the agent (i.e., NCI or a pharmaceutical company) so that any regulatory responsibilities 
can be met in a timely fashion. 
7.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING
All participants receiving investigational agents will be evaluated for safety.   The safety parameters 
include all laboratory tests and hematological abnormalities, physical examination findings, and 
spontaneous reports of adverse events reported to the investigator by participants.  All toxicities 
encountered during the study will be evaluated according to the NCI criteria assigned to the 
protocol (CTCAE Version 3.0) and recorded prior to each course of therapy.  Life-threatening 
toxicities should be reported immediately to the Protocol Chair and Institutional Review Board 
(IRB). Protocols using CTEP supplied agents should also report these toxicities via the AdEERS 
system.


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Additional safety assessments and toxicity monitoring will be outlined in the protocol.
7.1
Serious Adverse Events
A serious adverse event (SAE) is any adverse drug experience at any dose that results  in any of the 
following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be life 
threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions in a participant who has never had seizure activity in the 
past that do not result in inpatient hospitalization, or the development of drug dependency or abuse.
Unless otherwise specified in the protocol, the study will utilize the Cancer Therapy Evaluation 
Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 for 
Toxicity and Adverse Event reporting.  A copy of the CTC or CTCAE Criteria can be downloaded 
from the CTEP home page (http://ctep.info.nih.gov).  
7.2 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is delineated in the 
protocol.
Participating Institutions must report serious adverse events for CTEP trials online using AdEERS.  
This applies to any medical event equivalent to an unexpected grade 2 with a possible, probable or 
definite attribution, most grade 3 and all grade 4 and grade 5 (death) toxicities regardless of study 
phase or attribution. 
In addition, the Participating Institutions must report the serious adverse events to the Protocol 
Chair and the Coordinating Center (Lead Institution) at the time SAEs are submitted. 
The Lead Institution will maintain documentation of all Adverse Event Reporting and be 
responsible for communicating all SAEs to all Participating sites.
7.3 Guidelines for Processing IND Safety Reports 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse experiences 
that are possibly related to the investigational agent. In compliance with these FDA regulations, 
CTEP will notify the Participating sites via the DF/HCC Lead Institution by the following methods:
IND Safety Reports: Investigators will be sent a copy of expedited adverse events which CTEP has 
sent to the FDA. CTEP will notify the Protocol Chair at the Lead Institution. Within 7 business days 
of receipt of the notification, the Lead Institution or designee will forward the letters to the 
Participating sites with protocol specific instructions for IRB submissions, participant notifications, 
etc. For routine IND Safety Reports, CTEP does not generally require an immediate revision to the 


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protocol and/or model informed consent documents. The investigators are to file a copy with their 
protocol file and send a copy to their IRB according to their local IRB’s policies and procedures.
8.0 PROTOCOL VIOLATIONS AND DEVIATIONS
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or “protocol 
deviation.”  All DF/HCC Protocol Chairs must adhere to those policies set by the DFCI IRB, the 
definitions for protocol violation and deviation as described by the DFCI IRB will be applied for 
reporting purposes for all institutions participating in the DF/HCC Multi-center Protocol. 
  
8.1 Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol.
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB prior 
to its initiation or implementation. 
8.2 Reporting Procedures
The Protocol Chair: is responsible for ensuring that clear documentation is available in the 
medical record to describe all protocol deviations and violations. 
The Protocol Chair will also be responsible for ensuring that all protocol violations/deviations are 
promptly reported per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from DFCI IRB. The 
Participating institution must submit the deviation request to the Protocol Chair and Lead Institution 
or designee, who will submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the 
deviation should be submitted to the participating site’s own IRB, per its policy.
Protocol violations occurring at a participating institution will be submitted to that site’s own IRB.   
A copy of the participating institution’s IRB report and determination will be forwarded to the 
DF/HCC Lead Institution or designee by mail, facsimile, or via e-mail within 10 business days after 
the original submission. 
Coordinating Center:  Upon receipt of the violation/deviation report from the participating 
institution, the DF/HCC Lead Institution or designee will submit the report to the Protocol Chair for 
review. Subsequently, the participating institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward all 
violation reports to CTEP via an internal DF/HCC process, as applicable.
9.0 QUALITY ASSURANCE
1) The quality assurance process for a clinical trial research study requires verification of protocol 
compliance and data accuracy. As the Coordinating Center, the DF/HCC Lead Institution or designee 
with the aid of the QACT provides quality assurance oversight for the DF/HCC Multi-center Protocol.
9.1 Ongoing Monitoring of Protocol Compliance


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All data submitted to the DF/HCC QACT will be monitored for timeliness of submission, completeness, 
and adherence to protocol requirements.  Monitoring will begin at the time of participant registration and 
will continue during protocol performance and completion.  The Lead Institution or designee and if 
applicable QACT Data Analysts assigned to the Protocol will perform the ongoing protocol compliance 
monitoring with the support of the participating institution’s Coordinators, the Principal Investigators, 
and the Protocol Chair. 
9.2 Evaluation of Participating Institution Performance
9.2.1
 Eligibility Checklist: Eligibility criteria are checked on a protocol-specific eligibility checklist 
and faxed to the DF/HCC QACT prior to registration on protocol.  A DF/HCC QACT Protocol Registrar 
reviews the checklist and informed consent document before the participant can be registered on a 
protocol.  The DF/HCC QACT cannot make exceptions to the eligibility requirements.
9.2.5  Accrual of Eligible Participants: Annual accrual rates for eligible participants enrolled onto 
therapeutic clinical trials is calculated for each institution. Institutions are expected to maintain the 
minimum annual average accrual as defined by the protocol grant or contract. 


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9.3 On-Site Auditing
9.3.1 DF/HCC Sponsored Trials
For all DF/HCC sponsored protocols:
The participating institutions may be required to submit subject source documents to the 
DF/HCC Lead Institution or designee for monitoring. Also, the participating institution may be 
subject to on-site monitoring conducted by the DF/HCC Lead Institution or designee.
After a participating site has accrued 4-5 participants, the QACT will be conducting an on-site 
audit. This is anticipated to occur within the first year of enrollment as specified in the protocol, 
section 13.3. One visit to each site will be planned during the 18 month expected enrollment 
period of the trial. If significant violations are uncovered during the audit, a follow-up audit 
may be requested. The final audit reports for the external sites will be reported to the Overall PI, 
as well as the DF/HCC Audit Subcommittee, as is standard practice.
9.3.2 Participating Institution
It is the participating institution’s responsibility to notify the DF/HCC Lead Institution or 
designee of all scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which 
involve the DF/HCC Multi-Center Protocol. All institutions will forward a copy of final audit 
and/or re-audit reports and corrective action plans (if applicable) to the DF/HCC Lead 
Institution or designee within 12 weeks after the audit date. 
9.3.3 Coordinating Center (Lead Institution or designee) 
The Protocol Chair will review all DF/HCC Multi-Center Protocol Final Audit reports and 
corrective action plans if applicable. The Lead Institution or designee must forward these 
reports to the DF/HCC QACT per DF/HCC policy for review by the DF/HCC Audit 
Subcommittee. Based upon the audit assessments the DF/HCC Audit Subcommittee could 
accept or conditionally accept the audit rating and final report. Conditional approval could 
require the Protocol Chair to implement recommendations or require further follow-up.  For 
unacceptable audits, the Audit Subcommittee would forward the final audit report and 
corrective action plan to the Clinical Investigations Policy and Oversight Committee and the 
DFCI IRB as applicable.
9.4 Sub-Standard Performance
The Protocol Chair, DFCI IRB and the NCI for CTEP trials, is charged with considering the 
totality of an institution’s performance in considering institutional participation in the DF/HCC 
Multi-Center Protocol.
9.4.1 Corrective Actions: Institutions that fail to meet the performance goals of accrual, submission 
of timely accurate data, and adherence to protocol requirements will be recommended for a six- 
month probation period. Such institutions must respond with a corrective action plan and must 
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the improved performance measures. Institutions that fail to demonstrate significant 
improvement will be considered by the Protocol Chair for revocation of participation.