Phase II Prospective Open Label Study of Pertuzumab, Trastuzumab, and Nab-Paclitaxel in Patients With HER-2 Positive Advanced Breast Cancer
Phase: PHASE2
Conditions: HER2-positive Breast Cancer, Recurrent Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer, Breast Adenocarcinoma, Inflammatory Breast Carcinoma
Sponsor: City of Hope Medical Center

Protocol 12147 
 
07/27/2017 
Packet:  23 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE:  
Phase II prospective open label study of pertuzumab, trastuzumab, and nab-paclitaxel 
in patients with HER-2 positive advanced breast cancer. 
 
CITY OF HOPE PROTOCOL NUMBER:     IRB# 12147            PROTOCOL DATE: 07/27/17 
 
Initial Submission 
 
Protocol dated 12/19/12  
 
 
 
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SITE: 
 
 
 
 
 
Breast Cancer  
TYPE:  
 
 
 
 
 
Phase II 
 
PRINCIPAL INVESTIGATOR: 
 
 
Joanne Mortimer, M.D. 
 
COLLABORATING INVESTIGATORS:  
 
                                                                                     Paul Frankel, PhD (Biostatistics) 
Peter Lee, PhD 
Ed Liu, M.D., Phd (Jackson Laboratory) 
Francesca Mengi, PhD (Jackson Laboratory) 
Jeffery Trent, PhD (TGEN) 
Emily (Shizhen) Wang, PhD (UC San Diego) 
 
 

Protocol 12147 
 
07/27/2017 
Packet:  23 
 
PARTICIPATING INVESTIGATORS:  
 
Yuan Yuan, M.D., Christina Yeon, M.D., 
James Waisman, M.D., Lusi Tumyan, M.D., 
Joseph Chao, M.D., Daneng Li, M.D., Lalit 
Vora, M.D., George Hajjar, M.D., Mina 
Sedrak, M.D., Niki Patel, M.D., Daphne 
Stewart, M.D.  
 
PARTICIPATING PATHOLOGISTS: 
 
Daniel Schmolze, M.D. 
 
PARTICIPATING INSTITUTIONS:  
City of Hope Comprehensive Cancer Center 
 
 
 
 
 
City of Hope Beckman Research Institute 
 
 
 
 
 
 
City of Hope South Pasadena  
 
 
 
 
 
 
City of Hope Antelope Valley 

Page 1 of 83 
 
IRB Protocol 12147 
Version: 17 
 
Version Date:  07/27/17 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE:  
Phase II prospective open label study of pertuzumab, trastuzumab, and nab-
paclitaxel in patients with HER-2 positive advanced breast cancer. 
 
City of Hope #:  12147   
Version:  July 27, 2017 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Joanne Mortimer, M.D. 
 
 
 
 
 
 
City of Hope National Medical Center 
 
 
 
 
 
 
Department of Medical Oncology 
 
 
 
 
 
 
T: 626-256-4673, x89200 
 
 
 
 
 
 
jmortimer@coh.org 
 
COLLABORATING INVESTIGATORS:  
Shiuan Chen, PhD  
                                                                                     Paul Frankel, PhD (Biostatistics) 
Robert Hickey, PhD 
Peter Lee, PhD 
Ed Liu, M.D. (Jackson Laboratory) 
Francesca Mengi, PhD (Jackson Laboratory) 
Jeffery Trent, PhD (TGEN) 
Emily (Shizhen) Wang, PhD (UC San Diego) 
Hua Yu, PhD 
 
PARTICIPATING INVESTIGATORS:  
Arti Hurria, MD 
Yuan Yuan, M.D., Christina Yeon, M.D., 
Samuel Chung, M.D., James Waisman, M.D., 
Lusi Tumyan, M.D., Joseph Chao, M.D., 
Nimit Sudan, M.D., Daneng Li, M.D., Lalit 
Vora, M.D., George Hajjar, M.D., Mina 
Sedrak, M.D., Niki Patel, M.D., 
Daniel Schmolze, M.D., George Somlo, M.D. 
 
PARTICIPATING INSTITUTIONS:  
 
City of Hope Comprehensive Cancer Center 
 
 
 
 
 
 
City of Hope Beckman Research Institute 
 
 
 
 
 
 
 
City of Hope South Pasadena  
 
 
 
 
 
 
 
City of Hope Antelope Valley 
Experimental Design Schema 
 Identification of patients with advanced (metastatic [MBC], or stage II-III locally 
advanced -including inflammatory [LABC]) breast cancer 
 Consent 

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 Work-up, including validation of HER2 positive tumor status, and, if feasible, 
procurement of archival tumor tissue and blood samples. Once eligibility criteria met : 
registration for treatment 
 Cycle length is 21 days. Therapy: Pertuzumab, Day 1 of each cycle; Nab-paclitaxel and  
trastuzumab, weekly. Total planned duration for patients with MBC: until progression; 
for patients with LABC: 6 cycles, followed by definitive surgery. 
 Staging studies/imaging for patients with MBC: every 9 weeks for surveillance and 
monitoring progression/response; for patients with LABC: breast/lymph node imaging 
and staging studies prior to initiating therapy, and as indicated prior to surgery. 
 Primary analysis of clinical data after progression (MBC) or completion after of 
neoadjuvant therapy (LABC). 
Protocol Synopsis 
Protocol Title 
 Phase II prospective open label study of pertuzumab, trastuzumab, and nab-paclitaxel in 
patients with HER-2 positive advanced breast cancer 
Brief Protocol Title for the Lay Public (if applicable) 
N/A 
Study Phase 
Phase II 
Participating Sites 
City of Hope  
Rationale for this Study 
Overexpression of HER2 occurs in 20-25% of breast cancers and has historically been 
associated with poorer prognosis.1  The addition of the monoclonal antibody trastuzumab 
to chemotherapy has significantly impacted progression free survival and overall survival 
both in the adjuvant and metastatic setting.2-6  
 
Unfortunately, in patients with MBC, disease progression on trastuzumab therapy generally 
occurs within approximately one year.  Multiple molecular mechanisms of trastuzumab 
resistance have been identified.7-10  One of the identified mechanisms is the development of 
heterodimerization between HER2 and EGFR or less importantly, HER2 and IGFR.11-13  
Pertuzumab is a monoclonal antibody that inhibits ligand-activated signaling and interfers 
with the dimerization process ofHER2 And other HER family members.  In order to 
overcome trastuzumab resistance, studies have combined pertuzumab with trastuzumab to 
gain synergistic inhibition of breast cancer cells with overexpression of HER2, with 
subsequent confirmation of clinical synergy.14-19 
 
The results of a Phase III study (CLEOPATRA) compairing docetaxel, pertuzumab, and 
trastuzumab versus docetaxel and trastuzumab revealed that the combination of 
pertuzumab, trastuzumab, and docetaxel had increased progression free survival to 18.4 
months compared to trastuzumab and docetaxel a at 12.4 months, with no increase in 
cardiotoxicity when given as first line treatment, for metastatic breast cancer. Overall 
survival at a median follow-up of 30 months has also favored the combination, with the 

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median not reached, vs. 37.6 months with docetaxel and trastuzumab.20,21 
Recent data suggest activity and safety when pertuzumab and tarstuzumab are combined 
with weekly paclitaxel.22 
 Nab-paclitaxel at the 100 mg/m2 wekly dose was chosen as the chemotherapeutic agent in 
our  study because it demonstrated improved acceptable safety profile and better response 
rate and progression free survival particularly in subsets of patients wih visceral metastasis 
when compared with docetaxel in phase II studies. Also a Phase III study showed 
improved PFS with every 3 week nab-paclitaxel compared to every 3 week paclitaxel, with 
less neurotoxicity and hypersensitivity.23,24 Furthermore, the ION 04-012 randomized 
phase II study compared nab-paclitaxel with or without trastuzumab in first line treatment 
of metastatic breast cancer.  This study demonstrated an overall response rate of 52.4% in 
HER-2 overexpressing patients with median PFS of 14.5 months, which includes HER2 
non-overexpressing patients.25.  
 
A combination therapy that can improve PFS with less toxicity in patients with HER-2 
overexpressing MBC would be a step forward in the treatment of this disease.  The 
addition of pertuzumab to nab-paclitaxel and trastuzumab has the potential to be such a 
combination therapy. 
   
More recently, a series of trials tested the feasibility and efficacy (as defined by complete 
pathologic response rate at surgery) of dual targeting neoadjuvant therapies in HER2+ 
locally advanced breast cancer. Based on the positive outcome of such trials including the 
Neosphere trial, the FDA recently approved the use of neoadjuvant dual targeting therapy 
with trastuzumab, pertuzumab, and a docetaxel.26 Recently updated NCCN guidelines 
allow for administration of any of the taxanes in such setting, in combination with dual 
HER2-targeting therapies 27.  Since the complete pathological response rate with 
pertuzumab, trastuzumab, and docetaxel has been reported in the Neosphere trial at 39.3%,  
(a quite high pCR rate considering that both estrogen receptor positive and negative tumors 
were included, and this pCR included only patients whose breast and lymph node tissues 
were void of evidence of cancer) the eligibility criteria for this trial will now allow to test 
the proposed pertuzumab, trastuzumab,  nab-paclitaxel regimen in the first line metastatic, 
AND neoadjuvant settings focusing on locally advanced breast cancer 
 
 
Objectives  
The primary objective of this study is to determine (1) efficacy of administration of 
pertuzumab in combination with trastuzumab with nab-paclitaxel in subjects with  HER-2 
overexpressing breast cancer (MBC) as measured by progression free survival (PFS), and 
(2) the efficacy as neoadjuvant treatment of the regimen in locally advanced HER2+ breast 
cancer (LABC) as measured by pathologic complete response (pCR).  
   
Secondary Objectives 
1) To evaluate the safety of pertuzumab when added to trastuzumab and nab-paclitaxel in 
MBC  and HER-2 overexpressing LABC as assessed by the frequency and severity of 
adverse events (AEs), abnormal treatment-related findings on physical examination, 

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laboratory tests, and vital signs;  
2) To evaluate the objective response rate (RECIST 1.1.) and duration of response in MBC  
3) To evaluate the response as assessed by residual cancer burden (RCB) score in LABC. 
4) To assess the progression free survival (MBC), relapse-free survival (LABC) and the 
overall survival in all patients. 
5, To perform  exploratory circulatory gene, microRNA and exosome profiling as well as 
protein and glycomic profiling.  
6, To assess the feasibility of molecular profiling in both primary and metastatic tumor 
samples 
7, To assess numerical and qualitative aspects of circulating tumor cells and circulating 
tumor-derived DNA.   
 
 
Study Design 
Phase II First line Advanced Breast Cancer Treatment Trial; Single-site; type of study: 
safety, preliminary efficacy.   
Endpoints 
Progression Free Survival, Objective Response Rate, Clinical Benefit Rate in the stage IV 
setting; Complete Pathologic Response and Relpase-free survival in the locally advanced 
setting; overall survival in all patients. 
Sample Size 
The sample size is to be 65 patients. All patients are to receive all study medications, and 
patients treated will be counted towards analysis. 

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Estimated Duration of the Study 
Study duration is expected to be 48 months; first patient to enroll in mid-2013, last patient to 
enroll by 12/2016. 
Summary of Subject Eligibility Criteria 
Inclusion Criteria: 
 
Disease Status 
Cytologically or histologically documented adenocarcinoma of breast; HER-2 positive 
biology only.  At least one  measurable site required for patients with MBC; Patients with 
LABC are accrued if they present with ≥ 2 cm primary, or any T size with documented 
lymph node involvement, or with inflammatory breast cancer (Stages II and III) 
 
Age Criteria and Life Expectancy 
Greater than 18 years of age, female patients 
 
Child Bearing Potential 
The effects of the proposed therapeutic agents (pertuzumab, nab-paclitaxel) on the 
developing fetus are unknown.  For this reason, women of child-bearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth control or 
abstinence) prior to study entry and for six months following duration of study 
participation.  Should a woman become pregnant or suspect that she is pregnant while 
participating on the trial, she should inform her treating physical immediately. 
 
Protocol-Specific Criteria 
1) HER2 by IHC (3+), or in case of IHC of 2+, positive by FISH (>2.0) or by alternative 
gene testing. 
2) ECOG  ≤ 1 
3) Organ function: 
Liver enzymes ≤ 2 x upper limit of institutional normal. 
Calculated or measured creatinine clearance of > 50 ml/min 
Left ventricular ejection fraction > 50% 
Absolute neutrophil count  1,500/l; platelets  100,000/l 
 
Informed Consent/Assent 
All subjects must have the ability to understand and the willingness to sign a written 
informed consent. 
 
Prior Therapy 
No prior therapies are allowed for the treatment of locally advanced or newly diagnosed 
metastatic breast cancer. Prior adjuvant therapy for preceeding stages II-III  breast cancer 
more than 12 months prior to enrollment into study is allowed. 
 
Exclusion Criteria 
Study-Specific Exclusions 

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1) Known active Hepatitis B, or C 
2) Known active HIV (necessitating  therapy) 
3) Pregnancy 
4) Neuropathy > grade 1 
5) Any other intercurrent medical/psychological problem deemed exclusionary by the 
treating physician or investigators/PI  
 
Non-Compliance 
Subjects will be excluded who, in the opinion of the investigator, may not be able to 
comply with the safety monitoring requirements of the study. 
Investigational Product Dosage and Administration 
Pertuzumab administered as 840 mg IV during cycle 1 followed by 420 mg IV every three 
weeks starting cycle 2. 
Trastuzumab loading dose of 4mg/kg for week one followed by 2 mg/kg IV weekly. 
Nab-paclitaxel 100 mg/m2 IV weekly.   
Clinical Observations and Tests to be Performed 
Laboratory studies will be required to be performed within a week prior to initiating therapy. 
Other diagnostic assessments should be performed within 28 days prior to initiating therapy 
(exception Echo/MUGA may be done within 42 days). 
Statistical Considerations 
To evaluate the combination of pertuzumab, trastuzumab and nab-paclitaxel in HER2+ breast 
cancer, we can combine the ability of this regimen to shrink/control the tumor in untreated 
breast cancer cases whether it is in a metastatic patient or in the neoadjuvant setting, as both are 
untreated HER2+ breast cancers. The assumption is that a promising result in one setting would 
translate into a promising result in the other.  To combine these two, we note that the Cleopatra 
trial20,21 observed a median PFS of 18.5 months in metastatic breast cancer with pertuzumab, 
trastuzumab and docetaxel. As a result, a success for an individual patient with MBC can be 
defined as PFS ≥ 18.5 months, with an observed success rate of 50%. In the neoadjuvant 
setting, a pCR rate (success rate) of 39.3% was observed with the pertuzumab, trastuzumab and 
docetaxel26. As a result, this study will be designed to declare the study successful if it at least 
matches response rate in the Cleopatra and Neosphere trials  due to the presumed lower toxicity 
and possibly improved efficacy over other taxanes such as docetaxel or paclitaxel when using 
nab-paclitaxel on the proposed dose and schedule.  65 patients will be accrued, with 25 
metastatic breast cancer (MBC) patients and 40 LABC patients who are to receive neoadjuvant 
therapy. 
At 
the 
final 
analysis, 
the 
matching 
target 
success 
rate 
would 
be 
(0.393*40+0.5*25)/65=43.4% or 28 successes. If the true success rate is 10% above the 
matching success rate this design has 94% power to declare a success. If the true success rate is 
10% below the matching success rate, this design has a type I error less than 5% (one sided).  
This design is equivalent to testing the null hypothesis H0: success rate is 33.4% against an 
alternative H1: success rate is 53.4%, with a type I error (one-sided) of 5% and a type II error of 
6% (94% power). These error estimates are conservative due to the slight underdispersion 
resulting from the combination of two binomials.  

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In addition to the combined endpoint, each strata will be evaluated independently.  With 25 
metastatic cancer patients, the median PFS will be estimated. If accrual is within 24 months, 
and follow-up is approximately 24 months after accrual completes, the probability of a true 
median survival of 24 months being less than 18.5 months is less than 20% (80% power), and 
the probability of a true median survival of 13 months exceeding 18.5 months is approximately 
13.4% (type I error, one sided).  This is assuming a non-parametric estimate of the median 
survival and uses the Brookmeyer-Crowley method.  This design is equivalent to testing the 
null hypothesis H0: median survival is 13 months against an alternative H1: median survival of 
24 months, with a type I error (one-sided) of 13.5% and a type II error less than 20% (80% 
power).   If accrual is longer, with follow-up after the last accrual unchanged, the type I and 
type II error are reduced. 
 
With 40 neoadjuvant cases, the probability of a true discouraging neoadjuvant pCR rate of 
29.3% exceeding the benchmark of 39.3% (16 or more) is 10% (type I error), and the 
probability of a true neoadjuvant pCR rate of 49.3% resulting in a observation below 39.3% (15 
or less) is less than 10% (>90% power). This design is equivalent to testing the null hypothesis 
H0: pCR rate is 29.3% against an alternative H1: pCR rate is 49.3%, with a type I error (one-
sided) of 10% and a type II error less than 10% (at least 90% power).  
The study is likely to accrue 2 patients per months in the locally advanced cohort , the 40 
patient LABC accrual should be met by the end of 2016. 
For interim analysis, no formal analysis is planned due to the time required to assess the PFS 
endpoint and the expected rapidity of accrual.  However, a report will be generated after 29 
patients have been accrued to review with the Sponsor and PI, with a report to the COH DSMB.  
At the final analysis, the PFS (for stage IV cases), the pathological complete response rate (for 
neoadjuvant cases) and toxicity/tolerability may refine the decision to pursue the combination, 
or may suggest restricting this combination to more fragile patients less able to receive more 
aggressive chemotherapy combinations. 
There will be interim analysis for toxicity. Specifically, if dose limiting toxicity (grade 3 or 
higher treatment-related non-hematologic toxicity other than readily reversible electrolyte 
abnormalities or diarrhea/ nausea/vomiting that lasts less than 24 hrs after treatment or any 
treatment related grade 4 toxicity) is observed in 2 of the first 6 patients treated during the first 
cycle of treatment (28 days), or in more than 30% of the patients thereafter, the study will hold 
accrual pending review by the COH DSMC, PI and Sponsor. 
Sponsor 
City of Hope/Genentech/Celgene Corporation 
 

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Table of Contents 
 
SECTION.................................................................................................................. PAGE 
Experimental Design Schema .......................................................................................................... 1 
Protocol Synopsis ............................................................................................................................. 2 
Objectives ........................................................................................................................... 3 
Secondary Objectives.......................................................................................................... 3 
1.0 Goals and Objectives (Scientific Aims) ................................................................................... 10 
2.0 Background and Rationale ....................................................................................................... 10 
3.0 Patient Eligibility ..................................................................................................................... 16 
4.0 Registration Procedures ........................................................................................................... 19 
5.0 Informed Consent ..................................................................................................................... 19 
6.0 Dose Assignment ..................................................................................................................... 20 
7.0 Treatment Plan ......................................................................................................................... 20 
8.0 Criteria for Starting Subsequent Cycles ................................................................................... 24 
9.0 Dose Delays/Modifications for Adverse Events ...................................................................... 25 
10.0 Monitoring and Blood draws ................................................................................................. 30 
11.0 Data Safety and Monitoring Plan ........................................................................................... 30 
12.0 Reporting of Unanticipated Problems and Adverse Events ................................................... 32 
13.0 Agent Information .................................................................................................................. 44 
14. 0 Endpoints/Statistical Analysis ............................................................................................... 65 
15. 0 Feasibility .............................................................................................................................. 67 
16. 0 Correlative Studies ................................................................................................................ 68 
17. 0 Study Calendar ...................................................................................................................... 68 
18. 0 Evaluation Criteria/Measurement of Effect .......................................................................... 71 
19.0 Data Reporting/Protocol Deviations ...................................................................................... 75 
20.0 Human Subject Issues ............................................................................................................ 77 
21. References ................................................................................................................................ 79 
 
 
 
 
 
 
 

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Abbreviation 
Meaning 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDS 
Investigational Drug Services 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
PR 
Partial Response 
SAE 
Serious Adverse Event 
 

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1.0 Goals and Objectives (Scientific Aims) 
1.1 The primary objective of this study is to determine (1) Efficacy of administration of 
pertuzumab in combination with trastuzumab with nab-paclitaxel in subjects with stage IV 
HER-2 overexpressing metastatic breast cancer (MBC) as measured by progression free 
survival (PFS), and (2) the efficacy as neoadjuvant treatment of the regimen in HER2+ 
locally advanced breast cancer (LABC) as defined by pathologic complete response (pCR).  
  
 
1.2 The secondary objectives of this study are:  
1) To evaluate the safety of pertuzumab when added to trastuzumab and nab-paclitaxel in  
HER-2 overexpressing MBC and LABC cancer as assessed by the frequency and severity of 
adverse events (AEs), abnormal findings on physical examination, laboratory tests, and vital 
signs;  
2) To evaluate the objective response rate (RECIST 1.1.) and duration of response in MBC. 
3) To evaluate efficacy of the regimen by assessing tumor response including assessment of 
residual cancer burden (RCB) scores  in LABC. 
4) To assess the progression free survival (MBC), relapse-free survival (LABC) and overall 
survival in all patients. 
5) To perform  exploratory circulatory gene, microRNA and exosome profiling as well as 
protein and glycomic profiling  
6) To assess the feasibility of molecular profiling in both primary and metastatic tumor 
samples 
7) To assess numerical and qualitative aspects of circulating tumor cells and circulating 
tumor-derived DNA.   
 
 
2.0 Background and Rationale 
2.1 Introduction/Rationale for Study 
Overexpression of HER2 occurs in 20-25% of breast cancers, and its over-expression has 
historically been associated with poorer prognosis.1  The addition of monoclonal antibody 
trastuzumab to chemotherapy has significantly impacted progression free survival and 
overall survival in the adjuvant and metastatic setting.2-6 Unfortunately, disease progression 
after trastuzumab therapy generally occurs within approximately one year.  Thus, there is a 
need for a combination therapy that can overcome trastuzumab resistance.  The rationale for 
this study proposal is to overcome trastuzumab resistance via the addition of pertuzumab in 
the treatment of HER2 positive metastatic breast cancer.  
 
2.2 Mechanisms of trastuzumab resistance: 
Trastuzumab activity is aimed at the subdomain IV of HER2 receptor extracellular domain 
where it blocks HER2 cleavage; stimulates antibody-dependent, cell-mediated cytotoxicity; 
and inhibits ligand-independent, HER2-mediated mitogenic signaling.  Multiple molecular 
mechanisms of trastuzumab resistance have been identified.7-10  These mechanisms include 
activation of downstream PI3K-signaling pathway, accumulation of a constitutively 

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activated HER2, and cross talk of HER2 with other growth factor receptors.  One of the 
proposed mechanisms to overcome HER2 resistance is to block heterodimerization between 
HER2 and other growth factor receptors to inhibit cross talk.11-13   
 
2.3 Pertuzumab 
Pertuzumab is a monoclonal antibody that binds to subdomain II of the extracellular domain 
of HER2 receptor.  Pertuzumab prevents the dimerization of HER2 with other ligand-
activated HER receptors, particularly HER2/EGFR and HER2/HER3 heterodimers.  
Although the HER2 binding site is different, the mechanism of action is similar to 
trastuzumab in that it stimulates antibody-dependent cytotoxicity and inhibits ligand-
independent signaling.  Due to this similar mechanism of action and unique binding sites, in 
order to overcome trastuzumab resistance, studies have combined pertuzumab with 
trastuzumab to gain synergistic inhibition of breast cancer cells with overexpression of 
HER2.  As a result, there is a more comprehensive blockade of HER2 signaling and greater 
antitumor activity than either agent alone as demonstrated in the preclinical and phase II 
clinical setting.14-20 
 A randomized phase III study (CLEOPATRA) showed that the combination of docetaxel, 
pertuzumab, and trastuzumab had increased progression free survival at 18.5 months 
compared to trastuzumab and docetaxel alone at 12.4 months with no increase in 
cardiotoxicity in first line metastatic breast cancer.20,21   
Recent data suggest activity and safety when pertuzumab and trastuzumab are combined 
with weekly paclitaxel as first line therapy.22 
 Nab-paclitaxel at the 100 mg/m2 wekly dose was chosen as the chemotherapeutic agent in 
our  study because it demonstrated improved acceptable safety profile and better response 
rate and progression free survival particularly in subsets of patients wih visceral metastasis 
when compared with docetaxel in phase II studies. Also a Phase III study showed improved 
PFS of every 3 week nab-paclitaxel compared with every 3 week paclitaxel with less 
neurotoxicity and hypersensitivity.22-24 Furthermore, the ION 04-012 randomized phase II 
study compared nab-paclitaxel with or without trastuzumab in first line treatment of 
metastatic breast cancer.  This study demonstrated an overall response rate of 52.4% in 
HER-2 overexpressing patients with median PFS of 14.5 months, with the study including 
HER2 non-overexpressing patients.25.  
In the neoadjuvant setting , both the NeoSphere trial combining pertuzumab and 
trasstuzumab26 and the NeoAltto study testing the EGFR and HER-2 dual tyrosin kinase-
targeting agent lapatinib with trastuzumab 28 proved that dual-biologic HER2 targeting is 
superior to single HER2 targeting, particularly when combined with chemotherapy. 
Partly based on mature analysis of neoadjuvant trial outcomes,29,30 and particularly based on 
the positive outcome in the Neosphere trial, the FDA recently approved the use of 
neoadjuvant dual targeting therapy with trastuzumab, pertuzumab, and a docetaxel.  NCCN 
guidelines allow for administartion of any of the taxanes in such setting, in combination 
with dual HER2-targeting therapies 27.  Since the complete pathological response rate with 
pertuzumab, trastuzumab, and docetaxel has been reported in the Neosphere trial at 39.3%,  
(a quite high pCR rate considering that both estrogen receptor positive and negative tumors 
were included, and this pCR rate included only patients whose breast and lymph node 
tissues were both void of evidence of invasive cancer) the eligibility criteria for our  trial 
will now allow to test the proposed pertuzumab, trastuzumab,  nab-paclitaxel regimen in the 

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first line metastatic, AND neoadjuvant settings.  To provide a potentially sensitive tool for 
pathologic response, assessment of residual cancer burden (RCB) scores have been 
proposed as a predictor of long-term outcome, in the neoadjuvant setting.31 We will perform 
this assay and  the results of such scoring  will now be included in the exploratory analysis. 
 
 
2.4 Nab-paclitaxel 
Nab-paclitaxel is a biologically interactive albumin-bound paclitaxel combining a protein 
with a chemotherapeutic agent in the particle form. This composition allows for a novel 
approach of increasing intra-tumoral concentrations of the drug by a receptor-mediated 
transport process allowing transcytosis across the endothelial cell. This albumin-specific 
receptor mediated process involves the binding of albumin to a specific receptor (gp60) on 
the intralumminal endothelial cell membrane, resulting in activation of a protein (caveolin-
1), which initiates an internalization process in the endothelial cell through the formation of 
caveolae, with transport of the intact albumin-bound chemotherapeutic complex via these 
caveolae to the underlying tumor interstitium. A protein specifically secreted by the tumor 
(SPARC) binds albumin, allowing release of the hydrophobic drug to the tumor cell 
membrane.32-34 
 
Following a series of phase I and II trials and demonstration of efficacy in the phase III 
setting, weekly nab-paclitaxel was chosen as the chemotherapeutic agent in this study 
because it demonstrated significantly improved progression free survival when compared 
with docetaxel in first line metastatic breast cancer with the benefit over 5 months.23,24,35-37  
Weekly nab-paclitaxel compared with every 3 week paclitaxel has also been shown to have 
less neurotoxicity and hypersensitivity based on randomized trials.23  While earlier trials 
showed that nab-paclitaxel at 150mg/m2 weekly was  superior to nab-paclitaxel 100mg/m2, 
a more recent trial suggested that toxicities associated with such dosing in comparison to 
weekly paclitaxel given at 90 mg/m2 were worse.38 Hence, we chose the dosing of 100 
mg/m2 in hopes to maintain the efficacy while minimizing toxicity.   
 
2.5 Overview of Proposed Study  
A combination therapy that can improve PFS with less toxicity in patients with stage IV 
HER-2 overexpressing MBC would be a step forward in the treatment of HER2 
overexpressing metastatic breast cancer.  We hypothesize that the addition of pertuzumab to 
weekly nab-paclitaxel and weekly trastuzumab is an effective treatment in metastatic breast 
cancer with less toxicity.  
The FDA recently approved the use of neoadjuvant dual targeting therapy with trastuzumab, 
pertuzumab, and a docetaxel, based on the assumption that the high pathologic complete 
response rate may be a surrogate marker for improved overall survival.26, 29, 30 NCCN 
guidelines allow for administration of any of the taxanes in such setting, in combination 
with dual HER2-targeting therapies27.  Since the complete pathological response rate with 
pertuzumab, trastuzumab, and docetaxel has been reported in the Neosphere trial at 39.3%,  
we put forward that trastuzumab, pertuzumab, and weekly nab-paclitaxel may improve the 
pathologic complete response rate further. 
Hence, the elgibility criteria for this trial will now allow to test the proposed pertuzumab, 
trastuzumab,  nab-paclitaxel regimen in the first line metastatic, AND neoadjuvant settings.  

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This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
and the applicable regulatory requirements.  Because all three drugs are approved for used in 
advanced breast cancer, but the three have never been studied together, an IND exemption 
has been provided by the FDA  for this study. 
 
2.6 Translational Research Component 
Serum samples procured prior to, during, and at the completion (on progression) of protocol 
therapy will be spun at 1,000 x g to remove tissue debris, and treated in one of several ways 
to optimize potential biomarker recovery. 
a) For protein biomarker discovery: protein recovery in the supernatant will be 
determined using a BCA protein analysis kit (Pierce Scientific) to obtain protein 
concentration, and 1ul and 5ul of supernatant will be examined by mass spectrometry 
to determine the mass profile of the fluid sample.  This will be done by spotting the 
fluid directly onto a target plate, (consisting of one or more of the following 
materials: stainless steel, an anionic (WCX-10), cationic (CM-10), neutral phase, 
metal ion binding(IMAC) or hydrophobic (H50) SELDI chip surface under detergent 
extraction conditions, washing the surfaces with the appropriate buffers, overlaying 
the bound proteins with an energy absorbing material (i.e., matrix) such as but not 
limited to: Sinapinic acid, CHCA, DHB, or super DHB, etc.,) and then analyzing the 
proteins bound to the target plate surface by matrix assisted laser desorption 
ionization (MALDI) mass spectrometry in both the negative ion and positive ion 
mode to maximize the type of protein signature identified. The chromatography-like 
surfaces (e.g., WCX-10, etc.,) present a way for performing solid-state 
chromatography, and is an ideal methodology for fractionating small volumes of 
patient fluid into several fractions that permit enrichment of specific classes of 
proteins within the available  patient samples.  
b) For glycomic biomarker discovery: the patient samples will be digested with MS 
grade trypsin, and the resulting glycopeptides/peptides will be treated with PNGase F 
to release N-linked glycosidic linkages.  The glycosidic linkages will be captured by 
micro-lectin chromatography, permethylated, and analyzed by electrospray ionization 
(ESI) mass spectrometry or by MALDI mass spectrometry.  The resulting mass 
spectra will then be “deconvoluted” against a Bruker supplied database containing the 
masses for intact sugars and fragments of sugars expected after laser induced 
fragmentation of these known sugars, (e.g., glucose, fructose, galactose, glucosamine, 
fucose, mannose, etc.), as well as branched chains of sugars common to mammalian 
cells.  PCA analysis will then be run on the various branched chain sugars identified 
in the fluid, to initially see if the relative abundance of one sugar isoform vs. another 
isoform can be predictive of the presence of cancer, or whether the node is free of 
cancer cells.  O-linked glycans will be isolated and analyzed by collection of the 
peptides passing through the first lectin column, and subjecting these 
peptides/glycopeptides to chemical cleavage followed by capture of the 0-glycan on 
an alternate lectin affinity chromatography matrix, then subjecting the glycans eluted 
from the matrix to permethylation, and analysis by mass spectrometry as described 
for the N-linked glycans. This part of the study will be carried out under the guidance 
of Robert Hickey Ph.D, pending availability of funding. 

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2.7 Exploratory Analysis of Cancer-associated MicroRNAs and Exosomes: 
Exploratory analysis of microRNA and exosome expression profile from serum samples 
procured prior to, during protocol treatment, and at progression, will be carried out in 
collaboration with Emily Wang, Ph.D., as part of an already approved and NIH-grant-
supported collaboration (IRB 09147). Cancer-secreted exosomes and miRNAs can be 
internalized by other cell types in the primary tumor microenvironment and pre-
/metastatic niches. MiRNAs loaded in these exosomes, which to a certain extent reflect 
the dysregulated miRNA profile in cancer cells, can thus be transferred to recipient niche 
cells to exert genome-wide regulation of gene expression. Cancer-derived miRNAs have 
been detected in the blood of cancer patients, where their levels distinguish cancer 
patients from healthy controls39,40. Previous studies from our and other groups have 
identified circulating miRNAs associated with the histopathological features of breast 
tumors and clinical outcomes in BC patients 41-45. Therefore, cancer-associated 
microRNAs and exosomes are novel non-invasive circulating biomarkers for breast 
cancer. This collaboration is supported by NIH grant (R01CA166020) and Breast Cancer 
Research Foundation-AACR Grant (12-60-26-WANG).  
 
2.8 Exploratory Analysis of Cancer-associated gene profiling of tumors, serum DNA 
analysis, and circulating tumor cell analysis: 
Additional components include exploratory analysis of gene expression profile of tissue, 
circulating tumor cells, and serum DNA, which is pending availability of funding.46-50  
Profiling will be carried out in the setting of various internal and external collaborations 
(all MTA supported, or grant supported).  Collaborators include Hua Yu, Peter Lee, 
Shiuan Chen, various COH cores. External collaborators with MTAs in place include 
TGEN (J. Trent and laboratory), The Jackson Laboratory (F. Mengi and Ed Liu), 
Agendia, Emily Wang (UC San Diego-R0-1 joint PI-ship). 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Schema 
 
 
 
 
 
 
 
 
 
 
Patients with newly diagnosed metastatic HER+  breast cancer and 12 months 
or beyond since adjuvant therapy, or patients with newly diagnosed locally 
advanced stages II-III HER2+  breast cancer 
ECOG: 0-1 
45
1) Pertuzumab administered as 840 mg IV during cycle 1 followed by 420mg IV every three 
weeks starting cycle 2. 
2) Trastuzumab loading dose of  4mg/kg then 2mg/kg IV every 1 week 
3) Nab-paclitaxel 100mg/m2 IV weekly 
Tumor assessment/CT scans: every 9 weeks for patients with MBC. 
Progression free survival assessment: every 9 weeks for patients with MBC 
CBC + chemistry+LFTs: every 3 weeks;Physician evaluation: every 3 weeksClinical Assessment 
every 3 weeks while on neoadjuvant therapy for LABC patients 
Baseline CT scan of chest, abdomen, pelvis, bone scan, or PET/CT  
Baseline CBC, chemistry, LFTs 

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3.0 Patient Eligibility 
 
3.1Inclusion Criteria: To be eligible, patients must meet all of these criteria. 
 
3.1.1 Disease Status 
Patients must be diagnosed with metastatic cytologically or histologically confirmed 
adenocarcinoma of the breast with HER2 over-expression or with newly diagnosed locally 
advanced (including inflammatory) breast cancer (LABC) with stage II-III disease.  
Patients with metastatic (stage IV) disease (MBC) must have measurable lesions.  
 
3.1.2 Age Criteria and Life Expectancy 
Greater than 18 years of age 
 
3.1.3 Child Bearing Potential 
The effects of the proposed therapeutic agents (pertuzumab, nab-paclitaxel, trastuzumab) 
on the developing fetus are unknown.  For this reason, women of child-bearing potential 
and men must agree to use adequate contraception (hormonal or barrier method of birth 
control or abstinence) prior to study entry and for six months following duration of study 
participation.  Should a woman become pregnant or suspect that she is pregnant while 
participating on the trial, she should inform her treating physical immediately. 
 
3.1.4 Protocol-Specific Criteria 
 
Tumor positive or negative for expression of hormone receptors (< 1% or 
>1%) and overexpressing HER2 by IHC (3+), or, HER2-amplified  by FISH 
or by alternative gene testing as per the latest ASCO/CAP guideline 
update.51 
 For patients with LABC, no prior therapy is allowed 
 For patients with MBC, prior adjuvant chemotherapy and trastuzumab more 
than or equal to 12 months prior to enrollment are allowed  
 No prior chemotherapy or trastuzumab for treatment of metastatic breast 
cancer 
 
LVEF ≥50% (determined by echocardiogram or multigated acquisition 
scan) within 42 days of treatment 
 
Eastern Oncology Group Performance Status of 0 or 1.  
 
Patients must have normal organ and marrow function as defined below 
(within 7 days prior to start of study treatment): 
- Hemoglobin ≥ 9g/dl 
- Leukocytes  ≥ 3.0 x 109/L 
- Absolute Neutrophil Count ≥ 1.5 x 109/L 
- Platelets ≥ 100 x 109/L 
- Total Bilirubin ≤ 1.3 mg/dl   (institutional upper limit of normal) 
- AST (SGOT)/ALT (SGPT)  ≤2 x institutional upper limit of normal  

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- Creatinine within normal institutional limits 
- Or  creatinine clearance >50 mL/min/1.73m2 for patients with creatinine 
levels above institutional normal (using Crockcroft-Gault Formula) 
 
All radiology studies(study required staging) must be performed within 35 
days prior to the start of therapy. 
 
No serious medical conditions such as myocardial infarction within 6 
months prior to entry, congestive heart failure, unstable ventricular 
arrhythmia, uncontrolled hypertension, uncontrolled diabetes mellitus, 
uncontrolled psychotic disorders, serious infections, active peptic ulcer 
disease, psychiatric illness, or any other medical conditions that might be 
aggravated by treatment or limit compliance 
 
Currently, no active second malignancy other than non-melanoma skin 
cancer. Note: Patients are not considered to have a “current active” 
malignancy if they have completed anti-cancer therapy and are considered 
by their physicians to have a less than 30% chance of relapse. 
 
All patients must have the ability to understand and the willingness to sign 
an informed consent 
 
Negative serum or urine Beta-hCG pregnancy test at screening for patients 
of child-bearing potential. 
 
3.1.5 Informed Consent/Assent 
All subjects must have the ability to understand and the willingness to sign a written 
informed consent. 
 
3.1.6 Prior Therapy 
No prior therapies (except for anti-estrogen therapy) are allowed for the treatment of the 
newly diagnosed metastatic breast cancer. Patients are allowed to have had prior 
chemotherapy for breast cancer in the adjuvant setting at least 12 months prior to 
enrollment into this study.  Patients with a prior diagnosis of malignancy treated ≥ 5 years 
ago are eligible, provided that they have not received prior nab-paclitaxel as part of their 
prior treatment regimen, and that they meet all eligibility criteria. 
 
3.2 Exclusion Criteria: A patient is rendered ineligible if any of these criteria applies. 
 
3.2.1 Study-Specific Exclusions 
1) Known active Hepatitis B or C (due to the potential for disease/treatment-related 
pharmacological and liver function-specific interactions). 
2) Known active HIV (due to the complexity and potential pharmacological interactions 
between the standard neoadjuvant therapeutic agents, and HAART). 
3) Prior breast cancer or other invasive malignancy treated within 5 years. 
4) Pregnancy 
5) Neuropathy > grade 1 
6) Any other intercurrent medical/psychological problem deemed exclusionary by the 
treating physician or investigators/PI.  
7) Cumulative dose of doxorubicin or equivalent of >360mg/m2 during prior adjuvant 
therapy  

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8) LVEF <50% during previous trastuzumab therapy 
9) Central nervous system metastases 
10) Another malignancy excluding basal cell skin cancer 
11) Pregnant women 
3.2.2 Non-Compliance 
Subjects will be excluded who, in the opinion of the investigator, may not be able to 
comply with the safety monitoring requirements of the study. 
 
3.3 Inclusion of Women and Minorities 
The study is open to women regardless of ethnicity. Female subjects of all racial/ethnic 
groups are eligible for this study if they meet the eligibility criteria specified in sections 
3.1 and 3.2. To address disparities in healthcare and breast cancer treatment among 
women from underserved populations, all efforts will be made to accrue subjects from 
ethnically diverse, underserved and minority populations. While efforts will be made to 
extend the accrual to a representative population, in a trial which will accrue 40 fully 
evaluable subjects, a balance must be struck between subject safety considerations and 
limitations on the number of individuals exposed to potentially toxic or ineffective 
treatments on the one hand and the need to explore gender, racial, and ethnic aspects of 
clinical research on the other.  If differences in outcome that correlate to racial or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to 
investigate those differences more fully. 
 
 
Table 1.0 
 
City of Hope Breast Patients, 2009  
 
 
By Sex 
By Ethnicity 
Site 
Total 
Female 
Male 
White 
Hispanic 
Black 
Asian 
Other 
Breast 
477 
476(99%) 
1 
(1%) 
255 
(53%) 
120 
(25%) 
38 
(8%) 
63 
(13%) 
1 
(1%) 
 
 
Table 2.0 
 
Accrual Goal for Women and Minorities on this Study 
 
 
By Sex 
By Ethnicity 
Site 
Accrual 
Goal 
Female 
Male 
White 
Hispanic 
African-
American 
Asian 
Other 
Breas
t 
45 
45 
(100%) 
0 (0%) 
20 (44%) 
12 (27%) 
4 (9%) 
8 (18%) 
1 (2%) 
 

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4.0 Registration Procedures 
     4.1 Registration Process 
To register a patient, the treating physician should contact the responsible Clinical Research 
Associate (CRA) in Clinical Trial Office (CTO) or the protocol nurse to determine whether 
the patient meets all of the eligibility criteria, and to assist with the informed consent process.  
After verifying the eligibility and receiving the signed informed consent, the CRA will 
confirm the drug dose, and register the patient onto the study. 
 
4.2 Registration Process 
1.   CRA assigned to this study will register patient for this protocol.  
 
2.   A patient failing to meet all protocol requirements may not be registered.   
 
3.   Pre-study laboratory tests, scans and x-rays must be completed prior to registration 
according to study calendar. 
 
4.   Patients must sign an informed consent prior to registration. 
 
5.   Confirm that the patient meets all inclusion and exclusion eligibility criteria for this 
protocol. 
 
6.   Complete the eligibility checklist. 
 
7.   Verify that all required pre-study tests were performed. 
 
8.  If the patient qualifies, the City of Hope coordinator will assign the patient's study ID 
number.   
 
5.0 Informed Consent  
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
will be done only after obtaining written informed consent.  Studies or procedures that were 
for clinical indications (not exclusively to determine study eligibility but consistent with good 
medical practice [GMP]) may be used for baseline values, even if the studies were done 
before informed consent was obtained.  Reference is made to Section 10.0 – Study Calendar. 
The investigational nature and objectives of the trial, the procedures and treatments involved 
and their attendant risks and discomforts, and potential alternative therapies will be carefully 
explained to the subject and a signed informed consent will be obtained.  Documentation of 
informed consent for screening will be maintained in the subject’s research chart and medical 
record. 
 

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6.0 Dose Assignment  
Pertuzumab administered as 840 mg IV during cycle 1 followed by 420 mg IV once every 
three weeks starting with cycle 2. 
Trastuzumab administered with loading dose of 4mg/kg IV for week one followed by 
2mg/kg IV given weekly. 
Nab-paclitaxel 100mg/m2 IV given weekly 
Dose reductions can occur as medically necessary as described below in section 9.2.1 
 
7.0 Treatment Plan 
7.1 Treatment Administration 
Treatments are planned to be delivered in the outpatient setting. 
Management and dose modification associated with adverse events are outlined in Section 
9.0   
Off Label: This proposal includes commercial agents for use in an investigational 
setting/trial. 
 
7.2  Dose Summary: 
 Pertuzumab administered as 840 mg IV during cycle 1 followed by 420 mg IV 
once every three weeks starting cycle 2. 
 Trastuzumab loading dose of 4mg/kg IV for week one followed by 2mg/kg IV 
weekly. 
 Nab-paclitaxel 100 mg/m2 IV weekly.   
 Treatment is scheduled to continue until:  
 
Disease progression for patients with MBC, and for a planned 6 cycles for 
patients with LABC 
 
Unmanageable toxicity  
 
Primary physician or patient request to discontinue therapy 
 
Study termination by the sponsors 
 
7.3  Details:  
 
7.3.1 Pertuzumab 
IV administration of pertuzumab should be performed in a setting with emergency 
equipment and staff who are trained to monitor medical situations and respond to 
medical emergencies. Patients should be monitored during and following completion 
of each pertuzumab infusion for any adverse effects. Since there is the potential for 
delayed onset infusion-associated reactions, patients should be warned of this 
possibility and instructed to contact the treating physician with any concerns. 
 
The initial pertuzumab dose should be administered over 60 minutes (± 10 minutes). 
Patients should be observed for fever, chills, and other infusion-associated symptoms 
for at least 60 minutes after the first infusion and for 30 minutes after subsequent 
infusions. If prior infusions were well tolerated, subsequent doses may be administered 
over 30 minutes (± 10 minutes). If symptoms occur, the infusion should be slowed, 
interrupted, or discontinued. When the patient’s symptoms have completely resolved, 

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the infusion may be continued at 50% of the rate prior to the reaction and increased in 
50% increments every 30 minutes if well tolerated. Infusions may be restarted at the 
full dose during the next cycle. Patients who experience pertuzumab infusion-
associated symptoms may be premedicated for subsequent. 
 
7.3.2 Nab-paclitaxel 
Nab-paclitaxel will be administered as an IV infusion over 30 minutes. 
Administration: Abraxane® is injected into a vein [intravenous (I.V.) infusion] over 
30 minutes.  The use of an in-line liter is not recommended. 
 
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. 
 
Dose: 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 nab-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) 
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 least 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 
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 Each mL of reconstituted product will contain 5 mg of Nab-
paclitaxel. 
7. Calculate the exact total dosing volume 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 
not necessary.  If used, in-line filters with pore sizes of <15μ should 
not be used. 
7.3.3 Trastuzumab 
Information provided here is mostly from the Herceptin® package insert.52  
 
Administration: Herceptin® will be administered intravenously over 30 minutes. The 
inital dose is a loading dose of 4mg/kg over 90 minutes, but subsequent weekly 
maintenance dose is 2mg/kg administered over 30- minutes.  DO NOT ADMINISTER 
AS AN IV PUSH OR BOLUS. 
 
Dose: Herceptin® will be reconstituted by appropriate study personnel and administered 
to the patient in the study site setting at 1-week intervals.   
 
Reconstitution and use of Herceptin®: 
 
The diluent provided has been formulated to maintain the stability and sterility 
of Herceptin®  for up to 28 days. Other diluents have not been shown to 
contain effective preservatives for Herceptin®. Each vial of Herceptin® 
should be reconstituted with ONLY 20 mL of BWFI, USP, 1.1% benzyl alcohol 
preserved, as supplied, to yield a multi-dose solution containing 21 mg/mL 
Trastuzumab. Use of all 30 mL of diluent results in a lower-than-intended 
dose of Herceptin®. THE REMAINDER (approximately 10 mL) OF THE 
DILUENT SHOULD BE DISCARDED. Immediately upon reconstitution with 
BWFI, the vial of Herceptin®  must be labeled in the area marked “Do not use 
after:” with the future date that is 28 days from the date of reconstitution. 
If the patient has known hypersensitivity to benzyl alcohol, Herceptin®  must 
be reconstituted with Sterile Water for Injection (see PRECAUTIONS). 

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Herceptin®  WHICH HAS BEEN RECONSTITUTED WITH SWFI MUST BE 
USED IMMEDIATELY AND ANY UNUSED PORTION DISCARDED. USE OF 
OTHER RECONSTITUTION DILUENTS SHOULD BE AVOIDED. 
Shaking the reconstituted Herceptin®  or causing excessive foaming during 
the addition of diluent may result in problems with dissolution and the 
amount of Herceptin®  that can be withdrawn from the vial. 
Use appropriate aseptic technique when performing the following reconstitution 
steps: 
 
1. Calculate the dose in milligram based on patients weight and adjust if 
the weight changes by > 10 % 
2. Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 
 
 
 
 
440 (mg/vial) 
3. Using sterile technique, prepare the vials for reconstitution. 
4. Swab the rubber stoppers with alcohol. 
5. Using a sterile syringe, slowly inject 21 mL of the diluent into the vial 
containing the lyophilized cake of Trastuzumab. The stream of diluent 
should be directed into the lyophilized cake. 
6. Swirl the vial gently to aid reconstitution. Trastuzumab may be 
sensitive to shear-induced stress, e.g., agitation or rapid expulsion 
from a syringe. DO NOT SHAKE. 
7. Slight foaming of the product upon reconstitution is not unusual. 
Allow the vial to stand undisturbed for approximately 5 minutes. The 
solution should be essentially free of visible particulates, clear to 
slightly opalescent, and colorless to pale yellow. 
8. Determine the number of mg of Trastuzumab needed, based on a 
loading dose of 4 mg Trastuzumab/kg body weight or a maintenance 
dose of 2 mg Trastuzumab/kg body weight.  
9. Calculate the volume of 21 mg/mL Trastuzumab solution and 
withdraw this amount from the vial and added it to an infusion bag 
containing 250 mL of 0.9% Sodium Chloride Injection, USP. 
10. DEXTROSE (5%) SOLUTION SHOULD NOT BE USED. Gently 
invert the bag to mix the solution. The reconstituted preparation results 
in a colorless to pale yellow transparent solution. Parenteral drug 
products should be inspected visually for particulates and discoloration 
prior to administration.  No incompatibilities between Herceptin® and 
polyvinylchloride or polyethylene bags have been observed. 

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11. Patients should be observed for fever and chills or other infusion-
associated symptoms (see ADVERSE REACTIONS). If prior 
infusions are well tolerated, subsequent weekly doses of 2 mg/kg 
Trastuzumab may be administered over 30 minutes. 
 
12. Herceptin® should not be mixed or diluted with other drugs. 
Herceptin® infusions should not be administered or mixed with 
Dextrose solutions. 
 
8.0 Criteria for Starting Subsequent Cycles 
Patients should meet the laboratory parameters and the performance status as outlined in 
section 3.0 before initiation of each cycle of therapy.  All toxicities (except alopecia and 
lymphopenia, anemia, hyperglycemia, hypoalbuminemia, elevated serum alkaline 
phosphatase) should have resolved to grade 1 or lesser severity before initiation of next 
cycle of therapy.  
 
Qualifying laboratory tests and procedures can be obtained up to 72 hours before planned 
initiation of therapy from cycle #2 and onwards. 
 
 8.1 Planned Duration of Therapy 
 
Therapy will continue until: 
 Disease progression for patients with MBC 
 6 cycles for patients with LABC 
 Unmanageable toxicity  
 Primary physician or patient request to discontinue therapy 
 Study termination by the sponsors 
 
8.2 Criteria for removal from Treatment 
Criteria for removal  
Removal of a patient from treatment will be based upon the following: unacceptable 
toxicities as assessed by the treatment team, based on the grade, duration, need for dose 
adjustment/modification of treatment; patient desires; or disease progression.  
 
Subject Follow up 
All patients having been enrolled and having received at least one dose of therapy will be 
evaluated for toxicity.  Patients will be followed for an indefinite amount of time after 
enrollment.  Subsequent to the 5-year mark, standard follow-up measures per tumor 
registry guidelines will apply. 
 
8.3 Supportive Care and other concomitant therapy: 
 
Supportive care will be at the treating physician’s discretion, and in line with standard 
practice. For usage of antiemetics, granulocyte and erythrocyte growth factors, physicians 
are advised to follow ASCO and NCCN guidelines, as appropriate. 

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9.0 Dose Delays/Modifications for Adverse Events 
 
9.1 Modifications due to toxicity during second and subsequent cycles  
Dose adjustments are to be made according to the organ system showing the greatest 
degree of toxicity.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
Therapy can be held until initiation of the next cycle of therapy. Treatment delay of > 6 
weeks will require reloading of pertuzumab and trastuzumab. 
 
9.2 Nab-paclitaxel (Abraxane) dose modifications 
Refer to section 7.0 for dose calculation of nab-paclitaxel 
ABRAXANE dosing should not be administered at the start of each cycle until the 
absolute neutrophil count returns to 1.5 x 109 cells/L and the platelet count returns to 
>100 x 109 cells/L.  For patients receiving weekly ABRAXANE, for each subsequent dose 
of ABRAXANE within a cycle (Days 8, 15), patients must have an ANC  1.0 x 109 
cells/L and platelets > 75 x 109 cells/L.  If the ANC and platelets are not adequate for 
treatment on Day 8, 15, and/or 22, the dose will be omitted and the total cycle length 
remains the same.  Administration of granulocyte growth factors are allowed according to 
institutional guidelines. 
 
9.2.1 Administration of ABRAXANE to Patients with Abnormal Hepatic Function 
ABRAXANE should only be administered if hepatic function is within the parameters 
established in the eligibility criteria.  Hepatic toxicity from taxanes may occur but it is 
uncommon.  Therefore, hepatic dysfunction that occurs while the patient is on study should 
prompt an evaluation to determine the cause, including the possibility of progressive 
metastatic disease and hepatotoxicity from concurrent medications. 
 
9.2.2 Dose Modification Table 
Use this table as a guideline to determine any necessary dose modifications.  The 
modification is dependent on the starting dose for the study.   
 
Table 3.0:  Dose Modification 
 
Dose Level 
ABRAXANE 
(mg/m2) 
Schedule 
0 
100 
Weekly 
-1 
90 
Weekly 
-2 
80 
Day 1,8, every 21 days 
-3 
60 
Day 1,8 every 21 days 

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Dose Reductions and guidelines for optional use of Growth Factors for Hematologic 
Toxicity 
 
The table below provides a guideline for implementing dose reductions and optional use of 
growth factor treatment for hematologic toxicity: 
 
Table 4.0:  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 < 1500 cells/mm3) 
OR 
For patients on weekly 
treatment whose next 
treatment within the cycle 
(Day 15) is omitted due to 
persistent neutropenia 
(ANC < 1000 cells/mm3). 
OR 
Neutropenia 
< 500 cells/mm3 for > 1 
week 
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 can be given as outlined below per 
discretion of primary oncologist.  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  1500 
cells/mm3.  
 
If G-CSF is given concurrently with weekly 
ABRAXANE, administration may begin the 
day after ABRAXANE is given and should 
stop at least 48 hours prior to when 
ABRAXANE is given the following week.   
Thrombocytopenia Grade 3 
or Grade 4* 
1st 
Occurrence 
Dose reduction to next lower level 
Recurrence 
Dose reduction to next lower level 
*See NCI Toxicity Criteria Scale for definition of Grade 3 and Grade 4 events. 
G-CSF Administration 
G-CSF administration is at the discretion of the primary oncologist and may be initiated 
prior to dose reduction. For QW study drug administration administer G-CSF 5 
mcg/kg/day (rounded to the nearest vial size per investigator/institution’s standard of 
care) 24 hours after chemotherapy and hold 48 hours prior to the next dose 
Sensory Neuropathy 
ABRAXANE should be withheld in patients who experience  Grade 2 sensory 
neuropathy.  Treatment may be resumed at the next lower dose level (see Table 3) in 
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resolution to Grade  1 should be the adverse event duration used for adverse event 
reporting.  In those patients who experience Grade 4 sensory neuropathy, study drug 
should be withheld, and treatment resumed at a reduction of 2 dose levels (Dose Level -
2; see Table 3) in subsequent cycles after the sensory neuropathy improves to  Grade 
1.   
Hypersensitivity Reactions 
Hypersensitivity reactions rarely occur.  If they do occur, minor symptoms such as 
flushing, skin reactions, dyspnea, lower back pain, 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 
reaction to ABRAXANE should not be re-challenged. It is not recommended to 
administer ABRAXANE to patients with prior hypersensitivity to a taxane. 
Other Toxicities 
If toxicities are  grade 3, except for anemia, and skin pain, 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 (see Table 3). 
Patients with skin pain > grade 2 may have their dose decreased one dose level. 
 
9.3 Trastuzumab Dose Modifications: 
 
The trastuzumab dose will not be modified.  
 
9.3.1 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.  
a)  Fever:  
 
 
For Grade 1-2 fever (38º-40ºC), stop infusion and give antipyretics.   Once 
temperature is <38ºC, resume infusion at a slower rate. 
 
For Grade 3-4 (>40ºC), stop infusion and give antipyretics. If temperature 
falls to <38ºC within 3 hours, resume infusion at a slower rate. If fever does not 
fall to <38ºC within 3 hours, inpatient monitoring and assessment for other 
possible causes of fever, such as infection, is advised. If temperature falls to <38ºC 
within 3 days, and the patient has no apparent sequelae of the febrile episode, she 
may be rechallenged at a slower rate. If temperature >38ºC persists for >3 days, 
and no other cause of the fever can be identified, treatment with trastuzumab will 
be permanently discontinued.   
b) Chills: 
Treat with acetaminophen and/or diphenhydramine. Meperidine may be given at 
the investigator’s discretion.  

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c) Hypersensitivity reaction (any grade):  
Stop infusion and administer   diphenhydramine. If symptoms resolve within 3 
hours, administer the next scheduled dose of trastuzumab at a slower rate. If 
symptoms take longer than 3 hours to resolve, further treatment with trastuzumab 
is at the discretion of the investigator. Patients experiencing CTC grade 3 
allergic/hypersensitivity reactions may be re-treated if, in the opinion of the 
investigator, the reaction was characteristic of an infusion reaction. These patients 
will receive appropriate premedications (steroids and antihistamines), will be 
closely monitored while receiving their next dose of trastuzumab (infused initially 
at a much slower rate), and must also be monitored for at least 8 hours after 
completion of the trastuzumab infusion, to make sure that they do not experience a 
delayed reaction after their premedications wear off. Treatment with trastuzumab 
will be permanently discontinued in any patient who experiences either an 
anaphylactic reaction (a CTC Grade 4 allergic/hypersensitivity reaction) or a grade 
3 reaction that is consistent with an allergic reaction (most often with the first dose 
of trastuzumab, characterized by bronchospasm and/or urticaria) to this agent.    
 
9.4 Pertuzumab Dose Modifications: 
 
The Pertuzumab dose will not be modified.  
 
As of 10 November 2010, data are available for 1327 patients with cancer and treated 
with pertuzumab in all company-sponsored trials (this number excludes ongoing 
blinded trials). Gastrointestinal toxicities (diarrhea, nausea, vomiting, abdominal pain) 
and fatigue are the most frequently reported adverse events (AEs) with single-agent 
therapy.  Diarrhea and rash are common events increased with pertuzumab in 
combination with chemotherapy compared with chemotherapy alone in one ongoing 
and one completed study in patients with ovarian cancer (Studies BO17931, 
TOC3258g). The most common AEs during dual therapy with pertuzumab and 
trastuzumab in MBC (based on Study BO17929) were diarrhea, fatigue, nausea and 
rash. The majority of these AEs were National Cancer Institute Common Toxicity 
Criteria (NCI-CTC) grade 1 or 2 in severity. 
 
The mechanisms behind diarrhea and rash are unknown, similar side effects are seen 
with other agents that cause HER1 inhibition. The most frequently occurring AEs 
during neoadjuvant treatment of patients with EBC (based on Study WO20697) with 
pertuzumab with/without trastuzumab in combination with docetaxel were alopecia, 
neutropenia, diarrhea, nausea, fatigue, rash and mucosal inflammation. Addition of 
pertuzumab to the trastuzumab plus docetaxel regimen did not notably affect the overall 
safety profile, and the tolerability of pertuzumab plus docetaxel was also broadly 
comparable to the triple regimen. Patients receiving trastuzumab and pertuzumab 
without docetaxel in the neoadjuvant setting reported notably fewer AEs across most 
body systems compared to patients receiving chemotherapy-containing treatment. 
Serious adverse events (SAEs) assessed as compatible with infusionrelated/ 
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(<1%) receiving pertuzumab. A low level of cardiac toxicities, predominantly 
asymptomatic declines in left ventricular ejection fraction (LVEF), has been reported. 
A total of eight patients (<1%) have experienced symptomatic cardiac failure across all 
studies to date. Of these eight patients, four were receiving pertuzumab in combination 
with trastuzumab. No clear association between the frequency, nature, and severity of 
pertuzumab-related toxicities and dose level has been observed, however the majority 
of trials have been performed with a schedule of 840 mg loading dose followed by 420 
mg every 3 weeks thereafter. 
 
Dose will be held or not based on cardiac monitoring as described under the heading for 
trastuzumab dose modification above.  
 
9.5 Cardiac Toxicity with pertuzumab and trastuzumab: 
All patients must have a baseline LVEF ≥ 50%. LVEF will be monitored regularly. If 
an investigator is concerned that an AE may be related to cardiac dysfunction, an 
additional LVEF measurement should be performed. Pertuzumab and trastuzumab will 
be discontinued in any patient who develops clinical signs and symptoms suggesting 
CHF, with the diagnosis confirmed by a suggestive chest X-ray and a drop in LVEF by 
ECHO or MUGA. CHF should be treated and monitored according to standard medical 
practice. 
At present, there are inadequate data available to assess the prognostic significance of 
asymptomatic drops of LVEF. However, to ensure the safety of patients in the trial, 
pertuzumab and trastuzumab must be interrupted in all patients for whom a drop of 
LVEF by ≥ 10 points to a value lower than 50 % is documented and must be 
discontinued if a repeat assessment within 3 weeks of the first assessment, using the 
same assessment method, confirms the drop of LVEF by ≥ 10 points to a value lower 
that 50% 
 
 
Withhold pertuzumab and Herceptin dosing for at least 3 weeks for either: 
 
a drop in LVEF to less than 40%  
 
a LVEF of 40% – 45% associated with a fall of  10% points below pretreatment 
values or lower  
Pertuzumab may be resumed if the LVEF has recovered to  45% or 40% – 45% 
associated with  10% points below pretreatment values.  
If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, 
or has declined further, discontinuation of pertuzumab and Herceptin should be 
strongly considered, unless the benefits for the individual patient are deemed to 
outweigh the risks. 
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discontinued.  
10.0 Monitoring and Blood draws 
After the study candidates consent to participating in the study, they will be evaluated 
with baseline CBC, chemistry, and liver function tests.  They will also undergo CT 
scan of the chest abdomen pelvis for initial staging and assessment of disease and 
bone scan (PET/CT scans are acceptable) for RECIST [version 1.1] measurements 
and in the case of patients with LABC, for baseline eligibility assessment (i.e., to 
exclude evidence for  distant metastasis)..   
 
The patients will undergo every three months cardiac monitoring by echocardiogram 
or MUGA scan while on treatment.  If there is a decrease in ejection fraction, patient 
will undergo more frequent cardiac monitoring as described above in the trastuzumab 
dose modification section. 
 
The patient will be monitored clinically by their primary oncologist every three weeks 
along with CBC, chemistry, and liver function tests.  Those with MBC will also 
undergo repeat imaging studies with CT scan of the chest, abdomen, and pelvis and 
bone scan (or, in case of PET/CT assessment as baseline, repeat testing with the same 
as appropriate) every 9 weeks.  They will continue to be treated with the combination 
therapy and monitored until progression. Patients enrolled with LABC will have their 
imaging studies repeated only as clinically indicated.  
 
11.0 Data Safety and Monitoring Plan 
 
A) Definition of Risk Level 
 
This is a Risk Level 3 study, as defined in the “City of Hope Data and Safety 
Monitoring Plan”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx 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. 
 
B) Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, 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. 
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 

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RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
 
Data and safety will be reported to the COH DSMC using the PMT report and 
submitted accoring to the timelines in Table 1 above.  Protocol specific data collection 
will include the following items: a summary of accrual, adverse events and treatement 
related mortality. 
 
C) Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change 
of an existing condition that occurs during or after treatment, whether or not it is 
considered to be related to the protocol intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it 
is not listed in the investigator’s brochure and/or package insert; is not listed at the 
specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any 
underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected 
event OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the 
adverse event 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or 
unexpected adverse event that results in any of the following outcomes: 
 Death 
 Is life-threatening experience (places the subject at immediate risk of death from 
the event as it occurred) 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
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 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary Malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasisas of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
Unanticipated problem (UP) – Any incident, experience, or outcome that meets all 
three of the following criteria: 
 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may have 
been caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
 
12.0 Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems: Most unanticipated problems must be reported to the COH 
DSMC and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that 
occurs during the study conduct will be reported to the DSMC and IRB by submitting 
electronically in iRIS (http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed 
by the physician, nurse, or reported by the patient, will be reported according to 
definitions and guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx 
and Table 2 below.  Those SAEs that require expedited reporting will be submitted 
electronically in iRIS (http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that 
do not meet the criteria of serious OR are not unanticipated problems will be reported 
only in the protocol continuation reports and PMT report (see Table 2 below). 
 
 

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Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of 
last day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 

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Externally Sponsored Studies 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days 
of last day of treatment 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations 
Director. The DSMC will review the case and make a determination as to whether the 
study will be suspended, terminated, amended, or allowed to continue without 
amendment. 
 
 
 
 
 
 
 
 
 

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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
 
 
12.1  Methods and Timing for Assessing AND Recording Safety Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, are collected and reported to the FDA, appropriate IRB(s), and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).  
 
12.1.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. 
After this period, investigators should only report SAEs that are attributed to prior study 
treatment. 
 
12.1.2 Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the pertuzumab, trastuzumab, and nab-paclitaxel combination, and actions 
taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
 
Yes 

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There is a plausible temporal relationship between the onset of the AE and administration 
of the pertuzumab, trastuzumab, and nab-paclitaxel combination, and the AE cannot be 
readily explained by the subject’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to the pertuzumab, 
trastuzumab, and nab-paclitaxel combination; and/or the AE abates or resolves upon 
discontinuation of the pertuzumab, trastuzumab and nab-paclitaxel combination or dose 
reduction and, if applicable, reappears upon re-challenge. 
 
No 
Evidence exists that the AE has an etiology other than the pertuzumab, trastuzumab and 
nab-paclitaxel (e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the AE has no plausible temporal relationship to 
pertuzumab, trastuzumab and nab-paclitaxel administration (e.g., cancer diagnosed 2 days 
after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For example, 
under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred 
to elevated hepatic enzymes or hepatitis. 
 
12.2 Procedures for Eliciting, Recording, and Reporting Adverse Events 
 
12.2.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include:  
 “How have you felt since your last clinical visit?” 
 “Have you had any new or changed health problems since you were last here?”  
 
12.2.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
5.1.2), regardless of attribution, will be reported to the appropriate parties. When 

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recording a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the single medical concept. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, report “Unexplained Death”. 
c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only 
if the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a medical or 
surgical procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE. For example, if a subject is hospitalized to 
undergo coronary bypass surgery, record the heart condition that necessitated the bypass as the 
SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
e. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 
90 days after the last dose of study drug, a report should be completed and expeditiously 
submitted to the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy 
should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as an SAE. Similarly, any 
congenital anomaly/birth defect in a child born to a female subject exposed to the {study 
drug} should be reported as an SAE. 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior pertuzumab, 
trastuzumab and nab-paclitaxel exposure. If the investigator should become aware of the 
development of cancer or a congenital anomaly in a subsequently conceived offspring of 
a female subject who participated in the study, this should be reported as an SAE.  
g. 
Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the 
Sponsor will agree to the reconciliation periodicity and format, but agree at minimum to 
exchange monthly line listings of cases received by the other party. If discrepancies are 

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identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. The 
responsible individuals for each party shall handle the matter on a case-by-case basis 
until satisfactory resolution. 
h.  
AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result of 
safety monitoring of the Product  
  
12.3 SAE Reporting to Celgene  
The Investigator will utilize the FDA MedWatch program for the reporting of adverse 
events and follow up information to those events.  Full information regarding these 
procedures is described on the FDA website. (http://www.fda.gov/medwatch/). 
The Sponsor-Investigator will also utilize the Celgene 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 
Celgene Corporation within 24 hours of the investigational staff’s knowledge.   
 
Celgene Corporation 
Drug Safety Department 
86 Morris Avenue 
Summit, NJ  07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
and 
 
Industry Contact: 
Norma Powers 
Director, Medical Operations 
Celgene Corporation 
86 Morris Avenue 
Summit, NJ  07901 
Mobile: 267-337-2720 
Fax: 908-673-2779 
Email: npowers@celgene.com 
 
 
Any AE that meets any criterion for an SAE requires the completion of an SAE Report 
Form in addition to being recorded on the AE page/screen of the CRF. All SAEs must 
be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of 
the event by facsimile, or other appropriate method, using the SAE Report Form, or 
approved equivalent form. This instruction pertains to initial SAE reports as well as any 
follow-up reports. 
 
The Investigator is required to ensure that the data on these forms is accurate and 
consistent. This requirement applies to all SAEs (regardless of relationship to IP) that 
occur during the study (SAE’s will be reported from the time the patient starts 

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treatment to at least 28 days after the last dose of investigational product.) , and those 
made known to the Investigator at anytime thereafter that are suspected of being related 
to IP. SAEs occurring prior to treatment will be captured. 
 
The SAE report should provide a detailed description of the SAE and include 
summaries of hospital records and other relevant documents. If a subject died and an 
autopsy has been performed, copies of the autopsy report and death certificate are to be 
sent to Celgene Drug Safety as soon as these become available. Any follow-up data will 
be detailed in a subsequent SAE Report Form, or approved equivalent form, and sent to 
Celgene Drug Safety. 
 
Where required by local legislation, the Investigator is responsible for informing the 
IRB/EC of the SAE and providing them with all relevant initial and follow-up 
information about the event. The Investigator must keep copies of all SAE information 
on file including correspondence with Celgene and the IRB/EC. 
 
 Safety Queries 
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site 
via facsimile or electronic mail. The response time is expected to be no more than five 
(5) business days. Urgent queries (e.g., missing causality assessment) may be handled 
by phone. 
 
Expedited Reporting of Adverse Events 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the IP based on the Investigator 
Brochure. 
Celgene or its authorized representative shall notify the Investigator of the following 
information: 
 Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (i.e., SUSAR); 
 Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 In Japan, measures taken in foreign countries to ensure patient safety, study reports 
that indicates potential risk of cancer, etc., or biannual SAE report according to the 
local regulations. 
Where required by local legislation, the Investigator shall notify his/her IRB/EC 
promptly of these new serious and unexpected AE(s) or significant risks to subjects. 
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Drug Safety 
86 Morris Avenue 

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Summit, N.J. 07901 
Toll Free:   
(800)-640-7854 
Phone:  
 
(908) 673-9667 
Fax: 
 
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
12.4 SAE Reporting to Genentech  
 
Investigators must report all SAEs to Genentech within the timelines described below. 
The completed Medwatch/case report should be faxed immediately upon completion to 
Genentech Drug Safety at: 
 
(650) 225-4682 
OR 
(650) 225-5288 
 
 Relevant follow-up information should be submitted to Genentech Drug Safety as soon as 
it becomes available. 
 Serious AE reports that are related to the combination of pertuzumab, trastuzumab, and 
nab-paclitaxel and AEs of Special Interest (regardless of causality)  will be transmitted to 
Genentech within fifteen (15) calendar days of the Awareness Date. 
 Serious AE reports that are unrelated to the pertuzumab, trastuzumab, and nab-paclitaxel 
will be transmitted to Genentech within thirty (30) calendar days of the Awareness Date. 
 Additional Reporting Requirements to Genentech include the following: 
 Any reports of pregnancy following the start of administration with the pertuzumab, 
trastuzumab, and nab-paclitaxel will be transmitted to Genentech within thirty (30) 
calendar days of the Awareness Date.  
 All Non-serious Adverse Events originating from the Study will be forwarded in a 
quarterly report to Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 

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 Adding to the original MedWatch 3500A report and submitting it as follow-up 
 Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (The patient identifiers are important so that the new 
information is added to the correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom and adverse event was reported. For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative noted 
above or the MSL assigned to the study. Relevant follow-up information should be submitted 
to Genentech Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 
 
 
Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the 
FDA apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following guidance 
and timelines: 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the use of 
pertuzumab. An unexpected adverse event is one that is not already described in the 
pertuzumab Investigator Brochure. Such reports are to be telephoned or faxed to the FDA 
and Genentech within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably or 
possibly related to the use of pertuzumab. An unexpected adverse event is one that is not 
already described in the pertuzumab investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the 
IND concerning similar events should be analyzed and the significance of the new report in 
light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 

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event. The FDA prefers these reports on a Medwatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter). 
 
Randomization Codes for blinded clinical trials 
 
The blind will be broken for ADR reports that are Serious and Unexpected, unless otherwise 
agreed with applicable regulatory authorities. 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be 
faxed to Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-5288 
 
And to the Site IRB: 
City of Hope IRB  
email: IRBeSubmit@coh.org  
Tel: 626-256-4673 ext.63374 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682    OR    (650) 225-5288 
 
IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied 
to Genentech. Copies of such reports should be faxed to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-5288 
 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study: 
 
 
Pertuzumab and trastuzumab  Protocols 
Email : herceptin-gsur@gene.com OR pertuzumab-gsur@gene.com  
Fax : 650-360-6908

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SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
 
AE / SAE FAX No: (650) 225-4682 
 
Alternate Fax No: (650) 225-5288 
 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[INSERT investigational product name] / 
[INSERT investigational product name] / 
[INSERT investigational product name] 
Follow-up Report Date 
[INSERT investigational product name] / 
[INSERT investigational product name] / 
[INSERT investigational product name] 
 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[INSERT investigational product name] - 
[INSERT investigational product name] - 
[INSERT investigational product name] 
 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
 
 
 
 
 
 
 

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13.0 Agent Information 
 
13.1 Drug Information on Pertuzumab 
 
Effects in Humans 
 
13.1.1  Pharmacokinetics 
Similar pharmacokinetics (PK) was observed across studies with no change in clearance 
at doses from 2.0 to 15.0 mg/kg (140 mg to 1050 mg for a 70 kg patient). A two 
compartment model adequately described the concentration-time data with a systemic 
serum clearance of approximately 0.24 L/day and a terminal half-life of approximately 17 
days for a typical patient. Based on these data, a dosing interval of three weeks (q3w) is 
recommended in clinical studies. In Phase II studies, a loading dose of 840 mg (followed 
by 420 mg q3w), was capable of attaining steady-state trough and peak concentrations by 
the second cycle. Population PK modeling of data from Phase Ia and Phase II studies 
supports the continued use of fixed, non-weight-based dosing in female patients 
(insufficient data for male patients). There was no evidence of an impact of pertuzumab 
on the PK of co-administered gemcitabine, docetaxel, capecitabine or erlotinib in Phase 
Ib studies. 
 
13.1.2  Efficacy 
Clinical activity has been observed in patients with HER2 low-expressing tumors who 
have received pertuzumab either as a single agent or in combination with cytotoxic 
chemotherapy. Complete responses have not been observed in any of these trials. 
In single agent pertuzumab studies partial responses or stable disease lasting ≥ 6 months 
have been observed in 15% of patients with ovarian cancer (study TOC2689g) and in 8% 
of patients with HER2 low-expressing breast cancer (BO16934). No responses were 
observed in clinical studies of single-agent pertuzumab in patients with hormone 
refractory prostate cancer (Studies BO17004 and TOC2682g) or NSCLC (Study 
TOC2752g). 
 
Partial responses were observed in 3 out of 15 patients (20%) with NSCLC who received 
pertuzumab in combination with erlotinib (Study WO20024). In Study TOC3258g 
pertuzumab with gemcitabine given to patients with platinum-resistant ovarian cancer 
showed prolongation of PFS over gemcitabine alone (Hazard ration [HR] 0.66; 95% CI: 
0.43, 1.03). However, in platinum-sensitive ovarian cancer patients, addition of 
pertuzumab to a carboplatin-based doublet of chemotherapy did not improve PFS (Study 
BO17931). In Study BO17929 four complete responses and 12 partial responses (24% 
objective response rate) were observed in patients with previously treated HER2-positive 
MBC following combined treatment with pertuzumab and trastuzumab. In Study 
WO20697 patients with EBC receiving triple combination neoadjuvant therapy of 
pertuzumab, trastuzumab and docetaxel had a pathological complete response (pCR) rate 
of 46%, compared with 29% in patients receiving trastuzumab plus docetaxel (P=0.0141, 
95% CI 21- 39). 
 
13.1.3 Safety 

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CONTRAINDICATIONS 
Known hypersensitivity to pertuzumab or to any other compound of the product 
 
WARNINGS AND PRECAUTIONS 
Risk of Allergic Reactions, Including Anaphylaxis and Infusion-Associated Symptoms 
and Respiratory Events 
Like other monoclonal antibodies, pertuzumab may cause infusion-associated symptoms 
such as fever, chills, hypotension, shortness of breath, skin rash, headache, nausea, and/or 
vomiting. Such reactions typically occur during or very shortly after an infusion but may 
also show a delayed onset. Infusion-associated symptoms tend to be more frequent and 
severe with the first infusion than subsequent infusions. Serious events compatible with 
infusion-associated reactions/hypersensitivity reactions (hypersensitivity, urticaria, 
pulmonary edema, fatal ARDS, anaphylaxis, hypertension & dyspnea) have been 
reported with pertuzumab. 
 
Intravenous administration of pertuzumab should be performed in a setting with 
emergency equipment and staff who are trained to monitor medical situations and 
respond to medical emergencies. Patients will be monitored during each pertuzumab 
infusion and following the completion of the infusion for any adverse effects as specified 
in the study protocol. If infusion-associated symptoms occur, patients must be monitored 
until complete resolution of signs and symptoms. Patients who experience infusion-
associated symptoms may be pre-medicated with antihistamines, paracetamol 
(acetaminophen) or corticosteroids for subsequent infusions. 
 
Patients should be monitored during and following completion of each pertuzumab 
infusion for any adverse effects. Since there is the potential for a delayed onset of 
infusion-associated reactions patients should be instructed to contact the treating 
physician with any concerns. 
 
Infusion of pertuzumab should be stopped in patients who develop dyspnea or clinically 
significant hypotension (defined per investigator discretion). Patients who experience an 
NCI-CTC Grade 4 allergic reaction or acute respiratory distress syndrome should not 
receive any further doses of pertuzumab. 
 
A low rate of respiratory events compatible with an infusion-associated reaction or 
hypersensitivity reaction/anaphylaxis has been reported. Although pertuzumab targets the 
HER2 receptor it inhibits heterodimerization with other members of the HER family (eg, 
EGFR [HER1]). Accordingly, it may cause toxicities associated with the use of EGFR 
inhibitors, such as interstitial lung disease. The few reports of interstitial lung disease 
occurring in pertuzumab-treated patients received so far also had evidence of alternative 
causes, eg, concomitant medication, preceding/concurrent neutropenia with potential 
infection or relevant medical history. 
 
 
13.1.4 Risk of Cardiac Dysfunction 

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HER2-targeted therapy, notably treatment with trastuzumab, is associated with cardiac 
dysfunction. In patients treated with trastuzumab, the incidence of left ventricular 
dysfunction was greatest among those who received concurrent treatment with 
anthracyclines. Because pertuzumab is also directed against HER2, there is a risk of 
cardiac dysfunction with pertuzumab treatment. 
 
All patients enrolled in pertuzumab studies undergo regular LVEF monitoring by 
echocardiography or MUGA scan. Monitoring of LVEF is advised while patients are 
receiving pertuzumab. If symptomatic left ventricular dysfunction develops (NCI-CTC 
Grade 3 or 4), the patient must discontinue pertuzumab. Left ventricular dysfunction, 
whether symptomatic or not, should be treated and followed according to standard 
medical practice. For further guidance, please see individual study protocols. 
Patients with significant cardiac disease or baseline LVEF below the institution’s lower 
limit of normal should not receive pertuzumab. Specific risk factors for pertuzumab 
associated cardiac dysfunction are not known at this time but are likely to be similar to 
the risk factors for trastuzumab-associated cardiac dysfunction and cardiac disease in 
general (low LVEF, prior or concurrent anthracyclines, hypertensive and/or ischemic 
heart disease etc). The risks of cardiac dysfunction with pertuzumab treatment should be 
carefully weighed against the potential benefit of pertuzumab in patients who have 
received prior anthracyclines. 
 
13.1.5 Serious Adverse Reactions 
List of preliminary adverse drug reactions: 
 Infusion-associated reactions (including pyrexia, chills, nausea, vomiting, 
 dyspnea, rash, urticaria, vision blurred, dizziness, headache, hypertension) 
 Hypersensitivity reactions including anaphylaxis 
 Rash 
 Abdominal pain 
 Diarrhea 
 Nausea 
 Vomiting 
 Cardiac dysfunction (asymptomatic decrease in left ventricular systolic 
 dysfunction or symptomatic as heart failure): 
 Neutropenia (exacerbation of chemotherapy-associated myelosuppression 
 including febrile neutropenia, neutropenic infection or neutropenic sepsis) 
 Asthenic conditions 
 
13.1.6  Non-Serious Adverse Reactions 
No additional non-serious adverse reactions. 
 
13.1.7  Interactions With Other Medicinal Products and Other Forms of interaction 
None known 
 
13.1.8  Use in Special Populations 
No studies have been performed in pediatric patients. Patients aged > 18 years have been 
included in studies to date ie, there is no exclusion based on advanced age. No studies 

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have been performed in patients with renal or hepatic impairment. 
 
13.1.9  Pregnancy 
Impairment of fertility: Long-term studies in animals have not been performed to 
evaluate the effect of pertuzumab on fertility. No fetal studies in humans have been 
performed but in the preclinical reproductive toxicity study in cynomolgus monkeys, 
there were findings of delayed renal development, oligohydramnios, and intrauterine 
death. Moreover, in the post-marketing setting, cases of oligohydramnios, some 
associated with fatal pulmonary hypoplasia of the fetus, have been reported in pregnant 
women receiving trastuzumab.  Therefore, pertuzumab should not be used in pregnant 
women. Because of the long half-life of pertuzumab women are to be warned not to 
become pregnant for at least 6 months after completion of treatment. For further 
guidance, please see individual study protocols. 
Nursing Mothers 
It is not known whether pertuzumab is excreted in human milk. As human IgG1 is 
secreted into human milk, and the potential for harm to the infant is unknown, 
pertuzumab should not be administered to nursing women. 
 
13.1.10  Overdose 
Safety in Phase I Studies / Information on MTD 
Five dose levels of pertuzumab ranging between 0.5 mg/kg and 15 mg/kg were evaluated 
in Study TOC2297g. Using body weight-based dosing, individual single doses ranged 
from 29 mg up to 1635 mg. Twenty-one patients received at least one dose of pertuzumab 
and all 21 experienced at least one AE. The maximum tolerated dose (MTD) was not 
reached at any dose level. The most commonly reported events were fatigue (52%), 
vomiting (52%), nausea (48%), diarrhea (29%), and rash (29%). The majority of AEs 
were NCI CTC Grade 1 or 2 in severity. Twelve patients in this study experienced at least 
one Grade 3 or 4 AE. Grade 3 or 4 AEs that were observed in two or more patients 
included dyspnea, pleural effusions, and abdominal pain. No relationship to dose level 
was observed for any of these common AEs. 
 
In a Japanese Phase I dose escalation study in 18 patients, pertuzumab was well tolerated 
up to maximum dose of 25mg/kg and the MTD was not reached. Individual single doses 
ranged from 215 mg up to 1728 mg. The safety profile was consistent with that observed 
in other phase I studies. The most common toxicities were diarrhea, rash, nausea, 
vomiting, and lymphopenia. No clear dose-relationship was observed. 
 
Drug Biochemistry 
Pertuzumab is a fully humanized monoclonal antibody based on the human IgG1 (κ) 
framework sequences and consists of two heavy chains (449 residues) and two light 
chains (214 residues). Like trastuzumab, pertuzumab is directed against the extracellular 
domain of HER2. However, it differs from trastuzumab in the epitope-binding regions of 
the light chain (12 amino acid differences) and heavy chain (29 amino acid differences). 
As a result, pertuzumab binds to an epitope within what is known as subdomain 2 of 
HER2 while the epitope for trastuzumab is localized to subdomain 4 [3.1, 3.2]. 
 

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Manufacturing Procedures 
Pertuzumab is produced in Chinese hamster ovary (CHO) cell cultures and purified by 
protein A column affinity chromatography, followed by ion-exchange column 
chromatography. Because of the high degree of homology between pertuzumab and 
trastuzumab, procedures similar to those developed for trastuzumab are used for the 
manufacturing process, the in-process controls, and the characterization of pertuzumab. 
 
No bovine-derived raw materials are used in the manufacture of pertuzumab. 
Each lot of the recombinant antibody produced for clinical purposes meets USP 
requirements for sterility and safety. In addition, each lot is extensively characterized and 
meets the required specifications for identity, purity, and potency. 
 
Clinical Formulation and Storage Requirements 
Pertuzumab drug product is provided as a single use formulation containing 30 mg/mL 
pertuzumab in 20 mM L-histidine acetate (pH 6.0), 120 mM sucrose and 0.02% 
polysorbate 20. Each 20 mL vial contains 420 mg of pertuzumab (14.0 mL/vial). Upon 
receipt of pertuzumab vials are to be refrigerated at 2°C–8°C (36°F–46°F) until use.  
Pertuzumab vials should not be used beyond the expiration date provided by the 
manufacturer. Because the formulation does not contain a preservative, the vial seal may 
only be punctured once. Any remaining solution should be discarded. Vial contents 
should be protected from light, and should not be frozen. 
 
The solution of pertuzumab for infusion, diluted in PVC or non-PVC polyolefin bags 
containing 0.9% Sodium Chloride Injection, USP, may be stored for up to 24 hours prior 
to use. Diluted pertuzumab has been shown to be stable for up to 24 hours at a 
temperature range of 2°C–25°C. However, since diluted pertuzumab contains no 
preservative, the diluted solution should be stored refrigerated (2°C–8°C). 
 
Support for Dose Regimen 
A dosing regimen of pertuzumab administered every 3 weeks to patients in Phase II 
studies (TOC2689g, BO16934) using a fixed 840 mg loading dose (equivalent to 12 
mg/kg for a 70 kg patient) for treatment cycle 1 followed by a fixed 420 mg 
“maintenance” dose (equivalent to 6 mg/kg) for subsequent treatment cycles resulted in 
steady-state serum trough concentrations of approximately 60 μg/mL by the second 
treatment cycle. In nonclinical dose-response xenograft studies using nude mice 
implanted with NSCLC and breast cancer tumors (low and high HER2 expression levels), 
> 80% suppression of tumor growth was achieved when steady-state trough 
concentrations of pertuzumab were 5-25 μg/mL. Thus the steady-state serum trough 
concentrations obtained in patients are in excess of concentrations shown to be 
efficacious in animal tumor models, and therefore expected to result in a biologic effect. 
 
A preliminary population PK analysis of the Phase Ia (TOC2297g) and Phase IIa 
(TOC2689g, BO16934) studies, comprising 153 patients (weight range: 45.0-150.6 kg) 
and 1458 concentration-time points, showed that the population variability of steady-state 
trough concentration and exposure were similar with fixed-, body surface area-, and 
weight-based dosing. A dose based on body-surface area or weight was not superior to a 

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fixed dose, supporting the continued use of a fixed dose of pertuzumab in female patients 
with MBC and ovarian cancer [5.12]. 
 
The dependence of pertuzumab serum clearance on body weight for both female and 
male patients will be evaluated further using all available clinical pharmacokinetic data 
from the Phase II studies. 
 
 
13.1.11 Risk of Cardiac Dysfunction 
HER2-targeted therapy, notably treatment with trastuzumab, is associated with cardiac 
dysfunction. In patients treated with trastuzumab, the incidence of left ventricular 
dysfunction was greatest among those who received concurrent treatment with 
anthracyclines. Because pertuzumab is also directed against HER2, there is a risk of 
cardiac dysfunction with pertuzumab treatment. 
 
All patients enrolled in pertuzumab studies undergo regular LVEF monitoring by 
echocardiography or MUGA scan. In pertuzumab single-agent Phase II studies, the 
incidence of LVEF decrease was similar to that reported with trastuzumab. A fall in 
LVEF of ≥ 10 percentage points to a LVEF value < 50% was observed in 21/302 patients 
(7%) who had a post-baseline LVEF assessment. Nine of these patients had received 
prior anthracycline treatment. In studies where the primary safety analysis has been 
completed, the incidence of cardiac dysfunction associated with pertuzumab in 
combination with chemotherapy, does not appear to be any greater than that associated 
with trastuzumab plus chemotherapy. In patients selected for good cardiac function at 
baseline and with minimal cardiac risks, the combination of trastuzumab and pertuzumab 
also appears to be well tolerated, with no increase in the rate of cardiac events reported to 
date, compared with rates in patients receiving trastuzumab alone. Furthermore, 
pertuzumab, trastuzumab and non-anthracycline based neoadjuvant chemotherapy did not 
result in any significantly greater incidence of LVEF decline in EBC patients than the 
incidence seen in patients receiving trastuzumab and chemotherapy. 
 
Overall, five symptomatic cardiac failure events have been reported in patients treated 
with pertuzumab from studies where the primary safety analysis has been completed. 
Two of these events occurred in patients with MBC who had received prior 
anthracyclines: one of these patients was treated with single agent pertuzumab (Study 
BO16934) and the second patient was receiving concomitant trastuzumab (Study 
TOC3487s). Two events occurred in patients with ovarian cancer, who were receiving 
concomitant chemotherapy (gemcitabine for one patient in Study TOC3258g and 
paclitaxel plus carboplatin for one patient in Study BO17931). The fifth event occurred in 
a patient with EBC receiving concomitant trastuzumab (Study WO20697). Three further 
events of CHF have been reported in ongoing studies. One event occurred in a patient 
with EBC (Study BO22280) who had just completed FEC treatment and was receiving 
concurrent docetaxel and trastuzumab. The second occurred in a patient with MBC 
(Study MO22324) who was treated with concomitant trastuzumab and capecitabine. This 
patient had a history of hypertensive heart disease, prior anthracycline (epirubicin) 
treatment and radiotherapy to the left chest. The third event occurred in a patient with 

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NSCLC (Study TOC4603g) who was receiving pertuzumab in combination with 
erlotinib. 
 
Patients with significant cardiac disease or baseline LVEF below the institution’s lower 
limit of normal should not receive pertuzumab. Specific risk factors for pertuzumab 
associated cardiac dysfunction are not known at this time but are likely to be similar to 
the risk factors for trastuzumab-associated cardiac dysfunction and cardiac disease in 
general (low LVEF, prior or concurrent anthracyclines, hypertensive and/or ischemic 
heart disease etc). The risks of cardiac dysfunction with pertuzumab treatment should be 
carefully weighed against the potential benefit of pertuzumab in patients who have 
received prior anthracyclines. 
 
Monitoring of LVEF is advised while patients are receiving pertuzumab. If symptomatic 
left ventricular dysfunction develops (NCI-CTC grade 3 or 4), the patient must 
discontinue pertuzumab. Left ventricular dysfunction, whether symptomatic or not, 
should be treated and followed according to standard medical practice until resolution or 
a final outcome. 
 
 
13.1.12 Risk of EGFR-Related Toxicities 
Although pertuzumab targets the HER2 receptor it inhibits heterodimerization with other 
members of the HER family (eg, EGFR [HER1]). Accordingly, it may cause toxicities 
associated with the use of EGFR inhibitors such as diarrhea, rash and other dermatologic 
toxicities (eg, dry skin, pruritus, nail disorders, mucositis). 
 
Diarrhea 
In the 7-week IV and 26-week toxicity studies in cynomolgus monkeys, there was a 
treatment-related increase in the incidence of diarrhea. Diarrhea has been observed in 
approximately 60% of patients (treatment-related diarrhea in 50% of patients) being 
treated with pertuzumab in Phase II single-agent studies, and up to approximately 70% of 
patients in combination therapy studies. Diarrhea was NCI-CTC grade 1 or 2 in the 
majority of cases. To prevent dehydration, early treatment of diarrhea with anti-diarrheal 
medication should be considered and patients treated with fluids and electrolyte 
replacement, as clinically indicated. 
 
Rash 
Rash has also been observed with EGFR inhibitors, mostly of mild to moderate intensity. 
Rash has been observed in approximately 17% of patients receiving pertuzumab in Phase 
II single-agent studies and up to 73% of patients in combination studies. The rash was 
generally of NCI-CTC grade 1 or 2 severity. Treatment recommendations for EGFR 
associated rash include topical or oral antibiotics, topical pimecrolimus, topical or (for 
severe reactions) systemic steroids [6.1]. These agents may be used in patients 
experiencing pertuzumab-related rash, as clinically indicated, although they have not 
been studied in this context. 
 
Risk of Neutropenia 

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Trastuzumab has been shown to increase NCI-CTC grades 3 and 4 neutropenia/febrile 
neutropenia when used in combination with higher dose (100 mg/m2) docetaxel in 
patients with MBC [6.2]. Pertuzumab, at a dose of 420 mg, was well tolerated in 
combination with docetaxel up to 75 mg/m2 in the Phase Ib study, BO17021. However, 
pertuzumab in combination with 100 mg/m2 docetaxel was not well-tolerated. Dose 
limiting toxicity was observed, including febrile neutropenia. In light of these data, 
patients receiving pertuzumab in combination with docetaxel in ongoing studies are 
treated initially with 75 mg/m2 docetaxel, and only patients who tolerate 75 mg/m2 are 
eligible for dose escalation to 100 mg/m2 (as described in the protocol dose escalation 
rules). This strategy is intended to ensure both tolerability and optimal individual patient 
exposure to docetaxel. Using this approach in the Phase II WO20697 study in patients 
receiving docetaxel with pertuzumab and/or trastuzumab as neoadjuvant therapy for 
EBC, between 56% and 71% of patients experienced a neutropenic AE, and 8% to 20% 
of patients required study drug dose modification. However, only 1 patient withdrew due 
to neutropenia. Patients receiving pertuzumab in combination with docetaxel or other 
cytotoxic agents should undergo careful hematological monitoring for neutropenia during 
treatment, and should be treated promptly with antibiotics and other supportive measures 
as clinically indicated. 
 
 
13.1.13 Precautions 
Special Care 
Laboratory and Diagnostic Tests 
Pertuzumab may contribute to a risk of cardiac dysfunction. Noninvasive cardiac 
monitoring, such as echocardiography, should be performed at scheduled time points, as 
specified in the study protocols, to ensure that pertuzumab treatment can be promptly 
withheld and medical treatment initiated if indicated. 
 
Drug–Drug Interactions/Drug–Laboratory Test Interactions 
Three Phase Ib and II studies have evaluated the pharmacokinetics of co-administered 
cytotoxic agents, gemcitabine, capecitabine, and docetaxel when administered with 
pertuzumab. These studies show that concomitant administration of pertuzumab does not 
affect the pharmacokinetics of these agents. The pharmacokinetics of erlotinib also 
appears to be unaltered by concomitant administration of pertuzumab, when compared to 
historical data from erlotinib NSCLC studies. 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Long-term studies in animals have not been performed to evaluate the carcinogenic 
potential of pertuzumab or its effect on fertility. 
 
Pregnancy 
No fetal studies in humans have been performed but pertuzumab caused 
oligohydramnios, delayed renal development and embryo-fetal deaths in pregnant 
cynomolgus monkeys. Moreover, in the post-marketing setting, cases of 
oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus, have 
been reported in pregnant women receiving trastuzumab (for further details, see 

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Herceptin Prescribing Information). Therefore, pertuzumab should not be used in 
pregnant women. Protocols for ongoing pertuzumab studies indicate that highly effective 
contraceptive measures must be used; continuous pregnancy monitoring must be 
performed during the trials and for 6 months after the last dose of study drug is 
administered. Because of the long half-life of pertuzumab women should be warned not 
to become pregnant for at least 6 months after completion of treatment 
 
Nursing Mothers 
It is not known whether pertuzumab is excreted in human milk. As human IgG1 is 
secreted into human milk, and the potential for harm to the infant is unknown, 
pertuzumab should not be administered to nursing women. 
 
Pediatric Use 
No studies have been performed in pediatric patients. 
 
 
13.1.14 Supplier 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA 94080-4990 U.S.A. 
F. Hoffmann-La Roche Ltd. 
Grenzacherstrasse 124 
Basel, Switzerland 
 
13.2 Drug Information on Nab-Paclitaxel (ABI-007; tradename: Abraxane®) 
ABRAXANE for Injectable Suspension (also known as ABI-007, nab-paclitaxel, paclitaxel 
protein-bound particles for injectable suspension) is an albumin-bound form of paclitaxel with 
a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a 
non-crystalline, amorphous state. ABRAXANE is supplied as a white to yellow, sterile, 
lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP 
prior to intravenous infusion. Each single-use vial contains 100 mg of paclitaxel and 
approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted suspension 
contains 5 mg paclitaxel. ABRAXANE is free of solvents.   The active agent in ABRAXANE 
is paclitaxel.  
 
In the United States, ABRAXANE for Injectable Suspension (paclitaxel protein-bound 
particles for injectable suspension) is indicated for the treatment of breast cancer after failure 
of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant 
chemotherapy. Prior therapy should have included an anthracycline unless clinically 
contraindicated. 
 
13.2.1 Risks and Contraindications 
Preclinical Studies with ABRAXANE  
Preclinical studies comparing ABRAXANE to Taxol® (paclitaxel ® EL solvent-based, 
BMS) demonstrated lower toxicities, with an MTD approximately 50% higher for 
ABRAXANE compared to Taxol.  At equal doses there was less myelosuppression and 

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improved efficacy in a xenograft tumor model of human mammary adenocarcinoma.  At 
equitoxic doses of paclitaxel, ABRAXANE treated groups showed more complete 
regressions, longer time to recurrence, longer doubling time, and prolonged survival. At 
equal dose, tumor paclitaxel area under the curve was 33% higher for ABRAXANE versus 
solvent based paclitaxel, indicating more effective intratumoral accumulation of 
ABRAXANE35 
 
13.2.2 Clinical Studies with Abraxane® 
Weekly for 3 Weeks, Every 4 Weeks Schedule 
Thirty-nine patients were enrolled into a Phase I study of ABRAXANE administered QW 
for 3 weeks followed by a 1 week rest in patients with advanced solid tumors36  The MTDs 
for heavily and lightly pre-treated patients were 100 and 150 mg/m2 respectively.  Dose 
limiting toxicities included grade 4 neutropenia and grade 3 sensory 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 14% of women treated with 
ABRAXANE 100 mg/m2 QW schedule.  ABRAXANE weekly regimen was well 
tolerated; 91% of 106 patients were treated at the full dose of 100 mg/m2 of ABRAXANE 
without dose reductions. Based on the activity and low toxicity documented with this 
schedule, the study was expanded to evaluate the efficacy and safety/tolerability of a 
higher dose of ABRAXANE 100 mg/m2 weekly regimen in 75 additional patients. Results 
of this dose-finding study confirm the dose of ABRAXANE 100 mg/m2 as the appropriate 
dose for further study in this patient population35 
In an open-label, randomized, multicenter phase II study comparing the antitumor 
response and toxicity of in two QW dosing regimens, ABRAXANE dosed Q3W, and 
Taxotere® (polysorbate solvent-based docetaxel Sanofi-Aventis] Q3W for the first-line 
treatment of metastatic breast cancer24, a total of 300 patients were randomized to one of 
four treatment arms: (A) ABRAXANE 300 mg/m2 IV Q3W, (n=76); (B) ABRAXANE 
100 mg/m2 (n=76); (C) ABRAXANE 150 mg/m2 QW (n=74) QW every 28 days; or (D) 
Taxotere 100 mg/m2 Q3W (n=74). The primary objective of the trial was to evaluate the 
antitumor activity and safety of three different ABRAXANE regimens to determine the 
optimal dose and frequency to be used. Secondary objectives included the comparisons of 
each treatment group with respect to efficacy and safety, specifically: ABRAXANE to 
Taxotere; ABRAXANE QW regimens to ABRAXANE Q3W regimen; and the two dose 
levels of QW ABRAXANE.  Patients received ABRAXANE as a 30-minute IV infusion 
without premedication; Taxotere was administered as a 60-minute infusion with 
corticosteroid premedication. Total of 75% of all patients were post-menopausal with a 
mean age of 53.9 years at randomization.   
Both ORRs and total response rates were higher in all ABRAXANE arms compared to the 
Taxotere arm. The investigator-reported ORRs were 46%, 63%, 74%, and 39%, for arms 
A, B, C, and D, respectively. This difference was statistically significant for both QW 
dosing arms of ABRAXANE compared with Taxotere, (P = 0.002 for arm B v D, and P 
<0.001 for arm v D). The corresponding investigator-reported total response rates were 

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72%, 83%, 91% and 69% for the four arms, respectively. This difference reached statistical 
significance for arms B and C compared to Taxotere (P = 0.009 for arm B v D, and 
p=0.005 for arm C v. D).  No significant difference in ORR was noted between the two 
weekly dosing arms (arm B vs. C, P = 0.24). A significant increase in PFS was observed in 
the 150 mg/m2 QW arm compared to the Taxotere arm (14.6 v 7.8 months, respectively, P 
= 0.012, hazard ratio 0.57).  No significant difference in PFS was found between the 
ABRAXANE 300 mg/m2 Q3W arm and Taxotere arm (A and D). Similarly, PFS was not 
significantly different between arms A and C, or arms B and D.  
All three ABRAXANE arms demonstrated a favorable safety profile when compared with 
the Taxotere arm. The most frequent hematologic adverse event was neutropenia, with 
significantly lower rates of Grade 3/4 neutropenia in all ABRAXANE arms (Grade 4, 5%, 
5%, 9%, 75% for arms A, B, C, D, respectively).  ABRAXANE also had lower rates of 
febrile neutropenia (1%, 1%, 1%, 8% for arms A, B, C, D, respectively) and fatigue (Grade 
3, 5%, 0%, 3%, 19% for arms A, B, C, D, respectively) compared to Taxotere. While the 
incidence of sensory neuropathy was similar in the ABRAXANE and Taxotere arms, the 
median time to improvement in patients with Grade 3 neuropathy was shorter in all three 
ABRAXANE arms (22, 22, 19 and 37 days in arms A, B, C and D, respectively).The 
ABRAXANE arms demonstrated improved safety and increased efficacy compared with 
Taxotere. All three ABRAXANE regimens produced lower rates of neutropenia, febrile 
neutropenia, and fatigue than Taxotere.24   
Continuous Weekly (QW) Schedule in Neoadjuvant Breast Cancer 
The NSABP studied the administration of ABRAXANE in a neoadjuvant setting to 
patients with locally advanced breast cancer at a dose of 100 mg/m2 QW for 12 weeks, 
with no break52.  Four cycles of FEC were administered sequentially based on patients’ 
HER2 status: HER2 negative patients received FEC-100 (F: 500 mg/m2, E: 100 mg/m2, C: 
500 mg/m2 Q3 weeks) and HER2 positive patients received weekly trastuzumab in addition 
to FEC-75 (F: 500 mg/m2, E: 75 mg/m2, C: 500 mg/m2 Q3 weeks).  Weekly trastuzumab 
was permitted during ABRAXANE and FEC-75 treatment at the discretion of the 
investigator.   The primary objective of the trial was to determine the pathologic complete 
response rate (pCR) in the breast.  At the time of initial report at SABCS 2006, 65 patients 
had been entered on study and were evaluable for cCR and safety.  Following 12 weeks of 
ABRAXANE, a clinical complete response rate (cCR) of 32% was noted.  The therapy 
was well tolerated, with 48/65 patients receiving 12 doses in 12 weeks and 13/65 receiving 
12 doses in 13-14 weeks.  The incidence of peripheral (sensory) neuropathy was low (11% 
grade 2, 5% grade 3) as was neutropenia (3% grade 3 and no grade 4). The authors 
concluded that the administration of ABRAXANE 100 mg/m2 QW x 12 was both effective 
and tolerable.  
At the time of this update, more than 20 abstracts and publications have been presented at 
major oncology conferences or published in medical journals related to ABRAXANE QW 
schedule in breast cancer, including completed and ongoing studies. 
 
13.2.3 Human Toxicity: 
Please refer to the Clinical Investigator’s Brochure for details of the Adverse Reactions in 
the overall Safety Database for Abraxane®. The following have been observed: 

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myelosuppression, nausea and vomiting, diarrhea, mucositis, infections, hypotension, 
abnormal ECG changes, cough, dyspnea, edema, sensory neuropathy, bilirubin/liver 
enzyme elevations, allergic reactions, alopecia, asthenia, arthralgia, and myalgia. During 
post marketing surveillance, rare cases of severe hypersensitivity reactions have occurred.  
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. 
 
13.2.4 Concomitant Medications/Precautions 
Supportive care, including but not limited to anti-emetic medications, may be administered 
at the discretion of the Investigator. Concurrent treatment with bisphosphonates is allowed.  
Erythropoietin and G-CSF may be administered at the discretion of the investigator, 
consistent with institutional guidelines.  
 
13.2.5 Storage and Stability 
Storage: Store the vials in original cartons at 20º C to 25º C (68º F to 77ºF). Retain in the 
original package to protect from bright light.  
Stability: Unopened vials of ABRAXANE are stable until the date indicated on the 
package when stored between 20ºC to 25ºC (68ºF to 77ºF), in the original package. Neither 
freezing nor refrigeration adversely affects the stability of the product.  
 
Stability of Reconstituted Suspension in the Vial  
Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2ºC to 
8ºC (36ºF to 46ºF) for a maximum of 8 hours if necessary. If not used immediately, each 
vial of reconstituted suspension should be replaced in the original carton to protect it from 
bright light. Discard any unused portion.  
 

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Stability of Reconstituted Suspension in the Infusion Bag  
The suspension for infusion prepared as recommended in an infusion bag should be used 
immediately, but may be stored at ambient temperature (approximately 25º C) and lighting 
conditions for up to 8 hours. 
 
13.2.6 Formulation/Agent Preparation 
Nab-paclitaxel, Abraxane®, is a -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. 
 
13.2.7 Supplier 
Abraxane® will be supplied by Celgene Corporation.  Each single-use vial contains 100 
mg of paclitaxel and approximately 900 mg of human albumin. Each milliliter (mL) of 
reconstituted suspension contains 5 mg paclitaxel. 
Celgene Corporation 
86 Morris Avenue 
Summit, N.J. 07901 
Toll Free:   
(800)-640-7854 
Phone:  
(908) 673-9667 
FAX:  
(908) 673-9115 
 
 
Drug Distribution and Destruction 
a. Drug Distribution 
ABRAXANE® will be distributed by Abraxis BioScience, LLC.  No supplies will be 
shipped to any site until regulatory approval has been obtained.  Investigational sites will 
be supplied with ABRAXANE® upon identification and screening of a potential trial 
subject.   
 
Upon identification of a potential subject, sites must fax a completed Drug Request Form 
to Abraxis BioScience, LLC.  Allow at least 5 working days for drug shipment.  There 
are no shipments on Fridays or holidays. 
b. Drug Return and Destruction 
If the investigational site does not have a policy, procedure or SOP detailing the process 
to follow for study drug destruction, the study drug must then be returned to Abraxis 
using the Drug Return Form provided in the package containing the study drug.  The 
following information must be recorded on the site’s pharmacy drug accountability log: 
quantity of vials to be returned, expiration date and lot number.  A copy of the Drug 
Return Form and the study drug should be returned to Abraxis Clinical Supplies Dept. 
using the mailing address on the packaging slip that came with the original study drug 
order.  A copy of the Drug Return Form should be retained at the clinical site.  In the 
event of study completion or termination, a copy of all pharmacy records (drug 
dispensing log, drug accountability log and any destruction memos) must be mailed to 
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If the investigational site has a policy, procedure or SOP detailing the process to follow 
for study drug destruction, the pharmacist or designee can choose to destroy the study 
drug on site.  The following information must be recorded on the site’s pharmacy drug 
accountability log: quantity of vials destroyed, expiration date and lot number.  The 
pharmacist must document that the study drug was destroyed in accordance with their 
institution’s drug destruction policy or SOP.  A drug destruction memo and the site’s 
drug destruction SOP/policy should be sent to Abraxis Medical Operations Dept.  A copy 
of the drug destruction memo should be retained at the clinical site.  In the event of study 
completion or termination, a copy of all pharmacy records (drug dispensing log, drug 
accountability log and any destruction memos) must be mailed to Abraxis Medical 
Operations. 
 
13.3 Drug Information for trastuzumab (Herceptin®) 
The below information is largely duplicated from the Herceptin package insert.53   
Relevant points are summarized as follows. 
 
Other names: none 
13.3.1 Mode of Action: recombinant DNA-derived humanized monoclonal antibody that 
selectively binds with high affinity in a cell-based assay to the extracellular domain of the 
human epidermal growth factor receptor 2 protein, HER2.  
Availability: Trastuzumab is commercially available 
 
13.3.2 Risks and Contraindications 
13.3.2.A Cardiotoxicity:  
Signs and symptoms of cardiac dysfunction, such as dyspnea, increased cough, 
paroxysmal nocturnal dyspnea, peripheral edema, S3 gallop, or reduced ejection fraction, 
have been observed in patients treated with trastuzumab. Congestive heart failure 
associated with trastuzumab therapy may be severe and has been associated with 
disabling cardiac failure, death, and mural thrombosis leading to stroke. The clinical 
status of patients in the trials who developed congestive heart failure was classified for 
severity using the New York Heart Association classification system (I-IV, where IV is 
the most severe level of cardiac failure). (See Table 6.0)  

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Table 6.0: Incidence and Severity of Cardiac Dysfunction  
  
Trastuzumab 
alone31 
n = 213 
Trastuzumab 
+ 
Paclitaxel32 
n = 91 
Paclitaxel32 
n = 95 
Trastuzumab + 
Anthracycline+ 
cyclophosphamide32 
n = 143 
Anthracycline+ 
cyclophosphamide32 
n = 135 
Any 
Cardiac 
Dysfunction 
7% 
11% 
1% 
28% 
7% 
Class III-IV 
5% 
4% 
1% 
19% 
3% 
31 (see reference): Open-label, single-agent Phase II study (94% received prior anthracyclines). 
32 (see reference): Randomized Phase III study comparing chemotherapy plus trastuzumab to chemotherapy alone, where chemotherapy is either 
anthracycline/cyclophosphamide or paclitaxel.  
Candidates for treatment with trastuzumab should undergo thorough baseline cardiac 
assessment including history and physical exam and one or more of the following: 
echocardiogram, and MUGA scan. There are no data regarding the most appropriate 
method of evaluation for the identification of patients at risk for developing 
cardiotoxicity. Monitoring may not identify all patients who will develop cardiac 
dysfunction.  
Extreme caution should be exercised in treating patients with pre-existing cardiac 
dysfunction.  
Patients receiving trastuzumab should undergo frequent monitoring for deteriorating 
cardiac function.  
The probability of cardiac dysfunction was highest in patients who received trastuzumab 
concurrently with anthracyclines. The data suggest that advanced age may increase the 
probability of cardiac dysfunction.  
Pre-existing cardiac disease or prior cardiotoxic therapy (e.g., anthracycline or radiation 
therapy to the chest) may decrease the ability to tolerate trastuzumab therapy; however, 
the data are not adequate to evaluate the correlation between trastuzumab-induced 
cardiotoxicity and these factors.  
Discontinuation of trastuzumab therapy should be strongly considered in patients who 
develop clinically significant congestive heart failure. In the clinical trials, most patients 
with cardiac dysfunction responded to appropriate medical therapy often including 
discontinuation of trastuzumab. The safety of continuation or resumption of trastuzumab 
in patients who have previously experienced cardiac toxicity has not been studied. There 
are insufficient data regarding discontinuation of trastuzumab therapy in patients with 
asymptomatic decreases in ejection fraction; such patients should be closely monitored 
for evidence of clinical deterioration.  
13.3.2.B Precautions  

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General: Trastuzumab therapy should be used with caution in patients with known 
hypersensitivity to trastuzumab, Chinese Hamster Ovary cell proteins, or any 
component of this product.  
Drug Interactions: There have been no formal drug interaction studies performed 
with trastuzumab in humans. Administration of paclitaxel in combination with 
trastuzumab resulted in a two-fold decrease in trastuzumab clearance in a non-human 
primate study and in a 1.5-fold increase in trastuzumab serum levels in clinical 
studies.  
Benzyl Alcohol: For patients with a known hypersensitivity to benzyl alcohol (the 
preservative in Bacteriostatic Water for Injection) reconstitute trastuzumab with 
Sterile Water for Injection (SWFI), USP. DISCARD THE SWFI-RECONSTITUTED 
TRASTUZUMAB VIAL FOLLOWING A SINGLE USE.  
Immunogenicity: Of 903 patients who have been evaluated, human anti-human 
antibody (HAHA) to trastuzumab was detected in one patient, who had no allergic 
manifestations.  
Carcinogenesis, Mutagenesis, Impairment of Fertility:  
Carcinogenesis: Trastuzumab has not been tested for its carcinogenic potential.  
Mutagenesis: No evidence of mutagenic activity was observed in Ames tests using 
six different test strains of bacteria, with and without metabolic activation, at 
concentrations of up to 5000 µg/mL trastuzumab. Human peripheral blood 
lymphocytes treated in vitro at concentrations of up to 5000 µg/plate trastuzumab, 
with and without metabolic activation, revealed no evidence of mutagenic potential. 
In an in vivo mutagenic assay (the micronucleus assay), no evidence of chromosomal 
damage to mouse bone marrow cells was observed following bolus intravenous doses 
of up to 118 mg/kg trastuzumab.  
Geriatric Use: Trastuzumab has specifically evaluated in 133 patients who were 65 
years of age or over. The risk of cardiac dysfunction may be increased in geriatric 
patients. The reported clinical experience is not adequate to determine whether older 
patients respond differently from younger patients. 
13.3.2.C Adverse Reactions 
Cardiac Failure/Dysfunction: For a description of cardiac toxicities, see above.  
Anemia and Leukopenia: An increased incidence of anemia and leukopenia was 
observed in treatment groups receiving trastuzumab and chemotherapy, especially in 
those receiving trastuzumab with AC The majority of these cytopenic events were 
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Hematologic toxicity is infrequent following the administration of trastuzumab as a 
single agent, with an incidence of Grade III toxicities for WBC, platelets, hemoglobin 
all <1%.  
Diarrhea: Of patients treated with trastuzumab as a single agent in various studies, 
25% experienced diarrhea. An increased incidence of diarrhea, primarily mild to 
moderate in severity, was observed in patients receiving trastuzumab in combination 
with chemotherapy.  
Infection: An increased incidence of infections, primarily mild upper respiratory 
infections of minor clinical significance or catheter infections, has been observed in 
patients receiving trastuzumab in combination with chemotherapy.  
Infusion Reactions: During the first infusion with trastuzumab, a symptom complex 
most commonly consisting of chills and/or fever was observed in about 40% of 
patients in clinical trials. The symptoms were usually mild to moderate in severity 
and were treated with acetaminophen, diphenhydramine, and meperidine (with or 
without reduction in the rate of trastuzumab infusion). Trastuzumab discontinuation is 
rarely necessary. Other signs and/or symptoms may include nausea, vomiting, pain 
(in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, rash 
and asthenia. The symptoms occur infrequently with subsequent trastuzumab 
infusions.  
 
Table 7.0: Adverse Events Occurring in > 5% of Patients or at 
Increased Incidence in the Trastuzumab Arms of Various Randomized Studies 
(Percent of Patients)30  
  
Single 
Agent 
n = 
352 
Trastuzumab 
+ Paclitaxel 
n = 91 
Paclitaxel 
Alone 
n = 95 
Trastuzumab 
+ AC 
n = 143 
AC 
Alone 
n = 
135 
Body as a Whole 
Pain 
47 
61 
62 
57 
42 
Asthenia 
42 
62 
57 
54 
55 
Fever 
36 
49 
23 
56 
34 
Chills 
32 
41 
4 
35 
11 
Headache 
26 
36 
28 
44 
31 
Abdominal pain 
22 
34 
22 
23 
18 
Back pain 
22 
34 
30 
27 
15 

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Infection 
20 
47 
27 
47 
31 
Flu syndrome 
10 
12 
5 
12 
6 
Accidental injury 
6 
13 
3 
9 
4 
Allergic Reaction 
3 
8 
2 
4 
2 
Cardiovascular 
Tachycardia 
5 
12 
4 
10 
5 
Congestive heart 
failure 
7 
11 
1 
28 
7 
Digestive 
Nausea 
33 
51 
9 
76 
77 
Diarrhea 
25 
45 
29 
45 
26 
Vomiting 
23 
37 
28 
53 
49 
Nausea and vomiting 
8 
14 
11 
18 
9 
Anorexia 
14 
24 
16 
31 
26 
Heme & Lymphatic 
Anemia 
4 
14 
9 
36 
26 
Leukopenia 
3 
24 
17 
52 
34 
Metabolic 
Peripheral edema 
10 
22 
20 
20 
17 
Edema 
8 
10 
8 
11 
5 
Musculoskeletal 
Bone pain 
7 
24 
18 
7 
7 
Arthralgia 
6 
37 
21 
8 
9 
Nervous 
Insomnia 
14 
25 
13 
29 
15 
Dizziness 
13 
22 
24 
24 
18 
Paresthesia 
9 
48 
39 
17 
11 
Depression 
6 
12 
13 
20 
12 
Peripheral neuritis 
2 
23 
16 
2 
2 
Neuropathy 
1 
13 
5 
4 
4 
Respiratory 

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Cough increased 
26 
41 
22 
43 
29 
Dyspnea 
22 
27 
26 
42 
25 
Rhinitis 
14 
22 
5 
22 
16 
Pharyngitis 
12 
22 
14 
30 
18 
Sinusitis 
9 
21 
7 
13 
6 
Skin 
Rash 
18 
38 
18 
27 
17 
Herpes simplex 
2 
12 
3 
7 
9 
Acne 
2 
11 
3 
3 
<1 
Urogenital 
Urinary tract 
infection 
5 
18 
14 
13 
7 
  Other serious adverse events  
The following other serious adverse events occurred in at least one patient on 
trastuzumab being treated in clinical trials: 
Body as a Whole: cellulitis, anaphylactoid reaction, ascites, hydrocephalus, radiation 
injury, deafness, amblyopia  
Cardiovascular: vascular thrombosis, pericardial effusion, heart arrest, hypotension, 
syncope, hemorrhage, shock, arrhythmia  
Digestive: hepatic failure, gastroenteritis, hematemesis, ileus, intestinal obstruction, 
colitis, esophageal ulcer, stomatitis, pancreatitis, hepatitis  
Endocrine: hypothyroidism  
Hematological: pancytopenia, acute leukemia, coagulation disorder, lymphangitis  
Metabolic: hypercalcemia, hypomagnesemia, hyponatremia, hypoglycemia, growth 
retardation, weight loss  
Musculoskeletal: pathological fractures, bone necrosis, myopathy  
Nervous: convulsion, ataxia, confusion, manic reaction  
Respiratory: apnea, pneumothorax, asthma, hypoxia, laryngitis  
Skin: herpes zoster, skin ulceration  

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Urogenital: hydronephrosis, kidney failure, cervical cancer, hematuria, hemorrhagic 
cystitis, pyelonephritis  
13.3.3 Supplier 
Trastuzumab will be ordered from the City of Hope pharmacy. 
 
13.3.4 Dose and Administration 
 
13.3.4. A Usual Dose  
The recommended initial loading dose is either 4 mg/kg trastuzumab administered as a 
90-minute infusion (if planning weekly dosing) or 8 mg/kg trastuzumab administered as a 
90-minute infusion (if planning every three week dosing). The recommended weekly 
maintenance dose is 2 mg/kg trastuzumab and can be administered as a 30-minute 
infusion if the initial loading dose was well tolerated. The recommended every three 
week maintenance dose is 6mg/kg trastuzumab and can be administered as a 30 minute 
infusion if the loading dose was well tolerated. Trastuzumab may be administered in an 
outpatient setting. Trastuzumab is to be diluted in saline for IV infusion. DO NOT 
ADMINISTER AS AN IV PUSH OR BOLUS (see Administration).  There is no 
change in dosage for obese patients. 
13.3.4. B Administration  
Treatment may be administered in an outpatient setting by administration of either a 4 
mg/kg trastuzumab loading dose by intravenous (IV) infusion over 90 minutes or 8mg/kg 
trastuzumab loading dose by intravenous infusion. DO NOT ADMINISTER AS AN IV 
PUSH OR BOLUS. Patients should be observed for fever and chills or other infusion-
associated symptoms (see ADVERSE REACTIONS). If prior infusions are well 
tolerated, subsequent weekly doses of 2 mg/kg trastuzumab may be administered over 30 
minutes, or subsequent doses of 6mg/kg trastuzumab may be administered every three 
weeks.  
Trastuzumab should not be mixed or diluted with other drugs. Trastuzumab 
infusions should not be administered or mixed with Dextrose solutions.  
13.3.5  Storage 
Vials of trastuzumab are stable at 2-8°C (36-46°F) prior to reconstitution. Do not use 
beyond the expiration date stamped on the vial. Discard any remaining multi-dose 
reconstituted solution after 28 days. If unpreserved SWFI (not supplied) is used, the 
reconstituted trastuzumab solution should be used immediately and any unused portion 
must be discarded. DO NOT FREEZE TRASTUZUMAB THAT HAS BEEN 
RECONSTITUTED.  
The solution of trastuzumab for infusion diluted in polyvinylchloride or polyethylene 
bags containing 0.9% Sodium Chloride Injection, USP, may be stored at 2-8°C (36-46°F) 

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for up to 24 hours prior to use. Diluted trastuzumab has been shown to be stable for up to 
24 hours at room temperature (2-25°C). However, since diluted trastuzumab contains no 
effective preservative, the reconstituted and diluted solution should be stored refrigerated 
(2-8°C). 
 
13.3.6  Structure and Molecular Weight 
Formula: 
C6470H10012N1726O2013S42 
Molecular Mass: 14531.5 g/mol 
Herceptin (Trastuzumab) is a recombinant DNA-derived humanized monoclonal 
antibody that selectively binds with high affinity in a cell-based assay (Kd = 5 nM) to the 
extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. 
The antibody is an IgG1 kappa that contains human framework regions with the 
complementarity-determining regions of a murine antibody (4D5) that binds to HER2.  
The humanized antibody against HER2 is produced by a mammalian cell (Chinese 
Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic 
gentamicin. Gentamicin is not detectable in the final product.  
13.3.7  Formulation/Agent Preparation 
Herceptin is a sterile, white to pale yellow, preservative-free lyophilized powder for 
intravenous (IV) administration. The nominal content of each Herceptin vial is 440 mg 
trastuzumab, 9.9 mg L-histidine HCl, 6.4 mg L-histidine, 400 mg trehalose dihydrate, and 
1.8 mg polysorbate 20, USP. Reconstitution with only 20 mL of the supplied 
Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a 
preservative, yields a multi-dose solution containing 21 mg/mL trastuzumab, at a pH of 
approximately 6.  
13.3.8  Preparation  
The diluent provided has been formulated to maintain the stability and sterility of 
HERCEPTIN for up to 28 days. Other diluents have not been shown to contain effective 
preservatives for HERCEPTIN. Each vial of Herceptin should be reconstituted with 
ONLY 20 mL of BWFI, USP, 1.1% benzyl alcohol preserved, as supplied, to yield a 
multi-dose solution containing 21 mg/mL trastuzumab. Use of all 30 mL of diluent 
results in a lower-than-intended dose of HERCEPTIN. THE REMAINDER 
(approximately 10 mL) OF THE DILUENT SHOULD BE DISCARDED. Immediately 
upon reconstitution with BWFI, the vial of Herceptin must be labeled in the area marked 
"Do not use after:" with the future date that is 28 days from the date of reconstitution.  
If the patient has known hypersensitivity to benzyl alcohol, Herceptin must be 
reconstituted with Sterile Water for Injection (see PRECAUTIONS). HERCEPTIN 
WHICH HAS BEEN RECONSTITUTED WITH SWFI MUST BE USED 

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IMMEDIATELY AND ANY UNUSED PORTION DISCARDED. USE OF OTHER 
RECONSTITUTION DILUENTS SHOULD BE AVOIDED.  
Shaking the reconstituted Herceptin or causing excessive foaming during the addition of 
diluent may result in problems with dissolution and the amount of Herceptin that can be 
withdrawn from the vial.  
Use appropriate aseptic technique when performing the following reconstitution steps:  
a. Using a sterile syringe, slowly inject 20 mL of the diluent into the vial containing the 
lyophilized cake of trastuzumab. The stream of diluent should be directed into the 
lyophilized cake.  
b. Swirl the vial gently to aid reconstitution. Trastuzumab may be sensitive to shear-
induced stress, e.g., agitation or rapid expulsion from a syringe. DO NOT SHAKE.  
c. Slight foaming of the product upon reconstitution is not unusual. Allow the vial to 
stand undisturbed for approximately 5 minutes. The solution should be essentially free of 
visible particulates, clear to slightly opalescent, and colorless to pale yellow.  
Determine the number in mg of trastuzumab needed, based on a loading dose of 4 mg 
trastuzumab/kg body weight or a maintenance dose of 2 mg trastuzumab/kg body weight. 
Calculate the volume of 21 mg/mL trastuzumab solution and withdraw this amount from 
the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride 
Injection, USP. DEXTROSE (5%) SOLUTION SHOULD NOT BE USED. Gently 
invert the bag to mix the solution. The reconstituted preparation results in a colorless to 
pale yellow transparent solution. Parenteral drug products should be inspected visually 
for particulates and discoloration prior to administration.  
No incompatibilities between Herceptin and polyvinylchloride or polyethylene bags have 
been observed.  
13.3.9 Stability 
A vial of Herceptin reconstituted with BWFI, as supplied, is stable for 28 days after 
reconstitution when stored refrigerated at 2-8°C (36-46°F), and the solution is preserved 
for multiple use. 
 
14.0 Endpoints/Statistical Analysis 
To evaluate the combination of pertuzumab, trastuzumab and nab-paclitaxel in HER2+ breast 
cancer, we can combine the ability of this regimen to shrink/control the tumor in untreated 
breast cancer cases whether it is in a metastatic patient or in the neoadjuvant setting, as both 
are untreated HER2+ breast cancers. The assumption is that a promising result in one setting 
would translate into a promising result in the other.  To combine these two, we note the 

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CLEOPATRA trial20,21 observed a median PFS of 18.5 months in metastatic breast cancer 
with pertuzumab, trastuzumab and docetaxel. As a result, a success for an individual patient 
can be defined as PFS>=18.5 months, with an observed success rate of 50% in 
CLEOPATRA. In the neoadjuvant setting, a pCR rate (success rate) of 39.3% was observed 
with the pertuzumab, trastuzumab and docetaxel.26  As a result, this study will be designed to 
declare the study successful if it at least matches CLEOPATRA for MBC patients and 
NEOSPHERE for LABC patients, respectively,  due to the presumed lower toxicity of using 
nab-paclitaxel on the proposed dose and schedule rather than docetaxel.  65 patients will be 
accrued, with 25 metastatic breast cancer  (MBC) patients and 40 LABC neoadjuvant cases. 
  
At 
the 
final 
analysis, 
the 
matching 
target 
success 
rate 
would 
be 
(0.393*40+0.5*25)/65=43.4% or 28 successes. If the true success rate is 10% above the 
matching success rate this design has 94% power to declare a success. If the true success rate 
is 10% below the matching success rate, this design has a type I error less than 5% (one 
sided).  This design is equivalent to testing the null hypothesis H0: success rate is 33.4% 
against an alternative H1: success rate is 53.4%, with a type I error (one-sided) of 5% and a 
type II error of 6% (94% power). These error estimates are conservative due to the slight 
underdispersion resulting from the combination of two binomials.  
 
In addition to the combined endpoint, each strata will be evaluated independently.  With 25 
metastatic cancer patients, the median PFS will be estimated. If accrual is within 24 months, 
and follow-up is approximately 24 months after accrual completes, the probability of a true 
median survival of 24 months being less than 18.5 months is less than 20% (80% power), and 
the probability of a true median survival of 13 months exceeding 18.5 months is 
approximately 13.4% (type I error, one sided).  This is assuming a non-parametric estimate 
of the median survival and uses the Brookmeyer-Crowley method.  This design is equivalent 
to testing the null hypothesis H0: median survival is 13 months against an alternative H1: 
median survival of 24 months, with a type I error (one-sided) of 13.5% and a type II error 
less than 20% (80% power).  If accrual is longer, with follow-up after the last accrual 
unchanged, the type I and type II error are reduced. 
 
With 40 neoadjuvant cases, the probability of a true discouraging neoadjuvant pCR rate of 
29.3% exceeding the benchmark of 39.3% (16 or more) is 10% (type I error), and the 
probability of a true neoadjuvant pCR rate of 49.3% resulting in a observation below 39.3% 
(15 or less) is less than 10% (>90% power). This design is equivalent to testing the null 
hypothesis H0: pCR rate is 29.3% against an alternative H1: pCR rate is 49.3%, with a type I 
error (one-sided) of 10% and a type II error less than 10% (at least 90% power).  
The study is likely to accrue 2 patients per months in the locally advanced cohort , the 40 
patient LABC accrual should be met by the end of 2016. 
 
 
For interim analysis, no formal analysis is planned due to the time required to assess the PFS 
endpoint and the expected rapidity of accrual.  However, a report will be generated after 29 
patients have been accrued to review with the Sponsor and PI, with a report to the COH 

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DSMB.  At the final analysis, the PFS (for stage IV cases), the pathological complete 
response rate (for neoadjuvant cases) and toxicity/tolerability may refine the decision to 
pursue the combination, or may suggest restricting this combination to more fragile patients 
less able to receive more aggressive chemotherapy combinations. 
 
The National Cancer Institute Common Toxicity Criteria Version 4.0 will be used to assess 
toxicities.  
 
There will be interim analysis for toxicity. Specifically, if dose limiting toxicity (grade 3 or 
higher treatment-related non-hematologic toxicity other than readily reversible electrolyte 
abnormalities or diarrhea/ nausea/vomiting that lasts less than 24 hrs after treatment or any 
treatment related grade 4 toxicity) is observed in 2 of the first 6 patients treated during the 
first cycle of treatment (28 days), or in more than 30% of the patients thereafter, the study 
will hold accrual pending review by the COH DSMC, PI and Sponsor. 
 
15. 0 Feasibility 
City of Hope (COH) Comprehensive Cancer Center is a private, non-sectarian, multi-
specialty hospital and research.  COH has been at the forefront of medical and basic science 
research since it was established in 1918. A formal research program structure was initiated 
in 1951 and expanded rapidly in terms of staff, facilities, and institutional support. Major 
groups of investigators were recruited and merged into the Research Institute. City of Hope 
has been continuously funded as an NCI-designated Cancer Center since 1975, with 
Comprehensive Cancer Center status as of 1998. The scientific goals of the Cancer Center 
are the provision of personalized, interdisciplinary care of the highest quality for every 
cancer patient seen at COH, the creation of a climate fostering collaboration among basic 
scientists, clinical researchers, and physicians; and the provision of cancer education and 
outreach programs into both the medical and lay communities in our region. Currently, COH 
is comprised of 178 basic science and clinical researchers from every major Department and 
Division of the Medical Center and the Beckman Research Institute of City of Hope. 
 
All research projects will be carried out in the outpatient facilities at City of Hope. Outpatient 
care is rendered in the Brawerman Ambulatory Care Center. The outpatient clinics service 
almost 5,000 patients per month. In addition, the investigational drug pharmacy, with a long 
track record of appropriate handling of CTEP-supplied and other investigational agents, has 
facilities for secure storage of agents at room temperature, -20 ºC and -70 ºC. Other facilities 
included in this new outpatient area are satellite laboratories, procedure suites, and 
biostatistical and data management offices. 
 
In 2005, COH opened the 340,000 sq ft state-of-the-art Helford Clinical Research Hospital 
incorporating the latest in medical, surgical, radiological, and communications technologies, 
combining modern diagnostic, radiology, and imaging tools in a digital environment. 
Surgical “super suites” include laparoscopic and robotic instrumentation and advanced 
information and audio/video systems, allowing multidisciplinary teams to effectively 
collaborate during procedures. COH has developed a substantial base of patients who have 
been entered on investigational cancer research trials. Accruals favor investigator-initiated 
interventional trials over externally-sponsored or cooperative group trials by 85% to 15%. 

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This bias is even more pronounced for non-interventional trials, where 89% of patients are 
entered onto investigator-initiated trials. In 2009, there were 1,694 patients accrued to 
intervention studies and 5,621 patients accrued to non-intervention studies at City of Hope. 
 
 
16. 0 Correlative Studies 
Tissue and blood samples may be collected under the current trial, and, under other 
institutionally IRB approved protocols (if signed independently) and in accordance with an 
IRB-approved HIPPA compliant and signed consent form. (IRB 05091 Tissue and blood 
library establishment for molecular, biochemoical, and histologic study of breast disease; 
IRB 08128 Characterization of circulating tumor cells to direct pre-operative and systemic 
therapy in patients with locally advanced or metastatic stage IV breast cancer).  Please refer 
to study calendar for timing of tissue and blood collections.   
 
Biopsy cores will go to the Pathology Core Lab under Dr. Peiguo Chu.  Optional biopsies of 
up to 65 samples will be conducted.  45 of those samples will be baseline biopsies, and 20 
additional biopsies may be collected at the end of study treatment.  The samples that are 
collected may be frozen and or parffin embedded.  They may be processed for further genetic 
and molecular profiling including but not exclusive to PTEN, p53, HER2, ER/PR based on 
specific IRB protocols approved by the institution.  Molecular profiling will be carried out at 
COH (Dr. P. Lee, Shiuan Chen and core labs), and as feasible, in collaboration with scientists 
at TGEN (under the leadership of Dr. Trent), the Jackson Laboratory (under the leadership of 
Dr. Ed Liu and Francesca Mengi, Dr. Emily Wang (UC San Diego, R01 supported), and in 
collaboration with Agendia – all under already approved MTAs in place. 
 
More over, 10 mL of blood will be drawn into CellSave tubes (Immunicon) for Circulating 
Tumor Cells enumeration and 10 mL of blood will be drawn into a CPT tube for assessment 
of glycan profile and two red top tubes with 7.5 mL each will be drawn, totaling 25 mL of 
blood drawn for research purposes.  One of the red top tubes will be assessed for a glycan 
and protein profile (Hickey laboratory), and the second tube will be used for micro RNA 
analysis (E. Wang laboratory).  Time points include pre-teratment, during treatment (see 
study calendar (optional draw), at the time of the subject’s end of study.   
 
17. 0 Study Calendar 
Baseline evaluations are to be conducted within 1 week prior to administration of protocol 
therapy.  Scans must be done within 4 weeks prior to the start of therapy.  Tests/procedures 
indicated for the following weeks maybe performed within ± three days of the indicated 
dates.  Brief interruptions and delays in the 21 day cycle may occasionally be required due to 
travel delays, airport closure, inclement weather, family responsibilities, security alerts, 
government holidays, etc. This can also extend to complications of disease or unrelated 
medical illness not related to disease progression. These delays will not be considered 
protocol violations.  Therapy can be delayed (after cycle 1) up to 3 days due to 
holidays/personal reasons.   

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Pre- 
Study 
Pre 
Cycle 
1 Day 
1 
Cycle 
1 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
Cycle 
2 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
Cycle 
3 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
Cycle 4 thru 
progression 
= same 
as Cycles 
1 & 2 
Follow-upe 
Trastuzumab 
 
 
Day 
(D) 1 
D 8 
D 15 
D 1 
D 8 
D 15 
D 1 
D 8 
D 15 
 
 
Pertuzumab 
 
 
D 1 
 
 
D1 
 
 
D 1 
 
 
 
 
nab-paclitaxel 
 
 
D 1 
D 8 
D 15 
D 1 
D 8 
D 15 
D 1 
D 8 
D 15 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
   X---------------------------------------------------------------------------------------------------------------------------------X   
Physical exam, Height, 
weight 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Vital signs 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
ECOG 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum chemistrya 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
   X------------------------------------------------------------------------------------------------------------------X  
For patients with MBC, tumor assessments (clinical) are repeated every 9 weeks.  Documentation 
(radiologic or clinical) must be provided for patients removed from study for progressive disease. 
Radiological assessment will be carried out at the conclusion of 9 weeks of therapy, as applicable  
(Mammogram, US, MRI, as deemed appropriate by the treatment team). Patietns will be assessed by 
clinical means every three weeks while receiving treatment for LABC. 
 
Tumor measurements as 
applicable (clinical) 
X 
 
 
Radiologic evaluation 
X 
 
Xh 
MUGA/ECHOb 
X 
 
 
B-HCGc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy (Optional)* 
  -IHC profiling 
  -Gene profiling 
X 
 
 
 
 
 
 
 
X 
 
 
X# 
 
Correlative Blood Draw 
(Optional) 
  -Glycan profiling 
  -CTC 
  -Micro RNA profiling 
X 
 
 
 
 
 
 
 
X 
 
 
X# 
At progression  
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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aAlbumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT}, sodium 
bEcho/MUGA: Baseline within 42 days of Day 1 of treatment (see section 3.1.4); Subsequent every 12 weeks ( See section 10.0) 
c Pregnancy test at baseline 
d Tissue and blood may be procured for patients who consent to blood draws and biopsy with possible tissue and blood storage for correlative studies. Correlative studies may include gene 
analysis, glycan profiling, and IHC panel profiling. 
e Follow up to be done every 3 months x 4 years; then every 6 months x 1 year.  After 5 years, follow up should be as per standard of clinical practices.  
h Requested as per standard of care.  
#for LABC, at the time of definitive breast surgery 
*As available, specimens will be analysed at COH with collaborators (Dr. Lee, Chen, core labs), as well as collaborators at TGEN – Dr. Trent-, MTA in place, Agendia-MTA in place, Jackson 
Laboratory-Drs. Mengi and Liu-MTA in place, UC San Diego-Dr. Emily Wang, R-01 supported).  In addition, as feasible, PDX models would be generated in collaborations at COH/through Jun 
Wu (core at COH) and with the Jackson Laboratory. 
 
 

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18. 0 Evaluation Criteria/Measurement of Effect 
 
18.1 Response Criteria  
For the purposes of this study, patients with MBC should be reevaluated for response 
every 9 weeks. Patients with LABC will be evaluated at the beginning of each cycle via 
physical exam, and at the time of planned definitive breast surgery by pathology.  
Imaging (prior to surgery) will be left to the treating physician’s discretion. 
 
Response and progression for MBC will be evaluated in this study using the new updated 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee version 1.1.  Per the new RECIST criteria, as disease response is 
not the primary endpoint of this trial, confirmatory scans following documentation of 
progression or response will not be required.  Rather, progression/response will be 
determined based on results of the single scan.  
 
18.2 Definitions 
Evaluable for objective response in MBC patients.  Only those patients who have 
measurable disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated below.  
(Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
 
18.3 Disease Parameters  
Measurable disease.  In patients with MBC, measurable lesions are defined as those that 
can be accurately measured in at least one dimension (longest diameter to be recorded) as 
>10mm with conventional techniques (CT, MRI, or caliper measurement) and as >20mm 
by chest X-ray (if clearly defined and surrounded by aerated lung.) Lymph nodes greater 
than 10mm on short axis are considered measureable as well. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <20 mm by chest X-ray or <10 mm using CT, MRI or caliper 
measurement), are considered non-measurable disease.  Organomegaly, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI are all non-measurable. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline. Lymph nodes less than 15mm in the short axis can 
not be used as target lesions.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically).  A sum of the longest diameter (LD) for all 
target lesions will be calculated and reported as the baseline sum LD.  The baseline sum 
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Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 10 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  
 
18.4 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 30 days before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of a treatment. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  These techniques should be performed with cuts of 10 mm or 
less in slice thickness contiguously.  Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm.  This applies to tumors of the chest, abdomen, and 
pelvis.  Head and neck tumors and those of extremities usually require specific protocols. 
 
Ultrasound (US):  Ultasound is  a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US might 
also be useful to confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated.  Their uses in this specific context 
require sophisticated equipment and a high level of expertise that may only be available in 
some centers.  Therefore, the utilization of such techniques for objective tumor response 
should be restricted to validation purposes in reference centers. However, such techniques 
may be useful to confirm complete pathological response when biopsies are obtained. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  

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Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
18.5 Response Criteria 
 
 18.5.1 Evaluation of Target Lesions in patients with MBC 
 
Complete Response (CR):Disappearance of all target lesions. Lymph node CR is when the 
lymph node has decreased to less than 10mm in the short axis. 
 
Partial Response (PR):  
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD):  
At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum LD 
recorded since the treatment started (including the baseline 
scan if that is the smallest), and at least a 5mm increase or the 
appearance of new lesions. 
 
Stable Disease (SD): 
 
 
Neither sufficient shrinkage to 
qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum LD since the treatment started 
 
        18.5.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  
Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level 
above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. However, 
unequivocal progression should not normally trump target 

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disease status.  It must be representative of overall disease 
status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances. 
 
          18.5.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of measurement criteria, but confirmation is not necessary. 
 
Table 10: Assessment of Best Overall Response Using Target and Non-Target Lesions 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
         18.5.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started.  

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18.6 Progression-Free Survival 
Progression-free survival is defined as the length of time between study enrollment and 
when objective evidence of disease progression is documented. 
 
18.7 Analysis of Secondary Endpoints 
The outcome status in terms of toxicity, reason off study, overall survival and laboratory 
correlates of all eligible patients will be reported. 
 
18.7.1 Overall Survival 
  Overall survival is defined as the length of time between study enrollment and death. 
 
Patients’ survival times will be measured from the initial date of treatment to the recorded 
date of death. Survival (both overall and progression-free) will be estimated by the Kaplan-
Meier method.  The corresponding median survival times (with 90% confidence limits) 
will be determined.  
 
18.7.2 Safety Profile 
Using NCI CTCAE (v4.0), the number of patients experiencing SAEs (serious adverse 
events) in each cycle of treatment, and for 30 days beyond the last protocol treatment 
administered, will be characterized by type of adverse event and grade, and by the time of 
onset in relation to the first day of therapy for each cycle.  Attribution of SAEs to treatment 
(unrelated, unlikely, possible, probable, or definite) will also be reported. We will also 
report the cumulative percentage (%) of patients experiencing treatment-related SAEs and 
its relationship to treatment duration.  
          
          18.8.  In patients with locally advanced breast cancer response will be assessed as 
pathologic complete response (pCR) in breast and lymph nodes at the time of definitive surgery 
vs. less than pCR; response will also be analyzed using residual cancer burden score  (RCB). 
19.0 Data Reporting/Protocol Deviations 
19.1 Data Reporting 
 
19.1.1 Confidentiality of Records 
The original data collection forms will be stored in the Department Clinical Trials Office, 
in a secure location.  When results of this study are reported in medical journals or at 
meetings, identification of those taking part will not be disclosed.  Medical records of 
subjects will be securely maintained in the strictest confidence, according to current legal 
requirements.  They will be made available for review, as required by the FDA, HHS, or 
other authorized users such as the NCI, Genentech and Celgene Corporation under the 
guidelines established by the Federal Privacy Act and rules for the protection of human 
subjects. 
19.1.2 Subject Consent Form 
At the time of registration, the original signed and dated Informed Consent form, HIPAA 
research authorization form, and the California Experimental Subject’s Bill of Rights (for 

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the medical record) and three copies (for the subject, the research record, and the 
Coordinating Center) must be available.  All Institutional, NCI, Federal, and State of 
California requirements and requirements by Genentech and Celgene Corporation, will be 
fulfilled. 
 
 
19.1.3 Data Collection Forms and Submission Schedule  
All data will be collected as per standard institutional timeline using data collection forms 
and electronic data entry as per COH standard.  Data will be stored in a secure location/and 
in secure format.   
 
19.1.3.1 Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research 
associate and signed by an authorized investigator prior to registering the subject.  See 
Section 4.3 for the registration procedure. 
19.1.3.2 Prior Therapy and On-Study Data 
Within a week of registration, the clinical research associate will submit on-study 
checklist form. 
 
19.1.3.3 Treatment Data 
Within four (4) weeks of completion of each course the following data should be 
recorded in the EDC: 
 
19.1.4.3.1 Treatment and Adverse Events 
 
19.1.4.3.2 Supplemental Data 
19.1.4.3.2 Flow Sheets 
 
19.1.3.4 Response/Off-Study/Follow-up 
Each time a patient is evaluated for response and/or new follow-up information is 
obtained, the CRA should record this in the appropriate section of the EDC. 
 
19.1.3.5 Results Reporting 
Preliminary and full results of this clinical and translational research trial may be         
reported   in abstract form(s) at national meeting(s) and in full manuscript form(s) in  
appropriately selected journal(s). The manuscripts/abstracts will be sent to Genetech for 
review before presentation or publication. 
 
19.2 Protocol Deviations 
 
19.2.1 Deviation Policy 
Planned deviations may be permitted in accordance with the COH policy on “Clinical 
Research Protocol Planned Deviations and Single Subject Exception.”  These planned 
deviations, considered Single Subject Exceptions, are considered an Amendment to the 
Protocol.  In addition, if contractually obligated, the sponsor must also approve any 
planned deviations. 
 
19.2.2 Reporting of Unplanned Deviations 

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All unplanned deviations will be reported to the COH DSMC who will forward to the IRB 
following review. 
19.2.3 Resolving Disputes 
If there is a dispute among the persons involved in the provision of research treatment, in 
regard to whether a treatment deviates from the protocol, resolution will be resolved in 
accordance with the Clinical Research Protocol Planned Deviations and Single Subject 
Exceptions policy. 
 
19.3 Reporting and Exclusions 
 
19.3.1 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
trastuzumab+pertuzumab + nab-paclitaxel. 
 
19.3.2 Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  In addition, patient 
response could be categorized in one of the following categories which would be 
considered a non-response:  stable disease, progressive disease, early death from malignant 
disease, early death from toxicity,  early death because of other cause, or unknown (not 
assessable, withdrew consent, insufficient data).    
 
All of the patients who met the eligibility criteria (with the exception of those who 
received no study medication) should be included in the main analysis of the response 
rates.  An incorrect treatment schedule or drug administration does not result in exclusion 
from the analysis of the response rate.    
 
All conclusions should be based on all eligible patients who receive any of the study drug.  
Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.).  However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported. 
 
 
20.0 Human Subject Issues 
20.1 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that 
complies with the federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of 
California Health and Safety code, Title 17,  must review and approve this protocol and the 
informed consent form prior to initiation of the study.  All institutional, NCI, Federal, and 
State of California regulations must be fulfilled. 
 

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20.2 Recruitment of Subjects 
Participants for this study will be recruited from among patients undergoing treatment at City 
of Hope Cancer Center for stage IV breast adenocarcinoma or locally advanced stage II-III 
breast cancer (including inflammatory breast cancer).  Patients will be recruited through 
encounters by the Breast Oncologists in the Department of Medical Oncology and/or Breast 
Surgical Oncologists of the Department of General Oncological Surgery.  They will be 
indentified, screened, consented, eligibility criteria established by members of a designated 
research team within the Breast Cancer Program, under the guidance and together with the PI 
and co-investigators and participating clinical investigators listed on the protocol. 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 Clinical Trials Office.  Patients may 
be screened for registration by calling the City of Hope Department of Clinical Trials Office, 
ext. 62468. 
This study will be performed at COH, and will be listed at www.clinicaltrials.gov. 
 
20.3 Confidentiality  
This research will be conducted in compliance with federal and state of California 
requirements relating to protected health information (PHI).  The study will record clinical 
characteristics, response to treatment by clinical, imaging, and pathological means, in addition 
to toxicities, and other outcomes, as appropriate (recurrence-free/overall survival). These 
findings, as well as data generated from the translational research investigations of procured 
biological specimens, will be linked to the subject’s identity using a coded study number 
designated by the statistician/Department of Bioinformatics and in conjunction with the 
Translational Research Core of COHCC. The principal investigator and the statistician, and 
laboratory technicians will have access to this information, but all information will be treated 
confidentially.  No identifiers will be used in any subsequent publication of these results.  
Financial Obligations and Compensation 
The study drug, Abraxane (nab-paclitaxel), will be provided by the manufacturer (Celgene 
Corporation) free of charge to patients on this study research. The study drug pertuzumab will 
be provided by the manufacturer (Genentech Inc.) free of charge to patients on this study 
research The Research lab draws, processing, and results will be free of charge as a part of 
research. Routine standard of care clinic visits, laboratory tests, and tumor imaging will be 
billed to the patient and/or the patient’s insurance.  Trastuzumab, the infusion center time, and 
routine nursing care involved in administering of these drugs and supportive medications 
during infusion will be billed to the patient and/or the patient’s insurance.  Medication and/or 
treatment needed for side effects of either study drug will be billed to the patient and/or the 
patient’s insurance.   
If there is a serious medical complication of the research, treatment will be available at City of 
Hope, but there will be no compensation to the subject for this injury.   
   
20.4 Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, 
purpose of the study, potential risks, alternatives and potential benefits, and all other 
information contained in the informed consent document.  In addition, they will review the 
experimental subject’s bill of rights and the HIPAA research authorization form.  Research 
subjects will be informed that they may withdraw from the study at any time and for any 

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reason without prejudice, including as applicable, their current or future care or employment 
at City of Hope or any relationship they have with City of Hope.  
 
21. References 
  
1. Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ 
hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer 
tissues. Clin Breast Cancer 2004;5:63-9. 
 
2. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast 
cancer. N Engl J Med 2011;365:1273-83. 
 
3. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody 
against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 
2001;344:783-92. 
 
4. Pegram MD, Pienkowski T, Northfelt DW, 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 2004;96:759-69. 
 
5. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational Study of the 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 1999;17:2639-48. 
 
6. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable 
HER2-positive breast cancer. N Engl J Med 2005;353:1673-84. 
 
7. Nahta R, Esteva FJ. Trastuzumab: triumphs and tribulations. Oncogene 2007;26:3637-43. 
 
8. Nahta R, Esteva FJ. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast 
Cancer Res 2006;8:215. 
 
9. Ozbay T, Durden DL, Liu T, O'Regan RM, Nahta R. In vitro evaluation of pan-PI3-kinase 
inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing 
breast cancer cells. Cancer Chemother Pharmacol 2010;65:697-706. 
 
10. Zhao Y, Liu H, Liu Z, et al. Overcoming trastuzumab resistance in breast cancer by targeting 
dysregulated glucose metabolism. Cancer Res 2011;71:4585-97. 
 
11. Ritter CA, Perez-Torres M, Rinehart C, et al. Human breast cancer cells selected for 
resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands 
and remain dependent on the ErbB receptor network. Clin Cancer Res 2007;13:4909-19. 

Page 80 of 83 
 
IRB Protocol 12147 
Version: 17 
 
Version Date:  07/27/17 
12. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I 
receptor/human epidermal growth factor receptor 2 heterodimerization contributes to 
trastuzumab resistance of breast cancer cells. Cancer Res 2005;65:11118-28. 
 
13. Ritter CA, Bianco R, Dugger T, et al. Mechanisms of resistance development against 
trastuzumab (Herceptin) in an in vivo breast cancer model. Int J Clin Pharmacol Ther 
2004;42:642-3. 
 
14. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab 
synergistically inhibit the survival of breast cancer cells. Cancer Res 2004;64:2343-6. 
 
15. Fuentes G, Scaltriti M, Baselga J, Verma CS. Synergy between trastuzumab and pertuzumab 
for human epidermal growth factor 2 (Her2) from colocalization: an in silico based mechanism. 
Breast Cancer Res 2011;13:R54. 
 
16. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in 
patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that 
progressed during prior trastuzumab therapy. J Clin Oncol 2010;28:1134-44. 
 
17. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced 
antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive 
human xenograft tumor models. Cancer Res 2009;69:9330-6. 
 
18. Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast 
cancer: implications for targeted therapy. Cancer Res 2008;68:5878-87. 
 
19. Yao E, Zhou W, Lee-Hoeflich ST, et al. Suppression of HER2/HER3-mediated growth of 
breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and 
pertuzumab. Clin Cancer Res 2009;15:4147-56. 
 
20. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for 
metastatic breast cancer. N Engl J Med 2012;366:109-19. 
 
21. Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-
positive metastatic breast cancer (CLEOPATRA study): overall survival results from a 
randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-71. 
 
22. Datko F, D'Andrea G, Dickler M et al. Phase II study of pertuzumab, trastuzumab, and 
weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic breast cancer. 
Cancer Res 2013; 72:(24) Suppl 3, SABCS 12-P5-18-20. 
 
23. O'Shaughnessy J, Gradishar WJ, Bhar P, Iglesias J. Nab-paclitaxel for first-line treatment of 
patients with metastatic breast cancer and poor prognostic factors: a retrospective analysis. 
Breast CAncer Res Treat. 2013;138:829-37. 

Page 81 of 83 
 
IRB Protocol 12147 
Version: 17 
 
Version Date:  07/27/17 
24. Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly longer progression-free survival 
with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J 
Clin Oncol 2009;27:3611-9. 
 
25. Mirtsching B, Cosgriff T, Harker G, Keaton M, Chidiac T, Min M. A phase II study of 
weekly nanoparticle albumin-bound paclitaxel with or without trastuzumab in metastatic breast 
cancer. Clin Breast Cancer 2011;11:121-8. 
 
26. Gianni L, Pienkowski T, Im YH et al. Efficacy and safety of neoadjuvant pertuzumab and 
tarstuzumab in women with locally advanced inflammatory, or early HER2-positive breast 
cancer (Neosphere): a randomised multicentre, open-label, phase 2 trial.  Lancet Oncol 2012; 
13:25-32. 
 
27.  www.nccn.org/professionals/physician_gls/pdf/breast.pdf. 
 
28. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive 
early breast cancer (NeoALTTO): a randomized, open-label, multicentre, phase 3 trial. Lancet 
2013;379:633-79. 
 
29. Cortazar P, Zhang L, Untch M et al. Meta-analysis results from collaborative trials in 
neoadjuvant breast cancer.  Cancer Research 2012;72:93s. 
 
30. Gianni L, Eiermann W, Semiglazov V et al. Follow-up results of NOAH, a randomized phase 
III trial evaluating neoadjuvant chemotherapy with tarstuzumab (CT-H) followed by adjuvant H 
versus CT alone, in patients with HER2-positive locally advanced breast cancer. J Cin Oncol 31 
2013; 15 suppl abstr 503. 
 
31. Symmans WF, Peitinger F, Hatzis C, et al. Measurement of residual breast cancer burden to 
predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25:4414-22. 
 
32. Desai NP, Trieu V, Hwang LY, Wu R, Soon-Shiong P, Gradishar WJ. Improved 
effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel 
in multiple xenografts as a function of HER2 and SPARC status. Anticancer Drugs 2008;19:899-
909. 
 
33. Desai N, Trieu V, Damascelli B, Soon-Shiong P. SPARC Expression Correlates with Tumor 
Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients. Transl Oncol 
2009;2:59-64. 
 
34. Desai N TV, Yao R, Labao E, Soon-Shiong P. . Increased endothelial transcytosis of 
nanoparticle albumin-bound paclitaxel (ABI-007) by gp60-receptors: a pathway inhibited by 
taxol. . In: Proc S Ant Breast Cancer Symp 2004; Abs 1071; 2004. 
 
35. Nyman DW, Campbell KJ, Hersh E, et al. Phase I and pharmacokinetics trial of ABI-007, a 
novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic 
malignancies. J Clin Oncol 2005;23:7785-93. 

Page 82 of 83 
 
IRB Protocol 12147 
Version: 17 
 
Version Date:  07/27/17 
36. Blum JL, Savin MA, Edelman G, et al. Phase II study of weekly albumin-bound paclitaxel 
for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer 
2007;7:850-6. 
 
37. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound 
paclitaxel compared to polyethylated castor oil-based paclitaxel in women with breast cancer. J 
Clin Oncol. 2005;23:7794-803. 
 
38. Rugo H, Barry WT, Moreno-Aspitia A, et al. CALGB 40502/NCCTG N063H: Randomized 
phase III trial of weekly paclitaxel compared to weekly nanoparticle albumin bound nab-
paclitaxel or ixabepilone with or without bevacizumab as first line therapy for locally recurrent 
or metasttaic breast cancer. J Clin Oncol 30, 2012 (suppl; abstr CRA 10024). 
 
39. Mitchell P. S., Parkin R. K., Kroh E. M., Fritz B. R., Wyman S. K., Pogosova-Agadjanyan  
E. L., Peterson A., Noteboom J., O'Briant K. C., Allen A., et al. (2008). Circulating microRNAs 
as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105, 10513-10518. 
 
40. Taylor D. D., and Gercel-Taylor C. (2008). MicroRNA signatures of tumor-derived 
exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110, 13-21. 
 
41. Heneghan H. M., Miller N., Lowery A. J., Sweeney K. J., Newell J., and Kerin M. J. (2010). 
Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg 
251, 499-505. 
 
42. Roth C., Rack B., Muller V., Janni W., Pantel K., and Schwarzenbach H. (2010). Circulating 
microRNAs as blood-based markers for patients with primary and metastatic breast cancer. 
Breast Cancer Res 12, R90. 
 
43. Wu X., Somlo G., Yu Y., Palomares M. R., Li A. X., Zhou W., Chow A., Yen Y., Rossi J. J., 
Gao H., et al. (2012). De novo sequencing of circulating miRNAs identifies novel markers 
predicting clinical outcome of locally advanced breast cancer. J Transl Med 10, 42. 
 
44. Zhu, W., Qin, W., Atasoy, U., and Sauter, E. R. (2009). Circulating microRNAs in breast 
cancer and healthy subjects. BMC Res Notes 2, 89. 
 
45. Jung  E. J., Santarpia L., Kim J., Esteva F. J., Moretti E., Buzdar A. U., Di Leo A., Le X. F., 
Bas, R. C., Jr., Park S. T., et al. (2012). Plasma microRNA 210 levels correlate with sensitivity 
to trastuzumab and tumor presence in breast cancer patients. Cancer 118, 2603-2614. 
             
46. Somlo G, Lau SK, Frankel P, et al. Multiple biomarker expression on circulating tumor cells 
in comparison to tumor tissues from primary and metastatic sites in patients with locally 
advanced/inflammatory, and stage IV breast cancer, using a novel detection technology. Breast 
Cancer Res Treat 2011;128:155-63. 
 
47. Somlo G FP, Cooc J, Lau SK, Dannenber K, Yim J, and Danenberg P. . Limited Gene 
Expression Profiling as Predictor of response to Neoadjuvant Chemotherapy (NCT) with 

Page 83 of 83 
 
IRB Protocol 12147 
Version: 17 
 
Version Date:  07/27/17 
Docetaxel, Doxorubicin, Cyclophosphamide (TAC), or AC and Nab-Paclitaxel and Carboplatin 
+/- Trastuzumab in Patients with Locally Advanced Breast Cancer Stage II-III and Inflammatory 
Breast Cancer. . In: Cancer Research; 2011:P2-09-17. 
 
48. Somlo G, P.H. Frankel, L. Vora, S. Lau, T.H. Luu, L. Kruper, J. Yim, Y. Yen, F. de Snoo, 
(2010) Gene signatures as predictors of response to neoadjuvant chemotherapy (NCT) with 
docetaxel, doxorubicin, cyclophosphamide (TAC), or AC and nab-paclitaxel (nab-P) and 
carboplatin ± trastuzumab in patients (pts) with stage II-III and inflammatory breast cancer 
(IBC).  J Clin Oncol 28:15s, (suppl; abstr 540). 
 
49. Chen Z, Feng J, Buzin CH, Liu Q, Weiss L, Kernstine K, Somlo G, Sommer S. Analysis of 
cancer mutation signatures in blood by a novel ultra-sensitive assay;monitoring of therapy or 
recurrence in non-metastatic breast cancer. PloS One 2009;4:e7220. 
 
50. S. Li, X. Wu, P. Frankel, H. Gao, G. Sun, F. De Snoo, J. Rossi, E. Wang, P. Roepman, 
Y.Yen, J. Peeters, L. Stork, G. Somlo; (2012) Correlation between miRNA (miR) and gene 
expression profiles (GEP) and response to neoadjuvant chemotherapy (NT) in patients with 
locally advanced and inflammatory breast cancer (BC). J Clin Oncol 30, 2012 (suppl;abstr 
10545). 
 
51. Wolf AC, Hammond EH, Hicks DG, et al.  Recommendations for human epidermal growth 
factor receptor testing in breast cancer: American Society of Clinical Oncology/College of 
American Patologists clinical practice guideline update. J Clin Oncol 2013; Epub October 7  
52.Robidoux A, Buzdar AU, Quinaux E, et al. A phase II neoadjuvant trial of sequential 
nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide 
in locally advanced breast cancer. Clin Breast Cancer 2010;10:81-6. 
 
52. Herceptin package insert. South San Francisco, CA: Genentech, Inc.; 2008.