Randomized Phase II Study of Docetaxel, Adriamycin, and Cytoxan (TAC) Versus Adriamycin/Cytoxan, Followed by Abraxane/Carboplatin (ACAC) +/- Trastuzumab as Neoadjuvant Therapy for Patients With Stage II-III Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: City of Hope Medical Center

IRB # 05015 
 
03/17/2009 
Packet: 24 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
 
TITLE:  
Randomized Phase II Study Of Docetaxel, Adriamycin, And Cytoxan (TAC) Versus Adriamycin/Cytoxan, 
Followed By ABI/Carboplatin (ACAC) +/- Trastuzumab As Neoadjuvant Therapy For Patients With Stage I-
III Breast Cancer. 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 05015  
 
PROTOCOL DATE: 03/17/09 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
Initial Review – Protocol dated 08/09/05 –  
       Packet: 00 
COH Amendment 01 
Dated 10/11/05 (Addition of Tower Group) 
01 
COH Amendment 02 
Dated 03/22/06 
02 
COH Amendment 03 
Dated 12/04/06 
03 
COH Amendment 04 
Dated 04/26/07 
04 
COH Amendment 05 
Dated 07/24/07 (Title page change only) 
05 
COH Amendment 06 
Dated 10/25/07 (Title page change only) 
06 
COH Amendment 07 
Dated 10/24/07  
07 
COH Amendment 08 
Dated 02/07/08  
08 
COH Amendment 09 
Dated 03/19/08 
09 
COH Amendment 10 
Dated 04/29/08 
10 
COH Amendment 11 
Dated 05/05/08 
11 
COH Amendment 12 
Dated 06/06/08 (Title Page change only) 
12 
COH Amendment 13 
Dated 07/15/08 
13 
COH Amendment 14 
Dated 08/11/08 
14 
COH Amendment 15 
Dated 03/17/09 
15 
COH Amendment 16 
Dated 09/24/09 (Title Page change only) 
16 
COH Amendment 17 
Dated 01/18/10 (Title Page change only) 
17 
COH Amendment 18 
Dated 08/19/10 (Title Page change only) 
18 
COH Amendment 19 
Dated 04/22/14 (Title Page change only) 
19 
COH Amendment 20 
Dated 03/09/15 (Title Page change only) 
20 
COH Amendment 21 
Dated 10/09/18 (PI Change only) 
21 
COH Amendment 22 
Dated 10/21/19 (Title Page change only) 
22 
COH Amendment 23 At Continuation 
Protocol Dated 03/17/09 (TP) 
23 
COH Amendment 24 At Continuation 
Protocol Dated 03/17/09 (TP) 
24 
 
 
SITE: 
Breast 
HISTOLOGY: 
Adenocarcinoma 
STAGE : 
II/III 
MODALITY: 
Chemotherapy +/- immunotherapy 
TYPE : 
Phase II 
 
PRINCIPAL INVESTIGATOR: 
Joanne Mortimer, M.D. 
 
COLLABORATING INVESTIGATOR(S): 
Analytical Pharmacology: Timothy Synold, Pharm.D. 
Surgery:  Benjamin Paz, M.D. 
Biostatistics: David Smith, Ph.D., Paul Frankel, Ph.D. 
Radiation Oncology: Jeffrey Wong, M.D. 
Diagnostic Radiology: Sally Shaw, M.D., Lalit Vora, M.D. 
Nursing Research: Betty Ferrell, Ph.D. 
Scientists:  Jack Shively, PhD., Steve Sommer, PhD., 
Medical Oncology: Yun Yen, M.D., 
Joanne Mortimer, M.D. 
Michael Press, M.D. (USC), 
 
Michael F. Clarke, M.D. (Stanford), Bruce Richard, Ph.D. (Stanford) 
 
 
PARTICIPATING CLINICIANS: 
Medical Oncology: Mihaela Cristea, M.D., Warren Chow, M.D.,   
Surgery: Carlos Garberoglio, M.D. 
Cathie T. Chung, M.D., Vincent Chung, M.D.,  
Nursing Research: Marcia Grant, DNSc, 
Marianna Koczywas, M.D., Lucille Leong, M.D., Dean Lim, M.D.,  
Laura Bourdeanu, NP, 
Robert Morgan, M.D., Jana Portnow, M.D.,  
Radiation Oncology: Richard Pezner, M.D. 
Przemyslaw Twardowski, M.D.,  
City of Hope Medical Group: 
Stephen J. Forman, M.D.  
Stephen Koehler, M.D.,  
Pharmacy: Rami Jin,  
 
 

IRB # 05015 
 
03/17/2009 
Packet: 24 
 
PARTICIPATING INSTITUTIONS: 
City of Hope National Medical Center 
 
City of Hope Medical Group, Pasadena CA 
 
University of Southern California 
 
Stanford University 

IRB # 05015 
1 
March 17, 2009 
Version 14 
CITY OF HOPE NATIONAL MEDICAL CENTER 
 
DEPARTMENT OF MEDICAL ONCOLOGY 
AND THERAPEUTICS RESEARCH 
1500 E. DUARTE ROAD 
DUARTE, CALIFORNIA 91010 
Telephone (626) 256-HOPE (4673) EXT. 62867 
 
IRB: 
05015 
TITLE: 
Randomized Phase II Study Of Docetaxel, Adriamycin, And Cytoxan 
(TAC) Versus Adriamycin/Cytoxan, Followed By 
Abraxane®/Carboplatin (ACAC) +/- Trastuzumab As Neoadjuvant 
Therapy For Patients With Stage I-III Breast Cancer 
 
VERSION NUMBER: 
14 
VERSION DATE: 
03/17/09 
 
SITE: 
Breast 
HISTOLOGY: 
Adenocarcinoma 
STAGE: 
I/II/III 
MODALITY: 
Chemotherapy +/- immunotherapy 
TYPE: 
Neoadjuvant therapy 
ARMS: 
TAC (Arm A) vs. ACAC (Arm B); ACAC + trastuzumab 
 
(Arm C) 
 
PRINCIPAL INVESTIGATOR: 
Joanne Mortimer, M.D. 
CO-PRINCIPAL INVESTIGATOR: 
Benjamin Paz, M.D. 
 
COLLABORATING -INVESTIGATORS: 
Terry Lee, PhD, Jack Shively PhD, Steven Sommer PhD, Sally Shaw 
M.D., Lalit Vora, M.D., Yun Yen, M.D., Paul Frankel PhD., Harry 
Openshaw, M.D.,David Smith, PhD., Timothy Synold, Pharm.D., 
Michael F. Clarke, M.D., Michael Press, M.D., Ph.D., Peter 
Danenberg Ph.D., Susan Kane, Ph.D., John Rossi Ph.D., Shiuan 
Chen, Ph.D., Sean Lau, M.D., Richard Bruce, Ph.D., Karen Aboody, 
Ph.D., Laura Bourdeanu, N.P., Betty Ferrell, Ph.D. 
PARTICIPATING INVESTIGATORS: 
Warren Chow, M.D., Stephen J. Forman, M.D., Carlos Garberoglio, 
M.D., Marcia Grant DNSc, Arti Hurria, M.D., Lucille Leong, M.D., 
Dean Lim, M.D., Mark McNamara, M.D., Robert Morgan, M.D., 
Richard Pezner M.D., Stephen Shibata, M.D., Przemyslaw 
Twardowski, M.D., Lawrence Wagman M.D., Thehang Luu, M.D., 
Jana Portnow M.D., Marianna Koczywas, M.D., Stephen Koehler, 
M.D., Mihaela Cristea, M.D., Vincent Chung, M.D., Cathie Chung, 
M.D., Cynthia Martel, M.D. 
 
PARTICIPANTS: 
City of Hope National Medical Center 
 
City of Hope Medical Group, Pasadena 
 
Stanford University 
 
Palo Alto Research Center 
 
University of Southern California 
INTERNAL REVIEW BOARD NUMBERS:  
 
DATE OF AMENDMENTS/REVISIONS: 
(1) 10/11/05 (2) 03/22/06 (3) 12/04/06 (4) 04/26/07 (5) 10/24/07 (6) 
02/07/08 (7) 03/19/08 (8) 07/15/08 (9) 08/11/08 (10) 03/17/09 
***************************************************************************************** 
CITY OF HOPE NATIONAL MEDICAL CENTER ASSUMES NO RESPONSIBILITY FOR THE USE OF THIS 
EXPERIMENTAL PROTOCOL OUTSIDE THE PARTICIPATING INSTITUTIONS 
 

IRB # 05015 
2 
March 17, 2009 
Version 14 
 
TABLE OF CONTENTS 
• 
SCHEMA 
• 
* Trastuzumab will be prescribed weekly together with carboplatin and Abraxane® to all patients with HER2 
overexpressing breast cancer; the first dose of trastuzumab will be administered at a loading dose of 4 mg/kg 
.OBJECTIVES 
9 
• 
OBJECTIVES 
10 
• 
1.2. 
To assess feasibility and efficacy as defined by Symmans Score response  of dose-dense doxorubicin 
and cyclophosphamide followed by carboplatin, Abraxane®, and trastuzumab (ATACT), in patients with HER-2 
positive breast cancer. 
10 
• 
1.3. 
To determine the proportion of patients with a positive sentinel lymph node (SLN) before neoadjuvant 
(preoperative)  chemotherapy will have metastases in nonSLNs (NSLNs) after neoadjuvant chemotherapy, and 
identify which clinicopathologic factors are associated with metastases in NSLNs after such chemotherapy in 
patients with a positive SLN before preoperative chemotherapy. 10 
• 
1.9. 
To assess the prognostic and predictive value of conventional pathological features (stage, estrogen and 
progesterone receptor and HER-2 status, presence of lymphovascular invasion, high grade) in comparison to 
such values derived, based upon the molecular approaches. 
10 
• 
1.11 
To procure tumor from the definitive surgical specimen for the purpose of establishing breast cancer 
stem cell lines 
10 
• 
2.0 
BACKGROUND 11 
2.3 
HER-2 overexpressing breast cancer 
12 
Approximately 25-30% of breast cancers can be characterized by overexpression of the 
HER-2 proto-oncogen, as documented either by immunohistochemical assessment of cell 
membrane or by FISH.  This group of patients is faced with a worse prognosis, due to a 
greater likelihood of developing distant metastases.  A humanized monoclonal antibody 
(trastuzumab, Herceptin®) has been developed and used successfully in the treatment of 
stage IV breast cancer (18-20). There is evidence of in vitro and in vivo synergism between 
trastuzumab, and some of the most effective chemotherapeutic agents, such as the taxanes, 
and platinum compounds (21).  Accordingly, in the metastatic setting combinations of 
trastuzumab and taxanes with or without platinum compounds such as carboplatin vs. 
administration of the chemotherapeutic agents alone resulted in improved progression-free 
survival and a trend towards overall survival (19,22).  Trastuzumab is currently undergoing 
evaluation in combination or in sequence to anthracycline, taxane, and platinum based 
therapies in the adjuvant and neoadjuvant setting in a variety of cooperative group trials.  In 
one provocative, prospective, randomized study of paclitaxel followed by 5-fluorouracil, 
epirubicin, and Cytoxan (FEC) +/- trastuzumab in patients with HER2 overexpressing 
tumors, a surprisingly high pathological complete response rate of 65% had been described 
in the group treated with trastuzumab (23). 
12 
2.4 
Recent developments in taxane delivery/formulation 
12 
Of the two taxanes in clinical use, paclitaxel has shown potentially improved activity when 
administered weekly, while the more traditional way of docetaxel administration is every 3 
weeks (23-29). The toxicity profiles of the two drugs are somewhat different, and are also 
schedule dependent.  Standard clinical practice calls for premedication with steroids, and, in 
the case of paclitaxel, (in order to alleviate cremophor vehicle-related problems) 
antihistamines are also part of the pre-treatment regimen. ABI-007 also known as 
Abraxane® (paclitaxel protein-bound particles for injectable suspension; (albumin-bound)) 

IRB # 05015 
3 
March 17, 2009 
Version 14 
a Cremophor EL-free of Paclitaxel for Injectable Suspension, is the first in its class of a 
biologically interactive compound combining a protein with a chemotherapeutic agent in 
the compound state. This composition provides a novel approach of increasing intra-tumoral 
concentration of the drug by a receptor-mediated transport process allowing transcytosis 
across the endothelial cell wall, thereby breaching the blood/tumor interface. This albumin-
specific receptor mediated process involves the binding of a specific receptor (gp60) on the 
endothelial cell wall, resulting in activation of a protein caveolin-1, which initiates an 
opening in the endothelial wall with formation of a little caves or caveolae, with transport of 
the albumin-bound chemotherapeutic complex via these caveolae to the underlying tumor 
interstitium. A protein specifically secreted by the tumor (SPARC) binds and entraps the 
albumin, allowing release of the hydrophobic drug to the tumor cell membrane. Abraxane® 
is the first biologically interactive compound leveraging this gp-60/caveolin-
1/caveolae/Sparc pathway to increase intra-tumoral concentration of the drug and reducing 
toxic drug in normal tissue. Abraxane® has undergone testing in patients with stage IV 
breast cancer, with encouraging preliminary results, leading to recent FDA approval of this 
agent in view of its ability to induce higher response rates in comparison to paclitaxel when 
given every 3 weeks at 260 mg/m2 (versus paclitaxel 175 mg/m2) (30).  A Phase I study of 
ABI-007 (Abraxane®) administered weekly for 3 weeks followed by a 1 week rest in 
patients with advanced solid tumors has recently been completed (31).  The MTDs for 
heavily and lightly pre-treated patients were 100 and 150 mg/m2 respectively.  Dose 
limiting toxicities included myelosuppression and peripheral neuropathy.  Premedication 
was not required, and unexpected, non-taxane associated toxicities were not observed.  In a 
Phase II trial in heavily pretreated patients with taxane-refractory metastatic breast cancer, 
objective antitumor responses occurred in 15% of women treated with Abraxane® 
100mg/m2 on this schedule (32).  Toxicity was minimal even without premedications or 
growth factors (G-CSF) usually routinely required with paclitaxel or docetaxel in this group 
of patients. Patients were considered taxane-refractory if they had progressive cancer while 
receiving paclitaxel, docetaxel or both. Abraxane® given weekly was active in patients 
refractory to paclitaxel (16% overall response rate and 37% disease control) and patients 
refractory to docetaxel (24% overall response and 35% disease control). Grade 3/4 
neutropenia without G-CSF in heavily pretreated patients was 15%. Other grade 3 toxicities, 
all below 4% were: anemia, neuropathy, nausea, vomiting and diarrhea. Results of this 
dose-finding study of weekly Abraxane® in heavily pretreated patients identified 
Abraxane® 100 mg/m2 as an appropriate dose for further study. It has proved activity in 
paclitaxel and docetaxel refractory patients with acceptable toxicity.  Preliminary data 
(personal communication from Dr. Andrew Seidman, Memorial Sloan-Kettering Cancer 
Center) suggest that weekly administration of Abraxane® at 100 mg/m2 and carboplatin at 
an AUC of 2 together with trastuzumab is feasible, and active, however, due to allergic 
reactions associated with carboplatin administration, steroid premedication may be required 
with such combination. 
12 
2.6 
Scientific questions/ hypotheses 
14 
2.6.6 
Will conventional prognostic and predictive markers become obsolete? 
18 
2.6.7 
Neurotoxicity as part of Quality of Life Assessment 
20 
2.6.8 
Barriers Study: Identification of delays of care between awareness of symptoms and 
receiving medical treatment by an oncologist. 
20 
• 
3.0 
DRUG INFORMATION 
22 
• 
3.1. 
Doxorubicin [NSC 123127] 22 

IRB # 05015 
4 
March 17, 2009 
Version 14 
3.3 
ABI-007; Abraxane® (paclitaxel protein-bound particles for injectable 
suspension; (albumin-bound)). 
25 
Preclinical studies comparing Abraxane® to Taxol demonstrated 
dramatically lower acute toxicities, with an LD10 approximately 3-fold 
higher for Abraxane® compared to Taxol.  At equal doses there was less 
myelosuppression and improved efficacy in a xenograft tumor model of 
human mammary adenocarcinoma.  At equitoxic doses of paclitaxel, 
Abraxane® was found to be markedly more efficacious than Taxol. 
26 
Clinical Studies with Abraxane® 
26 
Every 3 Weeks Schedule 
26 
Weekly for 3 Weeks, Every 4 Weeks Schedule 
26 
• 
3.4 
Cyclophosphamide (Cytoxan®) [NSC-26271] 31 
• 
3.5 
Carboplatin (Paraplatin®) (NSC-241240) (CBDCA) 
31 
Vial Strength   Diluent Volume 
32 
• 
3.6 
Filgrastim (Neupogen®) (r-metHuG-CSF) (NSC - 614629) 
33 
• 
3.8 
Trastuzumab (Herceptin®); NSC #688907 
36 
• 
Trastuzumab will be given at 4 mg/kg as a loading dose, and then a dose of 2 mg/kg will be repeated every week.  
The drug will be administered over 90 minutes; subsequent doses will be given over 30 minutes, if the loading 
dose was well tolerated. 
37 
• 
3.8.1 
Description 
37 
• 
Herceptin®, manufactured by Genentech Inc., is commercially available and is supplied as a freeze-dried 
preparation at a nominal content of 440 mg per vial for parenteral administration.  The drug is formulated in 
histidine, trehalose, and polysorbate 20.  Each 440-mg vial of trastuzumab is supplied with 20ml bacteriostatic 
water for injection, USP, 1.1% benzyl alcohol. Herceptin® vials must be stored in the refrigerator (2° C to 8°C). 
Do not freeze. 
37 
• 
The reconstituted formulation (440-mg vial) is designed for multiple use.  Unused drug may be stored for 28 
days at 2°C to 8°C (36°F to 46°F).  Reconstituted trastuzumab should be clear to slightly opalescent and 
colorless to pale yellow. 
37 
• 
3.8.2.     Preparation for Use 37 
• 
Trastuzumab may be sensitive to shear-induced stress (e.g., agitation or rapid expulsion from a syringe).  DO 
NOT SHAKE.  Vigorous handling of solutions of trastuzumab results in aggregation of the protein and may 
create cloudy solutions.  A 19-guage or larger needle should be used during drug admixture to avoid sheer-
induced stress.  Reconstitute each vial as follows, using aseptic technique: 37 
• 
1. 
Using a sterile syringe, slowly inject 20 mL of BWFI into the vial directing the stream into the 
lyophilized cake.  The vacuum in the vial will automatically draw the water from the syringe into the vial;
 
37 
• 
2. 
Swirl the vial gently to aid reconstitution.  DO NOT SHAKE.  The reconstituted solution contains 21 
mg/mL trastuzumab and will be added to 250 mL of 0.9% sodium chloride injection, USP. 
37 
• 
3.8.3  Known Potential Toxicities 
37 
• 
More Frequent Incidence (> 5%) 37 
• 
Infusion-associated symptoms: Chills and/or fever, occasionally accompanied by rigors, occurred in 
approximately 40% of subjects during the first infusion of trastuzumab.  The symptoms were usually mild to 
moderate in severity and were treated with acetaminophen and diphenhydramine (with our without reduction in 
the rate of trastuzumb infusion).  Meperidine for rigors is effective.  Other signs and/or symptoms may include 

IRB # 05015 
5 
March 17, 2009 
Version 14 
nausea, vomiting, pain, headache, dizziness, dyspnea, or rash.  The symptoms occurred less frequently with 
subsequent infusions.  Rarely, infusion reactions have results in death. 
37 
• 
Trastuzumab administration can result in the development of ventricular dysfunction and CHF.  Left ventricular 
function should be evaluated in all subjects prior to and during treatment with trastuzumab.  Discontinuation of 
trastuzumab treatment should be strongly considered in subjects who develop a clinically significant decrease in 
left ventricular function.  The incidence and severity of cardiac dysfunction appears to increase in subjects who 
receive trastuzumab in combination with anthracycline and cyclophosphamide (28% versus 7% when used as a 
single agent). 
37 
• 
The incidence of generalized pain, abdominal pain, and back pain appears to be more frequent in subjects 
receiving trastuzumab in combination with chemotherapy.  Occasionally pain at tumor sites has been reported.
 
38 
• 
The following have also been reported in >5% of subjects: diarrhea (25% of these), myalgia, peripheral edema, 
and weakness. 
38 
• 
Less Frequent Incidence (1 to 5%) 38 
• 
Allergic/hypersensitivity reactions that have been reported include rash, pruritus, urticaria, and anaphylaxis 
(rarely resulting in death) or anaphylactoid signs and symptoms (erythematous rash on the chest and beck, 
dyspnea, bronchospasm, angioedema, acute respiratory distress syndrome (ARDS), hypotension, wheezing, 
pleural effusions, pulmonary infiltrates, noncardiogenic pulmonary edema, and pulmonary insufficiency and 
hypoxia requiring supplemental oxygen or ventilatory support). 
38 
• 
Rare Incidence (<1%) 
38 
• 
Rare toxicities include abnormal liver function test, hepatitis, bone pain, tumor-site pain, pancytopenia, 
hypotension, anorexia, febrile neutropenia, worsening of pre-existing peripheral neuropathy, paresthesias, and 
thromboembolic disease. 
38 
• 
Pulmonary events that have been reported include pleural effusions, pulmonary infiltrates, and noncardiogenic 
pulmonary edema.  Pulmonary insufficiency and hypoxia requiring supplemental oxygen or ventilatory support, 
including ARDS, and death have occurred.  Most subjects with fatal events had significant, pre-existing 
pulmonary compromise secondary to intrinsic lung disease and/or malignant pulmonary involvement.  Because it 
appears that subjects with significant pre-existing pulmonary compromise may be at greater risk, these subjects 
should be treated with extreme caution.  Subjects experiencing any of the severe infusion-associated symptoms 
should have the trastuzumab infusion discontinued and appropriate medical therapy administered.  Subjects 
should be closely monitored until complete resolution of their symptoms.  In addition, subjects should be 
informed of the possibility of delayed severe reactions. 38 
• 
3.8.4  Nursing Guidelines 
38 
• 
The most common AEs related to trastuzumab are fever (> 38°C), chills, and occasional rigors, most often 
infusion-related after the initial dose.  Treat with acetaminophen as necessary.  Meperidine may be needed for 
rigors.  Instruct the subject and family to report any fever >101°F.  Subjects with underlying pulmonary 
pathology should be closely monitored. 
38 
• 
Transient, localized tumor-side pain may be experienced within 8 hours of infusion.  Advise the subject that 
acetaminophen is helpful. 
38 
• 
Provide symptomatic management of the possible mild-to-moderate nausea/vomiting/diarrhea.  Assess heart and 
lung sounds.  Monitor vital signs (resting pulse, BP).  Be alert to early signs of cardiotoxicity, i.e., dyspnea, 
steady weight gain, nonproductive cough, arrhythmias, tachycardia, and pulmonary rales.  Trastuzumab may 
potentiate heart failure when administered in combination with doxorubicin. 
39 
• 
Advise subjects of possible fatigue, loss of strength, and weakness.  Have subjects pace activities with frequent 
rest periods. 
39 
• 
4.0 
STAGING CRITERIA 
39 
DEFINITION OF TNM 
39 

IRB # 05015 
6 
March 17, 2009 
Version 14 
• 
5.0 
PATIENT ELIGIBILITY 
42 
• 
5.8. 
Patients must have an ejection fraction ≥ 50% on MUGA scan. 
42 
• 
5.9. 
Pretreatment laboratory parameters must have been performed within 1 week and x-ray parameters 
must have been performed within 4 weeks prior to the initiation of therapy 42 
• 
6.0 
DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION SCHEME 
43 
• 
7.0 
TREATMENT PLAN 
43 
• 
7.2 
All patients will undergo clip placement and core-biopsies of the primary site/s.  If a patient already 
underwent core biopsy and clip placement, and is otherwise eligible for study participation, repeat core biopsy 
and/or clip placement could be eliminated as per PI judgment.  If there is evidence of lymph node involvement 
by imaging, ultrasound-guided biopsy of such lymph node will be performed.  ER/PR receptor HER-2 status will 
be evaluated in addition to standard pathological assessment.  An attempt to procure 8-12 cores (as per COH 
practice) through a single biopsy entry site will be made in order to procure sufficient fresh frozen tissue (and if 
abundant tissue is procured embedded tissue) specimens.  HER-2 + is defined as 3+ by IHC, or amplified by 
FISH. 
43 
• 
8.0 
TOXICITIES MONITORED AND DOSAGE MODIFICATIONS 
46 
• 
8.1 
Toxicities and potential complications 
46 
Hypersensitivity Reactions 
55 
• 
 
8.3 DATA AND SAFETY MONITORING 
56 
 
 8.3.1 Definition of Risk Level 
56 
8.3.3 
Adverse Events 
57 
• 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
63 
• 
11. 
0 SPECIAL INSTRUCTIONS 
64 
11.1 
Tissue Specimen Processing and Designation 
64 
11.2 
Blood Specimen Processing and Designation 
68 
• 
12.0 
STATISTICAL CONSIDERATIONS 
71 
• 
Racial subgroups will be summarized.  No differences in outcome due to race are anticipated. Exploratory tests 
for interaction of regimen and race will be done, if accrual warrants.  No subgroup analyses (other than per stated 
stratification) are planned. 73 
• 
The cRNA product will be fragmented and hybridized to Affymetrix U133 2.0 arrays. These arrays contain 
greater than 54,000 probe sets allowing analysis of the expression level of more than 47,000 transcripts and 
variants, which include approximately 38,500 well-characterized human genes. Hybridization and data 
acquisition will be performed at the City of Hope Microarray Core Facility.  Experimental information and data 
acquisition will be performed using Affymetrix GeneChip Operating Software (GCOS). Gene expression values 
will be extracted from probe level data using Plier algorithm implemented in Affymetrix GeneChip RNA 
Expression Analysis Software (GREX). Prior to statistical analysis, systemic variations, associated with 
procedures such as IVT labeling, hybridization and scanning will be adjusted to a comparable level between 
arrays within the study. The background correction, normalization, and other preprocessing steps will be 
performed in R using the affy library (150,151). 
75 
• 
13.0 
REGISTRATION GUIDELINE 
76 
• 
14.0 
DATA SUBMISSION SCHEDULE 76 
• 
14.2 
An abbreviated Clinical Data Update System (CDUS) report will be generated quarterly. 
77 
• 
14.3 
Tracking log for tissue/blood samples /assignment of identifiers, log in/out for procured tissue 
specimens will be maintained by the individual processing and receiving centers (Anatomic Pathology, 
Pharmacology Core and Yen laboratory, and the receiving Sommer, Lee, Yen, Synold laboratories, and other end 

IRB # 05015 
7 
March 17, 2009 
Version 14 
users, as material for processing becomes available (microarray, immunohistochemical analysis) with the master 
tracking sheet maintained in the Department of Biostatistics and shared with Informatics. 
77 
• 
15.0 
MINORITIES AND WOMEN STATEMENT 77 
• 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 77 
• 
16.1 
All patients will have signed an informed consent for participation in research activities in accord with 
all institutional, NCI and Federal regulations, and will have been given a copy of the Experimental Subject's Bill 
of Rights. 
77 
• 
17.0 
PATHOLOGY REVIEW 
78 
• 
PHYSICAL WELL-BEING 93 
I have a lack of energy 
93 
I am forced to spend time in bed 
93 
• 
SOCIAL/FAMILY WELL-BEING 93 
Regardless of your current level of sexual activity, please 
93 
answer the following question.  If you prefer not to answer 
93 
I am satisfied with my sex life 
93 
0 
93 
• 
EMOTIONAL WELL-BEING 
94 
I feel sad 
94 
I am satisfied with how I am coping with my illness 
94 
• 
FUNCTIONAL WELL-BEING 
94 
• 
ADDITIONAL CONCERNS 
95 
I have trouble feeling the shape of small objects 
95 
• 
PHYSICAL WELL-BEING 96 
I have a lack of energy 
96 
I am forced to spend time in bed 
96 
• 
SOCIAL/FAMILY WELL-BEING 96 
Regardless of your current level of sexual activity, please 
96 
answer the following question.  If you prefer not to answer 
96 
I am satisfied with my sex life 
96 
0 
96 
• 
EMOTIONAL WELL-BEING 
97 
I feel sad 
97 
I am satisfied with how I am coping with my illness 
97 
• 
FUNCTIONAL WELL-BEING 
97 
• 
ADDITIONAL CONCERNS 
98 
I am bothered by hair loss 
98 
I worry that other members of my family might someday get the same illness I have 
98 
• 
Q1.  Does your pain feel like burning? 
102 
• 
Q2.  Does your pain feel like squeezing? 
102 
• 
Q3.  Does your pain feel like pressure? 
102 

IRB # 05015 
8 
March 17, 2009 
Version 14 
• 
Q5.  Does your pain feel like electric shocks? 103 
• 
Q6.  Does your pain feel like stabbing? 
103 
• 
Q8.  Is your pain provoked or increased by brushing on the painful area? 
103 
• 
Q9.  Is your pain provoked or increased by pressure on the painful area? 
103 
  Male 
2 
9. Diagnosis/Adverse Event Term                              Is this event cardiac in nature?    Yes        
No  
3 
10. Onset Date 
3 
11. Resolution Date 
3 
18. Treatment of the Event 
5 
APPENDICES 
A. 
Common Terminology Criteria for Adverse Events (CTCAE) version 3 
B. 
Quality of Life Questionnaire 
C. 
Interview Guide for Barriers of Care in Locally Advanced Breast Cancer 
D. 
Neuropathic Pain Symptom Inventory 
03/22/06 

IRB # 05015 
9 
March 17, 2009 
Version 14 
S C H E M A 
 
Biopsy of primary, clip placement, core biopsies and dominant/sentinel node biopsy 
 
 
 
 
 
 Arm A (Docetaxel/Doxorubicin/Cytoxan; TAC) 
HER-2 – patients will be randomized to 
 
 
 
 
 
Arm B (Doxorubicin/Cytoxan 
 Carboplatin/Abraxane®;ACAC) 
HER-2 + patients will receive Arm C (Doxorubicin/Cytoxan/Carboplatin/Abraxane® + Trastuzumab;ACAT) 
 
Arm A 
 
 
Docetaxel                                75 mg/m2 IV  
 
Doxorubicin                            50 mg/ m2 IV    
            Q 21 days  x   6 cycles 
 
Cytoxan                                 500 mg/ m2 IV 
 
 
Arms B and C 
 
 
Doxorubicin                            60 mg/ m2 IV  
  
                                                                                Q 14 days   x     4 cycles 
Cytoxan                                 600 mg/ m2 IV 
 
Followed by  
 
Carboplatin                       AUC 2         weekly x 3 and one week off           
Abraxane®                       100 mg/m2    weekly x 3 and one week off          
 
 
*Trastuzumab (Arm C)     2 mg/kg                      Q week x 12 weeks      
 
 
 
Neulasta™ or Neupogen® sc will be administered with all cycles of TAC and with all cycles of AC during ACAC; 
Neupogen will be administered during weeks 2 and 3 of each cycle of ACAC on Arms B & C. 
* Trastuzumab will be prescribed weekly together with carboplatin and Abraxane® to all patients with 
HER2 overexpressing breast cancer; the first dose of trastuzumab will be administered at a loading dose 
of 4 mg/kg .
x 3cycles 
03/19/08 

IRB # 05015 
10 
March 17, 2009 
Version 14 
OBJECTIVES 
 
1.1. 
To compare feasibility and efficacy - as defined by pathological complete response 
rate (pCR) - of docetaxel, doxorubicin, and cyclophosphamide (TAC) versus dose-
dense doxorubicin and cyclophosphamide followed by carboplatin and Abraxane® 
(ACAC) in patients with HER-2 negative breast cancer. 
1.2. 
To assess feasibility and efficacy as defined by Symmans Score response  of dose-
dense doxorubicin and cyclophosphamide followed by carboplatin, Abraxane®, and 
trastuzumab (ATACT), in patients with HER-2 positive breast cancer. 
1.3. 
To determine the proportion of patients with a positive sentinel lymph node (SLN) 
before neoadjuvant (preoperative)  chemotherapy will have metastases in nonSLNs 
(NSLNs) after neoadjuvant chemotherapy, and identify which clinicopathologic 
factors are associated with metastases in NSLNs after such chemotherapy in patients 
with a positive SLN before preoperative chemotherapy. 
1.4. 
To assess quality of life in all participating patients across the treatment groups in 
order to define the less toxic regimen.  To compare treatment-induced 
neuropathy/neuropathic pain in a subset of patients participating in this study. 
1.5. 
To identify issues involved in the delays between awareness of symptoms of locally 
advanced breast cancer (Stage III A-C) and receiving medical treatment. 
1.6. 
To identify specific mutations in tumor DNA in comparison to adjacent tissue and 
germ line DNA procured prior to, during, and subsequent to neoadjuvant 
chemotherapy, and to detect/measure the presence of such mutations in fragmented, 
circulating DNA from plasma, and correlate with the presence/characteristics of 
circulating tumor cells, in order to identify prognostic and predictive indicators of 
persisting/relapsed disease, and targets for therapy. 
1.7. 
To assess protein profiles in tumor, adjacent tissue and plasma prior to, during, and at 
completion of neoadjuvant chemotherapy, in order to establish prognostic and 
predictive indicators of outcome, markers of persistent/relapsed disease, and targets 
for therapy. 
1.8. 
To analyze tumor DNA to carry out microarray and RT-PCR analysis in addition to 
procuring genomic DNA from plasma to assess copy numbers/SNP/genomic 
polymorphism in genes for the purposes of establishing prognostic and predictive 
indicators of outcomes, markers of persistence/relapse disease, drug resistance, 
targets of therapy as well as drug metabolism. 
1.9. 
To assess the prognostic and predictive value of conventional pathological features 
(stage, estrogen and progesterone receptor and HER-2 status, presence of 
lymphovascular invasion, high grade) in comparison to such values derived, based 
upon the molecular approaches. 
 
1.11 
To procure tumor from the definitive surgical specimen for the purpose of 
establishing breast cancer stem cell lines 
03/22/06 
03/22/06 
12/4/06 
03/19/08 
03/19/08 
03/19/08 

IRB # 05015 
11 
March 17, 2009 
Version 14 
 
2.0 
BACKGROUND 
In spite of the rising incidence of breast cancer disease, specific mortality has decreased over 
the past few years.  There are two likely explanations for this phenomenon: increased 
awareness coupled with more effective screening allows for detection of early stage cancer 
with inherently better prognosis, and, modern day systemic therapy is better at preventing 
development, or, at the least allows for containment of systemic metastases (1,2).  
 
2.1 
Recent developments in systemic chemotherapy 
 
The currently used neoadjuvant regimens have mostly evolved from experience in the 
adjuvant setting, or after these combinations have undergone testing in patients with 
stage IV advanced disease.  More recently, there have been 2 adjuvant 
regimens/strategies that, when tested in prospective, randomized trials, resulted in 
improved relapse-free survival and trended toward better overall survival.  
Incorporation of docetaxel with doxorubicin (Adriamycin) and cyclophosphamide 
(Cytoxan) (TAC) proved to be a superior regimen in comparison to 5-FU, 
Adriamycin, and Cytoxan (FAC, [relapse-free survival: 82% vs. 74%]) when both 
combinations were given every 21 days for 6 treatment cycles; there was also a 
suggestion of overall survival benefit in patients who presented with fewer, 1-3 
axillary nodal metastases, in favor of TAC (3).  The second approach, dose-dense 
(every 2 weeks) sequential, or combined administration of Adriamycin, Cytoxan, and 
subsequent biweekly paclitaxel yielded better 4-year relapse-free survival (82 % vs. 
75%, RR: 0.74) and improved overall survival (RR:0.69) in comparison to 
administering the same agents every 3 weeks(4). Weekly administration of paclitaxel, 
in addition to every 3 week delivery of Adriamycin and Cytoxan -as part of another 
“dose-dense” strategy – may also be more effective in delaying relapse (5,6).  Newer 
combinations consisting of a taxane and platinum are currently undergoing evaluation 
both in the neoadjuvant and adjuvant setting, based on confirmed activity of such 
combinations in the treatment of metastatic breast cancer.  In such metastatic setting, 
combinations of carboplatin and a taxane have been found to be effective and safe 
when given on a variety of schedules, including weekly dose-dense administration (7-
9). 
 
2.2 
Recent developments in systemic neoadjuvant chemotherapy 
 
Recent data in the literature supports the notion that excellent pathological response 
to neoadjuvant chemotherapy may benefit patients in terms of relapse-free and 
overall survival (10, 11).  Data from MD Anderson (12) suggests that complete 
pathological response as well a minimal residual disease labeled as scores 0 and 1 by 
the Symmans classification, carry the same prognosis.  Administration of systemic 
chemotherapy before, rather then after surgical removal of a malignant tumor, does 
have theoretical advantages.  Such neoadjuvant chemotherapy may allow breast 
preservation in patients presenting with large tumors who otherwise would have 
undergone mastectomy.  The strategy may lead to better local control, prevent 
development of drug resistance, and, allows for better assessment of in vivo chemo-
sensitivity.  In general, overall survival has not been different among patients treated 
with identical duration/types of chemotherapy either prior to surgery, or in the 
adjuvant setting.  However, based on results from NSABP B-18, a study comparing 4 
03/19/08 

IRB # 05015 
12 
March 17, 2009 
Version 14 
cycles of adjuvant versus neoadjuvant Adriamycin and Cytoxan, accomplishment of 
complete pathological response (pCR) in patients treated on the neoadjuvant 
treatment arm was associated with improved relapse-free and overall survival (13,14).  
It has also become clear, that 4 cycles of an anthracycline containing regimen yield 
inferior complete pathological response rates (9.8%) in comparison to the same 
treatment, followed by 4 cycles of docetaxel (18.7%), as shown in NSABP B-27.  
More recently, 5 year follow-up data from this study revealed relapse free survival 
(Hazard Ratio [HR]: 0.33) and overall survival (HR: 0.45) advantage favoring 
patients who achieved pathological complete remissions in the breast as documented 
at the time of definitive surgery, suggesting that upfront aggressive and extended 
therapy will yield better outcome (15).  Other studies comparing 8 cycles of an 
anthracycline-containing regimen to fewer cycles of the same regimen followed by 
either weekly paclitaxel, or docetaxel given every 3 weeks, concur with the findings 
of NSABP-27: there seems to be additional benefit derived from sequentially 
incorporating taxanes into a neoadjuvant regimen (16,17).  While the above-described 
strategies do result in higher pCR rates, they remain relatively low at the 19-35% 
range.  Intuitively, as well as based on the provocative data from the quoted NSABP 
studies, accomplishment of pCR could be the first step in a strategy leading to 
improved relapse-free and overall survival. 
2.3 
HER-2 overexpressing breast cancer 
Approximately 25-30% of breast cancers can be characterized by overexpression of 
the HER-2 proto-oncogen, as documented either by immunohistochemical 
assessment of cell membrane or by FISH.  This group of patients is faced with a 
worse prognosis, due to a greater likelihood of developing distant metastases.  A 
humanized monoclonal antibody (trastuzumab, Herceptin®) has been developed and 
used successfully in the treatment of stage IV breast cancer (18-20). There is 
evidence of in vitro and in vivo synergism between trastuzumab, and some of the 
most effective chemotherapeutic agents, such as the taxanes, and platinum 
compounds (21).  Accordingly, in the metastatic setting combinations of trastuzumab 
and taxanes with or without platinum compounds such as carboplatin vs. 
administration of the chemotherapeutic agents alone resulted in improved 
progression-free survival and a trend towards overall survival (19,22).  Trastuzumab 
is currently undergoing evaluation in combination or in sequence to anthracycline, 
taxane, and platinum based therapies in the adjuvant and neoadjuvant setting in a 
variety of cooperative group trials.  In one provocative, prospective, randomized 
study of paclitaxel followed by 5-fluorouracil, epirubicin, and Cytoxan (FEC) +/- 
trastuzumab in patients with HER2 overexpressing tumors, a surprisingly high 
pathological complete response rate of 65% had been described in the group treated 
with trastuzumab (23). 
2.4 
Recent developments in taxane delivery/formulation 
Of the two taxanes in clinical use, paclitaxel has shown potentially improved activity 
when administered weekly, while the more traditional way of docetaxel 
administration is every 3 weeks (23-29). The toxicity profiles of the two drugs are 
somewhat different, and are also schedule dependent.  Standard clinical practice calls 
for premedication with steroids, and, in the case of paclitaxel, (in order to alleviate 
cremophor vehicle-related problems) antihistamines are also part of the pre-treatment 
regimen. ABI-007 also known as Abraxane® (paclitaxel protein-bound particles 
for injectable suspension; (albumin-bound)) a Cremophor EL-free of Paclitaxel 

IRB # 05015 
13 
March 17, 2009 
Version 14 
for Injectable Suspension, is the first in its class of a biologically interactive 
compound combining a protein with a chemotherapeutic agent in the compound 
state. This composition provides a novel approach of increasing intra-tumoral 
concentration of the drug by a receptor-mediated transport process allowing 
transcytosis across the endothelial cell wall, thereby breaching the blood/tumor 
interface. This albumin-specific receptor mediated process involves the binding 
of a specific receptor (gp60) on the endothelial cell wall, resulting in activation of 
a protein caveolin-1, which initiates an opening in the endothelial wall with 
formation of a little caves or caveolae, with transport of the albumin-bound 
chemotherapeutic complex via these caveolae to the underlying tumor 
interstitium. A protein specifically secreted by the tumor (SPARC) binds and 
entraps the albumin, allowing release of the hydrophobic drug to the tumor cell 
membrane. Abraxane® is the first biologically interactive compound leveraging 
this gp-60/caveolin-1/caveolae/Sparc pathway to increase intra-tumoral 
concentration of the drug and reducing toxic drug in normal tissue. Abraxane® 
has undergone testing in patients with stage IV breast cancer, with encouraging 
preliminary results, leading to recent FDA approval of this agent in view of its ability 
to induce higher response rates in comparison to paclitaxel when given every 3 weeks 
at 260 mg/m2 (versus paclitaxel 175 mg/m2) (30).  A Phase I study of ABI-007 
(Abraxane®) administered weekly for 3 weeks followed by a 1 week rest in patients 
with advanced solid tumors has recently been completed (31).  The MTDs for heavily 
and lightly pre-treated patients were 100 and 150 mg/m2 respectively.  Dose limiting 
toxicities included myelosuppression and peripheral neuropathy.  Premedication was 
not required, and unexpected, non-taxane associated toxicities were not observed.  In 
a Phase II trial in heavily pretreated patients with taxane-refractory metastatic breast 
cancer, objective antitumor responses occurred in 15% of women treated with 
Abraxane® 100mg/m2 on this schedule (32).  Toxicity was minimal even without 
premedications or growth factors (G-CSF) usually routinely required with paclitaxel 
or docetaxel in this group of patients. Patients were considered taxane-refractory if 
they had progressive cancer while receiving paclitaxel, docetaxel or both. Abraxane® 
given weekly was active in patients refractory to paclitaxel (16% overall response 
rate and 37% disease control) and patients refractory to docetaxel (24% overall 
response and 35% disease control). Grade 3/4 neutropenia without G-CSF in heavily 
pretreated patients was 15%. Other grade 3 toxicities, all below 4% were: anemia, 
neuropathy, nausea, vomiting and diarrhea. Results of this dose-finding study of 
weekly Abraxane® in heavily pretreated patients identified Abraxane® 100 mg/m2 
as an appropriate dose for further study. It has proved activity in paclitaxel and 
docetaxel refractory patients with acceptable toxicity.  Preliminary data (personal 
communication from Dr. Andrew Seidman, Memorial Sloan-Kettering Cancer 
Center) suggest that weekly administration of Abraxane® at 100 mg/m2 and 
carboplatin at an AUC of 2 together with trastuzumab is feasible, and active, 
however, due to allergic reactions associated with carboplatin administration, steroid 
premedication may be required with such combination. 
 
2.5 
Rationale for the proposed study design 
 
We hypothesize that accomplishment of pCR is a predictor of improved survival, as 
suggested by the results of NSABP -18 and 27.  While the optimal neoadjuvant 
chemotherapy regimen has not been established, comparison of the “front-runner” 
03/22/06 

IRB # 05015 
14 
March 17, 2009 
Version 14 
adjuvant strategies (6 cycles of docetaxel, doxorubicin, and cyclophosphamide 
[TAC]), versus a dose dense administration of Adriamycin and Cytoxan (AC), and a 
taxane may allow identification of the “better” regimen as defined by less toxicity 
using FACT-B and FACT-Taxane subscale -see Appendix- B, (33, 34), and by 
measurement of the pathological CR rate.  We propose that, with the incorporation of 
a less toxic, and possibly more effective taxane (ABI-007 [Abraxane®]) and the 
platinum agent carboplatin, a higher pCR may be accomplished, without substantially 
increasing toxicity.  To test this hypothesis, patients with HER-2 negative breast 
cancer will be randomized between TAC and dose-dense AC followed by weekly 
Abraxane® and carboplatin (ACAC).  All patients with HER-2 overexpressing breast 
cancer will be treated with ACAC and, in addition, weekly trastuzumab (Herceptin®) 
will be co-administered with Abraxane® and carboplatin.  
 
2.6 
Scientific questions/ hypotheses 
 
There are many important research questions that can be addressed best in the context 
of a neoadjuvant treatment trial, since serial assessment of malignant tissue first for 
diagnosis, and then for removal of the previously involved region of the breast is 
already part of standard clinical approach.  Capitalizing on this opportunity, 
procurement of cancerous and adjacent “host” environmental tissue, blood, and 
possibly other sources such as urine, both prior to and subsequent to therapy will 
allow for better definition of the tumor biology, predictors of treatment response, 
markers of relapse, target selection, and effective treatment strategies.   Here are just 
some of the scientific questions one can attempt to answer in the setting of the 
proposed study: 
2.6.1 
Do the presence of specific DNA mutations in the tumor –in comparison to 
the non-malignant host environment - allow for predicting outcome, provide a 
method for early detection of relapse, and identify targets/tools of therapy? 
We will look for specific mutations in genes known to be relevant in the 
development/progression of breast tumors; potential targets include genes for 
nuclear transcription factors (p53), apoptosis (PTEN, Phosphatidylinositol 3-
kinase subunit alfa (PI3-KCA), intracellular transducers (Ras), receptors 
(HER-2, epidermal growth factor receptor (EGFR) and the insulin –like 
growth factor I) (35-54).  We will apply bi-directional pyrophosphorolysis-
activated allelic specific amplification (Bi-PAP-A) measurement in 
comparison to adjacent tissue and germ line DNA (55). Once identified, we 
will examine the frequency of such mutations in plasma and the cellular 
components of blood, and assess their significance.  Listed are some of the 
possible findings: 
1. Larger tumors tend to have higher levels of the tumor-associated mutation 
in their blood. 
2. The frequency of the tumor-associated mutation will be reduced most 
dramatically in those patients that had the best response to chemotherapy. 
3. The mutation frequency in blood may increase during chemotherapy in 
some patients.  
4. Those patients with increased mutation frequency as a result of the 
chemotherapy have a poor prognosis because the increased frequency 
03/22/06 

IRB # 05015 
15 
March 17, 2009 
Version 14 
reflects an increase frequency of cells with metastatic potential that are 
shed into the blood. 
5. Those patients with increased mutation frequency in plasma will have a 
better prognosis since this component reflects fragmented DNA from 
dead cells. 
6. Those patients whose tumor progresses on chemotherapy will show an 
increased tumor mutation frequency in blood. 
7. In an individual patient, the frequency of specific mutations may increase 
during chemotherapy as a result of the general mutagenic affects of these 
agents. 
8. A subset of patients will be highly susceptible to the mutagenic effects of 
chemotherapy and these patients will have a poor prognosis since the 
residual cancer is mutagenized, providing increased genetic diversity for 
selection of metastatic clones. 
9.  An increase or decrease in circulating tumor DNA copy numbers will also 
correlate with the presence/caracteristics of circulating tumor cells. 
 
2.6.2 
Will identification of protein expression patterns allow for identification of 
predictors of outcome, markers of relapse, and targets/tools of therapy? 
Analysis of laser capture microdissected (LCM) tumor and host tissue will 
allow for extraction of proteins from frozen, or ethanol-preserved tissue, 
procured before, during, and after completion of neoadjuvant chemotherapy 
in order to subject the specimens to protein array analysis for the purpose of 
delineating and assessing the activity level of cellular pathways participating 
in cell cycle, apoptosis, or drug metabolism (56-58).  Proteomic analysis of 
the invasive tumor and host environment will allow generation of molecular 
profile and assessment of signal transduction activity based on  the detected 
pattern of  proteins.  Low molecular weight protein profiling by surface 
enhanced laser desorption ionization (SELDI), electron spray mass 
spectrometry (ES-MS), and matrix-assisted laser desorption mass 
spectrometry (MALDI-MS) may provide diagnostic, early and late warning 
signals, and targets of therapy tissue, serum, or body fluid.  Two-dimensional 
gel electrophoresis and immunohistochemical means as well and protein 
microarray may lead to specific validation of the proteomic profile of the 
tumor, surrounding tissue, and body fluids (59-66).  Further understanding of 
the relationship of the relevant protein and genetic markers could lead to 
more accurate estimation of risk of recurrence, resistance to therapy, and 
guide effective intervention. 
Studying of protein profile in serum may help to answer important biological 
and clinical questions.  Preliminary work suggest that such “signals” may be 
helpful in differentiating non-malignant and malignant processes in patients 
with ovarian and breast pathology (67-69).  We will search for signals of such 
protein profiles in plasma prior to, during, at completion of neoadjuvant 
chemotherapy, and during follow-up. 
Prior experience by our group has revealed predictors of adverse outcome by 
assessing tumor protein profile applying immunohistochemical methods.  For 
example, we have shown that overexpression of HER-2 protein, presence of 
 

IRB # 05015 
16 
March 17, 2009 
Version 14 
mutant p53, and low level expression of p21 and p27 have been associated 
with worse outcome in patients with high-risk primary breast cancer (70).  
Applying surface enhanced laser desorption ionization (SELDI), electron 
spray mass spectrometry (ES-MS), or matrix-assisted laser desorption mass 
spectrometry (MALDI-MS) will allow establishment of patterns of 
expression, and identification of specific proteins using 
immunohistochemistry, 2D gel electrophoresis and protein microarray.  One 
can then proceed to assess functional status as defined for example by degree 
of phosphorylation, and evaluate any correlation with adverse outcome (i.e. 
incomplete pathological response) (71-74).  Our findings may lead to a 
change in therapeutic strategy and identification of new treatment targets as 
well as development of novel diagnostic panels. 
2.6.3 
Will identification of patterns of gene expression and microarray analysis 
allow prediction of outcome and identification of targets of therapy? 
The anthracycline doxorubicin is an essential component of most current 
adjuvant and neoadjuvant treatment regimens.  It works, in part, through 
inhibition of topoisomerase 2 (TOP2) function and stabilization of the DNA-
TOP2 complex, eventually leading to DNA Double-strand break (DSB) upon 
colliding with the replication fork or the transcription apparatus (75).  
 
Genomic DNA is continuously exposed to endogenous and exogenous agents 
that elicit DNA damage.  Cellular response to genotoxic stress ranges from 
cell cycle arrest allowing for DNA repair, to apoptosis, if the damage is 
irreparable (76,77).   Replication of damaged DNA is prevented by cell cycle 
checkpoint controls, which are essential parts of the DNA-damage signaling 
network.  Repair of DNA DSB, as seen upon doxorubicin treatment, is carried 
out mainly through the actions of members of the phosphatidylinositol 
kinase-related kinase (PIKK) family: ATM, ATR and DNA-PK.   These 
kinases share sequence homology and many of the same substrate, but they 
are activated differently based on the type of genotoxic stress.  ATM is an 
integral part of the cell cycle checkpoint control, resulting in the activation of 
either apoptotic or anti-apoptotic signaling pathway(s) (76,77).  ATM 
primarily responds to agents that cause DNA double-strand breaks (DSBs), 
whereas ATR plays a role in response to drug-induced changes manifesting in 
the formation of bulky adducts to DNA, stalling of replication forks and 
generation of single-stranded DNA breaks.  DNA-PK holoenzyme binds to 
DNA strand breaks, recruits and activates DNA-PKcs, and plays an essential 
role in non-homologous end-joining (NHEJ) processes. 
 
The initial response to DNA damage is recruitment of several proteins to the 
damage site, with members of the MRN complex: Mre11, Rad50, and Nbs1 
(77) playing prominent roles.  For example, ATM undergoes 
autophosphorylation at S1981 and subsequently phosphorylates other 
downstream substrates, such as Chk2, which in turns phosphorylates several 
cyclin-dependent kinase (CDK) compounds, c-Abl, p53, and BRCA1.  This 
series of events will eventually result in cell accumulation in a specific cell 
cycle phase or leads to apoptosis (78-81).   

IRB # 05015 
17 
March 17, 2009 
Version 14 
 
High-mobility group A2 (HGMA2), also known as HMGI-C, is a non-histone 
chromosomal architectural transcription factor belonging to the HMGA 
family, which consists of 3 additional members: HMGA1a, HMGA1b, and 
HMGA1c (83).  HMGA2 level is elevated during embryogenesis, but is 
usually undetectable in normal adult tissues. 
HMGA2 expression is reported to be an indicator for poor prognosis and 
metastasis of breast cancer.  Our preliminary results indicate that the 
differential responsiveness of breast cancer cells to doxorubicin correlates 
well with the steady-state level of HMGA2.  The degree of expression of 
H2AX S139 phosphorylation, a TOP2 binder may also reflect on the status of 
damage signaling network.  HMGA2 confers selective sensitivity for 
doxorubicin in HS578T breast cancer cells, but not in breast cancer KCC1419 
cells, possibly via modulation of the cellular response to doxorubicin-elicited 
genotoxicity.   HMGA2 expression in breast cancer cells may provide a 
useful therapeutic marker for predicting chemosensitivity to doxorubicin 
treatment (82-86). 
2.6.4 
Are DNA or RNA expression panels by microarray analysis or by RT-PCR 
profile helpful in providing prognostic models and predicting therapeutic 
response? 
 
Gene expression profiles generated based on cDNA cloning from RNA 
extracted from frozen tissue can be performed regardless of whether the 
source of RNA is the entire tumor, fine needle/core biopsy, or microdissected 
specimens.  The majority of information currently in the literature has been 
derived from tumor tissue without separating cancer cells from the “host” 
environment.  Microarray analysis results in expression profiles that allow for 
separation of breast tumors into categories both for the purpose of predicting 
outcome and potentially guide therapy.  Indeed, attempts currently are 
underway to validate the prognostic and predictive value of limited 
sets/clusters of genes procured from primary breast tumors (87-95).  We have 
identified overexpression of the epidermal growth factor receptor (EGFR) by 
RT-PCR analysis performed of a 9-gene panel, as a potential adverse 
indicator of outcome in patients with high-risk breast cancer (70).  Others 
have successfully used RT-PCR technology for generating a validated 
prognostic scoring system in patients with early stage receptor positive breast 
cancer using a panel of 21 primers for genes including the estrogen and 
progesterone receptors, and HER-2 (96).  Such profiling may identify 
predictors of response to individual therapeutic agents and help in choosing 
the optimal therapy (97-102).  We will procure RNA from fresh and 
preservative-embedded cancerous and “host” tissue.  Decreasing the number 
of “targeted” genes down to a panel 6-10 genes, coupled with expression 
analysis by proteomics and immunohistochemical assessment may identify 
predictors and prognosticators of outcome as well as targets of therapy. 
2.6.5 
Will identification of loss of heterozygosity (LOH) in genes coding for 
specific enzymes associated with drug metabolism allow better drug and 
patient selection?  

IRB # 05015 
18 
March 17, 2009 
Version 14 
Genomic variations of key enzymes involved in drug metabolism may 
explain some of the variability in treatment outcome.  We, and others, have 
been exploring methods to identify predictors of drug resistance (103,104).  
In our prior pilot experience a specific CYP polymorphism was seen in high-
dose paclitaxel-treated patients (105).  We will analyze genomic DNA for the 
presence polymorphism in genes associated with drug metabolism prior to, 
during, and following completion of neoadjuvant chemotherapy, in order to 
identify predictors of complete response to a taxane-containing neoadjuvant 
regimen. 
2.6.6 
Will conventional prognostic and predictive markers become obsolete? 
Conventional pathological, immunohistochemical, and clinical features 
(stage, estrogen and progesterone receptor, presence of lymphovascular 
invasion, high grade) and information from the above described molecular 
approaches will be analyzed and compared for the purpose of generating 
prognostic and predictive models of outcome.  As part of this assessment, we 
would like to know what proportion of patients with a positive SLN before 
preoperative chemotherapy will have metastases in their NSLN after 
preoperative chemotherapy?  What are the clinicopathologic factors 
associated with metastases in NSLNs after preoperative chemotherapy in 
patients with a positive SLN before preoperative chemotherapy? 
 
 
Sentinel lymph node (SLN) biopsy has largely replaced routine ALND for 
women with clinically negative axilla.  Several single- and multi-
institutional reports have documented the accuracy of SLN biopsy by 
performing ALND after SLN biopsy (106-112).   These studies have 
demonstrated a low false negative rate.  Thus, if the SLN does not contain 
metastases, then the risk of non-sentinel lymph node (NSLN) metastases is 
very low.  ALND and its associated morbidities may be avoided in 
patients with a negative SLN biopsy. 
 
Approximately, 40% of patients with SLN metastases will also have 
metastases in NSLNs confirmed by ALND (113-121).  Table 1 lists 
several factors associated with increased risk of NSLN metastases.  Of 
these, tumor size (> 2 cm) and SLN metastasis size (> 2 mm) are the 
strongest prognostic factors. 
 
Table 1.  Factors associated with increased risk of NSLN metastases 
Factor 
Increase risk 
Primary tumor size 
> 2 cm 
Size of largest metastasis in SLN 
> 2 mm 
Lymphovascular invasion 
present 
Ratio of number of positive SLNs: total 
number of SLNs identified 
increased 
Number of SLNs with metastases 
> 1 
Extracapsular nodal extension 
present 
Multicentric breast cancer 
present 

IRB # 05015 
19 
March 17, 2009 
Version 14 
Estrogen receptor status 
negative 
Method of detection of SLN metastases 
frozen section > H&E > IHC 
 
The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 
was initiated to determine whether preoperative chemotherapy results in 
improved survival (13,14).  Women (n =1,523) were randomized to 
receive either postoperative doxorubicin and cyclophosphamide (AC) or 
preoperative AC.  While the investigators were not able to demonstrate a 
statistically significant improvement in overall survival, they did find an 
increased rate of lumpectomies (68% vs. 60%, p = 0.002) in the group 
receiving preoperative AC.  In addition, there was a 37% increase in the 
incidence of pathologically negative nodes after preoperative AC (57% vs. 
41%, p < 0.001) (122). 
 
Another randomized trial, NSABP B-27, determined the effect of adding 
doxetaxel (T) to preoperative AC.  In this study, the addition of 
preoperative T after preoperative AC increased the proportion of patients 
with negative axillary lymph nodes (58.2% vs. 50.8%, p < 0.001).  Of 
patients with a complete pathologic response, only 15.5% had positive 
nodes by pathology.  Downstaging had been observed by other 
investigators as well (15). 
 
The results of SLN biopsy after preoperative chemotherapy have been 
variable.  While some studies (123-127) have demonstrated low false 
negative rates after preoperative (neoadjuvant) chemotherapy, others have 
reported false negative rates greater than 10% (128-131).  Several 
explanations have been proposed.  Preoperative chemotherapy may 
selectively eradicate metastases in the SLN, but not in other axillary 
nodes.  As a result, a negative SLN biopsy may not accurately reflect the 
status of the axilla; so metastases in NSLNs may go untreated.  Another 
explanation is that preoperative chemotherapy causes scarring and fibrosis 
in the lymphatic vessels and lymph nodes, thus diverting tracer agents to 
NSLNs and leading to false-negative results (132).  
 
To overcome the limitations of SLN biopsy after preoperative 
chemotherapy, many surgeons are now performing SLN before 
preoperative chemotherapy.  This strategy eliminates the potential for 
selective eradication of metastases in the SLN or for scarring and fibrosis 
to lead to inaccurate lymphatic mapping.  Sabel et al. demonstrated the 
feasibility of this approach in 25 patients who underwent 26 SLN biopsy 
procedures before preoperative chemotherapy (133).  The SLN 
identification rate was 100%.  SLN metastases were identified in 13 
patients; of those, 8 had NSLN metastases confirmed by ALND after 
preoperative chemotherapy.  Schenk et al. preformed SLN biopsy on 21 
patients before preoperative chemotherapy (134).  SLN metastases were 
identified in 9 patients; of those, 6 had positive NSLNs confirmed by 
ALND after preoperative chemotherapy. 
 

IRB # 05015 
20 
March 17, 2009 
Version 14 
Currently, the standard of care in patients with a positive SLN before 
preoperative chemotherapy is a complete axillary node dissection after 
chemotherapy.  Since many patients with a positive SLN biopsy do not 
have NSLN metastases, and preoperative chemotherapy can eradicate 
lymph node metastases in many patients, some patients may have a very 
low risk (<10%) of NSLN metastases, and may be able to avoid 
mandatory axillary node dissection.  Presently, no study has evaluated 
clinical or pathologic factors that might predict the presence or absence of 
metastases in NSLNs, when the SLN is performed before preoperative 
chemotherapy.  We aim to determine the proportion of patients with a 
positive SLN before preoperative chemotherapy who have NSLN 
metastases after preoperative chemotherapy and to determine 
clinicopathologic factors which may be associated with these NSLN 
metastases. 
 
2.6.7 
Neurotoxicity as part of Quality of Life Assessment 
 
Clinical experience indicates that there is a wide spectrum of severity in 
cancer chemotherapy-associated peripheral neuropathies.  Patients with pre-
existing neuropathies are particularly at risk (135); and clearly the drug 
administered, dose-intensity, and total cumulative dose are all important 
determinations of severity.  Nerve length, as given by subject height, also has 
a positive correlation to the severity of nerve damage (136).  Peripheral 
neuropathy from paclitaxel procedures primarily sensory symptoms and signs 
in the distal distribution of the longest nerves of the body, a postulated “dying 
back” axonopathy resulting from disruption of axoplasmic transport from the 
drug’s effect on microtubule assembly (137).  A number of methods have 
been used to assess the incidence and severity of paclitaxel neuropathy.  Most 
investigational studies have used practical measures such as neurological 
examination, or standard toxicity scale measurements.  Significant 
interobserver variability occurs in grading peripheral neurological 
examination, or standard toxicity scale measurements.  Significant 
interobserver variability occurs in grading peripheral neuropathy by health 
care professionals (138); and as in other aspects of quality of life (139), the 
patients’ own assessment of neuropathy symptoms and functional limitations 
may be more meaningful.  Nerve conduction and quantitative sensory tests 
have been carried out in patients receiving high dose paclitaxel (140); but 
these objective measures have not been extensively used or validated in 
clinical studies of chemotherapy associated neuropathies.  In the present 
protocol, these objective measures will be used to assess docetaxel/paclitaxel 
neuropathy, compare the degree of neuropathy in the 2 regimens (TAC versus 
ACAC), and correlate changes with quality of life measures. 
 
2.6.8 
Barriers Study: Identification of delays of care between awareness of 
symptoms and receiving medical treatment by an oncologist. 
 
Despite decreased mortality of breast cancer partially attributed to increased 
awareness and more effective screening, many patients still present for 
treatment after extended delays.  Understanding that these delays may lead to 

IRB # 05015 
21 
March 17, 2009 
Version 14 
a possible higher stage and possible worse prognosis, we would like to 
interview a subgroup of patients to identify some issues involved in the 
barriers leading to treatment delay.  The central issues we would like to 
evaluate are issues involved in the delay of treatment once symptoms appear, 
and the outcomes of having a delayed diagnosis.  The patient population we 
will evaluate are those with stage III (A-C) breast cancer who were aware of 
symptoms or of the possibility of breast cancer and still had a delay of 
seeking or receiving treatment for 3 months or more. The framework with 
which we would like to examine the barriers to treatment include: 
 
A) Patient barriers - fears of diagnosis, belief that treatment will be painful, 
fear of bodily mutilation or harm, other cultural beliefs about cancer and 
revealing the diagnosis, and sense of fatalism. 
B) Professional barriers – delays by primary care physicians in getting 
appropriate diagnosis and treatment.  
C) System Barriers – issues such as managed care, access to care, financial 
issues and women’s understanding of the healthcare system. 
 
The standard of care we will use for appropriate initial evaluation and 
diagnosis is the National Comprehensive Cancer Network guidelines.  We 
understand the sensitive nature of these questions and special care will be 
taken to understand patient feelings and to not evoke a sense of guilt or 
shame. 
 
 
 
2.6.9 
Breast Cancer Stem Cells: Originators of Metastasis and Resistance? 
 
While a substantial portion of patients will demonstrate complete 
disappearance of pathologically detectable tumors (CR) after completion 
of neoadjuvant chemotherapy, relapses even in this patient population, and 
especially in those with persistent disease at the time of completion of 
chemotherapy, are frequent.  One can postulate many reasons for such 
lack of efficacy with our current best chemotherapy, including 
pharmacodynamic, pharmacokinetic, and pharmacogenomic differences in 
tumors and in patients.    It is also possible, that the most resistant tumor 
cells are actually clonogenic and pluripotent tumor stem cells, with 
inherent and/or acquired treatment resistance and ability to self-renew and 
invade.  Delineation of mechanisms of such resistance and ability to 
multiply and metastasize is of crucial importance, in order to target this 
tumor population.  Tumor conglomerates still persisting after aggressive 
neoadjuvant therapy are most likely to be enriched for such cancer stem 
cells, hence procurement of such tumors together with the establishment 
of cell lines for the purpose of characterization of specific signal pathways 
as targets of effective therapeutic intervention is crucial. (141-145)   
Implantation of the tumor cells will be carried out in the Clarke 
Laboratory after procurement of tumor tissue according to the described 
methodology below and will be transported to the Clarke laboratory in 
Stanford.  
 
12/4/06 

IRB # 05015 
22 
March 17, 2009 
Version 14 
The City of Hope will have access to all xenograft tumors established 
from tumors sent to Stanford.  Cells harvested in the xenograph will be 
processed, stored, used to establish tumors as secondary recipients and 
once that secondary recipient is made available to City of Hope we will 
establish a xenographt line here.  Frozen cells will be available as well.  
Collaborative data will be accessible to selected members of City of Hope 
and appropriate of City of Hope will be included as authors in all 
manuscripts that arise from this materials, such as Stanford. 
 
3.0 
DRUG INFORMATION 
3.1. 
Doxorubicin [NSC 123127] 
3.1.1. Mechanism of Action:  Doxorubicin, an anthracycline is known to engage in 
oxidation-reduction reactions, generating free radicals and to intercalate with 
DNA thus preventing DNA and RNA synthesis.  In addition, the drug can 
cause alterations in membrane and topoisomerase II function. 
3.1.2. Toxicity:  Alopecia, nausea, vomiting, mucositis, phlebitis at the site of 
injection, tissue necrosis at the site of extravasation are all frequently reported 
side effects.  Severe cardiomyopathy occurs predominantly at higher 
cumulative doses, in excess of 450 mg/m2.  Acute cardiac toxicities, not 
predictable based on preceding medical evaluation, have also been described.  
Myelosuppression, predominantly leukopenia and granulocytopenia, occurs 
about 2 weeks post injection.  Anemia and thrombocytopenia occur to a 
substantially lesser degree.  Secondary hematological malignancy and 
dysplasia had been reported in patients following chemotherapy with 
doxorubicin-containing combination with an incidence of < 0.25%. 
3.1.3. Pharmaceutical Data:  Doxorubicin is supplied in 10 and 50 mg vials as a red-
orange, freeze-dried powder with up to 2 years of storage ability.  
Reconstitution can be done in normal saline or sterile water. 
3.1.4.  Stability: Doxorubicin is chemically stable for 24 hours at room temperature 
and for 48 hours under refrigeration.  Reconstituted solution should be used 
within 8 hours.  Preservatives should not be used with diluents due to the 
potential to worsen the effects of extravasation. 
3.1.5. Doxorubicin is commercially available. 
3.2 
Docetaxel (Taxotere®) (RP56976) (NSC-628503) 
DESCRIPTION 
3.2.1 
Origin: In the late 1960’s, the National Cancer Institute large-scale plant 
screening program found that a crude extract of the bark from the Pacific 
yew, Taxus brevifolia, had activity against the P388 mouse leukemia.  In 
1971, Wani, Taylor et al. isolated and characterized paclitaxel (Taxol ®), the 
active principle of the extract.  It has become evident that paclitaxel (Taxol®) 
has activity against several human malignancies including refractory ovarian 
caner and breast cancer. 

IRB # 05015 
23 
March 17, 2009 
Version 14 
Several years ago, researchers at Rhone-Poulenc Rorer with the cooperation 
of the French “Centre National de Recherche Scientifique (CNRS)” were able 
to prepare doxetaxel (Taxotere ®), a semisynthetic analog of paclitaxel, using 
a precursor extracted from the needles of the European yew, Taxus baccata, a 
renewable source.  
3.2.1 
Name and Chemical Information: 
Chemical Name: 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1, 7β, 10β-
trihydroxy-9-oxotax-11-ene-13α-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-
hydroxy-3 phenylpropionate 
 
-Empirical formula: 
C43H53O14N 
 
-Molecular weight: 
807.9 
 
-Appearance:  
White powder 
3.2.2 
Mechanism of action: In vitro, docetaxel promotes tubulin assembly in 
microtubules and inhibits depolymerization thus stabilizing microtubules, 
which is different from the action of other spindle poisons in clinical use.  
This can lead to bundles of microtubules in the cell, which by blocking cells 
in the M phase of the cell cycle, results in the inability of the cells to divide. 
Comparing docetaxel and paclitaxel using the “tubulin in vitro assay,” the 
concentration required to provide 50% inhibition of microtubule disassembly 
(or IC50) is 0.2μM for docetaxel and 0.4 μM for paclitaxel. 
3.2.3 
TOXICOLOGY 
The major toxic effect of docetaxel, which limits dose, is neutropenia.  Other 
toxic effects, which may be seen, include leukopenia, thrombocytopenia, 
anemia, asthenia, dysgeusia, myalgia, arthralgia, nail changes and 
conjunctivitis.  Severe anaphylactoid reactions, characterized by a flush 
associated with hypo-or hypertension, with out without dyspnea, may occur.  
Other toxicities include cutaneous reactions (e.g., skin rash, desquamation 
following localized prurignious maculopapular eruption, skin erythema with 
edema), hypersensitivity reactions (flushing, pruritus, fever, chills, rigors, 
lower back pain), dyspnea with restrictive pulmonary syndrome, pleural 
effusions, arrhythmias, pericardial effusions, fluid retention syndrome, 
ascites, myopathy, digestive tract toxicities (nausea, vomiting, oral mucositis, 
diarrhea, anorexia), alopecia, extravasation reaction (erythema, swelling, 
tenderness, pustules), reversible peripheral phlebitis, peripheral edema, 
reversible increase in liver function tests, hepatic failure and neurotoxicity 
(reversible dysesthesias or paresthesias, peripheral neuropathy, seizure, 
headache, lethargy or somnolence).  Patients with SGOT > 1.5 times normal 
and alkaline phosphatase > 2.5 times normal appear to have decreased 
docetaxel clearance and appear to be more likely to suffer sever toxicity, 
including drug-related death. 
3.2.4 
PHARMACOLOGY 

IRB # 05015 
24 
March 17, 2009 
Version 14 
Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic 
compounds, caution should be exercised when handling and preparing 
docetaxel solutions.  The use of gloves is recommended.  Please refer to 
Handling and Disposal section.   
If docetaxel concentrate, initial diluted solution, or final dilution for infusion 
should come into contact with the skin, immediately and thoroughly wash 
with soap and water.  If docetaxel concentrate, initial diluted solution, or final 
dilution for infusion should come into contact with mucosa, immediate and 
thoroughly wash with water. 
Docetaxel for Injection Concentrate requires two dilutions prior to 
administration.  Please follow the preparation instruction provided below.  
Note: Both the docetaxel for Injection Concentrate and the diluent vials 
contain an overfill. 
How Supplied: Docetaxel for Injection Concentrate is supplied in a single-
dose vial as a sterile, pyrogen-free, non-aqueous, viscous solution with an 
accompanying sterile, non-pyrogenic, diluent (13% enthanol in Water for 
Injection) vial.  The following strengths are available: 80 mg and 20 mg 
strengths are available. 
Storage: Store between 2 and 25°C (36 and 77°F).  Retain in the original 
package to protect from bright light.  Freezing does not adversely affect the 
product. 
Preparation of the Initial Diluted Solution: Gather the appropriate number of 
vials of docetaxel for Injection Concentrate and diluent (13% Ethanol in 
Water for Injection).  If the vials were refrigerated, allow them to stand at 
room temperature for approximately 5 minutes.  Aseptically withdrawn the 
contents of the appropriate diluent vial into a syringe and transfer it to the 
appropriate vial of docetaxel for Injection Concentrate.  If the procedure is 
followed as described, an Initial diluted solution of 10 mg docetaxel/ will 
result.  Gently rotate the initial diluted solution for approximately 15 seconds 
to assure full mixture of the concentrate and diluent.  The initial diluted 
docetaxel solution (10 mg doxetaxel/ml) should be clear; however, there may 
be some foam on top of the solution due to the polysorbate 80.  Allow the 
solution to stand for a few minutes to allow any foam to dissipate.  It is not 
required to all foam dissipate prior to continuing the preparation process.  The 
initial diluted solution may be used immediately or stored either in the 
refrigerator or at room temperature for a maximum of 8 hours. 
Preparation of the Final Dilution for Infusion: Aseptically withdraw the 
required amount of initial diluted docetaxel solution (10 mg docetaxel/ml) 
with a calibrated syringe and inject into a 250 ml infusion bag or bottle of 
other 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a 
final concentration of 0.3 to 0.74 mg/ml.  If a dose greater than 200 mg of 
docetaxel is required, use a large volume of the infusion vehicle so that a 
concentration of 0.74 mg/ml doxetaxel is not exceeded.  Thoroughly mix the 
infusion by manual rotation.  As with all parenteral products, docetaxel 
should be inspected visually for particulate matter or discoloration prior to 

IRB # 05015 
25 
March 17, 2009 
Version 14 
administration whenever the solution and container permit.  If the docetaxel 
for Injection initial diluted solution or final dilution for infusion is not clear or 
appears to have precipitation, these should be discarded. 
Contact of the docetaxel concentrate with plasticized PVC equipment or 
devices used to prepare solutions for infusion is not recommended.  In order 
to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl 
phthalate), which may be leached from PVC infusion bags or sets, the final 
docetaxel dilution for infusion should be stored in bottles (glass, 
polypropylene) or plastic bags (polypropylene, polyolefin) and administered 
through polyethylene-lined administration sets. 
Administration: The drug will be administered to the patients as a 1-hour IV 
infusion under ambient room temperature and lighting conditions.  Please 
refer to the approved package labeling for complete prescribing and toxicity 
information. 
Stability: The initial diluted solution may be used immediately or stored 
either in the refrigerator or at room temperature for a maximum of 8 hours. 
Docetaxel infusion solution, if stored between 2 and 25°C (36 and 77°F) is 
stable for 4 hours.  Fully prepared docetaxel infusion solution (in either 
0.9% Sodium Chloride solution or 5% Dextrose solution) should be used 
within 4 hours (including the 1 hour IV administration). 
Handling and Disposal: Procedures for proper handling and disposal of 
anticancer drugs should be considered.  Several guidelines on this subject 
have been published.  There is no general agreement that all of the 
procedures recommended in the guidelines are necessary or appropriate.  
Supplier: This drug is commercially available for purchase by a third 
party. 
3.3 ABI-007; Abraxane® (paclitaxel protein-bound particles for injectable suspension; 
(albumin-bound)).  
3.3.1 
General:  Abraxane® is a unique protein formulation of a non-crystalline, 
amorphous form of paclitaxel in an insoluble compound state.  Abraxane® 
has been developed to reduce the toxicities associated with Taxol® 
(paclitaxel) Injection (in which paclitaxel-from the native crystalline form-is 
in solution with CremophorEL/ethanol as the solvent) while maintaining or 
improving its chemotherapeutic effect. 
3.3.2 
The Product:  Abraxane® is a Cremophor-free formulation of paclitaxel 
albumin for injectable suspension.  Each 50 mL vial contains 100 mg of 
paclitaxel, and human albumin, as a white to off-white sterile lyophilized 
powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection 
USP. 
3.3.3 Preclinical and Clinical Experience:Preclinical Studies with Abraxane® 

IRB # 05015 
26 
March 17, 2009 
Version 14 
Preclinical studies comparing Abraxane® to Taxol demonstrated dramatically 
lower acute toxicities, with an LD10 approximately 3-fold higher for 
Abraxane® compared to Taxol.  At equal doses there was less 
myelosuppression and improved efficacy in a xenograft tumor model of 
human mammary adenocarcinoma.  At equitoxic doses of paclitaxel, 
Abraxane® was found to be markedly more efficacious than Taxol. 
 
Clinical Studies with Abraxane® 
Every 3 Weeks Schedule 
In a phase I study, the maximum tolerated dose (MTD) of Abraxane® was 
determined to be 300 mg/m2 by 30 minute infusion every 3 weeks, without 
premedication or G-CSF support. Two multicenter phase II studies have 
evaluated 2 dose levels of Abraxane® (300 mg/m2, n=63, and 175 mg/m2, 
n=43) in patients with metastatic breast cancer. The overall response rates in 
these 2 phase II trials were 40% (95% CI 25-54%) for the 175 mg/m2 dose, 
and 48% (95% CI 35-60%) for the 300 mg/m2 dose.  Of 39 patients receiving 
300 mg/m2 as first-line therapy for metastatic breast cancer, 64% (95% CI 49-
79%) responded.  This was contrasted with a 45% response rate in similar 
patients at the lower dose level. Grade 4 neutropenia was noted in 24% of 
patients at the higher dose level, occurred primarily during the first cycle and 
resolved rapidly (146).  
 
A Phase III trial in patients with metastatic breast cancer compared 
Abraxane® 260 mg/m2 to Taxol 175 mg/m2 given every 3 weeks (30).  
Significantly higher efficacy for Abraxane® vs Taxol was demonstrated as 
measured by overall response rates (33% vs 19%, p<0.001) and time to tumor 
progression (5.2 vs 3.7 months, p=0.029). The overall median survival was 
65.0 weeks for the Abraxane® group and 55.3 weeks for the Taxol group 
(p=0.329). In 2nd-or greater-line patients, median survival in the Abraxane® 
arm was significantly improved (56.4 vs 46.7 weeks, p=0.016). Despite a 
49% higher dose of paclitaxel administered to patients in the Abraxane® 
group than in the Taxol group, the incidence of treatment-related Grade 3/4 
neutropenia was significantly less (25% vs. 31% and 9% vs. 22%, 
respectively). The Abraxane® group also had a higher mean neutrophil nadir 
(1.67 vs 1.31 x 109/L; p = 0.046) suggesting that Cremophor® may have 
contributed to this toxicity. Grade 3 sensory neuropathy occurred in 10% of 
Abraxane® treated patients and 2% of those treated with Taxol. No grade 4 
sensory neuropathy occured in either study group.  Of the patients who 
developed grade 3 sensory neuropathy while on Abraxane®, 58% had 
documented rapid improvement in symptoms after a median of 22 days and 
42% of patients were able to resume treatment at a reduced dose. Only 3% of 
patients that received Abraxane® discontinued treatment due to peripheral 
neuropathy. 
 
Weekly for 3 Weeks, Every 4 Weeks Schedule 
A Phase I study of Abraxane® administered weekly for 3 weeks followed by 
1 week rest in patients with advanced solid tumors has been completed (31).  
The MTDs for heavily and lightly pre-treated patients were 100 and 
150mg/m2 respectively. These doses are significantly higher than paclitaxel.  
12/4/06 

IRB # 05015 
27 
March 17, 2009 
Version 14 
Dose limiting toxicities included myelosuppression and peripheral 
neuropathy.  Pre-medication was not required, and unexpected, non-taxane 
associated toxicities were not observed.   
 
In a Phase II trial in heavily pretreated patients with taxane-refractory 
metastatic breast cancer, objective antitumor responses occurred in 15% of 
women treated with Abraxane®  100mg/m2 on this schedule (32).  Toxicity 
was minimal even without premedications or growth factors (G-CSF) usually 
routinely required with paclitaxel or docetaxel in this group of patients. 
Patients were considered taxane-refractory if they had progressive cancer 
while receiving paclitaxel, docetaxel or both. Abraxane®  given weekly was 
active in patients refractory to paclitaxel (16% overall response rate and 37% 
disease control) and patients refractory to docetaxel (24% overall response 
and 35% disease control). Grade 3/4 neutropenia without G-CSF in heavily 
pretreated patients was 15%. Other grade 3 toxicities, all below 4% were: 
anemia, neuropathy, nausea, vomiting and diarrhea. Results of this dose-
finding study of weekly Abraxane®  in heavily pretreated patients identified 
Abraxane®  100 mg/m2 as an appropriate dose for further study. It has proven 
activity in paclitaxel and docetaxel refractory patients with acceptable toxicity 
(32). 
 
3.3.4 
Human Toxicity:  Please refer to the Clinical Investigator’s Brochure for 
details of the Adverse Reactions in the overall Safety Database for 
Abraxane® (147). 
Table 1. Frequency of Adverse Events in a Randomized Phase III Study on an 
Every-3-Weeks Schedule 
 
Percent of Patients 
 
 
 
ABRAXANE® 
260/30minb  
(n=229) 
Paclitaxel Injection  
175/3hc,d   
(n=225) 
Bone Marrow 
 
 
  Neutropenia 
         < 2.0 x 109/L  
         < 0.5 x 109/L 
 
80 
9 
 
82 
22 
  Thrombocytopenia 
     < 100 x 109/L  
     < 50 x 109/L  
 
2 
<1 
 
3 
1 
  Anemia  
      < 11 g/L  
      < 8 g/L  
 
33 
1 
 
25 
<1 
  Infections  
24 
20 
  Febrile Neutropenia 
2 
1 
  Bleeding 
2 
2 
Hypersensitivity Reactione 
 
 
  All  
4 
12 
  Severef 
0 
2 
Cardiovascular  
 
 
 Vital Sign Changesg 
 
 
12/4/06 

IRB # 05015 
28 
March 17, 2009 
Version 14 
 
Percent of Patients 
 
 
 
ABRAXANE® 
260/30minb  
(n=229) 
Paclitaxel Injection  
175/3hc,d   
(n=225) 
     Bradycardia  
<1 
<1 
     Hypotension  
5 
5 
 Severe Cardiovascular Eventsf 
3 
4 
Abnormal ECG 
 
 
  All patients 
60 
52 
  Patients with Normal Baseline  
35 
30 
Respiratory 
 
 
  Cough 
6 
6 
  Dyspnea   
12 
9 
Sensory Neuropathy 
 
 
  Any Symptoms  
71 
56 
  Severe Symptomsf 
10 
2 
Myalgia / Arthralgia 
 
 
  Any Symptoms  
44 
49 
  Severe Symptomsf 
8 
4 
 
 
 
 
 
 
ABRAXANE® 
260/30minb  
(n=229) 
Paclitaxel Injection  
175/3hc,d   
(n=225) 
Asthenia 
 
 
  Any Symptoms 
47 
38 
  Severe Symptomsf 
8 
3 
Fluid Retention/Edema 
 
 
  Any Symptoms 
10 
8 
  Severe Symptomsf 
0 
1 
Gastrointestinal 
 
 
  Nausea  
 
 
        Any symptoms 
30 
21 
        Severe symptomsf 
3 
<1 
  Vomiting 
 
 
       Any symptoms 
18 
9 
      Severe Symptomsf 
4 
1 
  Diarrhea 
 
 
     Any Symptoms 
26 
15 
     Severe Symptomsf 
<1 
1 
  Mucositis 
 
 
     Any Symptoms 
7 
7 
    Severe Symptomsf 
<1 
0 
Alopecia 
90 
94 
Hepatic (Patients with Normal 
Baseline) 
 
 
  Bilirubin Elevations  
7 
7 
  Alkaline Phosphatase Elevations  
36 
31 
  AST (SGOT) Elevations  
39 
32 
Injection Site Reaction 
1 
1 
a  Based on worst grade 
b  Abraxane® dose in mg/m2/duration in minutes 

IRB # 05015 
29 
March 17, 2009 
Version 14 
c  paclitaxel injection dose in mg/m2/duration in hours 
d  paclitaxel injection pts received premedication 
e  Includes treatment-related events related to hypersensitivity  (e.g.,  flushing, dyspnea, chest pain, hypotension) that 
began on a day of dosing. 
f  Severe events are defined as at least grade 3 toxicity 
g  During study drug dosing. 
 
Pregnancy 
Abraxane® may cause fetal harm when administered to a pregnant woman. A 
developmental toxicity study in rats showed that no gross external, soft tissue or 
skeletal fetal alterations were caused by Abraxane® at doses of 0.5 mg/kg/day. 
Higher doses of Abraxane® resulted in significant maternal toxicity. This was 
evidenced by increased mortality, reduction in body weight gain, reduced 
terminal body weight, reduced food intake, and embryo-fetal lethality. Dose-
related increases in malformations, variations, fetal deaths and/or resorptions 
occurred in pregnant rats that were administered intravenous doses of 1 or 2 
mg/kg/day of Abraxane®. 
There are no adequate and well-controlled studies of Abraxane® in pregnant 
women. If Abraxane® is used during pregnancy, or if the patient becomes 
pregnant while receiving this drug, the patient should be apprised of the potential 
hazard to the fetus. Women of childbearing potential should be advised to avoid 
becoming pregnant. 
 
Nursing Mothers 
It is not known whether paclitaxel (and therefore Abraxane®) is excreted in 
human milk. It has been reported that following IV administration of 14C- 
paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in 
milk were higher than in plasma and declined in parallel with the plasma 
concentrations. Because many drugs are excreted in human milk and because of 
the potential for serious adverse reactions in nursing infants, it is recommended 
that nursing be discontinued when receiving Abraxane® therapy. 
 
3.3.5 
Pharmaceutical Information:  Abraxane® Administration 
NOTE:  It is not a requirement to use filter needles in the preparation of, 
or in-line filters during the administration of Abraxane®.  In any event, 
filters of pore-size less than 15 micrometers must not be used. 
Abraxane® will be reconstituted by appropriate study personnel and 
administered to the patient in the study site setting at 1-week intervals.  The 
investigator will calculate the body surface area (BSA) of the patient in order 
to determine the total amount of paclitaxel to be administered. 
Reconstitution and use of Abraxane®: 
1. Calculate the patient’s body surface area at the beginning of the study and 
if the weight changes by >10%. 
2. Calculate the total dose (in mg) to be administered by: 
Total Dose (mg) = BSA x (study dose mg/m2) 
3. Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 
 
 
 
 
100 (mg/vial) 

IRB # 05015 
30 
March 17, 2009 
Version 14 
Round up the number of vials to be reconstituted to the next higher whole 
number when a fractional number of vials is obtained by the above 
formula (eg, if the total number of vials = 4.05 or 4.5, then 5 vials would 
be reconstituted). 
4. Using sterile technique, prepare the vials for reconstitution. 
5. Swab the rubber stoppers with alcohol. 
6. Reconstitute each Abraxane® vial by using a sterile syringe to inject 20 
mL of 0.9% Sodium Chloride Injection, USP or equivalent into each vial 
over a period of not less than 1 minute (Note:  Change the syringes after 
reconstituting every 3 vials). 
• 
Slowly inject the 20mL of 0.9% Sodium Chloride Injection, USP,, 
using the sterile syringe directing the solution flow onto the inside 
wall of the vial. 
• 
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP 
solution directly onto the lyophilized cake as this will result in 
foaming. 
• 
Once the injection is complete, allow the vial to sit for a minimum of 
5 minutes to ensure proper wetting of the lyophilized cake/power. 
• 
Gently swirl and/or invert the vial slowly for at east 2 minutes until 
complete dissolution of any cake;/powder occurs.  Avoid generation 
of foam. 
• 
If foaming or clumping occurs, stand solution for at least 15 minutes 
until foam subsides. 
• 
Each mL of reconstituted product will contain 5 mg of paclitaxel. 
7. Calculate the exact total dosing volume (to the nearest mL) of 5 mg/mL 
suspension required for the patient: 
Dosing volume (mL) = Total dose (mg)/5 (mg/mL) 
8. The reconstituted sample should be milky and homogeneous without 
visible particulates. If unsuspended powder is visible, the vial should be 
gently inverted again to ensure complete resuspension, prior to use. 
9. Once the exact volume of reconstituted Abraxane® has been withdrawn 
from the vials, discard any excess solution left over in accordance with 
standard operating procedures. 
10. Inject the calculated dosing volume of reconstituted Abraxane® 
suspension into an empty sterile, standard PVC IV bag using an injection 
port.  Inject perpendicularly into the center of the injection port to avoid 
dislodging plastic material into the IV bag.  Repeat steps 10 and 11 until 
the patient’s entire required dose is injected into the IV bag. 
11. Administer the calculated dosing volume of reconstituted Abraxane® 
suspension by IV infusion over 30 minutes.  The use of in-line filters is 

IRB # 05015 
31 
March 17, 2009 
Version 14 
not necessary.  If used, in-line filters with pore sizes of <15μ should not 
be used. 
12. Unopened vials of Abraxane are stable until the date indicated on the 
package when stored between 20°C to 25°C (68°F to 77°F), in the 
original package.  Reconstituted Abraxane should be used immediately, 
but may be refrigerated at 2 °C to 8 °C (36°F to 46°F) for a maximum of 
8 hours if necessary.  If not used immediately, each vial of reconstituted 
suspension should be bright light. Discard any unused portion.  Neither 
freezing nor refrigeration adversely affects the reconstituted the stability 
of the product. Some settling of the reconstituted suspension may occur.  
Ensure complete resuspension by mild agitation before use.  Discard the 
reconstituted suspension if precipitates are observed.  The suspension for 
infusion prepared as recommended in an infusion bag is stable at ambient 
temperature (approximately 25°C) and lighting conditions for up to 8 
hours. 
13. Store the vials in original cartons at 20°C to 25°C (68°F to 77°F).  Retain 
in the original package too protect from bright light. 
3.4 
Cyclophosphamide (Cytoxan®) [NSC-26271] 
3.4.1 
Mode of Action:  Cyclophosphamide is a weak alkylating agent.  The drug 
undergoes enzymatic oxidation and additional multi-step processes resulting 
in end products with increased alkylating properties. 
3.4.2 
Toxicities:  Alopecia, nausea, vomiting, stomatitis, diarrhea, skin rash, 
pancytopenia, sterility, decreased gonadal function, hemorrhagic cystitis, 
syndrome of inappropriate antidiuretic hormone secretion, immune 
suppression, interstitial pulmonary fibrosis, leukemogenic potential, and at 
extremely high doses, myocardial necrosis. 
3.4.3 
Pharmaceutical Data:  Cyclophosphamide is available in 1 and 2 gram vials 
containing white powder.  The drug can be reconstituted in normal saline or 
5% dextrose and water.  The drug should be diluted in approximately 250ml 
of diluent and infused over 1 hour. 
3.4.4 
Stability:  Store at room temperature.  Do not store at temperatures above 90 
degrees F. 
3.4.5 
Cyclophosphamide is commercially available. 
3.5 
Carboplatin (Paraplatin®) (NSC-241240) (CBDCA) 
3.5.1 
Description 
Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and 
is an analog of cisplatin, producing intrastrand DNA cross-links. 
3.5.2 
Toxicology 

IRB # 05015 
32 
March 17, 2009 
Version 14 
Human Toxicology: Side effects of carboplatin (CBDCA) include 
myelosuppression, nausea, vomiting, abdominal pain, diarrhea and 
constipation. Other toxicities include allergic reaction (including 
hypersensitivity, i.e., rash, urticaria, erythema, pruritus, bronchospasm and 
hypotension), peripheral neuropathy, paresthesia, loss of hair, hearing loss, 
visual disturbances and change in taste.  Serum creatinine elevations and 
blood urea elevations have occurred, as well as abnormal liver function tests 
and decreased serum electrolyte values.  Although rare, pain, asthenia, 
cardiovascular, respiratory, genitourinary and mucosal side effects have 
occurred in some patients.  Cancer-associated hemolytic uremic syndrome 
has been reported rarely.  Carboplatin may cause fetal harm; therefore women 
of childbearing potential should be advised to avoid becoming pregnant.  The 
renal effects of nephrotoxic compounds may be potentiated by carboplatin.  
Carboplatin is contraindicated in patients with a history of severe allergic 
reactions to cisplatin or other platinum-containing compounds or mannitol.  
This drug should not be used in patients with severe bone marrow depression 
or significant bleeding.  The occurrence of acute leukemia has been reported 
rarely in patients treated with anthracycline/alkylator combination 
chemotherapy. 
3.5.3 
Pharmacology 
Pharmacokinetics:  The difference in potencies of carboplatin and cisplatin 
are due to differences in equation rates.  The initial half-life is 1.1–2.0 hours 
and the post-distributional half-life is 2.6–5.9 hours.  Sixty-five percent of the 
dose is excreted in the urine within twelve hours.  Carboplatin is not bound to 
plasma proteins. 
Formulation: Carboplatin is supplied as a sterile lyophilized powder available 
in single-dose vials containing 50 mg, 150 mg and 450 mg of carboplatin for 
administration by intravenous injection.  Each vial contains equal parts by 
weight of carboplatin and mannitol.  Immediately before use, the content of 
each vial must be reconstituted with either Sterile Water for Injection, USP, 
5% Dextrose in Water, or 0.9% Sodium Chloride Injection, USP, according to 
the following schedule: 
 
Vial Strength  
 
Diluent Volume 
50 mg                                           5 mL 
150 mg                                         15 mL 
450 mg                                         45 mL 
 
 
These dilutions all produce a carboplatin concentration of 10 mg/ml.  
Carboplatin can be further diluted to concentrations as low as 0.5 mg/ml with 
5% Dextrose in Water or 0.9% Sodium Chloride Injection, USP (NS). 
Storage and Stability: Unopened vials of carboplatin for injection are stable 
for the life indicated on the package when stored at controlled room 
temperature 15–30 ˚C, and protected from light.  When reconstituted as 
directed, the solution of carboplatin exhibits no decomposition for 8 hours at 
room temperature (25 ˚C).  Like cisplatin, this drug should not be given 

IRB # 05015 
33 
March 17, 2009 
Version 14 
through aluminum needles.  Caution: The single-use lyophilized dosage form 
contains no antibacterial preservatives.  Therefore, it is advised that the 
reconstituted product be discarded eight hours after dilution. 
Administration: Intravenous. 
Supplier: Carboplatin is commercially available. 
 
3.6 
Filgrastim (Neupogen®) (r-metHuG-CSF) (NSC - 614629) 
3.6.1 
Description:  Filgrastim is a human granulocyte colony-stimulating factor (G-
CSF), produced by recombinant DNA technology.  NEUPOGEN® is the 
Amgen Inc. trademark for filgrastim, recombinant methionyl human 
granulocyte colony stimulating factor (r-metHuG-CSF). 
3.6.2 
Contraindications:  NEUPOGEN® is contraindicated in patients with known 
hypersensitivity to E. coli-derived proteins, filgrastim, or any component of 
the product. 
3.6.3 
Adverse Reactions:  The only consistently observed clinical toxicity 
described with Neupogen® is medullary bone pain. Other clinical toxicities 
that have been described include skin rash, and cutaneous vasculitis.  Since 
commercial introduction of Neupogen®, there have been rare reports of 
allergic-type reactions.  Biochemical abnormalities that may occur include 
increases in alkaline phosphatase, uric acid, and lactate deydrogenase. 
3.6.4 
Dilution/Storage:  If required, NEUPOGEN® may be diluted in 5% dextrose.  
NEUPOGEN® diluted to concentrations between 5 and 15 mcg/mL should 
be protected from adsorption to plastic materials by addition of Albumin 
(Human) to a final concentration of 2 mg/mL.  Do not dilute with saline at 
any time; product may precipitate. 
NEUPOGEN® should be stored in the refrigerator at 2-8 degrees Centigrade 
(36-46 degrees Fahrenheit).  Do not freeze.  Avoid shaking.  Prior to 
injection, NEUPOGEN® may be allowed to reach room temperature for a 
maximum of 24 hours.  Any vial left at room temperature for greater than 24 
hours should be discarded. 
3.6.5 
How Supplied:  Commercial NEUPOGEN® is available in 1 mL and 1.6 mL 
vials at a concentration of 300 mcg/mL.  Discard unused portions.  Use only 
one dose per vial; do not reenter the vial.  Do not save unused drug for later 
administration. 
 
3.7 
Pegfilgrastim (NeulastaTM) 
3.7.1 
DESCRIPTION 
Pegfilgrastim (NeulastaTM) is a covalent conjugate of recombinant methionyl 
human G-CSF (Filgrastim) and monomethoxypolyethylene glycol.  Studies 
on cellular proliferation, receptor binding, and neutrophil function 

IRB # 05015 
34 
March 17, 2009 
Version 14 
demonstrate that filgrastim and pegfilgrastim have the same mechanism of 
action.  Pegfilgrastim has reduced renal clearance and prolonged persistence 
in vivo compared with filgrastim. 
Pegfilgrastim is indicated to decrease the incidence of infection, as 
manifested by febrile neutropenia, in patients with nonmyeloid malignancies 
receiving myelosuppressive anti-cancer drugs associated with a clinically 
significant incidence of febrile neutropenia. 
Pegfilgrastim was evaluated in 2 randomized, double-blind, active-control 
studies, using doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered 
every 21 days for up to 4 cycles in the treatment of patients with high-risk 
stage II or stage III/IV breast cancer.  Study 1 investigated the utility of a 
fixed dose of pegfilgrastim.  Study 2 used a weight-adjusted dose.  In the 
absence of growth-factor support, similar chemotherapy regimens have been 
reported to result in a 100% incidence of severe neutropenia [absolute 
neutrophil count (ANC) <0.5 x 109/L] with a mean duration of 5 to 7 days, 
and a 30 to 40% incidence of febrile neutropenia. 
In study 1,157 subjects were randomized to receive a single subcutaneous 
(SC) dose of 6 mg of pegfilgrastim on Day 2 of each chemotherapy cycle or 
filgrastim 5 mg/kg/day SC beginning on Day 2 of each cycle.  In study 2,310 
subjects were randomized to receive a single SC injection of pegfilgrastim at 
100 mg/kg on Day 2 or filgrastim 5 mg/kg/day SC beginning on Day 2 of 
each cycle of chemotherapy. 
Both studies met the primary objective of demonstrating that the mean days 
of severe neutropenia (ANC <0.5 x 109/L) of pegfilgrastim-treated patients 
did not exceed that of filgrastim -treated patients by more than 1 day in Cycle 
1 of chemotherapy.  The rates of febrile neutropenia were 13% and 9% for 
pegfilgrastim vs 20% and 18% for filgrastim in studies 1 and 2, respectively. 
Other secondary endpoints included days of severe neutropenia in Cycles 2 to 
4, the depth of ANC nadir in Cycles 1 to 4, and the time to ANC recovery 
after nadir.  In both studies, the results for the secondary endpoints were 
similar between the 2 treatment groups. 
The safety and efficacy of once-per-cycle pegfilgrastim was also found to be 
comparable to daily filgrastim in phase 2 studies in patients with non-small 
cell lung cancer being treated with carboplatin and paclitaxel and patients 
with non Hodgkin’s lymphoma (NHL) or Hodgkin’s lymphoma being treated 
with ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin) 
or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) 
chemotherapy. 
3.7.2 
TOXICOLOGY 
The most common adverse event attributed to pegfilgrastim in clinical trials 
was medullary bone pain, reported in 26% of subjects, which was comparable 
to the incidence in filgrastim -treated patients.  This bone pain was generally 
reported to be of mild-to-moderate severity.  Approximately 12% of all 

IRB # 05015 
35 
March 17, 2009 
Version 14 
subjects utilized non-narcotic analgesics and less than 6% utilized narcotic 
analgesics in association with bone pain.  No patients withdrew from the 
study due to bone pain.  Reversible elevations in LDH, alkaline phosphatase 
and uric acid have been observed in clinical trials.  Pegfilgrastim has been 
associated with leukocytosis (defined as WBC >100. x 109/L) in <1% of 465 
subjects with nonmyeloid malignancies, when observed is was not associated 
with any adverse event.  Transient thrombocytopenia has also been noted in 
patients receiving filgrastim. 
Pegfilgrastim is contraindicated inpatients with known hypersensitivity to E. 
coli-derived proteins, pegfilgrastim, filgrastim, or any other component of the 
product. 
Rare cases of splenic rupture have been reported following the administration 
of the parent compound of pegfilgrastim, filgrastim, for PBPC mobilization in 
both healthy donors and patients with cancer.  Some of these cases were fatal. 
Pegfilgrastim has not been evaluated in this setting.  Patients receiving 
pegfilgrastim who report left upper abdominal or shoulder tip pain should be 
evaluated for an enlarged spleen or splenic rupture. 
Adult respiratory distress syndrome (ARDS) has been reported in neutropenic 
patients with sepsis receiving filgrastim, the parent compound of 
pegfilgrastim, and is postulated to be secondary to an influx of neutrophils to 
sites of inflammation in the lungs.  Neutropenic patients receiving 
pegfilgrastim who develop fever, lung infiltrates, or respiratory distress 
should be evaluated for the possibility of ARDS.  In the event that ARDS 
occurs, pegfilgrastim should be discontinued and/or withheld until resolution 
of ARDS and patients should receive appropriate medical management for 
this condition. 
Allergic-type reactions, including analyphylaxis, skin rash, and urticaria, 
occurring on initial or subsequent treatment have been reported with the 
parent compound of pegfilgrastim, filgrastim.  In some cases, symptoms have 
recurred with rechallenge, suggesting a causal relationship.  Allergic-type 
reactions to pegfilgrastim have not been observed in clinical trials.  If a 
serious allergic reaction or anaphylactic reaction occurs, appropriate therapy 
should be administered and further use of pegfilgrastim should be 
discontinued. 
Severe sickle cell crisis have been reported in patients with sickle cell disease 
(specifically homozygous sickle cell anemia, sickle/hemoglobin C disease, 
and sickle b+ thalassemia) who received filgrastim, the parent compound of 
pegfilgrastim, for PBPC mobilization or following chemotherapy.  One of 
these cases was fatal. 
There are no adequate and well-controlled studies in pregnant women.  The 
risks of the study drug to an unborn or newborn child, are not known. In 
addition, it is not known whether pegfilgrastim is secreted in human milk.  
Therefore, pregnant or nursing mothers may not take part in this study. 

IRB # 05015 
36 
March 17, 2009 
Version 14 
No formal drug interaction studies between pegfilgrastim and other drugs 
have been performed.  Drugs such as lithium may potentiate the release of 
neutrophils; patients receiving lithium and pegfilgrastim should have more 
frequent monitoring of neutrophil counts. 
The maximum amount of pegfilgrastim that can be safely administered in 
single or multiple doses has not been determined.  Single doses of 300 
mcg/kg have been administered SC to 8 normal volunteers and 3 patients with 
non-small cell lung cancer without serious adverse effects.  These subjects 
experienced a mean maximum ANC of 55 x 109/L, with a corresponding 
mean maximum WBC of 67 x 109/L.  The absolute maximum ANC observed 
was 96 x 109/L with a corresponding absolute maximum WBC observed of 
120 x 109/L.  The duration of leukocytosis ranged from 6 to 13 days.  
Leukapheresis should be considered in the management of symptomatic 
individuals. 
For prescribing information and a comprehensive list of adverse events 
associated with pegfilgrastim, refer to the drug package insert. 
3.7.3 
PHARMACOLOGY 
Pegfilgrastim (NeulastaTM) is a clear, colorless, sterile liquid.  It is supplied as 
a preservative-free solution containing 6 mg (0.6 mL) of pegfilgrastim (10 
mg/mL) in a single-dose syringe with a 27 gauge, ½ inch needle with an 
UltraSafe® Needle Guard.  The formulation is 10 mg pegfilgrastim (PER-
metHuG-CSF) per mL of solution containing acetate (0.35 mg), sorbitol (30 
mg), polysorbate 20 (0.02 mg), and sodium (0.02 mg) in water for injection, 
USP, pH 4.0.  Each dispensing pack contains 1 pre-filled syringe. 
Storage and Stability:  Pegfilgrastim should be stored refrigerated at 2 to 8ºC 
(36 to 46ºF); syringes should be kept in their carton to protect from light until 
time of use.  Shaking should be avoided.  Before injection, pegfilgrastim may 
be allowed to reach room temperature for a maximum of 48 hours but should 
be protected from light.  Pegfilgrastim left at room temperature for more than 
48 hours should be discarded.  Freezing should be avoided; however, if 
accidentally frozen, pegfilgrastim should be allowed to thaw in the 
refrigerator before administration.  If frozen a second time, pegfligrastim 
should be discarded. 
Administration:  No preparation is required for administration of 
pegfilgrastim.  Each subject will receive a fixed dose of 6 mg of 
pegfilgrastim. The entire contents of the 0.6 mL pre-filled syringe should be 
administered subcutaneously irrespective of the subject’s actual weight. 
Supplier:  Pegfilgrastim is commercially available and should be purchased 
by a third party.   
3.8  Trastuzumab (Herceptin®); NSC #688907 

IRB # 05015 
37 
March 17, 2009 
Version 14 
Trastuzumab will be given at 4 mg/kg as a loading dose, and then a dose of 2 mg/kg will be 
repeated every week.  The drug will be administered over 90 minutes; subsequent doses will 
be given over 30 minutes, if the loading dose was well tolerated. 
3.8.1 
Description 
Herceptin®, manufactured by Genentech Inc., is commercially available and 
is supplied as a freeze-dried preparation at a nominal content of 440 mg per 
vial for parenteral administration.  The drug is formulated in histidine, 
trehalose, and polysorbate 20.  Each 440-mg vial of trastuzumab is supplied 
with 20ml bacteriostatic water for injection, USP, 1.1% benzyl alcohol. 
Herceptin® vials must be stored in the refrigerator (2° C to 8°C). Do not 
freeze. 
The reconstituted formulation (440-mg vial) is designed for multiple use.  
Unused drug may be stored for 28 days at 2°C to 8°C (36°F to 46°F).  
Reconstituted trastuzumab should be clear to slightly opalescent and colorless 
to pale yellow. 
3.8.2.     Preparation for Use  
Trastuzumab may be sensitive to shear-induced stress (e.g., agitation or rapid 
expulsion from a syringe).  DO NOT SHAKE.  Vigorous handling of solutions of 
trastuzumab results in aggregation of the protein and may create cloudy solutions.  A 
19-guage or larger needle should be used during drug admixture to avoid sheer-
induced stress.  Reconstitute each vial as follows, using aseptic technique: 
1. Using a sterile syringe, slowly inject 20 mL of BWFI into the vial directing the 
stream into the lyophilized cake.  The vacuum in the vial will automatically draw 
the water from the syringe into the vial; 
2. Swirl the vial gently to aid reconstitution.  DO NOT SHAKE.  The reconstituted 
solution contains 21 mg/mL trastuzumab and will be added to 250 mL of 0.9% 
sodium chloride injection, USP. 
            3.8.3  Known Potential Toxicities 
More Frequent Incidence (> 5%) 
Infusion-associated symptoms: Chills and/or fever, occasionally accompanied by 
rigors, occurred in approximately 40% of subjects during the first infusion of 
trastuzumab.  The symptoms were usually mild to moderate in severity and were 
treated with acetaminophen and diphenhydramine (with our without reduction in the 
rate of trastuzumb infusion).  Meperidine for rigors is effective.  Other signs and/or 
symptoms may include nausea, vomiting, pain, headache, dizziness, dyspnea, or rash.  
The symptoms occurred less frequently with subsequent infusions.  Rarely, infusion 
reactions have results in death.  
Trastuzumab administration can result in the development of ventricular dysfunction 
and CHF.  Left ventricular function should be evaluated in all subjects prior to and 
during treatment with trastuzumab.  Discontinuation of trastuzumab treatment should 

IRB # 05015 
38 
March 17, 2009 
Version 14 
be strongly considered in subjects who develop a clinically significant decrease in left 
ventricular function.  The incidence and severity of cardiac dysfunction appears to 
increase in subjects who receive trastuzumab in combination with anthracycline and 
cyclophosphamide (28% versus 7% when used as a single agent). 
The incidence of generalized pain, abdominal pain, and back pain appears to be more 
frequent in subjects receiving trastuzumab in combination with chemotherapy.  
Occasionally pain at tumor sites has been reported.   
The following have also been reported in >5% of subjects: diarrhea (25% of these), 
myalgia, peripheral edema, and weakness. 
Less Frequent Incidence (1 to 5%) 
Allergic/hypersensitivity reactions that have been reported include rash, pruritus, 
urticaria, and anaphylaxis (rarely resulting in death) or anaphylactoid signs and 
symptoms (erythematous rash on the chest and beck, dyspnea, bronchospasm, 
angioedema, acute respiratory distress syndrome (ARDS), hypotension, wheezing, 
pleural effusions, pulmonary infiltrates, noncardiogenic pulmonary edema, and 
pulmonary insufficiency and hypoxia requiring supplemental oxygen or ventilatory 
support). 
Rare Incidence (<1%) 
Rare toxicities include abnormal liver function test, hepatitis, bone pain, tumor-site 
pain, pancytopenia, hypotension, anorexia, febrile neutropenia, worsening of pre-
existing peripheral neuropathy, paresthesias, and thromboembolic disease. 
Pulmonary events that have been reported include pleural effusions, pulmonary 
infiltrates, and noncardiogenic pulmonary edema.  Pulmonary insufficiency and 
hypoxia requiring supplemental oxygen or ventilatory support, including ARDS, and 
death have occurred.  Most subjects with fatal events had significant, pre-existing 
pulmonary compromise secondary to intrinsic lung disease and/or malignant 
pulmonary involvement.  Because it appears that subjects with significant pre-
existing pulmonary compromise may be at greater risk, these subjects should be 
treated with extreme caution.  Subjects experiencing any of the severe infusion-
associated symptoms should have the trastuzumab infusion discontinued and 
appropriate medical therapy administered.  Subjects should be closely monitored until 
complete resolution of their symptoms.  In addition, subjects should be informed of 
the possibility of delayed severe reactions. 
3.8.4  Nursing Guidelines 
The most common AEs related to trastuzumab are fever (> 38°C), chills, and 
occasional rigors, most often infusion-related after the initial dose.  Treat with 
acetaminophen as necessary.  Meperidine may be needed for rigors.  Instruct the 
subject and family to report any fever >101°F.  Subjects with underlying pulmonary 
pathology should be closely monitored.  
Transient, localized tumor-side pain may be experienced within 8 hours of infusion.  
Advise the subject that acetaminophen is helpful. 

IRB # 05015 
39 
March 17, 2009 
Version 14 
Provide symptomatic management of the possible mild-to-moderate 
nausea/vomiting/diarrhea.  Assess heart and lung sounds.  Monitor vital signs (resting 
pulse, BP).  Be alert to early signs of cardiotoxicity, i.e., dyspnea, steady weight gain, 
nonproductive cough, arrhythmias, tachycardia, and pulmonary rales.  Trastuzumab 
may potentiate heart failure when administered in combination with doxorubicin.  
Advise subjects of possible fatigue, loss of strength, and weakness.  Have subjects 
pace activities with frequent rest periods. 
4.0 
STAGING CRITERIA 
DEFINITION OF TNM 
Primary Tumor (T) 
Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic 
classification.  If the measurement is made by the physical examination, the examiner will 
use the major headings (T1, T2, or T3).  If other measurements, such as mammographic or 
pathologic measurements, are used, the subsets of T1 can be used.  Tumors should be 
measured to the nearest 0.1-cm increment. 
Table 1.  TNM Staging System for Breast Cancer 
 
Changes in Breast Cancer staging, Sixth Edition of the American Joint Committee on Cancer Staging Manual 
 
Primary Tumor (T) 
 
• 
TX 
• 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
Ductal carcinoma in situ 
Tis (LCIS) 
Lobular carcinoma in situ 
Tis (Paget) 
Paget’s disease of the nipple with no tumor 
Note:  Paget’s disease associated with a tumor is classified according to the size of the tumor 
T1 
Tumor < 2 cm in greatest dimension 
T1mic 
Microinvasion 0.1 cm or less in greatest dimension 
T1a 
Tumor more than 0.1 cm but not more than 0.5 cm in greatest 
dimension 
T1b 
Tumor more than 0.5 cm but not more than 1 cm in greatest 
dimension 
T1c 
Tumor more than 1 cm but not more than 2 cm in greatest 
dimension 
T2 
Tumor >2 cm but not >5 cm in greatest dimension 
T3 
Tumor >5 cm in greatest dimension 
T4 
Tumor of any size with direct extension to (a) chest wall or (b) skin, 
only as described below 
T4a 
Extension to chest wall not including pectoralis muscle 
T4b 
Edema (including peau d’orange) or ulceration of the skin of the 
breast or satellite skin nodules confined to the same level 
• 
T4c 
Both T4a and T4b 
 

IRB # 05015 
40 
March 17, 2009 
Version 14 
• 
T4d 
Inflammatory carcinoma 
Regional Lymph Nodes Clinical (N) 
 
• 
NX 
Regional lymph nodes cannot be assessed (e.g., previously 
removed) 
N0 
No regional lymph node metastasis 
N1 
• 
Metastasis to movable ipsilateral axillary lymph node (s) 
N2 
Metastases in ipsilateral axillary lymph nodes fixed or matted, or in 
clinically apparenta ipsilateral internal mammary nodes in the 
absence of clinically evident axillary lymph node metastasis 
N2a 
Metastases in ipsilateral axillary lymph nodes fixed to one another 
(matted) or to other structures 
N2b 
Metastasis only in clinically apparenta ipsilateral internal mammary 
nodes and in the absence of clinically evident axillary lymph node 
metastasis. 
• 
N3 
Metastasis in ipsilateral infraclavicular lymph node (s) with or 
without axillary lymph node involvement, or in clinically apparenta 
ipsilateral internal mammary lymph node (s) and in the presence of 
clinically evident axillary lymph node metastasis; or metastasis in 
ipsilateral supraclavicular lymph node (s) with or without axillary or 
internal mammary lymph node involvement. 
N3a 
Metastasis in ipsilateral infraclavicular lymph node (s) 
N3b 
Metastasis in ipsilateral internal mammary lymph node (s) and 
axillary lymph node (s) 
N3c 
Metastasis in ipsilateral supraclavicular lymph node (s) 
Note: Isolated tumor cells are defined as single tumor cells or small cell clusters not greater than 0.2 mm, 
usually detected only by immunohistochemical (IHC) or molecular methods but which may be verified on 
hematoxylin and cosin stains.  Isolated tumor cells do not usually show evidence of malignant activity, e.g., 
proliferation or stromal reaction. 
aClinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical 
examination or grossly visible pathologically. 
Pathologic (PN)b 
 
• 
PNX 
Regional lymph nodes cannot be assessed (eg, previously 
removed or not removed for pathologic study) 
PN0 
No regional lymph node metastasis histologically, no additional 
examination for isolated tumor cells.  
PN0(i-) 
No regional lymph node metastasis histologically, negative IHC 
PN0(i+) 
No regional lymph node metastasis histologically, positive IHC, no 
IHC cluster >0.2 mm 
PN0(mol-)  
No regional lymph node metastasis histologically, negative 
molecular findings (RT-PCR)c 
• 
PN0(mol+) 
No regional lymph node metastasis histologically, positive 
molecular findings (RT-PCR)c 
PN1 
Metastasis in one to three axillary lymph nodes and/or in internal 
mammary nodes with microscopic disease detected by sentinel 
lymph node dissection but not clinically apparent 
PN1mi 
Micrometastasis (greater than 0.2 mm, none greater than 2.0 mm) 
PN1a 
Metastasis in one to three axillary lymph nodes 
PN1b 
Metastasis in internal mammary nodes with microscopic disease 
detected by sentinel lymph node dissection but not clinically 
apparent 
PN1c 
Metastasis in one to three axillary lymph nodes and in internal 
mammary lymph nodes with microscopic disease detected by 
sentinel lymph node dissection but not clinically apparent 

IRB # 05015 
41 
March 17, 2009 
Version 14 
PN2 
Metastasis in four to nine axillary lymph nodes, or in clinically 
apparent* internal mammary lymph nodes in the absence of 
axillary lymph node metastasis 
PN2a 
Metastasis in four to nine axillary lymph nodes (at least one tumor 
deposit >2.0 mm) 
PN2b 
Metastasis in clinically apparent* internal mammary lymph nodes 
in the absence of axillary lymph node metastasis 
PN3 
• 
Metastasis in 10 or more axillary lymph nodes, or in 
infraclavicular lymph nodes, or in clinically apparent ipsilateral 
internal mammary lymph nodes in the presence of one or more 
positive axillary lymph nodes; or in more than three axilliary 
lymph nodes with clinically negative microscopic metastasis in 
internal mammary lymph nodes; or in ipsitlateral 
supraclavicular lymph nodes. 
PN3a 
Metastasis in 10 or more axillary lymph nodes (at least one tumor 
deposit ≥2.0 mm), or metastasis to the infraclvicular lymph nodes 
PN3b 
Metastasis in clinically apparent ipsilateral internal mammary 
lymph nodes in the presence of one or more positive axillary lymph 
nodes; or in more than three auxiliary lymph nodes and in internal 
mammary lymph nodes with microscopic disease detected by 
sentinel lymph node dissection but not clinically apparent 
PN3c 
Metastasis in ipsilateral supraclavicular lymph nodes 
b Classification is based on axillary lymph node dissection with or without sentinel lymph node dissection.  
Classification or grossly visible pathologically lymph node dissection without subsequent axillary node 
dissection is designated “(sn)” for “sentinel node” [e.g., pN0 (I+)(sn)]. 
c RT-PCR, reverse transcriptase-polymerase chain reaction. 
 
Stage Grouping: 
Stage Grouping 
Tumor (T) 
Node (N) 
Metastasis (M) 
0 
Tis 
N0 
M0 
I 
T1a 
N0 
M0 
IIA 
T0 
N1 
M0 
 
T1a 
N1 
M0 
 
T2 
N0 
M0 
IIB 
T2 
N1 
M0 
 
T3 
N0 
M0 
IIIA 
T0 
N2 
M0 
 
T1a 
N2 
M0 
 
T2 
N2 
M0 
 
T3 
N1 
M0 
 
T3 
N2 
M0 
IIIB 
T4 
N0 
M0 
 
T4 
N1 
M0 
 
T4 
N2 
M0 
IIIC 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
Note: Stage designation may be changed if postsurgical imaging studies reveal the presence of 
distant metastases, provided that the studies are carried out within 4 mo of diagnosis in the absence 
of disease progression and provided that the patient has not received neoadjuvant therapy.  aT1 
includes T1mic  

IRB # 05015 
42 
March 17, 2009 
Version 14 
5.0 
PATIENT ELIGIBILITY 
Patients are eligible if they fulfill all of the listed criteria: 
 
5.1. 
Patients must have histologically proven stage I (limited to T1C N0 M0), II or III 
infiltrating ductal and lobular carcinoma; inflammatory breast cancer is allowed. 
5.2. 
Patients must not have received any anti-estrogen treatment for any indication other 
than breast cancer prevention (with tamoxifen, raloxifen, or an aromatase inhibitor), 
and/or could not have received such therapy for at least five years prior to enrollment 
into this study. 
5.3. 
Patients must have an ECOG performance status of < 2 or KPS of > 70. 
5.4. 
Patients must be ≥ 18 years old. 
5.5. 
Bilirubin ≤ the upper limit of normal (except for patients with Gilbert’s disease), 
instead of the current bilirubin < 1.5 mg/dl. 
5.6. 
Creatinine ≤ 1.2 mg/dl and calculated or measured creatinine clearance > 70 cc/min. 
5.7. 
Neutrophil count ≥ 1500/ul, platelet count ≥ 100,000/ul. 
5.8. 
Patients must have an ejection fraction ≥ 50% on MUGA scan. 
5.9. 
Pretreatment laboratory parameters must have been performed within 1 week and x-
ray parameters must have been performed within 4 weeks prior to the initiation of 
therapy 
5.10. 
All patients must have signed an informed consent document in accordance with 
institutional and federal guidelines. 
5.11. 
In regards to the exploratory barriers study, patients must have histologically proven 
stage III breast cancer who have experienced a 3 month or greater delay from initial 
symptoms/suspicion of possible breast disease as identified the principal investigator. 
Patients are ineligible if they fit any of the listed criteria: 
5.12. 
History of prior malignant disease, (except for squamous or basal cell skin carcinoma, and 
stage I or in situ cervical carcinoma) within the previous 5 years.  History of non-invasive ( 
in situ) breast carcinoma within the previous 5 years. 
5.13. 
History of any significant (and active) cardiovascular disease 
5.14. 
> Grade 1 neuropathy, pre-existing from any medical condition  
5.15. 
Any intercurrent/co-morbid medical or psychological condition, which, in the opinion 
of the principal investigator would interfere with safety and timely delivery of the 
assigned, planned treatment. 
5.16. 
Current pregnancy.  Patients are to utilize effective contraceptive methods (other then 
hormonal methods) while undergoing treatment on this study. 
03/22/06 
12/4/06 
12/4/06 
04/26/07 

IRB # 05015 
43 
March 17, 2009 
Version 14 
5.17. 
Patients with prior radiation to the chest wall or local regional areas (i.e., prior 
radiation for lymphoma, etc) are ineligible. 
5.18. 
Patients with a documented sensitivity to E. coli-derived products. 
 
6.0      DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION SCHEME 
6.1 
Patients will be stratified by stage and receptor status 
6.2 
Descriptive factors include HER-2 and ER/PR receptor status, grade, age, the number 
of axillary nodes involved with metastasis, and presence of vascular invasion. 
6.3 
Patients with HER-2 negative tumors will be randomized to TAC (Arm A) or ACAC 
arm (Arm B) by phone call to the Department of Biostatistics at the time of accession 
to the protocol.  Patients with HER-2 overexpressing tumors will be receiving ACAC 
and trastuzumab (Arm C).  Randomization for those with HER-2 negative disease 
will be by permuted blocks within strata. Patients who withdraw prior to treatment 
will be replaced at a randomly selected subsequent registration occasion.  The 
analysis will thus be on an as-treated basis. 
7.0 
TREATMENT PLAN 
7.1 
Patients with biopsy-proven, clinically/radiographically stage I (limited to T1C N0 
M0), II (including T2N0) and stage III breast carcinoma (as agreed upon by the 
primary breast surgeon, medical oncologist, and diagnostic radiologist) will be 
offered participation and asked to sign the IRB-approved, informed consent form.  
7.2 
All patients will undergo clip placement and core-biopsies of the primary site/s.  If a 
patient already underwent core biopsy and clip placement, and is otherwise 
eligible for study participation, repeat core biopsy and/or clip placement could be 
eliminated as per PI judgment.  If there is evidence of lymph node involvement by 
imaging, ultrasound-guided biopsy of such lymph node will be performed.  ER/PR 
receptor HER-2 status will be evaluated in addition to standard pathological 
assessment.  An attempt to procure 8-12 cores (as per COH practice) through a single 
biopsy entry site will be made in order to procure sufficient fresh frozen tissue (and if 
abundant tissue is procured embedded tissue) specimens.  HER-2 + is defined as 3+ 
by IHC, or amplified by FISH. 
7.3 
Once the primary diagnosis is established, and provided that ultrasound-guided 
lymph node biopsy is negative or could not be performed, sentinel node 
mapping/biopsy will be carried out to establish the presence or absence of lymph 
node metastasis. 
7.4 
Placement of a central venous device is recommended prior to initiating 
chemotherapy.   
7.5 
Patients with HER-2 negative disease will be randomized to undergo treatment with 
either 6 cycles of TAC (Arm A) or 4 cycles of AC given every 2 weeks, followed by 
3 weekly doses of carboplatin and Abraxane® and one week of no treatment, 
repeated for 3 treatment cycles (ACAC, Arm B).  Patients with HER-2 
12/4/06 
04/26/07 

IRB # 05015 
44 
March 17, 2009 
Version 14 
overexpressing tumors will also receive ACAC, but they will also receive 
trastuzumab during the carboplatin/Abraxane® phase of therapy. (Arm C). 
 
Arm A  
Agent  
 
Dose 
 
Route  
Schedule 
    
Doxorubicin 
 
50 mg/m2 
IVP         
Q 3 weeks x 6 
 
Cyclophosphamide 
500 mg/m2 
IV, 1 hour 
Q 3 weeks x 6 
 
Docetaxel 
 
75 mg/m2 
IV, 1 hour 
Q 3 weeks x 6 
 
Filgrastim 
 
300 ug  
sc 
 
days 2-10 
 
or pegfilgrastim 
6 mg 
 
sc 
 
day   2 
Arm B  
Agent  
 
Dose 
 
Route  
Schedule 
 
Doxorubicin 
 
60 mg/m2 
IVP         
Q 2 weeks x 4 
 
Cyclophosphamide 
600 mg/m2 
IV, 1 hour 
Q 2 weeks x 4 
 
Filgrastim 
 
300 ug  
sc 
 
days 2-10 
 
 
or pegfilgrastim 
6 mg 
 
sc 
 
day   2 
 
Carboplatin 
 
AUC 2  
IV, 1 hour 
weekly x 3, 1 week off 
 
 (Abraxane®)         100 mg/m2                 IV, 30 min 
weekly x 3, 1 week off 
 
Filgrastim 
 
300 ug  
sc 
 
weeks+ 2 & 3,  
 
 
 
 
 
 
 
days 9-12, 16-19 
 
 
 
 
 
 
 
 
 
 
Arm C  
Agent  
 
Dose 
 
Route  
Schedule 
 
Doxorubicin 
 
60 mg/m2 
IVP        
Q 2 weeks x 4 
 
Cyclophosphamide 
600 mg/m2 
IV, 1 hour 
Q 2 weeks x 4 
 
Filgrastim 
 
300 ug  
sc 
 
days 2-10  
 
 
or pegfilgrastim 
6 mg 
 
sc 
 
day  2 
 
 
Carboplatin 
 
AUC 2  
IV, 1 hour 
weekly x 3, 1 week off  
 
(Abraxane®)     
100 mg/m2  
IV, 30 min 
             weekly x 3, 1 
week off 
 
Filgrastim 
 
300 ug  
sc 
 
week+ 2 & 3, days 9-
12,  
 
 
 
 
 
 
16-19  
 
 
 
 
 
 
 
 
 
 
 
Trastuzumab  
2 mg/kg 
IV 
 
weekly   x 12 
(A loading dose of 4 mg/kg will be administered) 
Q 4 wks x 3 
Q 4 wks x 3 
03/19/08 
7/15/08 
7/15/08 

IRB # 05015 
45 
March 17, 2009 
Version 14 
 
+ Patients on Arms B and C will receive filgrastim on days 9-12, and 16-19 with each cycle, regardless whether the ANC dropped below < 
1000/μL.  However, should there be a delay of the second weekly dose of Abraxane and carboplatin at any given cycle, G-CSF then would be 
administered for all subsequent cycles inclusive of the first week of therapy on Days 2-5. 
 
7.6 
Patients on Arms B and C will receive filgrastim on days 9-12, and 16-19 with each 
cycle, regardless whether the ANC dropped below < 1000/μL.  However, should 
there be a delay of the second weekly dose of Abraxane and carboplatin at any given 
cycle, G-CSF then would be administered for all subsequent cycles inclusive of the 
first week of therapy on Days 2-5. 
7.7 
The use of erythropoietin growth factors is encouraged as per ASCO guidelines. 
7.8 
There will be no prophylactic administration of drugs to pre-empt cardiac, or 
neurotoxicity.  If needed, symptomatic management of neuropathy, myalgias, or 
arthralgias are recommended as per the discretion of the treating physician, who is 
allowed to appropriate pain medications, anti-inflammatory agents, antidepressants, 
nutritional supplements, with mandatory careful documentation of the prescribed 
agents. 
7.9 
Actual body weight will be used for patients whose weight is ≤ 30% above ideal.  For 
all others, the weight used to calculate the dose will be topped off at 30% above their 
ideal body weight.  To further clarify, this same rule will be applied when calculating 
the dose of carboplatin.  Carboplatin AUC-2 will be calculated using the Calvert 
formula; however, the serum creatinine will be capped at no lower than 0 .7 mg/dl: 
patients with a serum creatinine of ≤ 0.7 mg/dl will have their  dose calculated based 
on a creatinine value of 0.7 mg/dl, while patients with a serum creatinine of > 0.7 
mg/dl will have their dose calculated based on the actual measured value.   
7.10 
Ideal body weight formula will be used as follows: 50 kg + 2.3 times the number of 
inches over 5 ft. for males and 45.5 + 2.3 times the number of inches of 5 ft for 
females.  
However, the dose of trastuzumab will be calculated based on actual body weight, 
since this was the methods used in the pivotal randomized trials by NSABP and the 
Intergroup. 
7.11 
Definitive surgical intervention (breast preservation or mastectomy) will be carried 
out preferably within 4 weeks after the last dose of chemotherapy.  Patients with 
documented axillary nodal involvement (as documented earlier by ultrasound-guided, 
or mapping/sentinel node procedure) will undergo axillary node dissection.  Those 
with negative sentinel node biopsy (negative, or with < 2 mm focal involvement 
either by H&E or by immunohistochemistry prior to neoadjuvant treatment) will not 
undergo formal axillary node dissection. 
7.12 
Following definitive surgery, patients are recommended to undergo local regional 
radiation therapy as per standard radiation therapy guidelines.   Sites of relapse and 
relapse-free and overall survival will be documented during the follow-up period. 
7.13 
Patients with ER/PR receptor positive tumors are advised to receive adjuvant anti-
estrogen therapy according to standard guidelines.  
03/19/08 
7/15/08 
7/15/08 
08/11/08 

IRB # 05015 
46 
March 17, 2009 
Version 14 
7.14 
In addition to all patients participating in the Quality of Life study (see schedule of 
interviews in the Study Calendar Section) 20 patients each randomized to receive 
treatment either on Arm A (TAC), or B or C (ACAC) will be offered a more detailed 
assessment of neurotoxicity (See study calendar). 
7.15 
Exploratory analysis of “Barriers to treatment”. Among the patients with stage III 
breast cancer who have experienced a 3-month or greater delay in treatment, patients 
will be offered participation in qualitative interviews. A subgroup of up to 20 patients 
will be selected.  Patients will be interviewed to explore the issues involved in the 
barriers and delay in seeking diagnosis once symptoms appear. Drs. Betty Ferrell and 
Marcia Grant who are experts in qualitative interviews will conduct the tape-recorded 
interviews.  An interview guide will be used as provided in appendix C.  
8.0 
TOXICITIES MONITORED AND DOSAGE MODIFICATIONS 
8.1 
Toxicities and potential complications 
8.1.1 
The side effects associated with the use of the individual drugs are listed 
under section 3.0.  There will be no dose modifications for trastuzumab, 
cyclophosphamide or doxorubicin. 
8.1.2 
Trastuzumab: 
8.1.2.1 Infusion-associated symptoms: 
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.  Treat fever and chills as follows: 
• 
Fever  
• 
Treatment 
Grade 1 (38°C - 39°C) 
Grade 2 (39.1°C - 40°C) 
• 
Stop infusion and give antipyretics.  
Once temperature is < 38°C, resume 
infusion at slower rate. 
• 
Grade 3/4 (>40°C 
for < 24 hours/> 24 
hours) 
• 
Grade 4 (> 40°C 
for > 24 hours) 
 
• 
Stop infusion immediately. 
• 
Give antipyretics. 
• 
Monitor patient for minimum of 1 hour 
• 
If temp drops to < 38°C within 3 hours, 
resume infusion at a slower rate 
• 
If fever does not resolve within 3 hours, 
inpatient monitoring is strongly 
recommended. 
• 
Subsequent administration is at the 
investigator’s discretion. 
 
03/22/06 
03/22/06 
03/19/08 

IRB # 05015 
47 
March 17, 2009 
Version 14 
Chills can be treated with acetaminophen and/or diphenhydramine 
hydrochloride.  Meperidine may be used at the investigator’s 
discretion.  
8.1.2.2 Cardiac dysfunction and trastuzumab: 
• 
During treatment, MUGA scan/echocardiogram will be performed at the discretion of the treating physician 
based on symptoms of congestive heart failure (CHF).  The same procedure (MUGA scan/echocardiogram) must 
be used as was used prestudy (if done at prestudy). 
• 
Trastuzumab therapy will be held if the patient develops signs and symptoms of CHF (i.e., dyspnea, tachycardia, 
cough, neck vein distention, cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral 
edema, etc.) 
• 
Trastuzumab therapy will be discontinued permanently if the ejection fractions fall below institutional lower 
limits of normal at any time during treatment. 
• 
If trastuzumab therapy is discontinued, patient may continue treatment with ACAC, at the discretion of the 
treating physician. 
 
8.1.3 
Dose Modification for Docetaxel: 
8.1.3.1 Neutropenia: 
If ANC on day of chemotherapy is: 
> 1,000/mm3 
 
Proceed with treatment as planned. 
< 1,000/mm3 
Delay docetaxel treatment, continue G-CSF (if 
patient was initially given Neulesta, delay 
chemotherapy until recovery, and prescribe 
filgrastim for subsequent cycles), and recheck 
counts every 2-3 days per MD’s discretion. 
IF MORE THAN ONE WEEK DELAY: 
ANC > 1000/mm3 
Treat with 25% dose reduction for docetaxel 
(for this and all subsequent cycles). 
ANC < 1000/mm3 
Continue G-CSF and recheck counts in one 
additional week. 
AFTER TWO WEEK DELAY: 
ANC > 1000/mm3 
Treat with 25% dose reduction for docetaxel 
(for this and all subsequent cycles). 
ANC < 1000/mm3 
Remove patient from protocol treatment.  
8.1.3.2 Neutropenic fever: 
If at any time, the patient experiences neutropenic fever (fever > 
101.5°F [38.5°C] with ANC < 1,000/mm3), dose reduce docetaxel by 
25% for this and all subsequent cycles. 

IRB # 05015 
48 
March 17, 2009 
Version 14 
8.1.3.3 Thrombocytopenia: 
If platelet count on day of chemotherapy is: 
> 100,000/mm3 
Begin treatment as planned 
< 100,000/mm3 
Delay start of cycle and recheck counts every   
2-3 days.   
AFTER ONE WEEK DELAY:   
Platelets > 100,000/mm3 
Treat with 25% dose reduction for 
docetaxel (for this and subsequent 
cycles). 
Platelets < 100,000/mm3 
Recheck counts every 2-3 days. 
AFTER TWO WEEK DELAY: 
Platelets > 100,000/mm3 
Treat with 25% dose reduction for 
docetaxel. 
Platelets < 100,000/mm3 
Remove patient from protocol 
treatment. 
If during any part of a treatment cycle the patient has a platelet count 
of < 10,000/mm3 or requires a platelet transfusion, then the dose of 
docetaxel will be reduced 25% for this and all subsequent cycles. 
Dose modifications for abnormal liver function: 
Docetaxel treatment must be held for abnormal bilirubin; treatment 
may not be given until bilirubin returns to normal.  Dose adjustments 
for docetaxel are as follows: 
 
 
Bilirubin 
Alkaline 
phosphatase 
SGOT 
Action 
> ULN       or      > 5 x ULN     or  > 5 x ULN 
Wait < 3 weeks.  If 
recovered*, reduce 
docetaxel dose by 
25% for this and 
subsequent cycles. 
< ULN  and  < 5 x ULN  and  1.6 x to ≤ 5 x ULN 
                                                       
 
Reduce docetaxel 
dose 25% for this and 
subsequent cycles. 
12/4/06 

IRB # 05015 
49 
March 17, 2009 
Version 14 
 
 
 
        * - Bilirubin < ULN and alkaline phosphatase <5 x ULN and SGOT < 5 x ULN. 
If docetaxel is held for greater than three weeks, no further docetaxel 
treatment will be given.  While docetaxel is held, both 
cyclophosphamide and doxorubicin will be held. 
AFTER ONE WEEK DELAY:   
Platelets > 100,000/mm3 
Treat with 25% dose reduction for 
docetaxel (for this and subsequent 
cycles). 
Platelets < 100,000/mm3 
Recheck counts every 2-3 days. 
AFTER TWO WEEK DELAY: 
Platelets > 100,000/mm3 
Treat with 25% dose reduction for 
docetaxel. 
Platelets < 100,000/mm3 
Remove patient from protocol 
treatment. 
If during any part of a treatment cycle the patient has a platelet count 
of < 10,000/mm3 or requires a platelet transfusion, then the dose of 
docetaxel will be reduced 25% for this and all subsequent cycles. 
8.1.3.4 Neuropathy (motor or sensory): 
If Grade < 2, proceed with full dose of drug(s) scheduled for that day. 
If Grade > 3, delay treatment with docetaxel until recovery to Grade 
< 2. 
If delay of > 3 weeks is required, remove patient from protocol 
treatment.  
8.1.3.5 Stomatitis: 
If Grade 1, proceed with full dose of drugs scheduled for that day. 
If Grade >2, hold scheduled chemotherapy (docetaxel and 
doxorubicin and cyclophphosphamide) until recovery to Grade < 1 
is documented. 
If delay of > 3 weeks is required, remove patient from protocol 
treatment. 
8.1.3.6 Docetaxel Hypersensitivity Reactions: 
Docetaxel premedications consit of dexamethason 8 mg orally, 
BID, given prior to, on the day, and after administration of 
chemotherapy.  The dose can be adjusted if docetaxel is tolerated, 

IRB # 05015 
50 
March 17, 2009 
Version 14 
to 4 mg BID prior to, on the day, and the day after chemotherapy.  
Docetaxel treatment shall be discontinued for Grade 4 docetaxel 
hypersensitivity reactions.  There are no docetaxel dose reductions 
for hypersensitivity reactions.  
 
Hypersensitivity 
Treatment Guidelines 
Grade 1 
• 
Consider decreasing the rate of infusion until 
recovery from symptoms; closely monitor patient. 
• 
Resume docetaxel infusion at the planned initial 
rate after symptoms resolve on that day of 
treatment. 
Grade 2 
• 
Interrupt docetaxel infusion immediately. 
• 
Give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor patient until 
symptoms resolve. 
• 
Resume docetaxel infusion after recovery of 
symptoms; depending on the physician’s 
assessment of the patient, infusion should be 
resumed at a slower rate, then increased 
incrementally to the initial planned rate. 
• 
Depending on the intensity of the reaction 
observed, additional oral or IV premedication with 
an antihistamine should also be given for the next 
cycle of treatment, and the rate of infusion should 
be decreased initially and then increased back to 
the recommended 1-hour. 
Grade 3 
• 
Immediately discontinue docetaxel infusion. 
• 
Give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV and/or epinephrine as 
needed; monitor patient until resolution of 
symptoms. 
• 
Resume docetaxel infusion after recovery of 
symptoms on that day of treatment; depending on 
the physician’s assessment of the patient, infusion 
should be resumed at a slower rate, then increased 
incrementally to the initial planned rate. 
• 
Depending on the intensity of the reaction 
observed, additional oral or IV premedication with 
an antihistamine should also be given for the next 
cycle of treatment, and the rate of infusion should 
be decreased initially and then increased back to 
the recommended 1-hour. 
Grade 4 
• 
NO FURTHER DOCETAXEL THERAPY. 
 
8.1.3.7 Fluid retention due to docetaxel: 
Treatment of Fluid Retention 

IRB # 05015 
51 
March 17, 2009 
Version 14 
No dose reduction for fluid retention is planned.  Patients developing 
new onset of symptomatic edema, or other signs of increasing fluid 
retention, are to be treated with oral diuretics.  Regimens that were 
found to be effective in the management of fluid retention due to 
docetaxel are listed below: 
• 
Hydrochlorothiazide 25mg po qd up to tid. Potassium supplementation 
should be given as needed. 
• 
Furosemide 40 mg po qd if edema is not responsive to 
hydrochlorothiazide.  Potassium supplementation should be given as 
needed. 
• 
If this regimen is ineffective after a two week trial, the patient may be 
treated with furosemide 20 mg po qd plus metolazone 2.5 mg po qd 
with potassium supplementation as needed. 
 
Further therapy should be customized depending upon the clinical 
situation. 
 
8.1.4 
Dose Modifications for Carboplatin and Abraxane® 
8.1.4.1 General Considerations 
a. A repeat course of therapy may only be given when granulocytes > 
1,000/µl and platelets > 100,000/µl.  If treatment start is delayed more 
than three weeks for any toxicity, patient should be removed from 
protocol treatment.   
b. Doses which have been reduced for toxicity will not be re-escalated. 
c. Treatment may be delayed no more than 3 weeks. 
d. If Grade 3 or 4 myelosuppression is experienced at the -2 dose level and 
does not recover in 2 weeks, remove the patient from protocol treatment. 
e. If any toxicity occurs that requires dose reduction and the patient is 
already receiving the -2 dose level, the patient should be removed from 
protocol treatment. 
8.1.4.2 Dose Levels 
LEVEL 
DRUG 
Starting dose 
Carboplatin AUC = 2, Day1 
-1 
Carboplatin AUC = 1.5, Day 1 
-2 
Carboplatin AUC = 1, Day 1 
 
Carboplatin AUC-2 will be calculated using the Calvert formula; 
however, the serum creatinine will be capped at no lower than 0 .7 
mg/dl: patients with a serum creatinine of ≤ 0.7 mg/dl will have their 
8/11/08 

IRB # 05015 
52 
March 17, 2009 
Version 14 
dose calculated based on a creatinine value of 0.7 mg/dl, while 
patients with a serum creatinine of > 0.7 mg/dl will have their dose 
calculated based on the actual measured value.  Dose adjustments are 
to be made according to the system showing the greatest degree of 
toxicity (see Section 8.1 for information on the NCI-CTCAE). 
8.1.4.3 Dose modification for hematologic toxicity will be based on blood 
counts obtained in preparation for the first day of new cycle of 
chemotherapy.  A repeat course of therapy will only be given when 
granulocytes > 1,000/µL and platelets > 100,000/µL.  If Day 1 is 
delayed less than 1 week, (CBC to be checked every 2-3 days) due to 
a granulocyte count of < 1,000/µL, the patient should receive the 
same chemotherapy dose that she received during the previous course, 
and start G-CSF.  If the second or third weekly dose of the cycle is 
delayed between 1-2 weeks while the patient is already receiving  G-
CSF, or the patient experiences febrile neutropenia, the doses of both 
Abraxane® and carboplatin should be reduced one level. A dose 
delay of between 1-2 weeks of any cycle or weekly doses within any 
cycle due to platelets < 100,000/µL will necessitate a reduction of 
carboplatin by one dose level.  No more than 3 weeks of delay will be 
allowed, following a second reduction of carboplatin.  Once platelets 
recover, patients can continue with Abraxane.  Weekly doses of 
carboplatin and nab-paclitaxel will be allowed to be replaced as long 
as the delay is < 14 days.  Following a second reduction of 
carboplatin, or need to stop carboplatin due to thrombocytopenia, 
patients could continue with Abraxane.  Should there be a need of 
more than 2 dose reductions of Abraxane, the patient will be taken off 
study.   
8.1.4.3.1 
Neulesta dose will be reduced to 3 mg given 
subcutaneously, if significant (grade 2 or greater 
musculoskeletal toxicity is experienced by the patient. 
8.1.4.4 Adjustments for Renal Toxicity 
Calculated Creatinine Clearance 
Dose Level 
Clcr < 25 ml/minute 
 
Delay chemotherapy by a minimum of 
one week until Clcr > 25 ml/minute then 
reduce carboplatin dose one level. 
Abraxane® will be administered on 
schedule, while carboplatin is on hold 
Clcr > 25 ml/minute 
No chemotherapy delay or dose 
reduction required. 
 
 
8.1.4.5 Adjustments for Hepatic Toxicity (for carboplatin and Abraxane®)  
3/22/06 
3/22/06 
7/15/08

IRB # 05015 
53 
March 17, 2009 
Version 14 
a.Bilirubin 
Total Bilirubin 
Dose Level 
< institutional upper 
limit of normal 
No delay or dose reduction required 
> 2 - < 3 x institutional 
upper limit of normal 
Delay chemotherapy until bilirubin < the 
institutional upper limit of normal, then reduce 
dose one level. 
> 3 x institutional 
upper limit of normal 
Delay chemotherapy until bilirubin < the 
institutional upper limit of normal then reduce 
dose two levels. 
 
SGOT or Alkaline Phosphatase 
SGOT or Alkaline Phosphatase 
Dose Level 
< 2 x institutional upper limit of 
normal 
No delay or dose reduction required 
> 2 - < 5 x institutional upper limit 
of normal 
Delay in of both carboplatin and Abraxane® 
chemotherapy until enzymes < 2 x 
institutional upper limit or normal then 
administer same dose as previous course. 
> 5 - < 20 x institutional upper 
limit of normal 
Delay chemotherapy until enzymes < 2 x 
institutional upper limit of normal, then 
reduce dose one level 
> 20 x institutional upper limit of 
normal 
Delay chemotherapy until enzymes < 2 x 
institutional upper limit of normal, then 
reduce dose two levels. 
 
8.1.4.6 Adjustments for Neuropathy-sensory 
 
Degree of Numbness/other 
peripheral neuropathy 
Dose Level 
Grade 2 
Delay chemotherapy until peripheral 
neuropathy resolves to < grade 2, then 
administer at the next lower dose level. 
Grade 3 and Grade 4 
Delay chemotherapy until peripheral 
neuropathy resolves to < grade 2, then 
reduce Abraxane® dose one level, and 
carboplatin 2 dose levels. 
Grade 4 
Delay chemotherapy until peripheral 
neuropathy resolves to grade 2, then reduce 
Abraxane ™ and carboplatin by 2 dose 
levels. 
03/22/06 

IRB # 05015 
54 
March 17, 2009 
Version 14 
 
8.1.4.7 Other Toxicities Not Listed Above 
Hypersensitivity reactions are rare. If they do occur, minor symptoms 
such as flushing, skin reactions, dyspnea, hypotension, or tachycardia 
may require temporary interruption of the infusion.  However, severe 
reactions, such as hypotension requiring treatment, dyspnea requiring 
bronchodilators, angioedema or generalized urticaria require 
immediate discontinuation of study drug administration and 
aggressive symptomatic therapy.  Patients who develop severe 
hypersensitivity reactions to carboplatin and/or Abraxane® may be 
re-challenged following premedication that the institution would 
typically use for intravenous paclitaxel (intravenous steroid, 
antihistamines, and with using a slower infusion rate for carboplatin).  
If severe hypersensitivity reaction to Abraxane is seen do not re-
challenge. 
For all other toxicities excluding Grade 3 hyperglycemia, anemia, 
SGPT elevation, 4 nausea and vomiting (which will be management 
symptomatically), reduce drug according to the following.  If any 
toxicity occurs that required a dose reduction and the patient is 
already receiving the -2 Dose Level, the patient should be removed 
from protocol treatment. 
 
Grade 1-2 
Delay chemotherapy until resolution of toxicity to 
Grade 0, then administer same dose level as 
previous course. 
Grade 3 
Contact Study Coordinator and delay chemotherapy 
until resolution of toxicity to Grade 0, then reduce 
dose one level. 
Grade 4 
Contact Study Coordinator and delay chemotherapy 
until resolution of toxicity to Grade 0, then reduce 
dose two levels. 
 
8.1.5. Dose adjustment for Abraxane® (ABI-007).  
Abraxane® should be withheld in patients who experience ≥ Grade 2 peripheral 
neuropathy.  Treatment may be resumed at the next lower dose level (see Table 2) after 
the peripheral neuropathy improves to ≤ Grade 1. The time to resolution to Grade ≤ 1 
should be the adverse event duration used for adverse event reporting.  In those patients 
who experience Grade 4 peripheral neuropathy, study drug should be withheld, and 
treatment resumed at a reduction of 2 dose levels (Dose Level -2; see Table 2) in 
subsequent cycles after the peripheral neuropathy improves to ≤ Grade 1.  
Table 2. 
 
3/22/06 
03/19/08 

IRB # 05015 
55 
March 17, 2009 
Version 14 
 
Dose Level
Abraxane® 
(mg/m2) 
0 
100 
-1 
80 
-2 
65 
 
 
 
Table 3.:  Use of G-CSF and Dose reductions for Hematologic Toxicity 
Adverse Event 
Occurrence 
Action to be Taken 
ANC < 500 cells/mm3 (nadir 
count) with neutropenic 
fever > 38° 
OR 
Delay of next cycle due to 
persistent neutropenia 
(ANC < 1000 cells/mm3) 
 
 
Any Occurrence 
At the first occurrence of a hematological 
toxicity (as outlined in the Adverse Event 
column), the same dose is maintained and 
G-CSF is given as outlined below.  In the 
event that a hematological toxicity re-
occurs in the face of G-CSF, dose 
reduction to the next lower level will be 
required for subsequent cycles once ANC 
is ≥ 1,000 cells/mm3.  
 
 
1st Occurrence 
Dose reduction to next lower level 
Thrombocytopenia Grade 3 
or Grade 4* 
Recurrence 
Dose reduction to next lower level 
*See NCI CTCAE Version 3.0 for definition of Grade 3 and Grade 4 events. 
Hypersensitivity Reactions  
Hypersensitivity reactions are rare. If they do occur, minor symptoms such as flushing, skin 
reactions, dyspnea, hypotension, or tachycardia may require temporary interruption of the 
infusion.  However, severe reactions, such as hypotension requiring treatment, dyspnea 
requiring bronchodilators, angioedema or generalized urticaria require immediate 
discontinuation of study drug administration and aggressive symptomatic therapy.  Patients who 
experience a severe hypersensitivity reactions to Abraxane should not be re-challenged. 
 
Adjustments for Cardiac Toxicity 
Clinical Signs 
Action Required 
Cardiac arrhythmia with evidence 
of AV nodal block (e.g., Mobitz 
type 1 or 2 or total heart block). 
Discontinue chemotherapy and contact 
Study Coordinator. 
Asymptomatic bradycardia 
No delay or dose reduction required. 
 
 

IRB # 05015 
56 
March 17, 2009 
Version 14 
Other Toxicities 
If toxicities are ≤ grade 2, manage symptomatically if possible, and retreat without dose 
reduction. 
 
If toxicities are ≥ grade 3, except for anemia, treatment should be withheld until resolution to ≤ 
grade 1 or baseline if baseline was greater than grade 1, then reinstituted, if medically 
appropriate, at the next lower dose level. 
 
8.1.6 
Up to two weeks of delay of any given dose of therapy is allowed once, and 
up to one week of dose delay of any given dose of therapy is allowed twice, 
in order to allow recovery to acceptable functional/toxicity grade level as per 
the list under eligibility criteria, before a patient is taken off study. 
8.1.7 
For patients randomized to receive treatment on Arm A filgrastim 300 μg 
between days 2-10, or pegfilgrastim 6 mg on day 2 will be given 
subcutaneously after each cycle.  Filgrastim can be held if the ANC is on the 
rise from the nadir and is > 1000μ/L for 3 consecutive days. 
8.1.8 
Patients on Arms B and C are will receive filgrastim on days 9-12, and 16-19 
with each cycle, regardless whether the ANC dropped below < 1000/μL.  
However, should there be a delay of the second weekly dose of Abraxane and 
carboplatin at any given cycle, G-CSF then would be administered for all 
subsequent cycles inclusive of the first week of therapy on Days 2-5.   
8.2 
The study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0, publish date December 12th, 2003 for toxicity and Adverse 
Event Reporting.  A copy of the CTCAE version 3.0 is given in Appendix B.  
Additionally, a copy of the CTCAE version 3.0 can also be downloaded from the 
CTEP home page http://ctep.cancer.gov/reporting/ctc.html 
 
 
 
8.3 
DATA AND SAFETY MONITORING 
 
 
 
8.3.1 Definition of Risk Level 
This is a Risk Level 3 study, as defined in the “Guidance, Policy and Procedures 
for Data and Safety Monitoring for In-House Trials at City of Hope”, 
http://www.infosci.coh.org/gcrc/doc/dsmp.doc because it is a Phase II clinical 
trial where the risks are at least balanced by the potential benefit to subjects and 
the importance of the knowledge that may result. 
 
8.3.2. Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, at least two Collaborating 
Investigators, CRA, protocol nurse, and statistician is responsible for monitoring the data 
and safety of this study, including implementation of any stopping rules for safety and 
efficacy.  
 
3/22/06 
3/19/08 
3/19/08 
3/19/08 
7/15/08 

IRB # 05015 
57 
March 17, 2009 
Version 14 
Reporting of data to the DSMB will occur at intervals separated by no more than six 
months, groups of 17 patients treated, or after a treatment related death.  This report (the 
PMT report) will include a summary of accrual, adverse events and treatment related 
mortality.  This report is in addition to reports as specified in section 8.4 
8.3.3 Adverse Events 
 
Reporting: Adverse events must be reported to the COH DSMB, IRB, and 
GCRC (if GCRC supported) according to definitions and guidelines described in 
section 8.4.  SAEs will be monitored by the PMT.  Less then serious adverse 
events will be reported only at the time of protocol continuation reports.  
 
 
8.4 
ADVERSE EVENT MANAGEMENT GUIDELINES 
 
8.4.1  Background 
 
These adverse event management guidelines are intended to ensure the safety 
of each patient while attempting to characterize the safety and tolerability of 
the test products. In agreeing to the provisions of this protocol, the 
investigator accepts all legal responsibilities for prompt notification of SAEs. 
The PI must submit the original and one copy of the report to the DSMB, 
American Biosciences (see below for address) and the IRB office.   
 
All STEAEs (Serious Treatment Emergent Adverse Events) should be 
recorded on a MedWatch 3500 Form and submitted to the FDA as soon as 
possible. A copy of this MedWatch 3500 Form should be faxed within 24 
hours to: 
 
 
1) Abraxis BioScience, LLC  
     Drug Safety and Surveillance Department 
     4505 Emperor Blvd, Suite 400 
Durham, NC  27703 
Ph: 919-433-8515 (8am-5pm EST, normal business days and hours) 
Ph: 919-606-1832 (24hr hotline) 
Fax: 919-433-8402 
E-mail: SAE-REPORTING@abraxisbio.com  
 
 
 
and 
 
Abraxis BioScience, LLC.  
200 Somerset Corporate Blvd – Suite 8000 
Bridgewater, NJ  08807 
Office: 908-393-8248 
Fax: 908-393-8304 
Cell: 267-337-2720 
E-mail: AbraxisMedAffairs@abraxisbio.com 
 
3/22/06 
03/22/06 
03/22/06 

IRB # 05015 
58 
March 17, 2009 
Version 14 
For more detailed guidelines please access the following web site: 
http://www.cityofhope.org/resed/irb/hsguideline.htm. The PI/COH IRB in 
turn will be responsible for reporting the SAEs to the appropriate regulatory 
authorities, including the FDA. 
 
Adverse events occurring during the study will be graded according to the 
NCI Common Toxicity Criteria Scale CTCAE version 3.0, where applicable. 
Adverse events that are not included on the toxicity scale will be designated 
as Grade 1 = mild, Grade 2 =moderate, Grade 3 = severe, Grade 4 = life-
threatening, and Grade 5 = death. The investigator should evaluate all adverse 
events and should make an immediate effort to determine their etiology. 
Adverse events that are determined not to be possibly, probably, or definitely 
related to study drug may not require further evaluation but will need to be 
recorded on the CRFs. Study medications may be interrupted for an adverse 
event at the discretion of the investigator. Patients requiring toxicity 
management should be assessed and evaluated at least weekly as indicated by 
the severity of the event. 
 
 
8.4.2  Definition of an Adverse Event (AE) 
 
An adverse event is any untoward medical occurrence in a patient receiving a 
marketed pharmaceutical product or in a patient who is participating on a 
clinical trial who is receiving an investigational or non-investigational 
pharmaceutical agent. The AE does not necessarily have a causal relationship 
with the patient’s treatment. Therefore, an adverse event can be any 
unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered to be related to 
the medicinal product. In cancer clinical trials, many AEs are in fact related to 
progression of the patient’s underlying malignancy. 
 
An adverse event includes: 
• an exacerbation of a pre-existing illness; 
• an increase in frequency or intensity of a pre-existing episodic event or 
condition; 
• a condition detected or diagnosed after study drug administration even 
though it may have been present prior to the start of the study; 
• continuously persistent disease or symptoms that were present at Baseline 
and worsen following the start of the study. 
 
An adverse event does not include: 
• medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, or 
transfusion); however, the condition that leads to the procedure is an adverse 
event.  
• pre-existing diseases, conditions, or laboratory abnormalities present or 
detected at the start of the study that do not worsen; 
• hospitalizations or procedures that are done for elective purposes not related 
to an untoward medical occurrence (eg, hospitalizations for cosmetic or 
elective surgery or social/convenience admissions); 

IRB # 05015 
59 
March 17, 2009 
Version 14 
• the disease being studied or signs/symptoms associated with the disease 
unless more severe than expected for the patient's condition; 
• overdose of study drug without any clinical signs or symptoms. 
 
8.4.3  Definition of a Serious Adverse Event (SAE) 
 
Definition 
A serious adverse event as defined by ICH is any adverse experience that 
at any dose meets any of the following conditions: 
 
• 
results in death 
• 
is life-threatening (The patient was at risk of death at the time of the event. It 
does not refer to an event which hypothetically might have caused death if it 
were more severe) 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity, or 
• 
is a congenital anomaly/birth defect 
 
Note: Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations; for example, important 
medical events may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the outcomes listed in the definition above. Any adverse event is 
considered a serious adverse event if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. 
Hospitalizations that do not meet this criteria are: 
 
• 
reasons described in the protocol, e.g., drug administration, protocol-required 
testing 
• 
social reason in the absence of an AE 
• surgery or procedure planned prior to entry into the trial 
 
"Serious" Versus "Severe" Adverse Events 
There will be an acknowledged distinction between serious and severe 
AEs.  Assessment of seriousness will be made solely by the serious 
criteria listed above.  Severity of AEs will be graded according to the NCI 
Common Terminology Criteria for Adverse Events v3.0. Therefore, 
serious events will not be automatically considered severe.  For example, a 
stroke that results in only a limited degree of disability may be considered 
a mild (not severe) stroke, but it would still meet serious criteria and thus, 
be captured as an SAE.  Similarly, severe events may not always be 
serious.  An example would be an episode of severe, transient nausea 
which persists for several hours. This would be classified as a "severe" 
episode of nausea, but if it did not require treatment, intervention, or 
somehow meet other serious criteria, it would not be considered an SAE. 
 
Nonserious Adverse Events 
Any adverse event that is not an SAE is, by default, a non-serious AE.  

IRB # 05015 
60 
March 17, 2009 
Version 14 
8.4.3.1 Adverse Events Emerging Subsequent to Study Cessation 
For 30 days subsequent to study completion or withdrawal, new 
onset adverse events will be captured.  Follow up of these events 
will follow the same procedure as described above for AEs 
observed during the study period. 
 
8.4.4  Time Frame for considering an event to be a reportable AE or SAE 
 
The investigator is responsible for recording, reporting and following all 
adverse events, regardless of causality, observed during the study period, 
starting with the registration of the patient and ending at the time the patient 
goes off study or 30 days after patient’s last dose of study drug, whichever is 
later. The investigator should follow adverse events until they are resolved or 
stabilized, the patient is lost to follow-up, or the event is otherwise explained. 
Events occurring within 30 days prior to study drug administration should be 
recorded as pre-treatment signs and symptoms. 
 
8.4.5 
 Lack of Efficacy is not considered an AE or SAE 
 
“Lack of efficacy” (progressive disease) is not considered an adverse event. 
The signs and symptoms or clinical sequelae resulting from lack of efficacy 
should be reported if they fulfill the adverse event or SAE definitions. 
 
8.4.6 
 Patient Reporting of AEs and SAEs 
 
Patients are to be encouraged to call the site to report any unexpected 
symptoms or problems they encounter between office visits. These events 
should be considered in the same fashion as if they had been reported at a 
scheduled office visit. At each scheduled office visit, after the patient has had 
an opportunity to spontaneously mention any problems, the investigator 
should inquire about adverse events by asking the following standard 
questions: 
• Have you had any (other) medical problems since your last clinic visit? 
• Have you taken any new prescribed or over-the-counter medicines or 
herbal/vitamin preparations, other than those given to you in this study, since 
your last visit/assessment? 
• Have any new procedures been performed since your last study visit? 
 
8.4.7  Investigator Reporting of AEs and SAEs 
 
The investigator or designee must completely and promptly record each 
adverse event in the source documentation and in the appropriate CRF, 
regardless of relationship to study drug as determined by the investigator. The 
Principal Investigator must assess AE/SAE causality for any patients treated 
at his/her site and for any patients treated under the direct care of his/her sub-
investigators. The investigator should attempt, if possible, to establish a 
diagnosis based on the patient's signs and symptoms. When a diagnosis for 
the reported signs or symptoms is known, the investigator should report the 
diagnosis, not the symptoms, as the adverse event. 

IRB # 05015 
61 
March 17, 2009 
Version 14 
 
Clinically significant laboratory abnormalities present at the Baseline visit 
will be recorded as pre-treatment signs and symptoms. After study treatment 
administration, Grade 1 and Grade 2 laboratory abnormalities will not be 
recorded as adverse events unless considered clinically significant by the 
investigator. All Grade 3 and Grade 4 laboratory abnormalities will be 
recorded as adverse events. Grade 4 laboratory abnormalities will be reported 
as serious except in those cases when the abnormality is associated with a 
SAE that has already been reported. The investigator must follow all SAEs 
observed during the study, until these events have resolved or stabilized, the 
patient is lost to follow-up, or the events are otherwise explained. 
 
8.4.7.1 Safety Reporting Requirements and Timelines 
 
The Sponsor-Investigator will utilize the Abraxis SAE Completion 
Form for the reporting of adverse events and follow up information 
to those events.  
 
All serious adverse events regardless of severity or relationship must be 
reported to Abraxis BioScience, LLC and Abraxis Oncology within 24 
hours of the investigational staff’s knowledge.   
 
Abraxis BioScience, LLC.  
Drug Safety and Surveillance Department 
4505 Emperor Blvd, Suite 400 
Durham, NC  27703 
Ph: 919-433-8515 (8am-5pm EST, normal business days and hours) 
Ph: 919-606-1832 (24hr hotline) 
Fax: 919-433-8402 
E-mail: SAE-REPORTING@abraxisbio.com  
 
 
Abraxis BioScience, LLC.  
200 Somerset Corporate Blvd – Suite 8000 
Bridgewater, NJ  08807 
Office: 908-393-8248 
Fax: 908-393-8304 
Cell: 267-337-2720 
E-mail: AbraxisMedAffairs@abraxisbio.com 
 
In addition, the Sponsor-Investigator will adhere to the safety 
reporting requirements and timelines described in the Clinical Trial 
Agreement with Abraxis BioScience, LLC.  
   
The Sponsor-Investigator will provide full and timely cooperation 
with any requests from Abraxis, governing IRB, institution, or 
regulatory agency with any requests regarding reports of individual 
reports of adverse events. 
 

IRB # 05015 
62 
March 17, 2009 
Version 14 
8.4.8 
 Additional Investigator Responsibilities on Follow-up of SAEs 
 
The investigator and supporting personnel responsible for patient care should 
institute any supplemental investigations of SAEs based on their clinical 
judgment of likely causative factors. This may include extra clinical 
laboratory tests, physical examinations or consulting an appropriate specialist. 
ABI may also request the investigator to conduct supplemental assessments. 
The results of any additional assessments conducted must be reported to ABI. 
If a patient dies during participation in the study and an autopsy is performed, 
a copy of the report must be submitted to ABI. If a patient dies during the 
follow-up period for the SAE, the event causing the death will be reported as 
part of that SAE. The relationship between the SAE and the death should be 
specifically addressed. 
 
8.4.9  Sponsor Notification of Post-Study SAEs 
The investigator should notify DSMB, IRB, ABI of any death or SAE 
occurring after a patient has withdrawn from the study, when such death or 
SAE may reasonably be related to the medication used in the study. However, 
investigators are not obligated to actively seek adverse events in former study 
participants. 
 

IRB # 05015 
63 
March 17, 2009 
Version 14 
9.0 Study Calendar 
• 
 
Prior to 
chemo
Rx 
On day of 
chemoRx 
Prior to 
treatment 
Within 24 
hours 
after 
chemoRx 
Midway 
through 
chemoRx
# 
Within 3 
weeks 
prior to 
surgery 
Surgery 
Q 6 
months 
 
Yearly 
 
H&P including standard neurological 
evaluation 
X% 
X 
 
 
X 
 
X 
  
X 
CBC, ANC, platelet count 
X% 
X@ 
 
 
X 
 
 
X 
Comprehensive chem., Mg,  
X% 
X@ 
 
 
X 
 
 
X 
PT/PTT 
X% 
 
 
 
X 
 
 
 
Blood samples for buffy coat/DNA 
extraction, proteomics (circulating 
tumor cells ) 
X+ 
X+ 
 
X+ 
X+ 
 
X+  
 
• 
Urinalysis 
X% 
 
 
 
 
 
 
 
Core biopsies, node biopsy, 
procurement of fresh frozen and 
preservative embedded tissue, 
microdissection  
X*** 
 
 
X* 
 
 
X§ 
 
 
Creatinine Clearance - Calculated or 
measured 
X% 
 
 
 
 
 
 
 
Mammogram/US 
X 
 
 
 
Xa 
 
 
X 
MRI of breast and PET as feasible 
Xa 
 
 
 
Xa 
 
 
 
CT chest + abdomen 
Xa 
 
 
 
 
 
 
 
Bone scan 
X 
 
 
 
 
 
 
 
MUGA scan or Echocardiogram/EKG 
X 
 
 
 
 
 
XX 
 
Detailed neurological evaluation  (see  
11.3 and appendix D)† 
X 
 
 
X 
X 
 
XX 
 
Urine pregnancy test 
X% 
 
 
 
 
 
 
 
QOL questionnaire  
X 
 
 
X 
X 
 
XX 
 
a 
As per the indications for breast MRI in the American Society of Breast Surgeons and American Society of Breast Diseases 
guidelines/recommendations. 
* 
Optional 
** 
Every 3 months, for the first year 
*** In order to be eligible, patients do need to agree to undergo core biopsy and clip placement as indicated prior to initiation of 
neoadjuvant therapy. 
# 
Midway thru chemo: Arm A – after 3rd cycle of TAC / Arm B – after AC 
X+  See section 11.2.1.2 for specific tubes to be drawn. 
† 
For those pts. participating in the separate detailed neuropathy/neuropathic pain assessment subset evaluation. 
§ 
An attempt will be made to procure fresh surgical specimen tissue of the residual primary tumor at the time of definitive operative 
procedure for the purpose of generating cell lines or xenographts. 
% 
Pretreatment laboratory parameters must be performed within 1 week of Cycle 1 Day 1 
@ 
May be done done up to 72 hours prior to treatment 
 
 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
10.1 
Patients will be evaluated for tumor response with the primary endpoint being 
pathological complete response from invasive cancer at the time of definitive surgery. 
Pathological response is defined as complete resolution of invasive tumor both in 
breast and (if applicable) in dissected axillary lymph nodes.  PCR rates will be 
compared between the two primary treatment arms (A and B) and will be descriptive 
for patients on arm C. 
03/22/06 
12/4/06 
12/4/06 
02/07/08 
3/19/08 
7/15/08 
3/17/098 

IRB # 05015 
64 
March 17, 2009 
Version 14 
10.2 
Toxicities (CTCAE version 3.0) and QOL outcome will be compared between Arms 
A and B, and will be descriptive for patients on Arm C. 
10.3 
Relapse-free and overall survival data will be collected but will not constitute 
endpoints.  Overall survival is defined as the time from first day of treatment to time 
of death due to any cause.  If a patient is still alive, survival time is censored at the 
time of last follow-up.  Relapse-free survival is defined as the time from first day of 
treatment to the first observation of disease progression or death due to any cause.  If 
a patient has not progressed or died, progression-free survival is censored at the time 
of last follow-up. 
10.4 
Biological/molecular parameters will be assessed in an exploratory manner, and in an 
attempt to generate hypotheses for future validation studies. 
11. 0 
SPECIAL INSTRUCTIONS 
Tissue and body fluid samples will be collected under this IRB approved clinical protocol in 
accordance with the IRB-approved HIPPA compliant and signed consent form. 
 
11.1 
Tissue Specimen Processing and Designation 
 
11.1.1 Core and other biopsy specimens (lumpectomy/mastectomy specimens/lymph nodes) 
will be fresh frozen according to standard procedure by the Department of Anatomic 
Pathology.   Core biopsies (estimated 12 specimens from biopsy), and larger tissue 
samples from biopsy or resections of subsequent post-chemotherapy specimens will 
be stored both fresh frozen, and, in case of abundance, specimens will be embedded.  
H&E and immunohistochemical analysis will be carried out by Dr. Wilczynski. 
    
An attempt will be made to obtain core biopsy specimens halfway through the 
neoadjuvant chemotherapy course, but this biopsy will be optional and patients may 
elect to opt out.  
 
Specimens will undergo LCM in batches every 4-8 weeks, pending the speed of 
accrual, under the supervision of Dr. Wilczynski.  
  
All specimens will be logged in and out using a master logbook, and stored according 
to standards developed by the Department of Anatomic Pathology.  A unique patient 
identifier (specific for this study) will be assigned to each patient and 
subclassification (for example: 1prestromaS: patient #1, pre-chemotherapy stroma 
specimen for the Sommer lab; 1capostL: patient # 1, post-chemotherapy cancer 
specimen for the Lee lab, etc).  
 
11.1.2 Sample Design 
Core biopsies of primary tumors (an estimated 11 (up to 12-14 if feasible) specimens 
from biopsy) and larger tissue samples from biopsy or resections of subsequent post-
chemotherapy specimens will be procured in the following preservatives:  
 
3 (or more if feasible) specimens in formalin for Anatomic Pathology 
3 specimens in EDTA/ETOH for the translational research laboratory and/or 
Dr. Sommer’s laboratory for further distribution 
03/22/06 
03/22/06 
07/15/08 

IRB # 05015 
65 
March 17, 2009 
Version 14 
2 specimens in RNAlater to the translational research lab for further 
distribution 
3 specimens fresh frozen to the translational research lab for further 
distribution 
 
Core and other biopsy specimens will be fresh frozen according to standard procedure 
by the Department of Anatomic Pathology, Tissue collected in RNAlater (RNAlater 
is stores at room temperature) will be submerged in ten times the volume of the tissue 
and the will be less than 0.5 cm in at least one dimension.  The tissue will be 
submerged immediately after it is extracted from the patient and the vial kept upright 
so the tissue stays submerged in transit.  ETOH preserved, frozen and RNAlater 
samples will be delivered to the translational research laboratory for further 
distribution. 
 
11.1.2.1 
Mutational Analysis: Sommer Laboratory  
Following   laser capture microdissetion (LCM) cells procured from 
core biopsy specimens  (2 each pre- and midcourse during 
neoadjuvant therapy) will be separated containing representative cells 
of both tumor and host (non-malignant breast tissue) and will be 
provided for Bi-PAP mutational analysis for the Sommer laboratory.  
Each core biopsy is expected to weigh 150 milligrams; hence a 
minimum of about 200-300 malignant and “host” cells each per each 
core biopsy is expected to be available for analysis.  
The Sommer lab will also receive post-treatment residual tumor and 
normal tissue from the segmentectomy/mastectomy specimens.  
 
11.1.2.2 
Proteomics: Lee Laboratory   
 
Core and large biopsy specimens will be batched for laser capture 
microdissetion (LCM) and cells procured from 2 core biopsies (pre- 
and midcourse during neoadjuvant therapy) containing representative 
cells of both tumor and host (non-malignant breast tissue) will be 
provided for the Lee laboratory for proteomics analysis.   
The Lee lab will also receive post-treatment residual LCM tumor and 
normal tissue from the segmentectomy/mastectomy specimens. 
 
 
11.1.2.3 
RT-PCR and DNA microarray analysis 
 
Two core biopsy samples of the procured pre-treatment, mid-cycle, 
and from the post-chemotherapy lumpectomy or mastectomy will be 
used for RNA extraction and subsequent RT-PCR and possible 
microarray analysis. RNA will be extracted from multiple sections by 
Qiagene RNA extraction kits (Qiagene Inc., Valencia, CA).   
 
To confirm overexpression or underexpression of candidate genes,  
RT-PCR will be performed using an ABI PRISM® 7900HT Sequence 
Detection System (Applied Biosystems, Foster City, CA). Real-time 
PCR has been shown to be a reliable and accurate for quantitative 
determination of specific RNA expression in tissue samples.  Briefly, 
03/22/06 
07/15/08 

IRB # 05015 
66 
March 17, 2009 
Version 14 
RNA is isolated as described above and reverse transcribed to cDNA.  
Each cDNA sample as well as 3 none-template controls will be run in 
triplicate.  Using labeled oligonucleotide probes, florescent signals are 
generated at each PCR cycle by the 5’ nuclease activity of AmliTaq 
Gold DNA polymerse.  The standard curve of a housekeeping gene 
such as GAPDH, B-actin, or 18S will be used as normalization.. 
 
Gene expression analysis will be performed at a micro array core 
facility. The integrity of the starting total RNA will be evaluated on 
an Agilent Bioanalyzer 2100 (Agilent Technologies, Palo Alto, CA).  
single-stranded, then double-stranded cDNA will be synthesized from 
the polyA template to generate biotin-tagged cRNA that will be 
hydribized on an Affymetrix HG:U133A 2.0 array (Affymetrix, Inc., 
Santa Clara, CA).  Gene expression patterns from the microarray will 
be analyzed by the Department of Bioinformatics or designees.  Fresh 
frozen specimens will be provided for DNA analysis to assess copy 
numbers/SNP in Dr. Michael Press’ laboratory at USC and will be 
coordinated by and in collaboration with Dr. Yen’s laboratory, and 
with collaboration from the COH pathology core, spearheaded by Dr. 
Sean Lau. 
 
Gene expression analysis pending sufficient quantity of specimens 
will also be carried out in collaboration with Agendia Corporation 
under the recently City of Hope-approved material transfer agreement 
(MTA).  This goal is in line with the original objectives and goal of 
this study.  The statistical analysis of this collaboration will be carried 
out in collaboration with the study statistician Paul Frankel, PhD and 
the designated bioinformatics personnel (to be named) at Agendia, at 
the NCI of the Netherlands. 
 
Additional collaborators to assess RPT-CR and protein expression, 
bioimmunohistochemistry will include Michael Press Laboratory at 
USC as well as Response Genetics and the Danenberg Laboratory 
with whom the PI and the City of Hope signed a material transfer 
agreement (MTA).  Standard operating procedures according to the 
City of Hope standards are in place to keep samples deidentified for 
the outside investigators.  
 
 
11.1.2.4 
Clarke Lab Breast Tumor Dissociation Protocol 
 
 
 
Max Diehn, modified by Neethan Lobo, October 2006 
 
Specimen (either mastectomy or large segmentectomy) removed in 
OR using sterile instruments sent for inking by pathologist. Tissue 
sections are cut with sterile instruments and placed into 50-ml conical 
tubes containing RPMI/10% HICS/Ceftazidime/PSA on wet ice. 
Samples are kept at 4oC and shipped same day using overnight 
shipping to: 
 
Dalong Qian 
Stanford University 
12/4/06 
3/19/08 
03/17/09 

IRB # 05015 
67 
March 17, 2009 
Version 14 
Institute for Stem Cell and Regenerative Medicine 
1050 Arastradero Road 
Palo Alto, CA 94304 
Lab phone: (650) 724-0574 
Cell: (734) 330-3585 
  
Total time on ice will therefore be less than 24 hours total.  
 
Keep cells on ice or at 4°C for entire protocol 
 
1) Make sure to clean and autoclave all surgical instruments before 
processing tissue. We commonly employ the following equipment: 
razor blades or scalpels, tissue forceps, surgical scissors. Tools may 
be cleaned during the dissection by rinsing with 10% bleach 
followed by 70% EtOH.  
2) Put 5ml of Medium 199/H2CO3/Earl’s/25mM HEPES/pH 7.3 
supplemented with PSA into 10mm or 15mm plastic petri dish 
(cells will not adhere as much as with tissue culture dishes).  
Transfer tumor piece(s) to petri dish with tissue forceps. 
 
We routinely perform two separate procedures for human tumors: 
xenotransplantation and flow cytometry. This protocol will mainly 
deal with processing the tumor tissue for flow cytometry. 
 
3) Xenotransplantation: Using “L”-shaped forceps, cut 1-2mm 
cubes.  Transfer all pieces to a sterile eppendorf containing medium 
and keep on ice. Generally, we implant 2 pieces per mouse at 
different sites. We use a trocar to deliver the tissue into the upper fat 
pads of NOD/SCID mice. We also place an estrogen pellet into the 
back of the mouse if dealing with an ER+ breast tumor. All tumor 
chunks are coated with matrigel before engraftment. 
 
The following is based on our procedures for processing human breast 
tumors. Other tumor types may require alternate dissociation 
enzymes, digestion times, etc. 
 
4) If leaving tissue overnight: Put entire piece in RPMI w/ 10% HICS 
and ceftazidime and Pen/Strep/Ampho and leave on ice O/N.  In the 
morning, wash 1x with cold PBS, then proceed as follows. 
5) Make single cell suspension:  If specimen contains a significant 
amount of adipose tissue, trim this first.  Then cut tissue into slivers 
by holding with forceps and sliding prongs around razor blade.  
Next mince using slicing motion.  Once adequately disaggregated, 
bring total volume to 27 ml with media and add 3 ml of 2000 
unit/ml collagenase type 3 (10x) [Can adjust total vol based on size 
of specimen].  Add DNase to the digestion (5 Kunitz units/ml). 
Scrape cells off bottom of plate with razor blade before placing into 
incubator (37°C, 5% CO2) and mechanically dissociate by pipetting 
every 20 minutes.  Incubate for 2-4 hours, or until tissue is 
disaggregated.  Often we need to spike the digestion with an 

IRB # 05015 
68 
March 17, 2009 
Version 14 
additional 1.5 ml Collagenase Type III at ~1.5 hrs to achieve 
complete dissociation.  
6) Neutralizing: Add 10 mls of neutralizing media (RPMI 1640/10% 
HICS/PSA) per 20 mls of digestion media.  Mix by pipetting. 
7) Filtering: First pipette media over nylon mesh held over 50ml 
conical.  May need to change nylon mesh several times due to 
clogs.  Next pipette through 70 µm filter into a fresh 50ml conical.  
Tilt filter slightly to increase flow speed if it slows down.  Finally, 
pipette through 40 µm filter into a fresh 50ml conical.  Pellet cells 
for 5 min at 1000 RPM at 4°C. 
8) RBC lysis: Resuspend pellet in 5 ml of ACK buffer and incubate on 
ice for 2 minutes.  Bring up volume to 50 ml with HBSS w/ 2% 
HICS to stop lysis.  Pellet cells for 5 min at 1000 RPM at 4°C. 
a. Optional: can repeat 40 µm filtering to remove debris 
from RBC lysis if desired. 
9) Count cells: Bring up cells in an appropriate volume of HBSS w/ 
2% HICS.  Cells are now ready for staining. 
 
 
 
 
Optional: Freezing Tumor Samples 
 
1) Resuspend cells in 10% DMSO/80% DMEM/10%FBS at a 
concentration of 13 million cells/ml in cyrovials. 
2) Place in freezing chamber O/N in -80C. 
 
 
 
Transfer to liquid nitrogen for long term storage. 
 
Once City of Hope capabilities allow, cell line development and stem 
cell line identification will be carried out in the laboratories of Shiuan 
Chen, Jack Shively, Yun Yen, John Rossi and other COH 
collaborators as feasible. 
 
11.2 
Blood Specimen Processing and Designation 
 
11.2.1 Blood Samples 
 
11.2.1.1 
All blood specimens will be drawn using the following 
vacutainer tubes: 
                                                                                                           
Tubes #1-4 – 7 ml EDTA (purple-top) tube 
Tube #5      – One 7 ml Paxgene tube 
Tube #6-9   – Four - 10ml tubes containing EDTA 
anticoagulant and Catches preservative 
 
11.2.1.2 
Timing:  
Pre-chemotherapy:  
 
 
Tubes #: 1-9 
Mid-chemotherapy: 
 
 
Tubes #: 1-9 
Prior to definitive surgery: 
 
Tubes #: 1-9 
Every 3 months x 4: 
 
 
Tubes #: 1-5 
Every 6 months x 1 year : 
 
Tubes #: 6-9 
 
03/22/06 
3/19/08 
07/15/08 
07/15/08 
07/15/08 
03/17/09 

IRB # 05015 
69 
March 17, 2009 
Version 14 
11.2.1.3 
Specimen Handling: 
All EDTA tubes (purple top) will be kept on ice.  After 
centrifugation at 1100 rpm for 10 minutes at 4 degrees 
Celsius, the plasma will be transferred to Eppendorf tubes and 
centrifuged at 14000 rpm for 10 minutes at 4 degrees Celsius 
to separate the WBC fraction.  The plasma will be divided 
into 500 microliter aliquots and stored at -80 degrees Celsius.  
The WBC will be washed with a red cell lysis buffer, pelleted 
and stored at -80 degrees Celsius. 
The EDTA tubes will be delivered either to the translational 
research lab within 1 hour of procurement and centrifuged to 
separate the buffy coat and plasma fractions.   
Tube #5 is a PAXgene tube for stabilization of whole blood 
and subsequent isolation of cellular RNA.  After incubation 
for 2 hours at ambient temperature, the tube will be stored in a 
loose wire rack at -20 degrees Celsius for up to one year.  The 
RNA will be extracted following the protocol in the PAXgene 
Blood RNA Kit sold by QIAGEN.  The RNA will be 
analyzed by real-time PCR or micro array.  This tube will be 
procured for RNA extraction from PMN cells in Dr. Yen’s 
laboratory. 
Tubes # 6-9.  will be procured and shipped in order to 
quantitate, isolate, and characterize circulating tumor cells to 
the Bruce laboratory. 
 
After venipuncture, the initial 1/2 cc of blood will be 
discarded (or drawn into any pediatric tube, which is then 
discarded) to not contaminate the subsequent blood sample 
with skin epithelial cells.   
 
To test for the presence of tumor-like cells, the blood will be 
labeled with fluorescent molecules marking for Cytokeratin 
(CK), CD-45 and DAPI antibodies with subsequent 
processing for markers for ER, PR, HER2, EGFR and ERCC-
1 or other suitable markers. 
Blood will be collected in the 10ml tubes containing EDTA 
anticoagulant and Cytochex preservative.   These Rare Cell 
tubes are made by Streck and will be supplied by 
PARC/Bruce Laboratory.  The blood will be shipped at room 
temperature using overnight delivery in Styrofoam containers 
provided by PARC and samples will be marked as customary 
with an anonymized patient ID by the specialist taking the 
blood.   PARC personnel will have medical information 
relevant to the study, but the patient will be anonymous. 
  
Contact information for PARC/Bruce Lab: 
03/22/06 
03/19/08 
07/15/08 
07/15/08 
03/17/09 
07/15/08 

IRB # 05015 
70 
March 17, 2009 
Version 14 
Bruce Lab 
PARC (Palo Alto Research Center)  
3333 Coyote Hill Road 
Palo Alto, CA 94304 
Phone 650 812 4000 
 
11.2.2  Specimen Tracking: 
11.2.2.1 
The date of blood draw will be recorded.  For tracking 
purposes, the following will also be recorded upon receipt to 
the processing and receiving laboratories: 
a. 
Specimen ID number (all specimens will be 
anonymized by assigning a unique identifier, similarly 
to the process described under “Tissue specimen 
handling”, with coding provided by Biostatistics. 
b. 
Number and types of tubes received and date of 
receipt. 
c. 
Refrigerator location of stored cell pellet for DNA 
extraction and date of initial storage. 
d. 
Number of aliquots of plasma and serum (5-6 aliquots 
per tube expected), freezer location(s) stored, and 
date(s) of initial storage. 
11.2.2.2 
Liquid nitrogen tank location of stored PBMC and date of 
initial storage will be tracked. 
 
11.2.2.3 
Upon transfer of specimens to the Sommer, Lee, Yen, Synold 
and any other designated labs, tracking will include:  
 
a. 
Specimen ID number 
b. 
Lab to which specimen was sent 
c. 
Date of transfer 
11.2.2.4 
Upon return of data from the designated labs, the following 
will be recorded: 
a. 
Specimen ID number 
b. 
Date of run and run number (all specimens will be run 
in replicate for at least two runs in order to evaluate 
intra-and inter-essay reliability) 
c. 
Type of assay 
d. 
Lab performing assay 
e. 
Assay results 
 
11.3 
Assessment of peripheral neuropathy 
03/22/06 
3/22/06 
3/22/06 
07/15/08 

IRB # 05015 
71 
March 17, 2009 
Version 14 
Right peroneal nerve motor conduction studies are performed with the stimulating 
electrode at the ankle and the recording electrode 8 cm distally over the extensor 
digitorum brevis muscle.  For sensory conductions, the right sural nerve is stimulated 
antidromically in the posterior lower leg and recorded 14 cm distally at the lateral 
malleolus.  Quantitative sensory testing of vibratory and cold detection thresholds 
will be performed with the Case IV system one-time-period 4, 2, 1 Stepping 
Algorithm (145). The point of stimulation is immediately distal to the base of the nail 
of the right large toe for vibration and the dorsal surface of the right foot for cold. The 
relative changes in nerve conduction and quantitative sensory tests will be recorded 
and expressed as the logarithm to the base 2 of ratios of post chemotherapy/baseline 
determinations. (A logarithm ratio of 0 indicates no change, -1 indicates the value 
was reduced by half, +1 indicates an increase by a factor of 2, -2 indicates a reduction 
by a factor of 4, etc.)  
Peripheral neuropathy scores will be obtained by a modification of the method by 
Chaudhry et al (146).  As shown in Appendix, scores of 0-3 are given for each of 7 
categories: (1) sensory symptoms, (2) pin sensory loss, (3) vibration sensory loss, (4) 
strength, (5) deep tendon reflexes, (6) sural sensory nerve action potential (SNAP) 
amplitude, and (7) peroneal nerve compound muscle action potential (CMAP) 
amplitude. Percentage reduction of SNAP and CMAP will be determined on the basis 
of the lower limit of the laboratory normal. Sum of peripheral neuropathy composite 
scores could range from 0 (no impairment) to 21 maximum impairment on this scale). 
12.0 
STATISTICAL CONSIDERATIONS 
This is a randomized phase II study of neoadjuvant chemotherapy regimens in patients with 
stages I-III breast cancer.  The primary objectives include comparison of toxicity and efficacy 
and Quality of Life endpoint.  Efficacy will be defined by comparing the percentage of 
patients whose definitive surgical specimens following neoadjuvant therapy are scored by our 
pathology collaborators as either Symmans scores 0 or 1 versus all others, between TAC 
versus ACAC in patients with HER-2 negative breast cancer, and establishment of toxicity 
profile and efficacy with ACAC and trastuzumab in patients with HER-2 overexpressing 
breast cancer.  
This will be a randomized Phase II trial, with two strata.  
Stratum 1: Patients with HER-2/neu- tumors. 
In the stratum of patients that have her2/neu negative tumors, patients will be randomized to 
either Arm A (TAC) or Arm B (ACAC).  A Simon optimum two-stage design will be used to 
evaluate the activity of the treatment in terms of pathological complete response (pCR) rate 
following neoadjuvant chemotherapy in each of the two parallel arms. If a response rate in an 
arm is promising, that arm can be considered for further study as neoadjuvant chemotherapy.  
If both arms are deemed promising, the preferred arm, based on a superior pCR rate, will be 
chosen for future evaluation providing toxicity and safety are acceptable.  
Using a two-stage Simon optimum design, the initial stage of accrual will consist of 34 
patients, 17 randomly assigned to each arm.  Accrual will continue without interruption until 
all of the first 34 patients have been assessed for their neoadjuvant response following 
definitive surgery. That interim analysis is expected to occur approximately 9 months into the 
study.  If, at that point, less than 4 subjects have a pCR, on an arm, then accrual to that arm 
will be stopped.  If 4 or more experience a pCR in the first 17 patients on an arm, an 
04/26/07 
03/19/08 

IRB # 05015 
72 
March 17, 2009 
Version 14 
additional 20 patients will be accrued during the second stage to that arm, for a total of 37 
patients on that arm.  As long as both arms remain open, patients will be randomly assigned 
to an arm. In either arm, if at least 11 patients obtain a pCR out of the total of 37 evaluable 
patients, the regimen will be regarded worthy of further testing.  Otherwise, further testing of 
the regimen corresponding to that arm would not be warranted. This two-stage design has at 
least 90% power to detect a true response rate of at least 40% in each arm. It yields at least a 
90% probability of a negative result if the true response rate is no more than 20% with at 
least a 55% probability of early stopping under the discouraging alternative. With 37 
evaluable patients in each arm, the 95% confidence interval for the response rate in an arm will 
have a half-width of ±16% or less. If neither arm is closed during the interim analysis, the total 
accrued on this stratum will be 74 patients. 
If both arms are deemed worthy of further study, the arm with the superior rate of 
pathological complete responses will be selected for future evaluation, providing other 
characteristics such as toxicity and safety are equal. Such a selection rule has less than a 20% 
chance of choosing the inferior arm (~80% power), if the inferior arm has a true response rate 
of 30% and the superior arm has a true response rate of 40%.  
Stratum 2:  Patients with HER-2 positive tumors. 
Patients with HER-2 positive tumors will not be randomized due to the imperative to offer 
Herceptin®.  Due to concerns of potentially higher likelihood of cardiac toxicities if 
combined with TAC (Arm A), all HER-2 + patients will be accrued to Arm C (ACAC [Arm 
B] + Herceptin®). 
A Simon optimum two-stage design will also be used to evaluate the activity of the treatment 
for these strata in terms of pathological complete response (pCR) rate following neoadjuvant 
chemotherapy. The initial stage of accrual will consist of 15 patients.  Accrual will continue 
without interruption until all of the first 15 patients have been assessed for their neoadjuvant 
response following definitive surgery. That interim analysis is expected to occur 
approximately 9 months into the study.  If, at that point, less than 6 subjects have a pCR, then 
accrual to that arm will stop.  If 6 or more experience a pCR in the first 15 patients, an 
additional 17 patients will be accrued during the second stage to that arm.  If at least 13 
patients obtain a pCR out of the total of 32 evaluable patients, the regimen will be regarded 
worthy of further testing.  Otherwise, further testing of the regimen corresponding to that arm 
would not be warranted. This two-stage design has at least 80% power to detect a true 
response rate of at least 50%. It yields at least a 90% probability of a negative result if the 
true response rate is no more than 30% with at least a 72% probability of early negative 
stopping under the discouraging response rate. With 32 evaluable patients, the 95 % 
confidence interval for the response rate in an arm will have a half-width of ±18% or less.   
 Additional 8 patients (up to 40 total evaluable ) in Arm C have been added to increase the 
precision on the response rate and provide more opportunity for biopsy studies. 
Total evaluable patients to be accrued: Stratum 1 (Arms A and B): 74 patients’ Stratum 2 (Arm 
C): 40 patients. With current rate of accrual, the study will have been completed by the end of 
June 2009 at the latest. 
 

IRB # 05015 
73 
March 17, 2009 
Version 14 
.In any arm (on either stratum), if responses occur in patients that are accrued beyond the 
interim analysis point, and the arm was scheduled for closure based on the interim analysis, a 
stochastic curtailment procedure will be employed to assess whether an amendment to re-
open that arm is warranted.   
Total Patients Accrued: Stratum 1: 74 pts. Stratum 2: 40 patients. Total 114 patients. 
Expected time till completion of  accrual: June/09 
Correlative Statistics: 
Neoadjuvant chemotherapy provides researchers with a unique and valuable opportunity for 
correlative studies to explore many of the most critical questions in chemotherapy and every 
effort will be made to fully utilize the valuable resources obtained during the study. 
Mutations in DNA by Bi-PAP, protein expression by immunohistochemistry and mass 
spectrometry, gene expression by RT-PCR quantification, and DNA polymorphisms and 
array cluster analysis all on a variety of source material will create a considerable database.    
Standard descriptive methods will be used to summarize the baseline levels and the changes 
after treatment of the correlative assays.  This will allow us to examine whether observed 
patterns are consistent with the hypothesized patterns.  Patients who experience an objective 
response will be compared to those who did not – in terms of these correlates - and estimates 
of variation will be useful for planning further clinical research. In addition, these analytical 
measurements will be analyzed ensemble to seek correlational structure, and for use in 
exploratory models of response, survival, tumor characteristics, patient characteristics, and 
toxicity.  Formal testing of these comparisons is not planned, and any resultant reports will 
discuss the multiple comparisons issue. The analyses of the correlates will be exploratory and 
descriptive and will be used to better understand the effect of the various treatment arms on 
the subjects. 
Secondary objectives include quality of life comparisons among the treatment groups, and 
exploratory analysis of DNA, RNA, and proteomics profile of tumors and blood samples 
before, during, and after neoadjuvant therapy in order to identify prognostic, predictive, and 
target-identifying molecular markers for future validation studies. 
Racial subgroups will be summarized.  No differences in outcome due to race are anticipated. 
Exploratory tests for interaction of regimen and race will be done, if accrual warrants.  No 
subgroup analyses (other than per stated stratification) are planned. 
Quality of Life Comparisons: 
The main quality of life tool will be version 4 of the FACT-Taxane questionnaire, although 
FACT-B version 4 data will also be collected. The QOL questionnaires will be administered 
at baseline, midway through the neoadjuvant therapy (3 months), at completion of 
neoadjuvant chemotherapy (6 months), and at nine months and at one year. The primary 
comparison will be to examine the change from baseline to completion of neoadjuvant 
chemotherapy in the FACT-Taxane QOL scale and to compare those changes between the 
two different neoadjuvant therapies, TAC and ACAC. Herceptin is not thought to influence 
Taxane related toxicities and therefore the HER-2+ patients will not be considered separately 
for the QOL endpoint. As a result, there will be 74 patients treated with ACAC and 37 with 
TAC.  For each patient, the FACT-Taxane score difference from baseline to end of treatment 
will be recorded. A two-group comparison t-test will be used to evaluate the effect of 
neoadjuvant chemotherapy regimen. With these patient numbers, there is 83% power to 

IRB # 05015 
74 
March 17, 2009 
Version 14 
detect an effect size of 0.6 with a two-sided type I error of 5%. In case the patient stops the 
neoadjuvant chemotherapy prior to the 6 month QOL assessment, an attempt will be made to 
collect QOL at the time of drop out and last observation carried forward (LOCF) analysis 
will be used for missing data imputation if the reason for drop out was related to toxicity. 
Otherwise, that patient will be excluded from the QOL calculation. The FACT-B QOL data 
will also be reported and tabulated by neoadjuvant regimen according to the subscales in an 
exploratory fashion, and additional analysis of the other QOL time points will also be 
exploratory. 
The primary objective of the peripheral neuropathy aspect of this trial is to evaluate and 
compare the severity of neuropathy in the two arms of the study: TAC (group A) and ACAC 
(group B, without trastuzumab) by objective measures (nerve conduction, quantitative 
sensory tests, neuropathy composite score). Twenty subjects with stage II or IIIa disease from 
each group will be assessed prior to initiation of protocol chemotherapy (baseline), at 
completion of chemotherapy prior to surgery (18-20 weeks), and at 6 months. At each of 
these 3 time points in a single 60-90 minute appointment, subjects will undergo the 
following: a neurological examination focused on sensation, muscle weakness, and deep 
tendon reflexes; quantitative sensory tests of cold detection threshold (CDT) and vibration 
detection sensation threshold (VDT); and neurophysiological tests of peroneal nerve 
compound muscle action potential (CMAP) and sural nerve sensory nerve action potential 
(SNAP). Anticipated results are as follows: (1) change from baseline will be greater in group 
B than group A at the time point just after completion of chemotherapy; (2) change from 
baseline will be greater in group B than group A at six months and both groups will improve 
after the completion of chemotherapy; (3) nerve damage will be detected in both groups at 
both time points after chemotherapy (i.e., compared to baseline, there will be a decrease in 
peroneal CMAP amplitude, decrease in sural SNAP amplitude, increase in CDT, increase in 
VDT, and increase in neuropathy composite score).  
 
A second objective is to correlate objective measures of neuropathy (nerve conduction, 
quantitative sensory tests, and neuropathy composite score) with questionnaire/quality of life 
measures. In the 40 subjects, 5 objective measures (peroneal CMAP amplitude, sural SNAP 
amplitude, CDT, VDT, neuropathy composite score) repeated at 3 time points (baseline, 18-
20weeks, 6 months) will be compared to quality of life measurements at these time points. 
The hypothesis is that objective measurements of neuropathy will correlate negatively with 
quality of life measurements. 
 
The statistical power calculation is based on the first consideration that group B will show 
more nerve damage, using the composite score, than group A. A sample size of 20 in each 
group will have 80% power to detect a probability of 0.727 that the nerve damage is greater 
in a group B subject than in group A subject, using a Wilcoxon (Mann-Whitney) rank-sum 
test with 0.05 one-sided significance level.  Secondary considerations will be evaluated in an 
exploratory manner, and no correction for multiple comparisons will be employed. 
Barriers to treatment: 
 
Patients with evidence of clinical, or image-documented (mammography, ultrasound, etc) 
abnormality of the breast with subsequent proof of malignancy will be interviewed to identify 
reasons for delay of treatment if 3 or more months passed by between the onset of symptoms 
and initiation of enrollment on this treatment study.  We estimate that approximately 15-20% 
03/22/06 
03/22/06 

IRB # 05015 
75 
March 17, 2009 
Version 14 
of patients with locally advanced stage III disease may qualify for the interviewing process 
(See appendix C).  An exploratory analysis as to the cause of delay will be carried out and 
may serve as the starting point for a formal prospective trial.  
 
Microarray Analysis: 
The cRNA product will be fragmented and hybridized to Affymetrix U133 2.0 arrays. These 
arrays contain greater than 54,000 probe sets allowing analysis of the expression level of 
more than 47,000 transcripts and variants, which include approximately 38,500 well-
characterized human genes. Hybridization and data acquisition will be performed at the City 
of Hope Microarray Core Facility.  Experimental information and data acquisition will be 
performed using Affymetrix GeneChip Operating Software (GCOS). Gene expression values 
will be extracted from probe level data using Plier algorithm implemented in Affymetrix 
GeneChip RNA Expression Analysis Software (GREX). Prior to statistical analysis, systemic 
variations, associated with procedures such as IVT labeling, hybridization and scanning will 
be adjusted to a comparable level between arrays within the study. The background 
correction, normalization, and other preprocessing steps will be performed in R using the affy 
library (150,151). 
To assess the validity and reproducibility of experiments we will process replicate samples 
independently for a subset of subjects and determine the correlation between gene expression 
levels on replicate arrays. This will include M vs. A plots among replicates and other 
diagnostics for faulty chip data.  In addition we will determine whether replicate samples 
cluster tightly on hierarchical clustering analysis. We will also use Q-RT-PCR to 
independently determine the level of gene expression for selected genes in a subset of 
patients and will determine the correlation with microarray results. In addition we will 
correlate the relative changes in expression as determined by RT-PCR and microarrays. 
 
The formal statistical analysis will follow the regression framework developed by Zhao et al. 
(152). Let Yl=(Y1l, Y2l, …,YJl) denote the gene expression profiles on array l, where Yjl denotes 
the expression of the jth gene on array l (j=1,2…J; l=1,2…,L), and J is total number of genes 
on an array and L is total number of samples.  Let dl=0 or 1 denote whether a response is 
achieved. We are mainly interested in analyzing gene expression profiles at baseline to find 
the genes whose profiles are different between the responding patients and non-responding 
patients. To adjust other unmatched but important clinical variables (such as medical history 
or medications), we include them as covariates in the following regression model: 
yjl=δl+λl(αj+χj dl+βj’xl)+ξjl, where (δl, λl) are additive and multiplicative heterogeneity 
factors that need to be adjusted for as part of the normalization, xl is a vector of clinical 
covariates to be adjusted for in the analysis, (αj, χj , βj’) are the regression coefficients.  In 
particular, χj quantifies the difference of the jth gene between responding and non-responding 
patients. To avoid making a distributional assumption about ξjl, we will calculate the robust 
standard errors (SE) using estimating equations theory  (153).  We will carry out statistical 
inference by hypothesis testing for each gene. The null hypothesis (Ho) is that there is no 
differential expression for jth gene between the responding patients and non-responding 
patients. Statistically, Ho: χj=0, where j=1,2…J. We will test the null hypothesis by 
calculating the Z-score: Zj=χj/SEj, where SEj is the estimated standard error. The analysis 
results in a vector of Z-scores of length J.  The greater the Z-score is, the more likely this 
gene differentially expresses.  After we set up a threshold for type I error rate (e.g. 0.05), we 
will select the genes that are differentially expressed between t-MDS and non t-MDS 
12/4/06 
12/4/06 

IRB # 05015 
76 
March 17, 2009 
Version 14 
samples.  Recognizing the concern with multiple comparisons, we will adapt a modified 
Bonferroni’s correction proposed by Hochberg (154). 
 
The statistical power of detecting differentially expressed genes is defined as the percentage 
of truly differentially expressed genes being discovered using statistical method among all 
the genes spotted on the array. The power of detecting the differentially expressed genes 
between the responsive and non-responsive patients can potentially be affected by multiple 
factors such as the variance of gene expression levels, the differences of expression levels of 
positive genes between the two groups, the proportion of truly differentially expressed genes 
among all genes under investigation, the correlations of expression levels among genes, and 
the tolerance for false discovery rate (FDR)(155). The Affymetrix technology used in this 
project is far superior to its earlier technology with much reduced technical variation.  We 
will include additional longitudinal observations, and hence data become even more richer, 
resulting higher power.  The above primary endpoint calculations were based on the assumed 
Phase II response rate, but we expect to be able to detect consistent and reproducible genes 
responsible for the genetic etiology for response among the various patient subgroups. 
 
13.0 
REGISTRATION GUIDELINE 
Once all pretreatment evaluations have been performed, patients will be entered on study 
after review of patient eligibility by a member of the Department of Biostatistics.  Patients 
may be screened for registration by calling the City of Hope Department of Biostatistics, ext. 
62468. 
14.0 
DATA SUBMISSION SCHEDULE 
All primary data will be maintained by the Department of Biostatistics, City of Hope Cancer 
Research Center.  These will include eligibility checklist, pre-study and initial flow sheet, 
pathology report, study specific flow sheets as well as off-study information. 
14.1 
Data Collection Forms and Submission Schedule 
All data will be collected using COH Biostatistics Information Tracking System 
(BITS) data collection forms.  Copies of the completed forms will be submitted to 
City of Hope Department of Biostatistics for entry and stored in a secure location.  
The original data collection forms will reside at the originating institution in secure 
location. 
14.1.1 The data manager will complete the Eligibility Checklist Worksheet at the 
time of registration: 
14.1.2 Within two weeks of registration, the data manager will complete the On-
Study Form (Form OS). 
14.1.3 Within four weeks of completion of each course of treatment, the data 
manager must complete the following: 
14.1.3.1 
Treatment and Adverse Event Form 
14.1.3.2 
Supplemental Data Form (if applicable) 
12/4/06 
12/4/06 

IRB # 05015 
77 
March 17, 2009 
Version 14 
14.1.3.3 
Flow Sheets (These are to be submitted along with each 
treatment form) 
14.1.4 Each time a patient is evaluated for response and/or new follow-up 
information is obtained the data manager will complete the Response/Off-
Study/Follow-Up Form. 
14.1.5 Protocol deviations should be reported in a timely manner. (See 
http://www.infosci.coh.org/prot_office/cprmc/pd.asp) 
14.2 
An abbreviated Clinical Data Update System (CDUS) report will be generated 
quarterly. 
14.3 
Tracking log for tissue/blood samples /assignment of identifiers, log in/out for 
procured tissue specimens will be maintained by the individual processing and 
receiving centers (Anatomic Pathology, Pharmacology Core and Yen laboratory, and 
the receiving Sommer, Lee, Yen, Synold laboratories, and other end users, as material 
for processing becomes available (microarray, immunohistochemical analysis) with 
the master tracking sheet maintained in the Department of Biostatistics and shared 
with Informatics. 
14.4 
Analysis will be carried out in a joint effort between the Departments of Biostatistics 
and Informatics. 
15.0 
MINORITIES AND WOMEN STATEMENT 
The table below shows the distribution by sex and race of the patients accrued to therapeutic 
clinical studies at City of Hope for the past five years with the same primary site of disease 
targeted for this protocol (breast).  Our goal is to maintain our high accrual of women while 
continuing to increase the accrual of minority subjects. 
 
Accrual by Site, 1989-1994  Update 
 
 
By Sex 
By Ethnicity 
Site 
Total 
Female 
Male 
White 
Hispanic 
Black 
Asian 
Other 
Breast 
1060 
1059 (100%) 
1 (0%) 
801 (76%) 
110 (10%) 
36 (3%) 
70 (7%) 
43 (4%) 
 
Accrual Goal for Women and Minorities on this Study 
 
 
By Sex 
By Ethnicity 
Site 
Accrual 
Goal 
Female 
Male 
White 
Hispanic 
Black 
Asian 
Other 
Breast 
90 
90 (100%) 
0 (0%) 
54 (60%) 
15 (17%) 
6 (6.5%) 
9 (10%) 
6 (6.5%) 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 
All patients will have signed an informed consent for participation in research 
activities in accord with all institutional, NCI and Federal regulations, and will have 
been given a copy of the Experimental Subject's Bill of Rights. 

IRB # 05015 
78 
March 17, 2009 
Version 14 
17.0 
PATHOLOGY REVIEW 
All patients will have malignancy confirmed by review of their biopsy specimens by the 
Division of Pathology of the City of Hope National Medical Center,  
 
 
 
18.0 
REFERENCES 
 
 
1. 
Ries L, Eisner M, Kosary C, et al:  SEER cancer statistics review, 1975-2000., 2003. 
 
2. 
Wingo, PA, Cardinez, CJ, Landis SH, et al:  Long-term trends in cancer mortality in 
the United States. Cancer 97:3133-275, 2003. 
 
3. 
Nabholtz, J-M, Pienkowski, T, Mackey, J, Pawlicki, M, Guastalia, J-P, Vogel, C, et 
al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with 
FAC (5-flourouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of 
node positive breast cancer (BC) patients: interim analysis o f the BCIRG 001 study. 
Proc Am Soc Clin Oncol 21:36a, 2002. 
 
4. 
Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar W, et al: 
Randomized trial of dose-dense versus conventionally scheduled and sequential 
versus concurrent combination chemotherapy as postoperative adjuvant treatment of 
node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer 
and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-9, 2003. 
 
5. 
Buzdar AU, Singletary SE, Valero V, Booser DJ, Ibrahim NK, Rahman, et al: 
Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast 
cancer: preliminary data of a prospective randomized trial. Clin Cancer Res. 8:1073-
9, 2002. 
 
6. 
Seidman AD, Berry D, Cirrincione C, et al: Phase III study of weekly paclitaxel via 
1-hour infusion vs. standard 3-hour infusion every third week in the treatment of 
metastatic breast cancer, with trastuzumab for HER 2+ metastatic breast cancer 
(MBC), and randomized for trastuzumab for HER2 normal MBC. Proc Am Soc Clin 
Oncol 22:6s, 2004 
 
7. 
Fountzilas G, Kalofonos HP, Dafni U, Papadimitriou C, Bafaloukos D, Papakostas P. 
Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy 
in patients with advance breast cancer: a phase III study conducted by the Hellenic 
Cooperative Oncology Group. Ann Oncol 15:1517-1526, 2004. 
 
8. 
Burris H 3rd, Yardley D, Jones S, Houston G, Broome C, Thompson D, et al: Phase II 
trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment 
for patients with metastatic breast cancer. J Clin Oncol 22:1621-9, 2004. 
 

IRB # 05015 
79 
March 17, 2009 
Version 14 
9. 
Loesh D, Robert N, Asmar L, Gregurich MA, O’Rourke M, Dakhil S, et al: Phase II 
multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with 
advanced breast cancer. J Clin Oncol 20:3857-64, 2002. 
 
10. 
Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Rodiboux A, 
Margolese RG, et al.  Preoperative chemotherapy: updates of National Surgical 
Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26: 778-
785, 2008. 
 
11. 
Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, Symmans WF, et al.  
Response to neoadjuvant therapy and long-term survival in patients with triple-
negative breast cancer.  J Clin Oncol 26: 1275-1281, 2008. 
 
12. 
Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, et al. 
Measurement of residual breast cancer burden to predict survival after neoadjuvant 
chemotherapy.  J Clin Oncol 25: 4414-4422, 2007. 
 
13. 
Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapy on 
local-regional disease in women with operable breast cancer: findings from National 
Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15:2483-2493, 1997. 
 
14. 
Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in patients with 
operable breast cancer: nine-year results from National Surgical Adjuvant Breast and 
Bowel Project B-18. J Natl Cancer Inst Monogr 96-102, 2001. 
 
15. 
Bear HD, Anderson S, Smith RE, Robidoux A, Kahlenberg MS, Margolese RG, et al: 
A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide 
(AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by 
postoperative (postop) T in patients (pts) with operable carcinoma of the breast: 
results of NSABP B-27. Breast Cancer Res and Treat 88:S16, 2004. 
 
16. 
Hutcheon AW, Heys SD, Miller ID, et al: Improvements in survival in patients 
receiving primary chemotherapy with docetaxel for breast cancer: a randomized 
controlled trial. Cancer Res Treat 69:A506, 298, 2002. 
 
17. 
Green MC, Buzdar AU, Smith S, et al: Weekly paclitaxel followed by FAC as 
primary systemic chemotherapy of operable breast cancer improves pathologic 
complete remission rates when compared to every 3 week paclitaxel therapy followed 
by FAC: final results of a prospective, phase III randomized trial. Proc Am Soc Clin 
Oncol 21:35a, 2002. 
 
18. 
Cobleigh MA, Vogel, CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al: 
Multinational study of efficacy and safety of humanized anti-HER2 monoclonal 
antibody in women who have HER2-overexpressing metastatic breast cancer that has 
progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639, 1999. 
 

IRB # 05015 
80 
March 17, 2009 
Version 14 
19. 
Slamon DJ, Leyland JB, Shak S, et al: Use of chemotherapy plus a monoclonal 
antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl 
J Med 344:783-792, 2001. 
 
20. 
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al: 
Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-
Overexpressing metastatic breast cancer. J Clin Oncol 20: 719-726, 2002. 
 
21. 
Pegram MD, Pienkowski T, Northfelt DW, Eiermann W, Patel R, Fumoleau P, et al: 
Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, 
and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 
96:759-69, 2004. 
 
22. 
Robert NJ, Leyland-Jones, B, Asmar L, Belt RJ, Ilegbodu D, Loesch, DM, et al: 
Randomized phase III study of trastuzumab, paclitaxel, and carboplatin versus 
trastuzumab and paclitaxel in women with HER-2 overexpressing metastatic breast 
cancer: An update including survival. Proc Am Soc Clin Oncol 22: A573, 2004. 
 
23. 
Buzdar AU, Hunt K, Smith T, Francis D, Ewer M, Booser D, et al: Significantly 
higher pathological complete remission (PCR) rate following neoadjuvant therapy 
with trastuzumab (H), paclitaxel (P), and anthracycline-containing chemotherapy 
(CT): Initial results of a randomized trial in operable breast cancer (BC) with HER/2 
positive disease Proc Am Soc Clin Oncol 22:A520, 2004. 
 
24. 
Gianni L, Munzone E, Capri G, Villani F, Spreafico C, Tarenzi E, et al: Paclitaxel in 
metastatic breast cancer: a trial of two doses by a 3-hour infusion in patients with 
disease recurrence after prior therapy with anthracyclines. J Natl Cancer Inst 
87:1169-75, 1995. 
 
25. 
Seidman AD, Hudis CA, Albanel J, Tong W, Tepler J, Currie V, et al: Dose-dense 
therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast 
cancer. J Clin Oncol 16:3353-61, 1998. 
 
26. 
Lombardi D, Crivellari D, Scuderi C, Magri MD, Spazzapan S, Sorio R, et al: Long-
term, weekly one-hour infusion of paclitaxel in patients with metastatic breast cancer: 
a phase II monoinstitutional study. Tumori 90:285-8, 2004. 
 
27. 
Perez E, Rowland KM, Suman VJ, et al: N98-32-52: Efficacy and tolerability of two 
schedules of paclitaxel, carboplatin and trastuzumab in women with HER2 positive 
metastatic breast cancer: a North Central Cancer Treatment Group randomized phase 
II trial. Breast Cancer Res Treat 82:S47, 2003. 
 
28. 
Archer CD, Lowdell C, Sinnett HD, et al: Docetaxel: Response in patients who have 
received at least two prior chemotherapy regimens for metastatic breast cancer. Eur J 
Cancer 34:816-819, 1998. 
 

IRB # 05015 
81 
March 17, 2009 
Version 14 
29. 
Tabernero J, Climent MA, Lluch A, et al: A multicenter, randomized phase II study 
of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. Ann Oncol 
15:1358-1365, 2004. 
 
30. 
O’Shaughnessy J, Tjulandin S, Davidson N, Shaw H, Desai N, Hawkins MJ, et al: 
ABI-007 (ABRAXANE®), a nanoparticle albumin-bound paclitaxel demonstrates 
superior efficacy vs taxol in MBC: a phase III trial. Breast Can Res Treat [abstract 
#44], 2003. 
 
31. 
Campbell KJ, Hersh EM, Stopeck A, Glennie K, Simpson, GA, Taylor C, et al. A 
phase I study of Abraxane® adminisetered weekly for three doses every 4 weeks in 
patients with advanced non-hematologic malignancies. Proceedings ASCO, 21: 
abstract 403, 2002. 
 
32. 
O’Shaughnessy JA, Blum JL, Sandach JF, Savin M, Fenske E, Hawkings MJ, et al. 
Weekly nanoparticle-albumin paclitaxel (Abraxane) results in long-term disease 
control in patients with taxane-refractory metastatic breast cancer. Breast Can Res 
Treat 88: abstract 1070, 2004. 
 
33. 
Brady MJ, Cella DF, Mo F, Bonomi AE, Tulsky DS, Lloyd SR, et al: Reliability and 
validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life 
instrument. J Clin Oncol 15: 974-86, 1997. 
 
34. 
Cella D, Peterman A, Hudgens S, Webster K, Socinski MA. Measuring the side 
effects of taxane therapy in oncology: the functional assessment of cancer therapy-
taxane (FACT-taxane). Cancer 98: 822-31, 2003. 
 
35. 
Soussi T, Kato S, Levy, PP, Ishioka, C. Reassessment of the TP53 mutation database 
in human disease by data mining with a library of TP53 missense mutations. Human 
Mutat 25: 6-17, 2004. 
 
36. 
Bau MG, Arisio R, Cristini G, Bertone E, Campogrande M. Screening-detected breast 
carcinoma in a patient with Cowden syndrome. Breast 13:239-41, 2004. 
 
37. 
Pandolfi, Pier P. Breast Cancer – Loss of PTEN Predicts Resistance to Treatment. N 
Engl J Med 351:2337-2338, 2004. 
 
38. 
Zhang D, Bar-Eli M, Meloche S, Brodt P. Dual regulation of MMP-2 expression by 
the type 1 insulin-like growth factor receptor: the phosphatidylinositol 3-kinase/Akt 
and Raf/ERK pathways transmit opposing signals. J Biol Chem 279:19683-90, 2004. 
 
39. 
Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL. Herceptin®-
induced inhibition of phosphatidylinositol 3-kinase and Akt is required for antibody-
mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62:4132-41, 
2002. 
 
40. 
Thimmaiah KN, Easton J, Huang S, Veverka KA, Germain GS, Harwood FC, et al: 
Insulin-like growth factor I-mediated protection from rapamycin-induced apoptosis is 

IRB # 05015 
82 
March 17, 2009 
Version 14 
independent of Ras-Erk1-Erk2 and phosphatidylinositol 3’-kinase-Akt signaling 
pathways. Cancer Res 63:364-74, 2003. 
 
41. 
Bacus SS, Altomare DA, Lyass L, Chin DM, Farrell MP, Gurova K, et al: AKT2 is 
frequently upregulated in HER-2/neu-positive breast cancers and may contribute to 
tumor aggressiveness by enhancing cell survival. Oncogene 21:3532-40, 2002. 
 
42. 
Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, et al: PTEN promoter is 
methylated in a proportion of invasive breast cancers, Int J Cancer 112:407-10, 2004. 
 
43. 
Panigrahi AR, Pinder SE, Chan SY, Paish EC, Robertson JF, Ellis IO. The role of 
PTEN and its signaling pathways, including AKT, in breast cancer; an assessment of 
relationships with other prognostic factors and with outcome. J Pathol 204:93-100, 
2004. 
 
44. 
Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, et 
al: Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64: 7678-
81, 2004. 
 
45. 
Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, et al: The PIK3CA 
gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3: 
772-5, 2004. 
 
46. 
Mills GB, Kohn E, Lu Y, Eder A, Fang X, Wang H, et al: Linking molecular 
diagnostics to molecular therapeutics: targeting the PI3k pathway in breast cancer. 
Semin Oncol 30:93-104, 2003. 
 
47. 
Thompson JE, Thompson CB.  Putting the rap on Akt. J Clin Oncol, 22:4217-26, 
2004. 
 
48. 
Xu G, Zhang W, Bertram P, Zheng XF, McLeod H. Pharmacogenetics profiling of 
the P13K/PTEN-AKT-mTOR pathway in common human tumors. Int J Oncol 
24:893-900, 2004. 
 
49. 
Farhana L, Dawson MI, Huang Y, Zhang Y, Rishi AK, Reddy KB, et al: Apoptosis 
signaling by the novel compound 3-CI-AHPC involves increased EGFR proteolysis 
and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase 
activities. Oncogene 23:1874-84, 2004. 
 
50. 
Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor 
suppressor pathway. J Clin Oncol 22:2954-63, 2004. 
 
51. 
Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE , et al: A 
phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes 
tumor necrosis factor inhibition of insulin signaling through insulin receptor 
substrate-1. Proc Natl Acad Sci USA 98: 4640-5, 2001. 
 

IRB # 05015 
83 
March 17, 2009 
Version 14 
52. 
Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor 
suppressor phosphatase functions as a negative regulator of the phosphoinostide 3-
kinase.Akt pathway. Proc Natl Acad Scu USA 95:15587-91, 1998. 
 
53. 
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. 
Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a 
new model for anti-estrogen resistance. J Biol Chem 276:9817-24, 2001. 
 
54. 
Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, et al: Loss of 
PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the 
antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22:2812-22, 2003. 
 
55. 
Liu Q, Sommer SS. Detection of extremely rare alleles by bidirectional 
pyrophosphorolysis-activated polymerization allele-specific amplification (Bi-PAP-
A): measurement of mutation load in mammalian tissues. Biotechniques 36:156-66, 
2004. 
 
56. 
Page MJ, Amess B, Townsend RR, et al: Proteomic definition of normal human 
luminal and myoepithelial breast cells purified from reduction mammoplasties. Proc 
Natl Acad Sci USA 96:12589, 1996. 
 
57. 
Cowherd SM, Espina VA, Petriocoin EF 3rd, Liotta LA. Proteomic analysis of human 
breast cancer tissue with laser-capture microdessection and reverse-phase protein 
microarrays. Clin Breast Cancer 5: 385-92, 2004. 
 
58. 
Tangrea MA, Chuaqui RF, Gillespie JW, Ahram M, Gannot G, Wallis BS, et al: 
Expression mircodissection: operator-independent retrieval of cells for molecular 
profiling.  Diagn Mol Pathol 13:207-12, 2004. 
 
59. 
Posadas EM, Simpkins F, Liotta LA, MacDonald C, Kohn EC. Proteomic analysis for 
the early detection and rational treatment of cancer – realistic hope? Ann Oncol 16: 
16-22, 2005. 
 
60. 
Jones MD, Krutzsch H, Shu H, Zhao Y, Liotta LA, Kohn EC, et al: Proteomic 
analysis and identification of new biomarkers and therapeutic target for invasive 
ovarian cancer.  Proteomics 2:76-84, 2002. 
 
61. 
Pawlik TM, Fritsche H, Coombes KR, et al: Significant differences in ductal fluid 
protein expression in healthy women versus those with breast cancer identified by 
time-of-flight mass spectrometry. Breast Can Res Treat 88: A5018, 2004 
 
62. 
Sanders ME, XU BJ, Shakhtour B, et al: Protein profiling by MALSI-MS classifies 
breast tumors with high accuracy and distinguishes ductal carcinoma in situ from 
invasive mammary carcinoma. Breast Can Res Treat 88: S9, 2004. 
 
63. 
Mann M, Hendrickson RC, Pandey A. Analysis of proteins and proteomes by mass 
spectrometry. Annu Rev Biochem 70:437, 2001. 
 

IRB # 05015 
84 
March 17, 2009 
Version 14 
64. 
Banks RE, Dunn MJ, Forbes MA, et al: The potential use of laser capture 
microdissection to selectively obtain distinct populations of cells for proteomic 
analysis – preliminary findings. Electrophoresis 20:689, 1999. 
 
65. 
Emmert-Buck MR, Strausberg RL, Krizman DB, et al: Molecular profiling of clinical 
tissue specimens: feasibility and applications. Am J Pathol 156:1109, 2000. 
 
66. 
Paweletz CP, et al: Rapid protein profiling of cancer progression directly from human 
tissue using a protein biochip. Drug Dev Res 49:34, 2000. 
 
67. 
Li J, Zhang Z, Rosenzweig J, et al: Proteomics and bioinformatics approaches for 
identification of serum biomarkers to detect breast cancer. Clin Chem 48: 1296-1314, 
2002. 
 
68. 
Rui Z, Jian-Guo J, Yuan-Peng T, et al: Use of serological proteomic methods to find 
biomarkers associated with breast cancer. Proteomics 4:433, 2003. 
 
69. 
Mundhenke C, Meinhold-Heerlein I, van Bergen M, et al: Detection of DCIS and 
invasive ductal carcinoma in human serum by protein profiling (SELDI). Breast Can 
Res Treat 88: S9, 2004. 
 
70. 
Somlo G, Schneider S, Chu P, Ye W, Frankel P, Ruel C, et al: Gene and protein 
expression profile and prognosis in high-risk primary breast cancer PASCO 22:852s, 
2004. 
 
71. 
Caldwell RL, Caprioli RM. Tissue profiling by mass spectrometry: A review of 
methodlolgy and applications. Mos Cell Proteomics Epub, 2005. 
 
72. 
Reyzer ML, Caldwell RL, Dugger TC, Forbes JT, Ritter CA, Guiz M, et al. Early 
changes in protein expression detected by mass spectrometry predict tumor response 
to molecular therapeutics. Cancer Res 64:9093-100, 2004. 
 
73. 
Martin K, Steinberg TH, Cooley LA, Gee KR, Beechem JM, Patton WF. Quantitative 
analysis of protein phosphorylation status and protein kinase activity on microarrays 
using a novel fluorescent phosphorylation sensor dye.  Proteomics 3:1244-55, 2004. 
 
74. 
Carr KM, Rosenblatt K, Petricoin EF, Liotta LA, Genomic and proteomic approaches 
to study human cancer: prospects for true patient-tailored therapy. Annu Rev 
Genomics Hum Genet 1: 32, 2003. 
 
75. 
Li, TK and Liu, LF. Tumor cell death induced by topoisomerase-targeting drugs. Annu Rev 
Pharmacol Toxicol  41: 53-77, 2001. 
 
76. 
Motoyama, N and Naka, K. DNA damage tumor suppressor genes and genomic instability. 
Curr Opin Genet Dev 14: 11-6, 2004. 
 
77. 
Norbury, CJ and Zhivotovsky, B. DNA damage-induced apoptosis. Oncogene 23: 2797-808, 
2004. 

IRB # 05015 
85 
March 17, 2009 
Version 14 
 
78. 
Shiloh, Y, Andegeko, Y, and Tsarfaty, I. In search of drug treatment for genetic defects in the 
DNA damage response: the example of ataxia-telangiectasia. Semin Cancer Biol 14: 295-305, 
2004. 
 
79. 
Pearce, AK and Humphrey, TC. Integrating stress-response and cell-cycle checkpoint 
pathways. Trends Cell Biol 11: 426-33, 2001. 
 
80. 
Abraham, RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes 
Dev; 15: 2177-96, 2001. 
 
81. 
Rouse, J and Jackson, SP. Interfaces between the detection, signaling, and repair of DNA 
damage. Science; 297: 547-51, 2002. 
 
82. 
Reeves, R. Molecular biology of HMGA proteins: hubs of nuclear function. Gene; 277: 63-
81, 2001. 
 
83. 
Zhou, X, Benson, KF, Ashar, HR, and Chada, K. Mutation responsible for the mouse pygmy 
phenotype in the developmentally regulated factor HMGI-C. Nature; 376: 771-4, 1995. 
 
84. 
Hirning-Folz, U, Wilda, M, Rippe, V, Bullerdiek, J, and Hameister, H. The expression pattern 
of the Hmgic gene during development. Genes Chromosomes Cancer; 23: 350-7, 1998. 
 
85. 
Langelotz, C, Schmid, P, Jakob, C, et al. Expression of high-mobility-group-protein HMGI-C 
mRNA in the peripheral blood is an independent poor prognostic indicator for survival in 
metastatic breast cancer. Br J Cancer; 88: 1406-10, 2003. 
 
86. 
Sezer, O, Langelotz, C, Blohmer, JU, et al. Detection of HMGI-C in the peripheral blood of 
breast cancer patients. Eur J Cancer; 36: 1944-8, 2000. 
 
87. 
Symmans WF, Ayers M, Clark EA, et al: Total RNA yield and microarray gene 
expression profiles from fine-needle aspiration biopsy and core-needle biopsy 
samples of breast carcinoma. Cancer 97:2960-2971, 2003. 
 
88. 
Ellis M, Davis N, Coop A, et al: Development and validation of a method for using 
breast core needle biopsies for gene expression microarray analyses. Clin Cancer Res 
8:1155-1166, 2002. 
 
89. 
DeRisi J, Penland L, Brown PO, et al: Use of cDNA microarray to analyse gene 
expression patterns in human cancer. Nature Genet 14:457-460, 1996. 
 
90. 
Rosenwald A, Wright G, Wiestner A, et al: The proliferation gene expression 
signature is a quantitative integrator of oncogenic events that predicts survival in 
mantle cell lymphoma. Cancer Cell 3:185-197, 2003. 
 
91. 
Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumors. 
Nature 406:747, 2000. 
 

IRB # 05015 
86 
March 17, 2009 
Version 14 
92. 
van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al: A gene 
expression signature as a predictor of survival in breast cancer. N Engl J Med 
347:1999-2009, 2002. 
 
93. 
Sorlie T. Perou CM, Tibshirani R, et al: Gene expression patterns of breast 
carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad 
Sci USA 98:10869-10874, 2001. 
 
94. 
Hedenfalk I, Duggan D, Chen Y, et al: Gene-expression profiles in hereditary breast 
cancer. N Engl J Med 344:539-548, 2001. 
 
95. 
Gruvberger S, Ringner M, Chen Y, et al: Estrogen receptor status in breast cancer is 
associated with remarkably distinct gene expression patterns. Cancer Res 61: 5979-
5984, 2001. 
 
96. 
Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al: A multigene assay to 
predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 
351:2817-26, 2004. 
 
97. 
Thor AD, Berry DA, Budman DR, et al: erbB-2, p53, and efficacy of adjuvant 
therapy in lymph nose-positive breast cancer. J Natl Cancer Inst90:1346-1360, 1998. 
 
98. 
Ayers M, Summans WF, Stec J, et al: Gene expression profiles predict complete 
pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and 
cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22: 2284-2293, 2004. 
 
99. 
Chang JC, Wooten EC, Tsimelzon A, et al: Gene expression profiling for the 
prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 
362:362-369, 2003. 
 
100. 
Rouzier R, Anderson K, Hess KR, et al: Basal and luminal types of breast cancer 
defined by gene expression patterns respond differently to neoadjuvant 
chemotherapy. Breast Can Res Treat 88: A201, 2004. 
 
101. 
Pusztai L, Rouzier R, Rajan R, et al: Microtubule associated protein Tau is a 
predictive marker and modulator of response to paclitaxel-containing preoperative 
chemotherapy in breast cancer. Breast Can Res Treat 88: A112, 2004. 
 
102. 
Pusztai L, Wang J, Coombes K, Hoersch S, Ayers M, Ross J, et al: Cross platform 
comparison of multigene predictors of response to neoadjuvant paclitaxel/FAC 
chemotherapy in breast cancer generated by cDNA arrays and Affymetrix 
GeneChips. Proc Am Soc Clin Oncol 22:3s, 2004. 
 
103. 
Evans WE, McLeod HL.  Pharmacogenomics: drug disposition, drug targets, and side 
effects. N Engl J Med 348:538, 2003. 
 

IRB # 05015 
87 
March 17, 2009 
Version 14 
104. 
Lenz H, Dannenberg K, Leichman C, et al: p53 status, thymidylate synthase levels 
are predictors of chemotherapy efficacy in patients with advanced colorectal cancer. 
Proc Am Soc Clin Oncol 15:504, 1996. 
 
105. 
S. Marsh, G. Somlo, H. L. McLeod, X. Li, P. Frankel, C. R. King, W. D. Shannon, T. 
W. Synold: Pharmacogenetic analysis of paclitaxel in breast cancer.  Submitted for 
Proc Am Soc Clin Oncol 2005. 
 
106. 
Martin RC, Edwards MJ, Wong SL, et al.  Practical guidelines for optimal gamma 
probe detection of sentinel lymph nodes in breast cancer: results of a multi-
institutional study. Surgery. 2000;128:139-44. 
 
107. 
McMasters KM, Tuttle TM, Carlson DJ, et al.  Sentinel lymph node biopsy for breast 
cancer: a suitable alternative to routine axillary dissection in multi-institutional 
practice when optimal technique is used. J Clin Oncol 2000;18:2560-6. 
 
108. 
McMasters KM, Wong SL, Tuttle TM, et al.  Preoperative lymphoscintigraphy for 
breast cancer does not improve the ability to identify sentinel lymph nodes. Ann Surg 
2000;231:724-31. 
 
109. 
Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer – a 
multicenter validation study. N Engl J Med 1998;339:941-946. 
 
110. 
Giuliano AE, Kirgan DM, Guenther JM, and Morton DL. Lymphatic mapping and 
sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391-401. 
 
111. 
Krag DN, Weaver DL, Alex JC, and Fairbank JT. Surgical resection and 
radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. 
Surg Oncol 1993;2:335-340. 
 
112. 
Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy 
in the patient with breast cancer. JAMA 1996;276:1818-22. 
 
113. 
Reynolds C, Mick R, Donohue JH, et al. Sentinel lymph node biopsy with metastasis: 
can axillary dissection be avoided in some patients with breast cancer? J Clin Oncol. 
1999;17:1720-6. 
 
114. 
Chu KU, Turner RR, Hansen NM, et al. Do all patients with sentinel node metastasis 
from breast carcinoma need complete axillary node dissection? Ann Surg. 
1999;229:536-41. 
 
115. 
Wong SL, Edwards MJ, Chao C, et al. Predicting the status of the nonsentinel axillary 
nodes: a multicenter study. Arch Surg. 2001;136:563-8. 
 
116. 
Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogram for predicting the 
likelihood of additional nodal metastases in breast cancer patients with a positive 
sentinel node biopsy. Ann Surg Oncol. 2003;10:1140-51. 
 
03/22/06 

IRB # 05015 
88 
March 17, 2009 
Version 14 
117. 
Turner RR, Chu KU, Qi K, et al. Pathologic features associated with nonsentinel 
lymph node metastases in patients with metastatic breast carcinoma in a sentinel 
lymph node. Cancer. 2000;89:574-81. 
 
118. 
Hwang RF, Krishnamurthy S, Hunt KK, et al. Clinicopathologic factors predicting 
involvement of nonsentinel axillary nodes in women with breast cancer. Ann Surg 
Oncol. 2003;10:248-54. 
 
119. 
Kamath VJ, Giuliano R, Dauway EL, et al. Characteristics of the sentinel lymph node 
in breast cancer predict further involvement of higher-echelon nodes in the axilla: a 
study to evaluate the need for complete axillary lymph node dissection. Arch Surg. 
2001;136:688-92. 
 
120. 
Abdessalam SF, Zervos EE, Prasad M, et al. Predictors of positive axillary lymph 
nodes after sentinel lymph node biopsy in breast cancer. Am J Surg. 2001;182:316-
20. 
 
121. 
Degnim AC, Griffith KA, Sabel MS, et al. Clinicopathologic features of metastasis in 
nonsentinel lymph nodes of breast carcinoma patients. Cancer. 2003;98:2307-15. 
 
122. 
Fisher ER, Wang J, Bryant J, et al. Pathobiology of preoperative chemotherapy: 
findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol 
B-18. Cancer. 2002;95:681-95. 
 
123. 
Reitsamer R, Peintinger F, Rettenbacher L, Prokop E. Sentinel lymph node biopsy in 
breast cancer patients after neoadjuvant chemotherapy. J Surg Oncol. 2003; 84:63-7. 
 
124. 
Haid A, Tausch C, Lang A, et al. Is sentinel lymph node biopsy reliable and indicated 
after preoperative chemotherapy in patients with breast carcinoma? Cancer. 2001 
92:1080-4. 
 
125. 
Balch GC, Mithani SK, Richards KR, et al. Lymphatic mapping and sentinel 
lymphadenectomy after preoperative therapy for stage II and III breast cancer. Ann 
Surg Oncol. 2003;10:616-21. 
 
126. 
Tafra L, Verbanac KM, Lannin DR. Preoperative chemotherapy and sentinel 
lymphadenectomy for breast cancer. Am J Surg. 2001;182:312-5. 
 
127. 
Miller AR, Thomason VE, Yeh IT, et al. Analysis of sentinel lymph node mapping 
with immediate pathologic review in patients receiving preoperative chemotherapy 
for breast carcinoma. Ann Surg Oncol. 2002;9:243-7 
 
128. 
Stearns V, Ewing CA, Slack R, Penannen MF, et al. Sentinel lymphadenectomy after 
neoadjuvant chemotherapy for breast cancer may reliably represent the axilla except 
for inflammatory breast cancer. Ann Surg Oncol. 2002; 9:235-42. 
 
129. 
Breslin TM, Cohen L, Sahin et al. Sentinel lymph node biopsy is accurate after 
neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2000;18:3480-6. 

IRB # 05015 
89 
March 17, 2009 
Version 14 
 
130. 
Mamounas EP. Sentinel lymph node biopsy after neoadjuvant systemic therapy. Surg 
Clin North Am. 2003;83:931-42. 
 
131. 
Nason KS, Anderson BO, Byrd DR, et al. Increased false negative sentinel node 
biopsy rates after preoperative chemotherapy for invasive breast carcinoma. Cancer. 
2000;89:2187-94. 
 
132. 
Donnelly J, Parham DM, Hickish T, Chan HY, Skene AI. Axillary lymph node 
scarring and the association with tumour response following neoadjuvant 
chemoendocrine therapy for breast cancer. Breast. 2001 Feb;10(1):61-6. 
 
133. 
Sabel MS, Schott AF, Kleer CG, et al. Sentinel node biopsy prior to neoadjuvant 
chemotherapy. Am J Surg. 2003;186:102-5. 
 
134. 
Schrenk P, Hochreiner G, Fridrik M, Wayand W. Sentinel node biopsy performed 
before preoperative chemotherapy for axillary lymph node staging in breast cancer. 
Breast J. 2003; 9:282-7. 
 
135. 
Chaudhry V, Chaudhry M., Crawford TO, Simmons-O’Brien E, Griffin JW: Toxic 
neuropathy in patients with pre-existing neuropathy.  Neurology 60: 337-340, 2003. 
 
136. 
Openshaw, H., Beamon, K., Longmate, J., Synold, T., Slatkin, N.E., Somlo, G. The 
effect of height on paclitaxel nerve damage. J Neurooncology, 74: 207-10, 2005. 
 
137. 
Lipton RB, Apfel SC, Dutcher JP, Rosenberg R, Kaplan J, Berger A, Einzig AI, 
Wiernik P, Schamburg HH: Taxol produces a predominantly sensory neuropathy. 
Neurology 39: 368-373, 1989. 
 
138. 
Postma, T.J., Heimans, J.J., Muller, M.J., Ossenkoppele, G.J., Vermorken, J.B., and 
Aaronson, N.K., Pitfalls in grading severity of chemotherapy-induced peripheral 
neuropathy. Ann Oncol, 9: 739-44, 1998. 
 
139. 
Slevin, M.L., Plant, H., Lynch, D., Drinkwater, J., and Gregory, W.M., Who should 
measure quality of life, the doctor or the patient? Br J Cancer, 57: 109-12, 1988. 
 
140. 
Openshaw H, Beamon K, Synold TW, Slatkin N, Longmate J, Doroshow J, Somlo G:  
Neurophysiological study of peripheral neuropathy after high dose paclitaxel: lack of 
neuroprotective effect of amifostine. Clin Cancer Res 10:  461-467, 2004. 
 
141. 
Clarke MF and Becker MW.  Stem Cells: The real Culprits in Cancer?  Sci Am 295: 
52-9, 2006. 
 
142. 
Clarke MF and Fuller M. Stem Cells and Cancer: Two faces of Eve. Cell 124: 1111-
15, 2006. 
 
143. 
Clarke MF. A self-renewal assay for cancer stem cells. Cancer Chemother 
Pharmacol 56 (Suppl 1): s64-s68, 2005. 

IRB # 05015 
90 
March 17, 2009 
Version 14 
 
144. 
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF.  Prospective 
identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100: 3893-
88, 2003. 
 
145. 
Bafico A, Liu G, Goldin L, Harris V, Aaronson SA.  An autocrine mechanism for 
constitutive Wnt pathway activation in human cancer cells.  Cancer Cell 6: 497-506, 
2004. 
 
146. 
Ibrahim NK, Samuels B, Page R, et al.  Nanoparticle paclitaxel (ABI-007) in 
metastatic breast cancer (MBC): efficacy and evidence of dose-dependent activity in 
two multicenter phase II studies. Proc ASCO 2002 (abstract 209). 
 
147. 
Investigator’s Brochure, American BioScience, Inc. 
 
148. 
Dyck PJ, Zimmerman I, Gillen D, Johnson D, Karnes JL, O’Brien PC : Cool, warm, 
and heat-pain detection thresholds: testing methods and inferences about anatomic 
distribution of receptors. Neurology 43: 1500-1508, 1993. 
 
149. 
Chaudhry, V., Rowinsky, E.K., Sartorius, S.E., Donehower, R.C., and Cornblath, 
D.R., Peripheral neuropathy from taxol and cisplatin combination chemotherapy: 
clinical and electrophysiological studies. Ann Neurol, 35: 304-11, 1994. 
 
150. 
Ihaka R, Gentleman R. A language for data analysis and graphics. J Comput Graph 
Stat 5:299-314, 1996. 
 
151. 
R Development Core Team. A language and environment for statistical computing.  
Vienna, Austria: R Foundation for Statistical Computing, 2003. 
 
152. 
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U,l et al. 
Exploration, normalization, and summaries of high density oligonucleotide array 
probe level data.  Biostaticstics 4:249-264, 2003. 
 
153. 
Zhao LP, Prentice RL, and Breeden LL. Statistical modeling of large microarray data 
sets to identify stimulus-response profiles. PNAS 98:5631-3636, 2001. 
 
154. 
Prentice RL, Zhao LP. Estimating equations for parameters in means and covariance 
of multivariate discrete continuous responses.  Biometrics 47:825-839, 1991. 
 
155. 
Benjamini Y, Hochberg, Y. On the adaptive control of the false discovery rate in 
multiple testing with independent statistics. Journal of Educational and Behavioral 
Statistics 25:60-83, 2000. 

IRB # 05015 
91 
March 17, 2009 
Version 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) version 3 
 
 
 
 
CTEP home page http://ctep.cancer.gov/reporting/ctc.html 

IRB # 05015 
92 
March 17, 2009 
Version 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B 
 
 
QUALITY OF LIFE QUESTIONNAIRES 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
FACT-Taxane (Version 4) 
US English 
 
4/30/2009 
Copyright  1987, 1997 
 
Page 93 of 3 
 
Below is a list of statements that other people with your illness have said are important. By  
circling one (1) number per line, please indicate how true each statement has been for 
you during the past 7 days. 
 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GP1 
I have a lack of energy....................................................
...............................................................................
 
0 
1 
2 
3 
4 
 
GP2 
I have nausea.....................................................................
 
0 
1 
2 
3 
4 
 
GP3 
Because of my physical condition, I have trouble  
meeting the needs of my family........................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GP4 
I have pain.........................................................................
 
0 
1 
2 
3 
4 
 
GP5 
I am bothered by side effects of treatment........................
 
0 
1 
2 
3 
4 
 
GP6 
I feel ill..............................................................................
 
0 
1 
2 
3 
4 
 
GP7 
I am forced to spend time in bed ...............................  
 
0 
1 
2 
3 
4 
 
 
 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GS1 
I feel close to my friends...................................................
 
0 
1 
2 
3 
4 
 
GS2 
I get emotional support from my family...........................
 
0 
1 
2 
3 
4 
 
GS3 
I get support from my friends ...........................................
 
0 
1 
2 
3 
4 
 
GS4 
My family has accepted my illness...................................
 
0 
1 
2 
3 
4 
 
GS5 
I am satisfied with family communication about my 
illness ................................................................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GS6 
I feel close to my partner (or the person who is my 
main support) ....................................................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
Regardless of your current level of sexual activity, please  
answer the following question.  If you prefer not to answer  
it, please check this box           and go to the next section.     
     
  
     
 
 
     
 
 
Q1 
 
 
 
 
 
 
GS7 
I am satisfied with my sex life.......................................  
0 
1 
2 
3 
4 

 
FACT-Taxane (Version 4) 
US English 
 
4/30/2009 
Copyright  1987, 1997 
 
Page 94 of 3 
 
By circling one (1) number per line, please indicate how true each statement has been for you 
during the past 7 days. 
 
 
 
 
 
EMOTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GE1 
I feel sad......................................................................... 
 
0 
1 
2 
3 
4 
 
GE2 
I am satisfied with how I am coping with my illness ... 
 
0 
1 
2 
3 
4 
 
GE3 
I am losing hope in the fight against my illness.................
 
0 
1 
2 
3 
4 
 
GE4 
I feel nervous......................................................................
 
0 
1 
2 
3 
4 
 
GE5 
I worry about dying............................................................
 
0 
1 
2 
3 
4 
 
GE6 
I worry that my condition will get worse...........................
 
0 
1 
2 
3 
4 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GF1 
I am able to work (include work at home).........................
 
0 
1 
2 
3 
4 
 
GF2 
My work (include work at home) is fulfilling ...................
 
0 
1 
2 
3 
4 
 
GF3 
I am able to enjoy life ........................................................
 
0 
1 
2 
3 
4 
 
GF4 
I have accepted my illness .................................................
 
0 
1 
2 
3 
4 
 
GF5 
I am sleeping well..............................................................
 
0 
1 
2 
3 
4 
 
GF6 
I am enjoying the things I usually do for fun.....................
 
0 
1 
2 
3 
4 
 
GF7 
I am content with the quality of my life right now ............
 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 

 
FACT-Taxane (Version 4) 
US English 
 
4/30/2009 
Copyright  1987, 1997 
 
Page 95 of 3 
By circling one (1) number per line, please indicate how true each statement has 
been for you during the past 7 days. 
 
 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
NTX
1 
I have numbness or tingling in my hands ..........................
 
0 
1 
2 
3 
4 
 
NTX
2 
I have numbness or tingling in my feet..............................
 
0 
1 
2 
3 
4 
 
NTX
3 
I feel discomfort in my hands ...........................................
 
0 
1 
2 
3 
4 
 
NTX
4 
I feel discomfort in my feet................................................
 
0 
1 
2 
3 
4 
 
NTX
5 
I have joint pain or muscle cramps ....................................
 
0 
1 
2 
3 
4 
 
HI12 
I feel weak all over.............................................................
 
0 
1 
2 
3 
4 
 
NTX
6 
I have trouble hearing ........................................................
 
0 
1 
2 
3 
4 
 
NTX
7 
I get a ringing or buzzing in my ears .................................
 
0 
1 
2 
3 
4 
 
NTX
8 
I have trouble buttoning buttons ........................................
 
0 
1 
2 
3 
4 
 
NTX
9 
I have trouble feeling the shape of small objects  
when they are in my hand..................................................
 
0 
1 
2 
3 
4 
 
An6 
I have trouble walking .......................................................
 
0 
1 
2 
3 
4 
 
Tax1 
I feel bloated ......................................................................
 
0 
1 
2 
3 
4 
 
Tax2 
My hands are swollen ........................................................
 
0 
1 
2 
3 
4 
 
Tax3 
My legs or feet are swollen................................................
 
0 
1 
2 
3 
4 
 
Tax4 
I have pain in my fingertips ...............................................
 
0 
1 
2 
3 
4 
 
Tax5 
I am bothered by the way my hands or nails look .............
 
0 
1 
2 
3 
4 
 

 
FACT-B (Version 4) 
US English 
 
4/30/2009 
Copyright 1987, 1997 
Page 96 of 3 
 
 
Below is a list of statements that other people with your illness have said are important. By  
circling one (1) number per line, please indicate how true each statement has been for 
you during the past 7 days. 
 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GP1 
I have a lack of energy....................................................
........................................................................................ 
 
0 
1 
2 
3 
4 
 
GP2 
I have nausea.....................................................................
 
0 
1 
2 
3 
4 
 
GP3 
Because of my physical condition, I have trouble  
meeting the needs of my family........................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GP4 
I have pain.........................................................................
 
0 
1 
2 
3 
4 
 
GP5 
I am bothered by side effects of treatment........................
 
0 
1 
2 
3 
4 
 
GP6 
I feel ill..............................................................................
 
0 
1 
2 
3 
4 
 
GP7 
I am forced to spend time in bed.....................................
 
0 
1 
2 
3 
4 
 
 
 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GS1 
I feel close to my friends...................................................
 
0 
1 
2 
3 
4 
 
GS2 
I get emotional support from my family...........................
 
0 
1 
2 
3 
4 
 
GS3 
I get support from my friends ...........................................
 
0 
1 
2 
3 
4 
 
GS4 
My family has accepted my illness...................................
 
0 
1 
2 
3 
4 
 
GS5 
I am satisfied with family communication about my 
illness ................................................................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GS6 
I feel close to my partner (or the person who is my 
main support) ....................................................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
Regardless of your current level of sexual activity, please  
answer the following question.  If you prefer not to answer  
it, please check this box           and go to the next section.     
     
  
     
 
 
     
 
 
Q1 
 
 
 
 
 
 
GS7 
I am satisfied with my sex life.......................................  
0 
1 
2 
3 
4 

 
FACT-B (Version 4) 
US English 
 
4/30/2009 
Copyright 1987, 1997 
Page 97 of 3 
 
By circling one (1) number per line, please indicate how true each statement has 
been for you during the past 7 days. 
 
 
 
 
 
EMOTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GE1 
I feel sad.......................................................................... 
 
0 
1 
2 
3 
4 
 
GE2 
I am satisfied with how I am coping with my illness .....
 
0 
1 
2 
3 
4 
 
GE3 
I am losing hope in the fight against my illness.................
 
0 
1 
2 
3 
4 
 
GE4 
I feel nervous......................................................................
 
0 
1 
2 
3 
4 
 
GE5 
I worry about dying............................................................
 
0 
1 
2 
3 
4 
 
GE6 
I worry that my condition will get worse...........................
 
0 
1 
2 
3 
4 
 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GF1 
I am able to work (include work at home).........................
 
0 
1 
2 
3 
4 
 
GF2 
My work (include work at home) is fulfilling ...................
 
0 
1 
2 
3 
4 
 
GF3 
I am able to enjoy life ........................................................
 
0 
1 
2 
3 
4 
 
GF4 
I have accepted my illness .................................................
 
0 
1 
2 
3 
4 
 
GF5 
I am sleeping well..............................................................
 
0 
1 
2 
3 
4 
 
GF6 
I am enjoying the things I usually do for fun.....................
 
0 
1 
2 
3 
4 
 
GF7 
I am content with the quality of my life right now ............
 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 

 
FACT-B (Version 4) 
US English 
 
4/30/2009 
Copyright 1987, 1997 
Page 98 of 3 
By circling one (1) number per line, please indicate how true each statement has 
been for you during the past 7 days. 
 
 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
B1 
I have been short of breath.................................................
 
0 
1 
2 
3 
4 
 
B2 
I am self-conscious about the way I dress .........................
 
0 
1 
2 
3 
4 
 
B3 
One or both of my arms are swollen or tender...................
 
0 
1 
2 
3 
4 
 
B4 
I feel sexually attractive.....................................................
 
0 
1 
2 
3 
4 
 
B5 
I am bothered by hair loss............................................... 
 
0 
1 
2 
3 
4 
 
B6 
I worry that other members of my family might 
someday get the same illness I have ...........................
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
B7 
I worry about the effect of stress on my illness .................
 
0 
1 
2 
3 
4 
 
B8 
I am bothered by a change in weight .................................
 
0 
1 
2 
3 
4 
 
B9 
I am able to feel like a woman...........................................
 
0 
1 
2 
3 
4 
 
P2 
I have certain parts of my body where I experience 
significant pain...................................................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX C 
 
 
Interview Guide for Barriers of Care  
in Locally Advanced Breast Cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
Delays in Care in Locally Advanced Breast Cancer 
Interview Guide ** 
We are interested in knowing the issues involved in women who experienced a delay in seeking 
a diagnosis or care after experiencing breast symptoms.  
 
 
1.  Can you tell me about the first time from when you had symptoms of your breast 
until when you first got medical care by an oncologist? 
 
 
 
2.  Were there are are there fears or beliefs that might have influenced your decisions 
in seeking treatment by an oncologist? 
 
 
 
3.  Were there delays in getting appropriate diagnostic studies and treatment related to 
your health care providers? 
 
 
 
4. Are there any financial issues (health plans, insurance) that delayed getting 
treatment by an oncologist? 
 
 
 
** A meeting was convened with City of Hope Staff, George Somlo, M.D., Betty Ferrell, PhD, 
Gloria Juarez, RN, PhD, Virginia Sun, RN, MSN, Connie Munoz, MSW, Nellie Garcia, MSW 
and Annette Mercurio, to discuss barriers to women seeking diagnoses and care after 
experiencing breast symptoms. Questions for the interview guide were derived based on the 
clinical experiences of the researchers and review of the literature. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX D 
 
 
Neuropathic Pain Symptom Inventory 
 

 
 
 
 
 
Date: 
 
First name: 
 
 
 
 
 
 
Last name: 
 
Sex: 
 
Age: 
 
 
You are suffering from pain due to injury or disease of the nervous system.  This pain 
may be of several types.  You may have spontaneous pain, i.e. pain in the absence of any 
stimulation, which may be long-lasting or occur as brief attacks.  You may also have pain  
provoked or increased by brushing, pressure, or contact with cold in the painful area.  You may 
feel one or several types of pain.  This questionnaire has been developed to help your doctor to 
better evaluate and treat various types of pain you feel. 
 
 
We wish to know if you feel spontaneous pain, that is pain without any stimulation.  For 
each of the following questions, please select the number that best describes your average 
spontaneous pain severity during the past 24 h.  Select the number 0 if you have not felt such 
pain (circle one number only). 
 
Q1.  Does your pain feel like burning? 
No burning 
0    1    2    3    4    5    6    7    8    9    10 
 
 
Worst 
 
 
             
 
 
 
 
 
 
Burning 
 
 
 
 
 
 
 
 
 
 
imaginable 
 
Q2.  Does your pain feel like squeezing? 
No 
 
0    1    2    3    4    5    6    7    8    9    10 
 
 
Worst 
squeezing 
 
 
 
 
 
 
 
 
squeezing 
 
 
 
 
 
 
 
 
 
 
imaginable 
 
Q3.  Does your pain feel like pressure? 
No pressure 
0    1    2    3    4    5    6    7    8    9    10 
 
 
Worst 
 
 
 
 
 
 
 
 
 
 
pressure 
 
 
 
 
 
 
 
 
 
 
imaginable 
 
Q4.  During the past 24 h, your spontaneous pain has been present: 
 
Select the response that best describes your case. 
 
Permanently  
 
 
 
 
 
 
 
/__/ 
Between 8 and 12 h 
 
 
 
 
 
 
 
/__/ 
Between 4 and 7 h 
 
 
 
 
 
 
 
/__/ 
Between 1 and 3 h 
 
 
 
 
 
 
 
/__/ 
Less than 1 h  
 
 
 
 
 
 
 
/__/ 
 
 
We wish to know if you have brief attacks  of pain.  For each of the following questions, 
please select the number that best describes the average severity of your painful attacks during 
the past 24 h.  Select the number 0 if you have not felt such pain (circle one number only). 

 
 
 
 
Q5.  Does your pain feel like electric shocks? 
No electric 
0    1    2    3    4    5    6    7    8    9    10 
 
 
Worst electric 
shocks  
 
 
 
 
 
 
 
 
shocks 
 
 
 
 
 
 
 
 
 
 
imaginable 
 
Q6.  Does your pain feel like stabbing? 
No 
 
0    1    2    3    4    5    6    7    8    9    10 
 
 
Worst 
stabbing 
 
 
 
 
 
 
 
 
stabbing 
 
 
 
 
 
 
 
 
 
 
imaginable 
 
Q7.  During the past 24 h, how many of these pain attacks have you had? 
 
Select the response that best describes you case 
More that 20  
 
 
 
 
 
 
 
/__/ 
Between 11 and 20 
 
 
 
 
 
 
 
/__/ 
Between 6 and 10 
 
 
 
 
 
 
 
/__/ 
Between 1 and 5 
 
 
 
 
 
 
 
/__/ 
No pain attack  
 
 
 
 
 
 
 
/__/ 
 
 
We wish to know if you feel pain provoked or increased by brushing, pressure, contact 
with cold or warmth on the painful area.  For each of the following questions, please select the 
number that best describes the average severity of your provoked pain during the past 24 h.  
Select the number 0 if you have not felt such pain (circle one number only). 
 
Q8.  Is your pain provoked or increased by brushing on the painful area? 
No pain 
0    1    2    3    4    5    6    7    8    9    10 
 
 
Worst pain 
 
 
 
 
 
 
 
 
 
 
Imaginable 
 
Q9.  Is your pain provoked or increased by pressure on the painful area? 
No pain 
0    1    2    3    4    5    6    7    8     9    10 
 
 
Worst pain 
 
 
 
 
 
 
 
 
 
 
imaginable 
 
Q10.  Is your pain provoked or increased by contact with something cold on the painful area? 
No pain 
0    1   2    3    4    5    6    7    8    9    10  
 
Worst pain 
 
 
 
 
 
 
 
 
 
 
Imaginable 
 
 
We wish to know if your feel abnormal sensations in the painful area.  For each of the 
following questions, please select the number that best describes the average severity of your 
abnormal sensations during the past 24 h.  Select the number 0 if you have not felt such sensation 
(circle one number only). 
 
Q11.  Do you feel pins and needles? 
No pins 0    1    2    3    4    5    6    7    8    9    10  
 
Worst pins 
and needles 
 
 
 
 
 
 
 
 
and needles 
 
 
 
 
 
 
 
 
 
 
imaginable 
 
Q12.  Do you feel tingling? 
No tingling 
0    1    2    3    4    5    6    7    8    9    10  
 
Worst tingling 
 
 
 
 
 
 
 
 
 
 
imaginable. 

 
 
 
 
 
Results 
 
Total intensity score 
 
 
 
 
Subscores 
 
 
 
 
 
 
 
 
Burning (superficial) 
 
 
 
 
 
 
 
Spontaneous pain: 
1. 
Q1 = 
 
 
 
 
 
Q1 = 
 
 
 
/10 
 
 
 
 
 
 
 
Pressing (deep) 
 
 
 
 
 
 
 
spontaneous pain: 
2. 
(Q2 + Q3) = 
 
 
 
 
(Q2 + Q3)/2 =  
 
/10 
 
 
 
 
 
 
 
Paroxysmal pain: 
3. 
(Q8 + Q9 + Q10) = 
 
 
 
(Q5 + Q6)/2=  
 
/10 
 
 
 
 
 
 
 
Evoked pain: 
4.  
(Q8 + Q9 + Q10) = 
 
 
 
(Q8+Q9+Q10)/3= 
 
/10 
 
 
 
 
 
 
 
Paresthesia/dysesthesia: 
5. 
(Q11 + Q12) =  
 
 
 
(Q11 + Q12)/2 = 
 
/10 
 
(1 + 2 + 3 + 4 + 5) =  /100 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX E 
 
 
 
 
ABRAXIS SAE REPORTING FORM 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
 Fax form to: SAE Coordinator at 919-433-8402 
and Abraxis Oncology at 908-393-8304 
 
Email: SAE-REPORTING@abraxisbio.com and 
AbraxisMedAffairs@abraxisbio.com 
Tel: 919-433-8515 or 919-606-1832 (24 hours) 
1. Report Status:  
  Initial     
  Follow-up # 
 
2. Date of this Report:  
    
    
 
                                          DD                  MMM                          YYYY 
3. SAE occurred in:   
  Cycles 1-4     
  Cycles 5-8       
  Cycles 9-18 
4. Date of Birth 
  
  
  
      DD                  MMM                         YYYY  
5. Gender  
  Male 
  Female 
6. Height and Weight 
.
 cm   
.
 kg 
7. Race 
  Asian 
  Black, of African Heritage 
  Native Hawaiian or Other Pacific Islander 
  North American Indian or Alaska Native 
  White, Non-Hispanic and Non-Latino 
  White, Hispanic or Latino 
  Other, specify: ____________________ 
8. Reason for reporting (Check all that apply.) 
  Death*  (* Please attach death certificate) 
  Life-threatening (Immediately Life Threatening) 
  Required/prolonged hospitalization on  
      
  
   
 
            DD                  MMM                        YYYY            
 
  Persistent or significant disability/incapacity 
  Congenital anomaly/birth defect 
  Important medical event, * 
          Specify: _________________________________________
*   An important medical event is an event that requires medical or surgical 
intervention to prevent one of the other outcomes listed above 
 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
9. Diagnosis/Adverse Event Term                              Is this event cardiac in nature?    Yes 
       No 
     
 
 
10. Onset Date 
  
  
 
  
       DD                  MMM                        YYYY            
11. Resolution Date 
  
  
  
  
        DD                 MMM                        YYYY           
12. Outcome (Check one.) 
  Resolved                           
  Ongoing          
  This event ongoing at the time of death 
  Resolved with sequelae    
  Death (Check only for event that was primary cause of death.) 
 
IN CASE OF DEATH 
13. Date of Death 
  
  
 
       DD                   MMM                             YYYY  
14. Was an autopsy performed?
  Yes (Provide findings.) 
  No 
15. Is death certificate 
attached? 
  Yes 
  No 
  Not Available 
16. Describe Event: (Please include presenting signs and symptoms, relevant tests, procedures, treatment and dates) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
17. Relevant Tests/Lab Data                                                                                                                                                   
If this event is cardiac in nature, please provide this patient’s baseline and most recent echocardiogram results 
(including dates). 
 
 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
 
18. Treatment of the Event 
Name of Medication 
(Generic) 
Total Daily 
Dose 
Route  
Start Date 
(DD/MMM/YYYY) 
Stop Date 
(DD/MMM/YYYY) 
Indication  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures and/or Surgeries to treat event: 
 
 
 
 
 
 
 
19. Relevant concomitant medications taken within 2 weeks prior to onset of the event (including procedural 
medications)   
Name of Medication 
(Generic) 
Total Daily 
Dose 
Route 
Start Date 
(DD/MMM/YYYY) 
Stop Date 
(DD/MMM/YYYY) 
Indication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20. Relevant Medical History  
 
__________________________                   __________________________                ____________________________ 
 
__________________________                   __________________________                 ____________________________
 
__________________________                   __________________________                 ____________________________
 
Note: Attach additional sheet, if extra space is needed, 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
 
Abraxane (ABI-007) 
21a. Relationship to Abraxane (Check one.) 
 Not Related    
 Possibly Related    
 Probably Related    
 Definitely Related    
 Not Applicable     
22a. Investigator: Comments/Rationale regarding relationship 
 
 
 
23a. Abraxane Lot #:  
 
24a. Abraxane Expiration Date :  
 
25a. Date of  First Dose Abraxane  
    
 
  
  
          DD                   MMM                        YYYY            
26a. Abraxane Initial Dose (Calculated Total Dose) (mg) 
 
27a.  Total Number Doses 
of Abraxane Received 
 
28a. Date of Last Dose Abraxane Prior to SAE 
  
  
  
  
          DD                   MMM                       YYYY            
29a. Last Dose Abraxane Prior to 
SAE (mg) 
 
Action Taken Abraxane 
30a. Changes to Abraxane due to THIS event (Check all that apply): 
  None 
  Dose reduced on   __ __ / __ __ __ / __ __ __ __    to   ______ mg/m2  
                                                    DD           MMM               YYYY 
  Dose delayed on   __ __ / __ __ __ / __ __ __ __    and    Restarted on   __ __ / __ __ __ / __ __ __ __ 
                                                 DD           MMM               YYYY                                                DD           MMM               YYYY 
  Dose interrupted on   __ __ / __ __ __ / __ __ __ __ 
                                                              DD           MMM               YYYY 
  Permanently Discontinued on   __ __ / __ __ __ / __ __ __ __ 
                                                                              DD          MMM               YYYY 
31a. Did event abate after stopping or reducing Abraxane? 
   Yes    
   No    
   Not Applicable 
32a. If interrupted, did event reappear after reintroduction of Abraxane? 
   Yes    
   No    
   Not Applicable 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
 
Other Agent in Combination (specify):__________
 
(Complete sections 21b-32b in reference to the specified agent noted)   
21b. Relationship to agent (Check one.) 
 Not Related    
 Possibly Related    
 Probably Related    
 Definitely Related    
 Not Applicable    
22b. Investigator: Comments/Rationale regarding relationship to agent 
 
 
 
23b. Lot #:  
 
24b. Expiration Date :  
 
25b. Date of  First Dose 
    
 
  
  
          DD                   MMM                        YYYY            
26b. Initial Dose (Calculated Total Dose)  
 
27b.  Total Number Doses 
Received 
 
28b. Date of Last Dose Prior to SAE 
  
  
  
  
          DD                   MMM                       YYYY            
29b. Last Dose Prior to SAE (mg) 
 
Action Taken 
30b. Changes to agent due to THIS event (Check all that apply): 
  None 
  Dose reduced on   __ __ / __ __ __ / __ __ __ __    to   ______ mg/kg  
                                                    DD           MMM               YYYY 
  Dose delayed on   __ __ / __ __ __ / __ __ __ __    and    Restarted on   __ __ / __ __ __ / __ __ __ __ 
                                                 DD           MMM               YYYY                                                DD           MMM               YYYY 
  Dose interrupted on   __ __ / __ __ __ / __ __ __ __ 
                                                              DD           MMM               YYYY 
  Permanently Discontinued on   __ __ / __ __ __ / __ __ __ __ 
                                                                              DD          MMM               YYYY 
31b. Did event abate after stopping or reducing the agent? 
   Yes    
   No    
   Not Applicable 
32b. If interrupted, did event reappear after reintroduction of agent? 
   Yes    
   No    
   Not Applicable 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
 
Other Agent in Combination (specify):__________
 
(Complete sections 21c-32c in reference to the specified agent noted)   
21c. Relationship to agent (Check one.) 
 Not Related    
 Possibly Related    
 Probably Related    
 Definitely Related    
 Not Applicable    
22c. Investigator: Comments/Rationale regarding relationship to agent 
 
 
 
23c. Lot #:  
 
24c. Expiration Date :  
 
25c. Date of  First Dose 
    
 
  
  
          DD                   MMM                        YYYY            
26c. Initial Dose (Calculated Total Dose)  
 
27c.  Total Number Doses 
Received 
 
28c. Date of Last Dose Prior to SAE 
  
  
  
  
          DD                   MMM                       YYYY            
29c. Last Dose Prior to SAE (mg) 
 
Action Taken 
30c. Changes to agent due to THIS event (Check all that apply): 
  None 
  Dose reduced on   __ __ / __ __ __ / __ __ __ __    to   ______ mg/kg  
                                                    DD           MMM               YYYY 
  Dose delayed on   __ __ / __ __ __ / __ __ __ __    and    Restarted on   __ __ / __ __ __ / __ __ __ __ 
                                                 DD           MMM               YYYY                                                DD           MMM               YYYY 
  Dose interrupted on   __ __ / __ __ __ / __ __ __ __ 
                                                              DD           MMM               YYYY 
  Permanently Discontinued on   __ __ / __ __ __ / __ __ __ __ 
                                                                              DD          MMM               YYYY 
31c. Did event abate after stopping or reducing the agent? 
   Yes    
   No    
   Not Applicable 
32c. If interrupted, did event reappear after reintroduction of agent? 
   Yes    
   No    
   Not Applicable 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
 
Other Agent in Combination (specify):__________
 
(Complete sections 21d-32d in reference to the specified agent noted)   
21d. Relationship to agent (Check one.) 
 Not Related    
 Possibly Related    
 Probably Related    
 Definitely Related    
 Not Applicable    
22d. Investigator: Comments/Rationale regarding relationship to agent 
 
 
 
23d. Lot #:  
 
24d. Expiration Date :  
 
25d. Date of  First Dose 
    
 
  
  
          DD                   MMM                        YYYY            
26d. Initial Dose (Calculated Total Dose)  
 
27d.  Total Number Doses 
Received 
 
28d. Date of Last Dose Prior to SAE 
  
  
  
  
          DD                   MMM                       YYYY            
29d. Last Dose Prior to SAE (mg) 
 
Action Taken 
30d. Changes to agent due to THIS event (Check all that apply): 
  None 
  Dose reduced on   __ __ / __ __ __ / __ __ __ __    to   ______ mg/kg  
                                                    DD           MMM               YYYY 
  Dose delayed on   __ __ / __ __ __ / __ __ __ __    and    Restarted on   __ __ / __ __ __ / __ __ __ __ 
                                                 DD           MMM               YYYY                                                DD           MMM               YYYY 
  Dose interrupted on   __ __ / __ __ __ / __ __ __ __ 
                                                              DD           MMM               YYYY 
  Permanently Discontinued on   __ __ / __ __ __ / __ __ __ __ 
                                                                              DD          MMM               YYYY 
31d. Did event abate after stopping or reducing the agent? 
   Yes    
   No    
   Not Applicable 
32d. If interrupted, did event reappear after reintroduction of agent? 
   Yes    
   No    
   Not Applicable 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report  
 
 
Reporter Information  
33. Reporter’s Name: 
 
Address: 
 
 
34. Health Professional  
  Yes          
  No 
35. Phone Number 
36. (Print)  Investigator’s Name: 
 
 
37. (Print)  Investigator’s Address: 
 
 
 
 
38. Investigator’s Signature: _______________________________________________________ 
 
39. Date: 
  
  
 
                      DD             MMM                     YYYY 
 
 
 
Serious Adverse Event Report 

Abraxis Oncology 
CONFIDENTIAL 
Protocol ABX_______ 
Investigator Name 
Patient Number 
Patient Initials 
_____________________ 
 
 
Serious Adverse Event Report