Phase II Trial of Neoadjuvant Chemotherapy With Carboplatin and NAB-Paclitaxel in Patients With Locally Advanced and Inflammatory Triple Negative Breast Cancer
Phase: PHASE2
Conditions: Inflammatory Breast Cancer, Stage IIA Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Triple-negative Breast Cancer, Stage IIB Breast Cancer, Estrogen Receptor Negative, Progesterone Receptor Negative, HER2/Neu Negative
Sponsor: City of Hope Medical Center

IRB Protocol No. 11174 
Packet: 29 
 
Version Date:  06/09/2020 
 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD, DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY 
TITLE:  
PHASEII TRIAL OF NEOADJUVANT CHEMOTHERAPY WITH CARBOPLATIN 
ANDNAB-PACLITAXEL IN PATIENTS WITH LOCALLY ADVANCED AND 
INFLAMMATORY TRIPLE NEGATIVE BREAST CANCER 
 
CITY OF HOPE PROTOCOL NUMBER: 
11174  
PROTOCOL DATED: 06/09/2020 
 
INITIAL Approval 
 
Protocol Dated 12/27/2011 
 
 
Version 00 
 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
COH Amendment 01 
 
(Protocol Dated 02/13/2012) 
 
 
Version 01 
COH Amendment 02 
 
(Protocol Dated 02/23/2012) 
 
 
Version 02 
COH Amendment 03 
 
(Title page dated 08/14/2012) 
 
 
Version 03 
COH Amendment 04 
 
(Title page dated 08/22/2012) 
 
 
Version 04 
COH Amendment 05 
 
(Protocol Dated 10/18/2012) 
 
 
Version 05 
COH Amendment 06 
 
(Protocol Dated 10/18/2012) 
 
 
Version 06 
COH Amendment 07 
 
(Protocol Dated12/13/2012) 
 
 
Version 07 
COH Amendment 08 
 
(Title page dated 02/06/2013) 
 
 
Version 08 
COH Amendment 09 
 
(Title page dated 05/16/2013) 
 
 
Version 09 
COH Amendment 10 
 
(Protocol Dated 7/26/13) 
 
 
Version 10 
COH Amendment 11 
 
(Title Page Dated 10/08/13) 
 
 
Version 11 
COH Amendment 12 
 
(Protocol dated 10/11/13 Registration &DSMP) Version 12 
COH Amendment 13 
 
(Title Page Change dated 12/17/13) 
 
Version 13 
COH Amendment 14 
 
(Title Page dated 7/1/14) 
 
 
Version 14 
COH Amendment 15 
 
(Title Page dated 7/17/14 (Stewart) 
 
Version 15 
COH Amendment 16 
 
(Protocol dated 3/18/15) 
 
 
Version 16 
COH Amendment 17 
 
(Protocol dated 10/08/15 Expand Cohort) 
Version 17 
 
COH Amendment 18 
 
(Title Page dated 12/21/15) 
 
 
Version 18 
 
COH Amendment 19 
 
(Title Page dated 12/07/16) 
 
 
Version 19 
 
COH Amendment 20 
 
(Title Page dated 01/31/2017) 
 
 
Version 20 
 
COH Amendment 21 
 
(Personnel and Protocol dated 03/31/17)  
Version 21 
 
COH Amendment 22 
 
(PI change dated 07/27/2017) 
 
 
Version 22 
 
COH Amendment 23 
 
(Title Page dated 01/24/18) 
 
 
Version 23 
COH Amendment 24   
at Continuation (Title Page dated 02/27/18) 
Version 24 
COH Amendment 25   
(Protocol v23 dated 06/29/2018) 
 
Version 25 
COH Amendment 26    
(Protocol v24 dated 01/17/2019 and 
 
Version 26 
COH Amendment 27   
at Continuation (Title Page dated 02/16/20) 
Version 27 
COH Amendment 28   
(Protocol dated 06/09/2020) 
 
 
Version 28 
COH Amendment 29                   (Protocol dated 06/09/2020) (TP)                         Packet: 29 
 
SPONSOR/IND NUMBER:  City of Hope/N/A 
 
DISEASE SITE: 
Breast 
HISTOLOGY: 
Adenocarcinoma 
STAGE: 
Stage II/III  
MODALITY: 
Chemotherapy 

IRB Protocol No. 11174 
Packet: 29 
 
Version Date:  06/09/2020 
TYPE: 
 
Neoadjuvant therapy 
PHASE: 
 
Phase II 
 
PRINCIPAL INVESTIGATOR: 
Yuan Yuan, M.D, Ph.D. 
COLLABORATING INVESTIGATORS: 
 
 
 
 
 
Surgery: John Yim M.D.,,(COH) 
 
Pathology: 
Karl Gaal, M.D. (COH), Daniel Schmolze, M.D. (COH), 
Christina Wei, M.D. (COH) 
 
Scientists:   
Rahul Jandial, MD, PhD, Xiwei, Wu, PhD, Hua Yu, PhD, 
Shiuan Chen, PhD, John Burnett, M.D., Jun Wu, Peiguo 
Chu(COH) 
 
Michael Clarke, MD (Stanford)  
Ed Liu, M.D., PhD, Francesca Mengi, PhD (Jackson 
Laboratory) 
Emily (Shizhen) Wang, PhD, (UC San Diego)  
Jeffrey Trent, MD (TGEN) 
 
Medical Oncology: Joanne Mortimer M.D., George 
Somlo, M.D. 
 
Statistician: Paul Frankel, Ph.D. 
 
PARTICIPATING INVESTIGATORS: 
 
City of Hope 
Radiology: Sally Shaw, M.D., Lalit Vora, M.D., Lusi 
Tumyan, M.D. 
 
Hematology: Stephen J. Forman, M.D 
 
Radiation Oncology:  
 
Medical Oncology: Stephen Koehler, M.D., Jana 
Portnow M.D., Christine Yeon, M.D., Samuel Chung, 
M.D., James Waisman, M.D., Daphne Stewart, M.D., 
Daneng Li, M.D., Niki Tank, M.D., Mina Sedrak, M.D., 
James Shen, M.D.  
 
 
STUDY SPONSOR AND MONITOR: 
City of Hope National Medical Center 
 
 
PARTICIPATING CLINICAL SITES: 
City of Hope National Medical Center, Duarte, CA 
City of Hope, South Pasadena, CA 

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IRB Protocol No. 11174 
 
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CITY OF HOPE, 1500 E. DUARTE ROAD, DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY 
TITLE:  
PHASE II TRIAL OF NEOADJUVANT CHEMOTHERAPY WITH CARBOPLATIN 
AND NAB-PACLITAXEL IN PATIENTS WITH LOCALLY ADVANCED AND 
INFLAMMATORY TRIPLE NEGATIVE BREAST CANCER  
 
City of Hope #:  11174  
Protocol Version:  06/09/20 
 
PRINCIPAL INVESTIGATOR: 
Yuan Yuan, M.D., Ph.D. 
City of Hope National Medical Center 
Department of Medical Oncology 
T:  626-256-4673, x89200 
 
COLLABORATING INVESTIGATORS: 
 
 
 
 
 
Surgery: John Yim M.D., Courtney Vito, M.D., 
Laura Kruper M.D.(COH) 
Pathology:   
                    Karl Gaal, M.D. (COH) 
                    Daniel Schmolze, M.D. (COH) 
                    Christina Wei, M.D. (COH) 
Scientists:   
Rahul Jandial, MD, PhD,  
Xiwei, Wu, PhD, Hua Yu, PhD, Shiuan Chen, PhD, 
Peter Lee, PhD, 
Karineh Petrossian,  
John Burnett, M.D., Jun Wu, Peiguo Chu (COH) 
Michael Clarke, MD (Stanford)  
Ed Liu, M.D., PhD, Francesca Mengi, PhD (Jackson Laboratory) 
Jeffrey Trent, MD (TGEN) 
Emily (Shizhen) Wang, PhD, (UC San Diego) 
Medical Oncology:  Joanne Mortimer, MD  
Statistician: Paul Frankel, Ph.D. 
 
PARTICIPATING INVESTIGATORS: 
 
 
 
 
 
 
 
 
 
City of Hope  
Radiology: Sally Shaw, M.D., Lalit Vora, M.D., Lusi Tumyan, M.D. 
Hematology: Stephen J. Forman, M.D 
Radiation Oncology: Nayana Vora, M.D 
Medical Oncology: Stephen Koehler, M.D., Jana Portnow M.D., 
Christine Yeon, M.D., Samuel Chung, M.D., James Waisman, M.D., 
Daphne Stewart, M.D., Daneng Li, M.D., Niki Tank, M.D., Mina 
Sedrak, M.D., James Shen, M.D. 
 

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IRB Protocol No. 11174 
 
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STUDY SPONSOR AND MONITOR: 
City of Hope  
 
PARTICIPATING CLINICAL SITES: 
City of Hope, Duarte, CA 
City of Hope Medical Group, Pasadena, CA 

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IRB Protocol No. 11174 
 
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Experimental Design Schema 
• Identification of patients with locally advanced breast cancer/inflammatory breast cancer 
• Consent 
• Work-up, including validation of triple negative tumor status, and, if feasible, additional  
biopsy, procurement of blood samples, and imaging  
• Eligibility criteria met : registration for treatment 
• Therapy with 4 cycles of carboplatin (AUC 6) given every 4 weeks, nab-paclitaxel 100 mg/m2 
weekly. Total planed duration: 16 weeks 
• Imaging of the primary tumor, and sampling of the tumor (optional) and blood (optional), after 2 
cycles 
•  Re-imaging, followed by either breast conserving surgery (only for locally advanced breast 
cancer and not for inflammatory breast cancer)  or mastectomy, and lymph node 
assessment/node dissection, as per standard clinical practice 
• Analysis of clinical/correlative data, plan for follow-up randomized trial. 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
Protocol Title: 
PHASE II TRIAL OF NEOADJUVANT CHEMOTHERAPY WITH  CARBOPLATIN AND 
NAB-PACLITAXEL IN PATIENTS WITH LOCALLY ADVANCED AND INFLAMMATORY 
TRIPLE NEGATIVE 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: 
Despite a decrease in breast cancer-related mortality, primarily due to screening/detection at an 
earlier stage, thousands of patients still present with locally advanced (LABC) and inflammatory 
breast cancer (IBC), conditions associated with high rates of recurrence and poor survival. 
Neoadjuvant chemotherapy (NT) is applied in the majority of such cases to allow for optimal surgical 
intervention, and also aiming for complete/near-complete pathologic response (pCR), a surrogate 
marker/predictor for longer relapse-free and overall survival, especially in estrogen and progesterone 
receptor negative patients. 
Standard neoadjuvant therapy for locally advanced/inflammatory breast cancer results in pathological 
CR (pCR) in ~ 20-25 % of patients.  We have previously conducted a neoadjuvant trial comparing a 
novel regimen of dose-dense doxorubicin and cyclophosphamide followed by carboplatin and nab-
paclitaxel versus docetaxel, doxorubicin, and cyclophosphamide (TAC), in patients with locally 
advanced and inflammatory HER2- breast cancer. We documented the safety of combining 
carboplatin and nab-paclitaxel, but found no difference between the 2 regimens, and the pCR rate 
was somewhat disappointing at < 15%, with Symmans residual cancer burden (RCB) scores of 0-1 
approaching 30% with either regimen.  The combination of carboplatin and paclitaxel has been 
reported to be effective in triple negative breast cancer by others, with pCR rates of ~ 60% in the 
neoadjuvant setting, and without the use of anthracyclines. Nab-paclitaxel as a single agent results in 
over 60% response rate in the metastatic setting. 
We hypothesize, that nab-paclitaxel, based on its favorable toxicity profile and efficacy when compared 
to cremophor-based paclitaxel in a randomized phase III trial in metastatic breast cancer, and given on a 
weekly schedule, may further improve efficacy in combinations including carboplatin. The proposed 
trial will therefore include carboplatin and nab-paclitaxel in the treatment of triple negative disease to 
further improve pCR rate, and to avoid anthracycline-associated side effects including 
myelodysplasia and secondary hematological malignancies. 
Objectives: Primary Objective 
• To test the hypothesis that carboplatin + nab-paclitaxel therapy will demonstrate a promising 
neoadjuvant pCR rate for eligible patients. 
• To test the hypothesis that carboplatin + nab-paclitaxel therapy will demonstrate a promising 
Symmans 0-1 pathological response rate for eligible patients.. 

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Secondary Objectives 
• 
To evaluate the overall survival and event-free survival of eligible patients treated with 
carboplatin + nab-paclitaxel neoadjuvant chemotherapy.  
• 
To evaluate the toxicities and tolerance of carboplatin + nab-paclitaxel therapy in this patient 
population. 
• 
To evaluate the role of laboratory correlates in response, toxicity and survival endpoints.  
1. To procure tissue and perform analysis of gene and protein expression profiles of pre-
treatment primary tumor (estimated success rate: 80%) and residual tumors (25%) and 
lymph nodes (50%), including sequential assessment of cellular characteristics and gene and 
protein expression profiles and assessment of metastatic niche in lymph nodes. 
2.   To identify specific mutations in tumor DNA in comparison to adjacent tissue and germ 
line DNA procured prior to, during, and subsequent to neoadjuvant chemotherapy; and to 
detect/measure, as feasible, the presence of such mutations in fragmented, circulating DNA 
from plasma; and to correlate these mutations with the presence/characteristics of circulating 
tumor cells in order to identify prognostic and predictive indicators of persisting/relapsed 
disease and targets for therapy. 
3.  To assess RNA ((using Mammaprint/Blueprint and 44,000 Agilent 3platform gene array), 
miRNA and exosome and protein profiles in tumor, adjacent tissue and plasma prior to, 
during, and at completion of neoadjuvant chemotherapy in order to establish prognostic and 
predictive indicators of outcome, markers of persistent/relapsed disease, and targets for 
therapy. 
4.  To analyze tumor DNA and genomic DNA from plasma by microarray and RT-PCR 
analysis to assess copy numbers/SNP/genomic polymorphisms in genes for the purposes of 
establishing prognostic and predictive indicators of outcomes; markers of 
persistence/relapse disease, drug resistance, and drug metabolism; and targets of therapy. 
5.  To assess the prognostic and predictive value of conventional pathological features (stage, 
estrogen and progesterone receptor and HER-2 status, presence of lymphovascular invasion, 
high grade tumor status) in comparison to such values derived from the molecular 
approaches. 
6.  To procure tumor from the primary and definitive surgical specimen for the purpose of 
establishing breast cancer stem cell lines. 
7. To procure blood samples for the purpose of identifying and characterizing circulating 
tumor cells. 
Study Design: 
Phase II Neoadjuvant Chemotherapy Trial; Single-site; type of study: safety, efficacy, exploratory 
correlative marker analysis.  To permit early termination for a discouraging result, we will employ a 
two-stage design, with first stage accrual to 22 evaluable patients and final accrual to 45 evaluable 
patients (49 total patients).    An expanded cohort of 20 patients will be added at the end, given a 
promising result, to better explore the response rate in specific breast cancer subtypes.  
Endpoints: 
Pathological complete response (pCR) and Residual Cancer Burden (RCB) score (Symmans) 
Sample Size: 

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The sample size is to be 69 total patients.  Forty-five (45) evaluable and 49 total in two-stage design 
to evaluate if the combination holds promise, and an additional 20 (given promising results) in an 
expanded cohort to gain experience in specific breast cancer subsets. All patients are to receive all 
study medications, and patients treated will be included in any reported analysis. 

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Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
Disease Status 
Locally advanced (T2 and higher with or without lymph node involvement), and/or inflammatory 
breast cancer; triple negative biology only. 
Age Criteria and Life Expectancy 
Greater than 18 years of age, female patients 
Child Bearing Potential 
The effects of the proposed therapeutic agents (carboplatin, 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) Tumor negative for expression of hormone receptors (IHC < 10%) and not overexpressing 
HER2 by IHC (0-1), or, in case of IHC of 2, negative by FISH 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/µl; platelets ≥ 100,000/µl 
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 the newly diagnosed breast cancer. Patients with 
a prior diagnosis of malignancy treated ≥ 5 years ago are eligible, provided that they have not 
received prior taxanes or carboplatin as part of their prior treatment regimen, and that they meet all 
eligibility criteria. 
 
Exclusion Criteria: 
Study-Specific Exclusions 
1) Known active Hepatitis B, or C 

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2) Known active HIV (necessitating  therapy) 
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  
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: 
Nab-paclitaxel 100 mg/m2  weekly x 16 weeks 
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. 
Statistical Considerations: 
A two stage design is proposed based on detecting a promising pCR rate (using the MD Anderson 
criteria of lack of evidence of any residual invasive tumor in breast and/or regional lymph nodes) 
or a promising Symmans 0-1 pathological response. In the first stage, accrual will continue until 
22 patients are enrolled, with second stage accrual to an evaluable 45 and total of  49 patients. The 
design selected will meet our objectives and permits the early termination of the trial in the event 
that the therapy appears inferior to other neoadjuvant regimens. 
An expanded cohort of 20 patients (given the promising results in the first 45) will be added to 
better evaluate the response rates in specific subsets: basal, androgen receptor positive, 
immunomodulatory subtype, mesenchymal/stem cell like.   This will result in a total of 69 total 
patients.  
Study size is based on our therapeutic target of achieving with acceptable toxicity either a 
promising pCR rate or a promising Symmans 0-1 pathological response rate.  
We have chosen a design that simultaneously discriminates between pCR rate of 20% vs 38% and 
a Symmans response rate of 25% and 45%. 
In particular:  
If no more than four (4) Symmans 0-1 responses are observed and no more than three (3) pCRs 
are observed in the first 22 patients, the study will be terminated early and declared negative. If 
five (5) or more Symmans 0-1 responses or four (4) or more pCRs are observed in the first 22 
patients, an additional 23 patients will be accrued during the second stage of the study. If at least 
17 Symmans 0-1 responses (38%) or at least 14 pCRs are observed in the 45 evaluable  patients 
(31%), this combination would be considered worthy of further testing in this setting. 
This design yields at least 87% power to detect a true Symmans response rate of at least 45%. It 
yields at least 86% power to detect a true pCR rate of at least 38%. It yields at least .91 probability 
of a negative result if the true pCR response rate is no more than 20% and the Symmans 0-1 
response rate is no more than 25%.  This last probability is calculated assuming that pCR rate and 
the Symmans 0-1 rate are uncorrelated. As they are positively correlated, the probability will be 

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higher (type I error less than 9%).  
 
Given the promising results at 45 evaluable patients, the expanded cohort  of 20 patients will 
result in a total of 69 patients (~65 evaluable).  This will allow a better exploratory analysis of the 
response rate based on phenotypic and gene array profiling subsets: Approximately 40% are 
expected to be of the basal subtypes (~27 patients), androgen subtype 11% (~7 patients expected), 
tumor infiltrating lymphocyte/immunomodulatory subtype 25% (~17 patients), and 
mesenchymal/mesenchymal/stem cell like ~25% (~17 patients).  With 69 patients, there is an 89% 
chance of having 5 or more patients in even the smallest subset, and as a result, we should observe 
a pCR in all above subsets (e.g. 97% chance of observing at least one pCR with 5 patients if the 
true pCR response rate is 50%).  Dramatic reduction/lack of pCR in any subset will help guide 
future development of subset specific treatment additions to the backbone of nab-paclitaxel and 
carboplatin.  For the more common subsets, such as the basal subtype, the 95% CI for the pCR 
can be estimated with a half-width of at most 12% assuming 27 patients in that group.  The 
confidence interval will be larger or smaller depending on the exact number of patients in that 
group enrolled, and these estimates will be made for the pCR rate for all patients who initiated 
treatment and are eligible patients, along with all patients who were treated per protocol.  
Sponsor 
City of Hope 

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Table of Contents 
 
SECTION ................................................................................................................. PAGE 
Objectives: Primary Objective ............................................................................................ 4 
Secondary Objectives.......................................................................................................... 5 
Disease Status ........................................................................................................ 7 
Age Criteria and Life Expectancy .......................................................................... 7 
Child Bearing Potential .......................................................................................... 7 
Protocol-Specific Criteria ...................................................................................... 7 
Informed Consent/Assent ...................................................................................... 7 
Prior Therapy ......................................................................................................... 7 
Study-Specific Exclusions ..................................................................................... 7 
Non-Compliance .................................................................................................... 8 
1.0 
Goals and Objectives (Scientific Aims) ............................................................................ 20 
1.1 
Primary Objective ................................................................................................ 20 
1.2 
Secondary Objectives .......................................................................................... 20 
2.0 
Background ....................................................................................................................... 21 
2.1 
Introduction/Rationale for Development ............................................................. 21 
2.2 
Completed phase II randomized/stratified neoadjuvant trial ............................... 21 
2.3 
Carboplatin and nab-paclitaxel ............................................................................ 22 
2.4 
Molecular characterization of biopsy specimens ................................................. 22 
2.5 
Overview of proposed study ................................................................................ 23 
3.0 
Patient Eligibility .............................................................................................................. 23 
3.1 
Inclusion Criteria: To be eligible, patients must meet all of these criteria. ......... 23 
3.1.1 
Disease Status ......................................................................................... 23 
3.1.2 
Age Criteria and Life Expectancy........................................................... 23 
3.1.3 
Child Bearing Potential ........................................................................... 23 
3.1.4 
Protocol-Specific Criteria ....................................................................... 23 
3.1.5 
Informed Consent/Assent ....................................................................... 24 
3.1.6 
Prior Therapy .......................................................................................... 24 
3.2 
Exclusion Criteria: A patient is rendered ineligible if any of these criteria applies.24 
3.2.1 
Study-Specific Exclusions ...................................................................... 24 
3.2.2 
Non-Compliance ..................................................................................... 24 

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3.3 
Inclusion of Women and Minorities .................................................................... 24 
4.0 
Registration Procedures .................................................................................................... 25 
4.1 
To register a patient, the treating physician should contact the protocol nurse or the 
responsible Clinical Research Associate (CRA) in Clinical Trial Office (CTO) to 
complete the eligibility/registration form. The protocol nurse or CRA will contact the 
Data Coordinating Center at the City of Hope (626-256-4673, ext. 64267 or e-mail 
dcc@coh.org), EMAIL a copy of the completed eligibility checklist, required pre-study 
tests (per protocol – and may include laboratory, CT and pathology reports), signed 
Informed Consent, signed Patients' Bill of Rights and HIPAA authorization form to 
dcc@coh.org. ....................................................................................................... 25 
 
The COH DCC will log into the Electronic Data Capture (EDC) system and enter the 
patient’s study number. ........................................................................................ 26 
4.2 
Informed Consent ................................................................................................ 27 
4.3 
Dose Assignment ................................................................................................. 27 
5.0 
Treatment Program ........................................................................................................... 27 
5.1 
Treatment Overview ............................................................................................ 27 
5.1.1 
Dose summary ........................................................................................ 27 
5.1.2 
Details ..................................................................................................... 27 
5.1.3 
Criteria for Starting Subsequent Cycles .................................................. 28 
5.2 
Planned Duration of Therapy ............................................................................... 28 
5.3 
Criteria for Removal from Treatment .................................................................. 29 
5.3.1 
Criteria for Removal ............................................................................... 29 
5.3.2 
Subject Follow-Up .................................................................................. 29 
5.4 
Supportive Care and Other Concomitant Therapy ............................................... 29 
5.5 
Laboratory Studies ............................................................................................... 29 
5.6 
Additional Studies ................................................................................................ 29 
6.0 
Dose Delays/Modifications for Adverse Events ............................................................... 29 
6.1 
Modifications due to toxicity during second and subsequent cycles ................... 29 
6.2 
Carboplatin dose modifications for hematological toxicity ................................. 29 
6.2.1 
Neutrophils ............................................................................................. 29 
6.2.2 
Platelets ................................................................................................... 30 
6.2.3 
Dose Delay according to hematologic recovery: .................................... 30 
6.2.4 
Colony Stimulating Factors .................................................................... 30 
6.3 
Carboplatin dose modifications for non-hematological toxicity .......................... 31 
6.3.1 
Gastrointestinal Toxicity ......................................................................... 31 
6.3.2 
Hypersensitivity Reactions ..................................................................... 31 
6.3.3 
Other Toxicities ...................................................................................... 31 

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6.4 
Nab-paclitaxel (Abraxane) dose modifications.................................................... 31 
6.4.1 
Administration of Study Drug to Patients with Abnormal Hepatic Function
 
32 
6.4.2 
Dose Modification Table ........................................................................ 32 
7.0 
Data and Safety Monitoring .............................................................................................. 34 
7.1 
Definition of Risk Level ...................................................................................... 34 
7.2 
Monitoring and Personnel Responsible for Monitoring ...................................... 34 
7.3 
Definitions ........................................................................................................... 35 
7.4 
Reporting of Unanticipated Problems and Adverse Events Error! Bookmark not 
defined.39 
7.4.1 
Abnormal Laboratory Values ................................................................. 41 
7.4.2 
Pregnancy ............................................................................................... 41 
7.5 
Additional Reporting Guideline for Celgene ....................................................... 42 
8.0 
Agent Information ............................................................................................................. 44 
8.1 
Carboplatin (Paraplatin®) (NSC-241240) (CBDCA) ........................................... 44 
8.1.1 
Risks and Contraindications ................................................................... 44 
8.1.2 
Concomitant Medications/Precautions ................................................... 45 
8.1.3 
Dose and Administration ........................................................................ 45 
8.1.4 
Storage and Stability ............................................................................... 45 
8.1.5 
Structure and Molecular Weight ............................................................. 45 
8.1.6 
Formulation/Agent Preparation .............................................................. 45 
8.1.7 
Supplier ................................................................................................... 46 
8.2 
Nab-Paclitaxel (ABI-007; tradename: Abraxane®)............................................. 46 
8.2.1 
Risks and Contraindications ................................................................... 46 
8.2.2 
Concomitant Medications/Precautions ................................................... 48 
8.2.3 
Storage and Stability ............................................................................... 48 
8.2.4 
Formulation/Agent Preparation .............................................................. 49 
8.2.5 
Dose and Administration ........................................................................ 49 
8.2.6 
Supplier ................................................................................................... 51 
Drug Distribution and Destruction....................................................................... 51 
9.0 
Correlative/Special Studies ............................................................................................... 51 
9.1 
Tissue Specimen Processing and Designation ..................................................... 52 
9.1.1 
Fresh core and other tissue specimens .................................................... 52 
9.1.2. Fixed sample collections ......................................................................... 52 
9.1.3. RT-PCR and DNA microarray analysis .................................................. 52 

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9.1.4. Clarke Lab Protocol for breast tumor dissociation & implantation for xenografts
 
53 
9.2. 
Blood Specimen Processing and Designation ...................................................... 55 
1.2.1 
Blood Samples ........................................................................................ 55 
9.2.2. Specimen Handling: ................................................................................ 55 
9.2.3. Specimen Tracking: ................................................................................ 56 
10. 
Study Calendar .................................................................................................................. 56 
11. 
Evaluation Criteria/Measurement of Effect ...................................................................... 59 
11.1. 
Response Criteria ................................................................................................. 59 
12. 
Data Reporting/Protocol Deviations ................................................................................. 59 
12.1. 
Data Reporting ..................................................................................................... 59 
12.1.2. Confidentiality of Records ...................................................................... 59 
12.1.3. Subject Consent Form ............................................................................. 59 
12.1.4. Data Collection Forms and Submission Schedule .................................. 59 
12.2. 
Protocol Deviations .............................................................................................. 60 
12.2.2. Deviation Policy ..................................................................................... 60 
12.2.3. Reporting of Unplanned Deviations ....................................................... 60 
12.2.4. Resolving Disputes ................................................................................. 60 
13. 
Statistical Considerations .................................................................................................. 60 
13.1. 
Study Design/Endpoints ...................................................................................... 60 
13.1.1 Study Design ........................................................................................... 60 
13.2 
Sample Size/Accrual Rate.................................................................................... 61 
13.2.1 Study Size (45 study-eligible patients maximum) ............................... 61 
13.2.2  Accrual Rate .......................................................................................... 62 
13.3 
Stratification Factors ............................................................................................ 62 
13.4 
Analysis of Secondary Endpoints ........................................................................ 62 
13.4.1 Overall Survival ...................................................................................... 62 
13.4.2 Safety Profile .......................................................................................... 63 
13.5 
Reporting and Exclusions .................................................................................... 63 
13.5.1 Evaluation of Toxicity ............................................................................ 63 
13.5.2 Evaluation of Response .......................................................................... 63 
14. 
Human Subject Issues ....................................................................................................... 63 
14.1. 
Institutional Review Board .................................................................................. 63 
14.2. 
Recruitment of Subjects ....................................................................................... 63 
14.3. 
Confidentiality ..................................................................................................... 64 

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14.4. 
Informed Consent Processes ................................................................................ 64 
15. 
References ......................................................................................................................... 65 
Experimental Design Schema .......................................................................................................... 3 
Protocol Synopsis............................................................................................................................. 4 
Objectives: Primary Objective ............................................................................................ 4 
Secondary Objectives.......................................................................................................... 5 
Disease Status ........................................................................................................ 7 
Age Criteria and Life Expectancy .......................................................................... 7 
Child Bearing Potential .......................................................................................... 7 
Protocol-Specific Criteria ...................................................................................... 7 
Informed Consent/Assent ...................................................................................... 7 
Prior Therapy ......................................................................................................... 7 
Study-Specific Exclusions ..................................................................................... 7 
Non-Compliance .................................................................................................... 8 
Table of Contents ........................................................................................................................... 10 
Abbreviations ................................................................................................................................. 19 
1.0 
Goals and Objectives (Scientific Aims) ............................................................................ 20 
1.1 
Primary Objective ................................................................................................ 20 
1.2 
Secondary Objectives .......................................................................................... 20 
2.0 
Background ....................................................................................................................... 21 
2.1 
Introduction/Rationale for Development ............................................................. 21 
2.2 
Completed phase II randomized/stratified neoadjuvant trial ............................... 21 
2.3 
Carboplatin and nab-paclitaxel ............................................................................ 22 
2.4 
Molecular characterization of biopsy specimens ................................................. 22 
2.5 
Overview of proposed study ................................................................................ 23 
3.0 
Patient Eligibility .............................................................................................................. 23 
3.1 
Inclusion Criteria: To be eligible, patients must meet all of these criteria. ......... 23 
3.1.1 
Disease Status ......................................................................................... 23 
3.1.2 
Age Criteria and Life Expectancy........................................................... 23 
3.1.3 
Child Bearing Potential ........................................................................... 23 
3.1.4 
Protocol-Specific Criteria ....................................................................... 23 
3.1.5 
Informed Consent/Assent ....................................................................... 24 
3.1.6 
Prior Therapy .......................................................................................... 24 
3.2 
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3.2.1 
Study-Specific Exclusions ...................................................................... 24 
3.2.2 
Non-Compliance ..................................................................................... 24 
3.3 
Inclusion of Women and Minorities .................................................................... 24 
4.0 
Registration Procedures .................................................................................................... 25 
4.1 
Registration Process ............................................................................................. 25 
 
 
 
 
4.2 
Informed Consent ................................................................................................ 27 
4.3 
Dose Assignment ................................................................................................. 27 
5.0 
Treatment Program ........................................................................................................... 27 
5.1 
Treatment Overview ............................................................................................ 27 
5.1.1 
Dose summary ........................................................................................ 27 
5.1.2 
Details ..................................................................................................... 27 
5.1.3 
Criteria for Starting Subsequent Cycles .................................................. 28 
5.2 
Planned Duration of Therapy ............................................................................... 28 
5.3 
Criteria for Removal from Treatment .................................................................. 29 
5.3.1 
Criteria for Removal ............................................................................... 29 
5.3.2 
Subject Follow-Up .................................................................................. 29 
5.4 
Supportive Care and Other Concomitant Therapy ............................................... 29 
5.5 
Laboratory Studies ............................................................................................... 29 
5.6 
Additional Studies ................................................................................................ 29 
6.0 
Dose Delays/Modifications for Adverse Events ............................................................... 29 
6.1 
Modifications due to toxicity during second and subsequent cycles ................... 29 
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: ....................................................................................................................... 29 
6.2 
Carboplatin dose modifications for hematological toxicity ................................. 29 
6.2.1 
Neutrophils ............................................................................................. 29 
6.2.2 
Platelets ................................................................................................... 30 
6.2.3 
Dose Delay according to hematologic recovery: .................................... 30 
6.2.4 
Colony Stimulating Factors .................................................................... 30 

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6.3 
Carboplatin dose modifications for non-hematological toxicity .......................... 31 
6.3.1 
Gastrointestinal Toxicity ......................................................................... 31 
6.3.2 
Hypersensitivity Reactions ..................................................................... 31 
6.3.3 
Other Toxicities ...................................................................................... 31 
6.4 
Nab-paclitaxel (Abraxane) dose modifications.................................................... 31 
6.4.1 
Administration of Study Drug to Patients with Abnormal Hepatic Function
 
32 
6.4.2 
Dose Modification Table ........................................................................ 32 
7.0 
Data and Safety Monitoring and Adverse Event Reporting.............................................. 34 
7.1 
Definition of Risk Level ...................................... Error! Bookmark not defined. 
 
34 
34 
7.2 
Monitoring and Personnel Responsible for Monitoring 
7.3 
Definitions………………………………………………………………………37 
7.4        Reporting of Unanticipated Problems and Adverse events……………………39 
7.4.1 
Abnormal Laboratory Values ................................................................. 41 
7.4.2 
Pregnancy ............................................................................................... 41 
7.5 ....... Reporting of Serious Adverse Events- Celgene ReportingError! Bookmark not defined. 
8.0 
Agent Information ............................................................................................................. 44 
8.1 
Carboplatin (Paraplatin®) (NSC-241240) (CBDCA) ........................................... 44 
8.1.1 
Risks and Contraindications ................................................................... 44 
8.1.2 
Concomitant Medications/Precautions ................................................... 45 
8.1.3 
Dose and Administration ........................................................................ 45 
8.1.4 
Storage and Stability ............................................................................... 45 
8.1.5 
Structure and Molecular Weight ............................................................. 45 
8.1.6 
Formulation/Agent Preparation .............................................................. 45 
8.1.7 
Supplier ................................................................................................... 46 
8.2 
Nab-Paclitaxel (ABI-007; tradename: Abraxane®)............................................. 46 
8.2.1 
Risks and Contraindications ................................................................... 46 
8.2.2 
Concomitant Medications/Precautions ................................................... 48 
8.2.3 
Storage and Stability ............................................................................... 48 
8.2.4 
Formulation/Agent Preparation .............................................................. 49 
8.2.5 
Dose and Administration ........................................................................ 49 
8.2.6 
Supplier ................................................................................................... 51 
Drug Distribution and Destruction....................................................................... 51 

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9.0 
Correlative/Special Studies ............................................................................................... 51 
9.1 
Tissue Specimen Processing and Designation ..................................................... 52 
9.1.1 
Fresh core and other tissue specimens .................................................... 52 
9.1.2. Fixed sample collections ......................................................................... 52 
9.1.3. RT-PCR and DNA microarray analysis .................................................. 52 
9.1.4. Clarke Lab Protocol for breast tumor dissociation & implantation for xenografts
 
53 
9.2. 
Blood Specimen Processing and Designation ...................................................... 55 
1.2.1 
Blood Samples ........................................................................................ 55 
9.2.2. Specimen Handling: ................................................................................ 55 
9.2.3. Specimen Tracking: ................................................................................ 56 
10. 
Study Calendar .................................................................................................................. 56 
11. 
Evaluation Criteria/Measurement of Effect ...................................................................... 59 
11.1. 
Response Criteria ................................................................................................. 59 
12. 
Data Reporting/Protocol Deviations ................................................................................. 59 
12.1. 
Data Reporting ..................................................................................................... 59 
12.1.2. Confidentiality of Records ...................................................................... 59 
12.1.3. Subject Consent Form ............................................................................. 59 
12.1.4. Data Collection Forms and Submission Schedule .................................. 59 
12.2. 
Protocol Deviations .............................................................................................. 60 
12.2.2. Deviation Policy ..................................................................................... 60 
12.2.3. Reporting of Unplanned Deviations ....................................................... 60 
12.2.4. Resolving Disputes ................................................................................. 60 
13. 
Statistical Considerations .................................................................................................. 60 
13.1. 
Study Design/Endpoints ...................................................................................... 60 
13.1.1 Study Design ........................................................................................... 60 
13.2 
Sample Size/Accrual Rate.................................................................................... 61 
13.2.1 Study Size (45 study-eligible patients maximum) ............................... 61 
13.2.2  Accrual Rate .......................................................................................... 62 
13.3 
Stratification Factors ............................................................................................ 62 
13.4 
Analysis of Secondary Endpoints ........................................................................ 62 
13.4.1 Overall Survival ...................................................................................... 62 
13.4.2 Safety Profile .......................................................................................... 63 
13.5 
Reporting and Exclusions .................................................................................... 63 
13.5.1 Evaluation of Toxicity ............................................................................ 63 

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13.5.2 Evaluation of Response .......................................................................... 63 
14. 
Human Subject Issues ....................................................................................................... 63 
14.1. 
Institutional Review Board .................................................................................. 63 
14.2. 
Recruitment of Subjects ....................................................................................... 63 
14.3. 
Confidentiality ..................................................................................................... 64 
14.4. 
Informed Consent Processes ................................................................................ 64 
15. 
References ......................................................................................................................... 65 
 
 
 
 

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Abbreviations 
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 
DSMB 
Data Safety Monitoring Board 
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 
SD 
Stable Disease 
 

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1.0 Goals and Objectives (Scientific Aims) 
1.1 Primary Objective 
• 
To test the hypothesis that carboplatin + nab-paclitaxel therapy will demonstrate a 
promising neoadjuvant pCR rate for eligible patients. 
• 
To test the hypothesis that carboplatin + nab-paclitaxel therapy will demonstrate a 
promising Symmans 0-1 pathological response rate for eligible patients.  
1.2 Secondary Objectives 
• 
To evaluate the overall survival and event-free survival of eligible patients treated 
with carboplatin + nab-paclitaxel neoadjuvant chemotherapy.  
• 
To evaluate the toxicities and tolerance of carboplatin + nab-paclitaxel therapy in this 
patient population. 
• 
To evaluate the role of laboratory correlates in response, toxicity and survival 
endpoints.  
1. To procure tissue and perform analysis of gene and protein 
expression profiles of pre-treatment primary tumor (estimated 
success rate: 80%) and residual tumors (25%) and lymph nodes 
including the study of tumor niche (50%), studying sequential 
assessment of cellular characteristics and gene and protein 
expression profiles.  
2. To identify specific mutations in tumor DNA in comparison to 
adjacent tissue and germ line DNA procured prior to, during, and 
subsequent to neoadjuvant chemotherapy, and to detect/measure, 
as feasible, the presence of such mutations in fragmented 
circulating DNA from plasma, and to correlate these mutations 
with the presence/characteristics of circulating tumor cells in 
order to identify prognostic and predictive indicators of 
persisting/relapsed disease and targets for therapy. 
3. To assess RNA (using Mammaprint/Blueprint and 44,000 Agilent 
3platform gene array) , miRNA and exosome and protein profiles 
in tumor, adjacent tissue and plasma prior to, during, and at 
completion of neoadjuvant chemotherapy in order to establish 
prognostic and predictive indicators of outcome, markers of 
persistent/relapsed disease, and targets for therapy.32 
4. To analyze tumor DNA and genomic DNA from plasma by 
microarray 
and 
RT-PCR 
analysis 
to 
assess 
copy 
numbers/SNP/genomic polymorphisms in genes for the purposes 
of establishing prognostic and predictive indicators of outcomes; 
markers of persistence/relapse disease, drug resistance, and drug 
metabolism; and targets of therapy. 
5. To assess the prognostic and predictive value of conventional 
pathological features (stage, estrogen and progesterone receptor 
and HER-2 status, presence of lymphovascular invasion, high 
grade tumor status) in comparison to such values derived from the 
molecular approaches. 
6. To procure tumor from the primary and definitive surgical 
specimen for the purpose of establishing breast cancer stem cell 
lines. 

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7. To procure blood samples for the purpose of identifying and 
characterizing circulating tumor cells. 
 
2.0 Background 
2.1 Introduction/Rationale for Development 
Despite a decrease in breast cancer-related mortality, primarily due to screening/detection at an earlier 
stage, thousands of patients still present with locally advanced (LABC) and inflammatory breast 
cancer (IBC), conditions associated with high rates of recurrence and poor survival. Neoadjuvant 
chemotherapy (NT) is applied in the majority of such cases to allow for optimal surgical intervention, 
and also aiming for complete/near-complete pathologic response (pCR), a surrogate marker/predictor 
for longer relapse-free and overall survival (1), especially in estrogen and progesterone receptor 
negative patients. 
 
Standard neoadjuvant therapy for locally advanced/inflammatory breast cancer results in 
pathological CR (pCR) in ~ 20-25 % of patients.  We have previously conducted a neoadjuvant 
trial comparing a novel regimen of dose-dense doxorubicin and cyclophosphamide followed by 
carboplatin and nab-paclitaxel versus docetaxel, doxorubicin, and cyclophosphamide (TAC), in 
patients with locally advanced and inflammatory HER2- breast cancer. We documented the 
safety of combining carboplatin and nab-paclitaxel, but found no difference between the two 
regimens, and the pCR rate was somewhat disappointing at < 15%, with Symmans residual 
cancer burden (RCB) scores of 0-1 approaching 30% with either regimen (2, 3).  Platinum 
compounds are currently being tested as potentially useful therapeutic agents in the treatment 
of triple negative breast cancer (4-6). The combination of carboplatin and paclitaxel has been 
reported to be effective in triple negative breast cancer with pCR rates of ~ 60% in the 
neoadjuvant setting, and without the use of anthracyclines (7). Nab-paclitaxel, a formulation of 
paclitaxel within an albumin-nanoparticle may be associated with preferential tumor uptake (8-
11). It has been successfully evaluated in the metastatic setting on an variety of different 
schedules (12, 13) and, when given as a single agent on a weekly schedule, it resulted in an even 
higher ~ 60% response rate (14). In the neoadjuvant setting nab-paclitaxel has been evaluated 
as sequential therapy, and as part of combination with carboplatin (15, 2). Hence, the proposed 
trial aimed at triple negative breast cancer will include carboplatin and nab-paclitaxel to further 
improve pCR rate, and to avoid anthracycline-associated side effects including myelodysplasia 
and secondary hematological malignancies. 
 
2.2 Completed phase II randomized/stratified neoadjuvant trial 
We have rapidly completed a single institution phase II randomized/stratified neoadjuvant trial (2) in 
121 patients with LABC/IBC who received 6 cycles of docetaxel 75 mg/m2, doxorubicin 50 mg/m2, 
cyclophosphamide 500 mg/m2 with filgrastim support (TAC, arm A) versus a novel regimen of A 60 
mg/m2 and C 600 mg/m2 given every 2 weeks x 4, followed by 3 weekly doses of carboplatin (AUC 2) 
and nab-paclitaxel 100 mg/m2 repeated as 28 day cycles x 3 ( arm B). Patients with HER2 + BC 
received NT similar to arm B, but with the addition of 12 weekly doses of trastuzumab given together 
with carboplatin and nab-paclitaxel (arm C).  Patients treated for HER2+ disease experienced a 48% 
pCR, and 62% responded with Symmans residual cancer burden (RCB)  scores of 0-1 (3). When 
tumors were assessed by the 70-gene risk-profiling tool, Mammaprint (16), and the 80-gene profiling 
Blueprint (allowing for classification of tumors into basal [overlapping with the triple negative 

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phenotype], luminal, and HER2+ genotypes), pCR of 20% and 56% were observed in patients with 
basal and HER2+ LABC/IBCs. Mammaprint classified 100% of the basal, and 94% of the HER2+ 
molecular types as high risk. There was a significant correlation between the high-risk subtype, and 
pCR, suggesting that patients whose tumors were characterized by HER2+ and basal molecular 
profiles benefit most from these specific NTs.  An alternative regimen developed for stage IV 
metastatic breast cancer (MBC) by Brown University investigators, consisting 4 cycles of carboplatin 
at an AUC of 6 given every 4 weeks and weekly paclitaxel 80 mg/m2, had been tested in triple 
negative disease, and (in combination with trastuzumab) in HER2+ disease, with pCR rates of 67% 
and 76%, respectively, although the sample size was small (7). Early data with carboplatin and nab-
paclitaxel in combination with trastuzumab in the neoadjuvant setting suggests that such a schedule is 
feasible (Dr. William Sikov, verbal communication). 
 
2.3 Carboplatin and nab-paclitaxel 
Carboplatin and paclitaxel may provide superior pCR to previously tested standard regimens, and our 
own anthracycline-containing regimen (2), with acceptable levels of short and long term toxicity, 
possibly including a decreased risk of secondary leukemias and cardiac problems (17).  ABRAXANE 
(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 (8-10). 
  
2.4 Molecular characterization of biopsy specimens 
Molecular characterization of biopsy specimens of primary tumors procured prior to exposure to 
neoadjuvant chemotherapy (NT)  from different varieties of breast cancer subtypes, and of subsequent 
mid-treatment and intraoperative (procured during definitive surgery following completion of 
neoadjuvant therapy) samples should help to assess the predictive value of the pre-treatment and post-
treatment gene and protein expression profile for complete and near complete response, as a surrogate 
marker for survival.  Similarly, patterns of de novo and acquired resistance may emerge when 
assessment of pre- and post-treatment gene expression profiles are analyzed in a supervised manner of 
classification, using pathologic response as a classifier. Specimens from biopsies or surgical 
specimens will be preserved fresh-frozen, in RNAlater, and as FFPE, and when feasible, will also be 
subjected to cell sorting and inoculation in mouse fat pad to generate xenografts. DNA, RNA, and 
miRNA extraction, sequencing/characterization will be carried out in well-established collaboration 
with the City of Hope core laboratories and in collaboration with the Shiuan Chen, Karineh Petrossian 
laboratories, Peter Lee, Hua Yu, and Xiaochun Yu COH laboratories. External (MTA-covered or 
grant-supported) collaborators include TGEN (J. Trent), the Jackson Laboratory (Drs. Liu and Mengi), 
and and Agendia, Inc(16).  Additional collaboration includes (MTA-covered) NantOmics, for 
proteomics analysis.  Circulating tumor cells (CTCs) will be assessed in collaboration with 
Translational Research Core or Pathology Core pending resources. 
In addition, as an exploratory and hypothesis-generating investigation, tumor samples will ne assessed     
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markers of mesenchymal/stem-cell like (vimentin, ALDH staining through the anatomic pathology 
core) properties. (23-25). 
 
2.5 Overview of proposed study 
We hypothesize, that nab-paclitaxel, based on its favorable toxicity profile and efficacy when compared to 
cremophor-based paclitaxel in a randomized phase III trial in metastatic breast cancer, may further 
improve efficacy combinations including carboplatin.   A combination of carboplatin, given on day one of 
a 28-day cycle, and cremophor-based weekly paclitaxel reported to be quite effective when used in locally 
advanced and metastatic triple negative disease. The weekly schedule of nab-paclitaxel (when compared 
to either docetaxel, cremophor-based paclitaxel) yielded favorable response rates at doses 100 and 100 
mg/m2, as a single agent.  Our recently completed neoadjuvant trial demonstrated the feasibility of 
combining carboplatin weekly, and nab-paclitaxel weekly (2).  Reducing the frequency of carboplatin-
administration, while giving nab-paclitaxel weekly, is likely to decrease the potential for dose-frequency-
related, well-described risks of developing carboplatin-related allergy, while maintaining/impoving 
efficacy.  
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the 
applicable regulatory requirements. 
3.0 Patient Eligibility 
 
3.1 Inclusion Criteria: To be eligible, patients must meet all of these criteria. 
3.1.1 
Disease Status 
Patients must be diagnosed with locally advanced (T2 and higher with or without lymph node 
involvement), and/or inflammatory triple negative breast cancer. 
 
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 (carboplatin, 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. 
 
3.1.4 
Protocol-Specific Criteria 
• Tumor negative for expression of hormone receptors (< 10%) and not 
overexpressing HER2 by IHC (0-1), or, in case of IHC of 2, negative by 
FISH or by alternative gene testing. 
• 
Bilirubin < 1.5 mg/dL  

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• 
Patients must have adequate liver function: AST and ALT < 2 X upper limit of 
normal, alkaline phosphatase < 2 X upper limit of normal 
• 
Patients must have adequate bone marrow function: Platelets >100,000 cells/mm3, 
Hemoglobin > 9.0g/dL and ANC > 1,500 cells/mm3 
• 
Patients must have adequate renal function: creatinine <1.5 mg/dL is recommended; 
however, institutional norms are acceptable.  
• 
Left ventricular ejection fraction >50% 
• 
Women of childbearing potential and sexually active males must use an effective 
contraception method during treatment and for three months after completing 
treatment 
• 
Negative serum or urine β-hCG pregnancy test at screening for patients of 
childbearing 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 are allowed for the treatment of the newly diagnosed breast cancer. Patients with 
a prior diagnosis of malignancy treated ≥ 5 years ago are eligible, provided that they have not 
received prior taxanes or carboplatin 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.  
 
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 anyone regardless of ethnicity; however, breast cancer is rare in men compared to 
its incidence in women. Female subjects of all racial/ethnic groups are eligible for this study if they 

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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. 
 
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%) 
 
 
 
 
Accrual Goal for Women and Minorities on this Study 
 
 
By Sex 
By Ethnicity 
Site 
Accrual 
Goal 
Female 
Male 
White 
Hispanic 
African-
American 
Asian 
Other 
Breast 
45 
45 (100%) 
0 (0%) 
20 (44%) 
12 (27%) 
4 (9%) 
8 (18%) 
1 (2%) 
 
4.0 Registration Procedures 
4.1 To register a patient, the treating physician should contact the protocol nurse or 
the responsible Clinical Research Associate (CRA) in Clinical Trial Office (CTO) 
to complete the eligibility/registration form. The protocol nurse or CRA will 
contact the Data Coordinating Center at the City of Hope (626-256-4673, ext. 
64267 or e-mail dcc@coh.org), EMAIL a copy of the completed eligibility 
checklist, required pre-study tests (per protocol – and may include laboratory, CT 
and pathology reports), signed Informed Consent, signed Patients' Bill of Rights 
and HIPAA authorization form to dcc@coh.org.  
The patient registration process will be handled by the Department of  
Clinical Research Information 
Support (CRIS) Data Coordinating Center (DCC) at City of Hope.   
Documentation of current IRB 
approval must be on file with the DCC prior to registration of  
patients on this study for participating 
institution.  

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The steps below are to be taken when registering a patient: 
• 
The research staff must assure they have the most current and updated version of the protocol 
and informed consent prior to enrolling a patient.  If a question arises, please contact the Data 
Coordinating Center at 626-256-4673 extension 64267 or via email at  dcc@coh.org.   
• 
The study staff must assure that all prestudy laboratory tests, scans and x-rays have been 
completed prior to registration according to the study calendar 
• 
The  study staff must assure that the patient has signed an approved informed consent prior to 
registration/randomization, including the Experimental Subject Bill of Rights and appropriate 
HIPAA authorization. 
• 
The study staff must confirm that the patient meets all inclusion and exclusion eligibility 
criteria for the protocol.  The eligibility checklist (provided by the COH DCC) must be 
completed in its entirety. 
• 
Patients must be registered prior to initiation of treatment but no more than 5 working days 
prior to planned start of treatment.  A patient failing to meet all protocol requirements may 
not be registered.   
• 
Once a patient is eligible, all the pre-study requirements have been fulfilled, and the informed 
consent obtained, the research nurse or the data manager (study coordinator) will inform the 
COH Data Coordinating Center at (626) 256-4673, extension 64267; email dcc@coh.org and 
FAX (fax number 626 256-8794) a copy of the patient’s signed informed consent, , 
completed eligibility checklist and corresponding source documentation confirming 
eligibility (including pathology reports, lab reports, x-ray reports, etc.). 
 
The City of Hope Data Coordinating Center will: 
• 
Review all materials/source documentation to ensure the patient is eligible.   
• 
Ensure the consent form is valid and is signed correctly by all parties.  If additional 
information is needed or should there be any questions, the Data Coordinating Center will 
immediately contact the study staff and registration will not occur until all issues are 
resolved.   
• 
If there are questions regarding exceptions to the eligibility criteria, please contact he study 
Principal Investigator, as well as the COH DCC.  Documentation of IRB approval of 
exception will need to be submitted as well as the COH DCC. 
• 
Confirmation of Registration will be emailed/faxed to the  study staff noting the patient’s 
study number within 24 hours post receipt of a complete eligibility packet. 
• 
The COH DCC will call the research nurse or data manager (study coordinator) and verbally 
confirm the registration (if needed). 
• 
If the patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be cancelled.  The COH DCC should be notified of 
cancellations as soon as possible. 
The COH DCC will log into the Electronic Data Capture (EDC) system and enter the patient’s study 
number. 

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4.2 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. 
4.3 Dose Assignment  
Patients will receive carboplatin AUC of 6 on day 1 of a 28-day cycle, nab-paclitaxel, 100 mg/m2 
weekly. 
Dose reductions can occur as medically necessary as described below in section 6.0.  
 
5.0 Treatment Program 
5.1 Treatment Overview 
Treatments are planned to be delivered in the outpatient setting. 
Management and dose modification associated with adverse events are outlined in Section 6. 
Off label: This proposal includes a commercial agent for use in an investigational setting/trial. 
 
5.1.1 
Dose summary 
Carboplatin at AUC at 6 every 4 weeks (28 day cycles x 4). 
Nab-Paclitaxel 100 mg/m2 weekly x 16 weeks (28 day cycles  x 4). 
 
5.1.2 
Details 
 
For details of nab-paclitaxel dosing and administration, see Agent Information, section 8. 
 
Carboplatin will be administered as an intravenous infusion over 30 minutes.  
Carboplatin dose (mg) = 6 X (GFR + 25)  
(Calculated total dose is in mg -not mg/m2)  
The Creatinine Clearance (to replace GFR) will be calculated for each treatment course using the 
formula:  

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For Females:  
*Important: The serum creatinine level to be used in the following calculations must be 
greater than or equal to 0.7.  If the measured serum creatinine level is less than 0.7, use 0.7 
as the value in this calculation.   
 
CrCI = (140-age) X wt. in kg. X 0.85  
                                                                 72 X serum creatinine* 
Use calculated creatinine clearance for GFR in Calvert formula.  
 
Note: Remember to re-calculate the dose for each treatment cycle. The actual body weight 
should be used for all calculations. If the actual weight is greater than 1.2 times the ideal body 
weight, use 1.2 times the ideal body weight as the value in this calculation. 
Note: The GFR (calculated by Cockcroft-Gault or any other means using creatinine) used 
in the Calvert formula to calculate AUC-based dosing should not exceed 125 mL/min 
under any circumstance. 
By definition, this results in the following upper limits on the dose to be administered, by AUC 
target: 
AUC target 
(mg•min/mL) 
Maximum carboplatin dose 
(mg) 
2 
300 
3 
450 
4 
600 
5 
750 
6 
900 
                 
5.1.3 
Criteria for Starting Subsequent Cycles 
Patients should meet the laboratory parameters and the performance status as outlined in section 
3.1. before initiation of each cycle of therapy. All toxicities (except alopecia and lymphopenia, 
hyperglycemia, hypoalbuminemia, elevated serum alkaline phosphatase) should have resolved to 
grade 1 or lesser severity before initiation of the next cycle of therapy.  
Qualifying laboratory tests and procedures can be obtained up to 72 hours before planned initiation 
of therapy from the 2nd cycle onwards. 
 
5.2 Planned Duration of Therapy 
Four cycles, approximately 16 weeks. 
 

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5.3 Criteria for Removal from Treatment 
5.3.1 
Criteria for Removal 
Removal of a patient from treatment will be based on the following: unacceptable toxicities as 
assessed by the treatment team based on the grade, duration, need for dose adjustment/modification 
of treatment; patient desire; or disease progression.  
5.3.2 
Subject Follow-Up 
All patients enrolled and having received at least 1 dose of therapy will be evaluated for 
toxicity. Patients will be followed for an indefinite period of time after enrollment.  Subsequent to 
the 5-year mark, standard follow-up measures per tumor registry guidelines will apply. 
 
5.4 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/or NCCN guidelines, as appropriate. 
 
5.5 
Laboratory Studies 
See Section 10. Study Calendar 
. 
5.6 Additional Studies 
Reference is made to Section 9.0 for any correlative studies to be conducted under this protocol. 
 
6.0 Dose Delays/Modifications for Adverse Events 
 
6.1 
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, which may be delayed no more than 
two weeks to allow recovery from toxicity. Treatment delay of > 2 weeks due to toxicity will lead to 
removal of the patient from the study. 
 
6.2 
Carboplatin dose modifications for hematological toxicity  
6.2.1 
Neutrophils  
The following dose adjustments are based on the neutrophil nadir of the preceding treatment 
course.   
 

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Absolute Granulocyte Count 
Nadir 
Carboplatin 
Grade 3 (without fever) 
No change 
Grade 4 (without fever) 
1st episode 
Reduce AUC by 1 level 
and consider G-CSF support 
2nd episode 
Reduce AUC by 2 level 
And use G-CSF 
3rd episode 
Reduce AUC by 2 level 
And use G-CSF 
4th episode 
Off study 
Grade 3/4 (with fever) 
1st episode 
Reduce AUC by 1 level 
And use G-CSF 
2nd episode 
Reduce AUC by 2 level 
And use G-CSF 
3rd episode 
Off study 
 
6.2.2 
Platelets 
Nadir Platelet 
count 
Carboplatin 
Grade 3/4 
1st episode 
Reduce AUC by 1 level 
2ndepisode 
Reduce AUC by 2 levels 
3rd episode 
Reduce AUC by 2 levels 
4rth episode 
Off study 
 
6.2.3 
Dose Delay according to hematologic recovery: 
The hematologic parameters must meet the criteria specified in section 3.1.4 of the protocol on day 
1 of each treatment cycle. Treatment of both drugs should be delayed until recovery of the counts 
to the specified eligibility levels. Delay in treatment of more than 2 weeks due to toxicity will 
result in removal of the patient from the study.  
6.2.4 
Colony Stimulating Factors  
Patients should not routinely receive prophylactic colony stimulating factors (e.g., G-CSF; GM-
CSF) during cycle 1, unless the use is following the recommendations in section 6.1.1.  Subsequent 
use will be at the discretion of the treating physician.  
 

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6.3 
Carboplatin dose modifications for non-hematological toxicity  
6.3.1 
Gastrointestinal Toxicity  
Nausea and/or vomiting should be controlled with adequate antiemetic therapy. Prophylactic anti-
emetic therapy can be used at the discretion of the treating physician. Patients are encouraged to 
take plenty of oral fluids. If symptoms persist despite maximal anti-emetic therapy, treatment 
should be withheld until recovery to < grade 1. 
Diarrhea should be managed with appropriate anti-diarrheal therapy. Patients should be 
encouraged to take plenty of oral fluids. If symptoms do not decrease to grade 1 or less with 
adequate anti-diarrheal therapy, treatment should be held until recovery from symptoms to < grade 
1.   
6.3.2 
Hypersensitivity Reactions  
Caution: Patients who had a mild to moderate hypersensitivity reaction have been successfully 
rechallenged, but careful attention to prophylaxis and bedside monitoring of vital signs is 
recommended.  
Mild symptoms  
(e.g., mild flushing, rash, pruritus)  - Complete infusion.  Supervise at bedside. No treatment 
required.   
Moderate symptoms 
(e.g., moderate rash, flushing, mild dyspnea, chest discomfort) - Stop infusion. Give intravenous 
diphenhydramine 25 mg and intravenous dexamethasone 10 mg. Resume infusion after recovery of 
symptoms at a low rate, 20 mg/hr. For 15 minutes, then, if no further symptoms, at full dose rate 
until infusion is complete. If symptoms recur, stop infusion. Record toxicity on flow sheets.  
Severe life threatening symptoms  
(e.g., hypotension requiring pressor therapy, angioedema, respiratory distress requiring 
bronchodilation therapy, generalized urticaria) - Stop infusion. Give intravenous diphenhydramine 
and dexamethasone as above. Add epinephrine or bronchodialtors if indicated. If wheezing is 
present, that is not responsive to bronchodilators, epinephrine is recommended. Patient should be 
removed from further protocol therapy. Report as an adverse event.  
6.3.3 
Other Toxicities  
For any grade 3 or 4 toxicity not mentioned above, withhold both drugs until the patient recovers to 
grade 1 or less toxicity. The treatment should then be resumed at one lower dose level for 
carboplatin and same dose for Abraxane. For grade 2 toxicities, withhold treatment until the patient 
recovers, then resume treatment at a one dose-level reduction for carboplatin (permanent dose 
reduction) and same dose for Abraxane. For grade 1 toxicities, no dose reduction should be made.  
 
6.4 
Nab-paclitaxel (Abraxane) dose modifications 
Refer to section 8.2 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, 
22), 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.   

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6.4.1 
Administration of Study Drug to Patients with Abnormal Hepatic Function 
Study drug 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. 
6.4.2 
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 2:  Dose Modification 
 
Dose Level 
ABRAXANE 
(mg/m2) 
0 
100 
-1 
80 
-2 
60 
 
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 3:  Use of G-CSF and Dose reductions for Hematologic Toxicity 
Adverse Event 
Occurrence 
Action to be Taken 

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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 8 or 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 is given as outlined below.  In the event 
that a hematological toxicity re-occurs in the 
face of G-CSF, dose reduction to the next lower 
level will be required for subsequent cycles once 
ANC is ≥ 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.   
If a delay of more than 2 weeks is necessary 
even with the use of neutrophil growth factors 
and after dose adjustment to dose level minus 2, 
the patients will be taken off study 
 
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 
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 
For Q3W 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 until 
recovery to the predetermined neutrophil count.  
Sensory Neuropathy 
ABRAXANE should be withheld in patients who experience ≥ Grade 3 sensory neuropathy.  
Treatment may be resumed at the next lower dose level (see Table 2) in subsequent cycles after 
the sensory neuropathy improves to ≤ Grade 1. The time to resolution to Grade ≤ 1 should be 
the adverse event duration used for adverse event reporting.  In those patients who experience 
Grade 4 sensory neuropathy, study drug should be withheld, and treatment resumed at a 
reduction of 2 dose levels (Dose Level -2; see Table 2) in subsequent cycles after the sensory 
neuropathy improves to ≤ Grade 1.  Note: the investigator may elect to dose modify for Grade 3 
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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, 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 2). 
 
7.0 Data and Safety Monitoring 
7.1 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. 
 
 
7.2 Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, at least two Collaborating 
Investigators, CRA, protocol nurse, and statistician is responsible for monitoring the data 
and safety of this study, including implementation of any stopping rules for safety and 
efficacy.  
Data and safety will be reported to the COH DSMC using the PMT report and submitted 
according to the timelines in Table 1 below.  Protocol specific data collection will include 
the following items: summary of accrual, adverse events and treatment related mortality. 

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Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
Risk Level 
Phase 
Standard Reporting Requirement 
RL 1, RL2, and  
Expanded Access 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3 
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.  
 

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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] - 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 
existing hospitalization 
• 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 dyscrasias 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. 
 
 

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7.4 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/policy/Policies%20and%20Procedures/REVIEWING_AND_REP
ORTING_UNANTICIPATED_PROBLEMS.pdf.  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/policy/Policies%20and%20Procedures/REVIEWING_AND_REPORTING
_UNANTICIPATED_PROBLEMS.pdf 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). 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
DSMC Risk Level 3 and Risk Level 4 Protocol Reporting Timelines 
 
Required Reporting Timeframe to the 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 
Within 30 days of last active treatment/therapy 
  
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 

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Required Reporting Timeframe to the DSMC 
Attribution 
Unexpected 
Expected 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
 
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
After 30 days of last active treatment/therapy 
 
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 

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DSMC Risk Level 1 and Risk Level 2 Protocol Reporting Timelines 
 
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 
5 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
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 
No reporting required 
No reporting required 
  
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
 
COH IRB Adverse Event Reporting Timelines  
 

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Required Reporting Timeframe to COH IRB  
Attribution 
Unexpected 
Expected 
 
Death while on active treatment/therapy or within 30 days 
of the last day of active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days1 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 
Possibly, Probably, Definitely 
5 calendar days1 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 
Possibly, Probably, Definitely 
5 calendar days1 
Annual2 
Unlikely, Unrelated 
Annual2 
Annual2 
1 These events must be reported in the time frame if they meet the definition of an unanticipated problem. 
2 For studies that are not first in human, Phase I and first in pediatric trials, only grades 3-5 must be reported at annual review.  
 
 
 
7.4.1 
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• 
results in discontinuation from the study; 
• 
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or  
• 
Is judged to be of significant clinical importance. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion need 
to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF. If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
7.4.2 Pregnancy 
Females of Childbearing Potential: 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events. IP is to be discontinued 
immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 

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Celgene Drug Safety immediately by facsimile, or other appropriate method, using the Pregnancy 
Initial Report Form, or approved equivalent form. 
The female subject may be referred to an obstetrician-gynecologist (not necessarily one with 
reproductive toxicity experience) or another appropriate healthcare professional for further 
evaluation. 
The Investigator will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.  
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any of 
the serious criteria, it must be reported as an SAE to Celgene Drug Safety immediately by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
  
7.5Additional Reporting Guideline for Celgene 
 
The Sponsor-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 

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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 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. 

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• 
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 
Summit, N.J. 07901 
Toll Free:   
(800)-640-7854 
Phone:  
(908) 673-9667 
Fax: 
 
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
 
8.0 Agent Information 
 
8.1 
Carboplatin (Paraplatin®) (NSC-241240) (CBDCA) 
Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and is an analog of cisplatin, 
producing intrastrand DNA cross-links. 
 
8.1.1 
Risks and Contraindications 
Human Toxicology: Side effects of carboplatin (CBDCA) include myelosuppression, nausea, 
vomiting, abdominal pain, diarrhea and constipation. Other toxicities include allergic reaction 
(including hypersensitivity, i.e., rash, urticaria, erythema, pruritus, bronchospasm and 
hypotension), peripheral neuropathy, paresthesia, loss of hair, hearing loss, visual disturbances and 
change in taste.  Serum creatinine elevations and blood urea elevations have occurred, as well as 
abnormal liver function tests and decreased serum electrolyte values.  Although rare, pain, asthenia, 
cardiovascular, respiratory, genitourinary and mucosal side effects have occurred in some patients.  
Cancer-associated hemolytic uremic syndrome has been reported rarely. 
Carboplatin may cause fetal harm; therefore women of childbearing potential should be advised to 
avoid becoming pregnant. 
Contraindications: 
Carboplatin is contraindicated in patients with a history of severe allergic reactions to cisplatin or 
other platinum-containing compounds or mannitol.  
This drug should not be used in patients with severe bone marrow depression or significant 
bleeding. 

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8.1.2 
Concomitant Medications/Precautions 
The renal effects of nephrotoxic compounds may be potentiated by carboplatin. 
The occurrence of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator combination chemotherapy. 
 
8.1.3 
Dose and Administration 
Administration of Carboplatin is intravenous. 
See section 5.1 
 
8.1.4 
Storage and Stability 
Unopened vials of carboplatin for injection are stable for the life indicated on the package when 
stored at controlled room temperature 15–30 ˚C, and protected from light.  When reconstituted as 
directed, the solution of carboplatin exhibits no decomposition for 8 hours at room temperature (25 
˚C). 
Like cisplatin, this drug should not be given through aluminum needles. 
Caution: The single-use lyophilized dosage form contains no antibacterial preservatives.  
Therefore, it is advised that the reconstituted product be discarded eight hours after dilution. 
 
8.1.5 
Structure and Molecular Weight 
Chemical name:  platinum, diammine [1,1-cyclobutane-dicarboxylato(2-)-0,0’]-, (SP-4-2). 
Molecular formula:  C6H12N2O4Pt  
Molecular weight:  371.25 
 
8.1.6 
Formulation/Agent Preparation 
Carboplatin is supplied as a sterile lyophilized powder available in single-dose vials containing 50 
mg, 150 mg and 450 mg of carboplatin for administration by intravenous injection.  Each vial 
contains equal parts by weight of carboplatin and mannitol.  Immediately before use, the content of 
each vial must be reconstituted with either Sterile Water for Injection, USP, 5% Dextrose in Water, 
or 0.9% Sodium Chloride Injection, USP, according to the following schedule: 
Vial Strength  
 
Diluent Volume 
    50 mg                                          5 mL 
    150 mg                                        15 mL 
    450 mg                                        45 mL 
 
These dilutions all produce a carboplatin concentration of 10 mg/ml.  Carboplatin can be further 
diluted to concentrations as low as 0.5 mg/ml with 5% Dextrose in Water or 0.9% Sodium Chloride 
Injection, USP (NS). 
 

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8.1.7 
Supplier 
Carboplatin is commercially available. 
 
8.2 
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. 
 
8.2.1 
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 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 ABRAXANE (21).  
 
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 tumors (11).  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 125 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 population (12).  

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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 
cancer (14), 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 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.   
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 break (15).  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 

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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. 
 
Human Toxicity: 
Please refer to the Clinical Investigator’s Brochure for details of the Adverse Reactions in the overall 
Safety Database for Abraxane® (21). The following have been observed: 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. 
 
8.2.2 
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.  
 
8.2.3 
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.  

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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.  
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. 
 
8.2.4 
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. 
 
8.2.5 
Dose and Administration 
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 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) 
Actual body weight will be used for dosing calculation; 
Patients with body weight ≥ 1.2 x ideal body weight, maximum 1.2 x 
bodyweight will be used for dose calculation. 
 
3. Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 
 
 
 
 
100 (mg/vial) 
Round up the number of vials to be reconstituted to the next higher whole 
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(eg, if the total number of vials = 4.05 or 4.5, then 5 vials would be 
reconstituted). 
4. Using sterile technique, prepare the vials for reconstitution. 
5. Swab the rubber stoppers with alcohol. 
6. Reconstitute each Abraxane® vial by using a sterile syringe to inject 20 mL 
of 0.9% Sodium Chloride Injection, USP or equivalent into each vial over a 
period of not less than 1 minute (Note:  Change the syringes after 
reconstituting every 3 vials). 
• 
Slowly inject the 20mL of 0.9% Sodium Chloride Injection, USP,, using 
the sterile syringe directing the solution flow onto the inside wall of the 
vial. 
• 
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP solution 
directly onto the lyophilized cake as this will result in foaming. 
• 
Once the injection is complete, allow the vial to sit for a minimum of 5 
minutes to ensure proper wetting of the lyophilized cake/power. 
• 
Gently swirl and/or invert the vial slowly for at 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 minutes 
until foam subsides. 
• 
Each mL of reconstituted product will contain 5 mg of paclitaxel. 
7. Calculate the exact total dosing volume (to the nearest mL) of 5 mg/mL 
suspension required for the patient: 
Dosing volume (mL) = Total dose (mg)/5 (mg/mL) 
8. The reconstituted sample should be milky and homogeneous without visible 
particulates. If unsuspended powder is visible, the vial should be gently 
inverted again to ensure complete resuspension, prior to use. 
9. Once the exact volume of reconstituted Abraxane® has been withdrawn from 
the vials, discard any excess solution left over in accordance with standard 
operating procedures. 
10. Inject the calculated dosing volume of reconstituted Abraxane® suspension 
into an empty sterile, standard PVC IV bag using an injection port.  Inject 
perpendicularly into the center of the injection port to avoid dislodging 
plastic material into the IV bag.  Repeat steps 10 and 11 until the patient’s 
entire required dose is injected into the IV bag. 
11. Administer the calculated dosing volume of reconstituted Abraxane® 
suspension by IV infusion over 30 minutes.  The use of in-line filters is not 
necessary.  If used, in-line filters with pore sizes of <15μ should not be used. 

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8.2.6 
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 
Abraxis Medical Operations. 
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. 
 
9.0 Correlative/Special Studies 
Tissue and body fluid samples will be collected under this IRB approved clinical protocol in accordance 
with the IRB-approved HIPPA compliant and signed consent form. 

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9.1 
Tissue Specimen Processing and Designation 
9.1.1 
Fresh core and other tissue specimens  
Biopsies and lumpectomy/mastectomy specimens and, if feasible, lymph nodes will be fresh 
frozen according to standard procedure by the Department of Anatomic Pathology under Drs. 
Schmolze and P. Chu and in conjunction with the Translational Research Core and Anatomic 
Pathology Core, under the direction of Drs. Wu, Lee and Chen.  Core biopsies (estimated 6-12 
specimens from biopsy), and larger tissue samples from biopsy or resections of subsequent post-
chemotherapy specimens will be stored fresh frozen. In case of abundance, some specimens will also 
be embedded. H&E and immunohistochemical analysis will be carried out by or under the direction of 
Drs. Schmolze and P. Chu. 
Additional specimens (as feasible) will be processed fresh frozen, or RNA later and will be evaluated 
and explored for molecular characteristics in collaboration with internal (Dr. Hua Yu, Peter Lee, 
Shiuan Chen and laboratories, and external collaborators (TGEN-Dr. Jeff Trent; Jackson Laboratory:  
F. Mengi and Ed Liu), E. Wang (UC San Diego).  Fresh samples as feasible from pre-treatment and 
post-neoadjuvant surgical specimens will be processed for generating cell lines, xenografts under 
collaborative agreements or on house (Jun Wu, and above listed collaborators.) An attempt will be 
made to obtain core biopsy specimens halfway through the neoadjuvant chemotherapy course, but this 
biopsy will be optional and patients may elect to opt out.  
All specimens will be logged in and out using a master logbook, and stored according to standards 
developed by the Department of Anatomic Pathology and in conjunction with the Translational 
Research Core.  A unique patient identifier (specific for this study) will be assigned to each patient and 
subclassification. 
 
9.1.2. 
Fixed sample collections 
Core biopsies of primary tumors (an estimated 4-6 [as feasible] specimens from biopsy) and larger 
tissue samples from biopsy or resections of subsequent post-chemotherapy specimens will be 
procured in the following preservatives:  
• 
2-3  (or more if feasible) specimens in formalin for Anatomic Pathology 
• 
2-3 specimens in RNAlater to be sent to the translational research lab for further 
distribution 
Core and other biopsy specimens will be preserved according to standard procedure by the 
Department of Anatomic Pathology and the Translational Research Core.  Tissue collected in 
RNAlater (RNAlater is stored at room temperature) will be submerged in ten times the volume of 
the tissue and the will be less than 0.5 cm in at least one dimension.  The tissue will be submerged 
immediately after it is extracted from the patient and the vial kept upright so the tissue stays 
submerged in transit. Vials will be delivered to the translational research laboratory for further 
distribution to other collaborators listed on the face page of the protocol, as appropriate, pending 
availability of funding to perform the appropriate studies.  
 
9.1.3. 
RT-PCR and DNA microarray analysis 
Gene expression analysis, pending sufficient quantity of fresh frozen tissue specimens (9.1.1), will 
also be carried out in collaboration with Agendia Corporation under a City of Hope-approved 
material transfer agreement (MTA).  This goal is in line with the original objectives and goal of 
this study.  The statistical analysis will be carried out as a collaboration between the study 

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statistician, Paul Frankel, PhD, and the designated bioinformatics personnel (to be named) at 
Agendia, at the NCI of the Netherlands. 
MiRNA and DNA assessment will be carried out through the Sequencing Core and Translational 
Research Core and in collaboration with Xiwei Wu Ph.D, Emily Wang PhD, at UC San Diego. To 
assess RT-PCR and protein expression, and immunohistochemistry (from formalin-fixed material, 
9.1.2) as feasible  in addition to work performed by Dr. Daniel Schmolze, MD (City of Hope 
Anatomic Pathology).  Potential collaborations include Agendia (MTA in place), TGEN, Jackson 
Laboratory, NantOmics (all with MTAs in place).(21)  Standard operating procedures according to 
the City of Hope standards are in place to keep samples de-identified for the outside investigators. 
 
9.1.4. 
Clarke Lab Protocol for breast tumor dissociation & implantation for xenografts 
Xenographs will be generated in the Clarke laboratory at Stanford University (22), as well as on 
campus in collaboration with Jun Wu, PhD. 
Specimens (either mastectomy or large segmentectomy) will be removed in OR using sterile 
instruments and sent for inking by pathologist. Tissue sections are cut with sterile instruments and 
placed into 50-ml conical tubes containing RPMI/10% HICS/Ceftazidime/PSA on wet ice. Samples 
are kept at 4oC and shipped same day to Jun Wu on campus, or using overnight shipping to: 
Dalong Qian 
Stanford University 
Institute for Stem Cell and Regenerative Medicine 
1050 Arastradero Road 
Palo Alto, CA 94304 
Lab phone: (650) 724-0574 
Cell: (734) 330-3585 
Total time on ice will therefore be less than 24 hours. 
 
Keep cells on ice or at 4°C for entire protocol 
1) 
Make sure to clean and autoclave all surgical instruments before processing 
tissue. We commonly employ the following equipment: razor blades or scalpels, 
tissue forceps, surgical scissors. Tools may be cleaned during the dissection by 
rinsing with 10% bleach followed by 70% EtOH.  
2) 
Put 5ml of Medium 199/H2CO3/Earl’s/25mM HEPES/pH 7.3 supplemented with 
PSA into 10mm or 15mm plastic petri dish (cells will not adhere as much as with 
tissue culture dishes).  Transfer tumor piece(s) to petri dish with tissue forceps. 
We routinely perform two separate procedures for human tumors: xenotransplantation and flow 
cytometry. This protocol will mainly deal with processing the tumor tissue for flow cytometry. 
3) 
Xenotransplantation: Using “L”-shaped forceps, cut 1-2mm cubes.  Transfer all 
pieces to a sterile eppendorf tube containing medium and keep on ice. Generally, we 
implant 2 pieces per mouse at different sites. We use a trocar to deliver the tissue into 
the upper fat pads of NOD/SCID mice. We also place an estrogen pellet into the back 
of the mouse if dealing with an ER+ breast tumor. All tumor chunks are coated with 
matrigel before engraftment. 

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The following is based on our procedures for processing human breast tumors. Other tumor 
types may require alternate dissociation enzymes, digestion times, etc. 
4) 
If leaving tissue overnight: Put entire piece in RPMI w/ 10% HICS and 
ceftazidime and Pen/Strep/Ampho and leave on ice O/N.  In the morning, wash 1x 
with cold PBS, then proceed as follows. 
5) 
Make single cell suspension:  If specimen contains a significant amount of 
adipose tissue, trim this first.  Then cut tissue into slivers by holding with forceps and 
sliding prongs around razor blade.  Next mince using slicing motion.  Once 
adequately disaggregated, bring total volume to 27 ml with media and add 3 ml of 
2000 unit/ml collagenase type 3 (10x) [Can adjust total vol based on size of 
specimen].  Add DNase to the digestion (5 Kunitz units/ml). Scrape cells off bottom 
of plate with razor blade before placing into incubator (37°C, 5% CO2) and 
mechanically dissociate by pipetting every 20 minutes.  Incubate for 2-4 hours, or 
until tissue is disaggregated.  Often we need to spike the digestion with an additional 
1.5 ml Collagenase Type III at ~1.5 hrs to achieve complete dissociation.  
6) 
Neutralizing: Add 10 mls of neutralizing media (RPMI 1640/10% HICS/PSA) 
per 20 mls of digestion media.  Mix by pipetting. 
7) 
Filtering: First pipette media over nylon mesh held over 50ml conical.  May 
need to change nylon mesh several times due to clogs.  Next pipette through 70 µm 
filter into a fresh 50ml conical.  Tilt filter slightly to increase flow speed if it slows 
down.  Finally, pipette through 40 µm filter into a fresh 50ml conical.  Pellet cells for 
5 min at 1000 RPM at 4°C. 
8) 
RBC lysis: Resuspend pellet in 5 ml of ACK buffer and incubate on ice for 2 
minutes.  Bring up volume to 50 ml with HBSS w/ 2% HICS to stop lysis.  Pellet 
cells for 5 min at 1000 RPM at 4°C. 
Optional: can repeat 40 µm filtering to remove debris from RBC lysis if 
desired. 
9) 
Count cells: Bring up cells in an appropriate volume of HBSS w/ 2% HICS.  
Cells are now ready for staining. 
Optional: Freezing Tumor Samples 
1) 
Resuspend cells in 10% DMSO/80% DMEM/10%FBS at a concentration of 13 
million cells/ml in cyrovials. 
2) 
Place in freezing chamber O/N in –80C. 
3) 
Transfer to liquid nitrogen for long term storage. 
Once City of Hope capabilities allow, cell line development and stem cell line identification 
will be carried out in the laboratories of Drs.   Xiwei Wu, Peter Lee, Shiuan Chen, and other 
COH collaborators as feasible.  Xenografts as feasible will also be generated – using the above 
technique or modifications as necessary), in the core at COH, by Jun Wu, or by the Lee, or 
Chen Laboratories. 
 
9.1.5 Non-coding RNA-based prognostic biomarkers in TNBC 
Long noncoding RNA (lncRNA) are cellular RNAs larger than 200 nucleotides in length that are 
overexpressed in various cancers, including breast cancer. Non-coding RNAs regulate cellular processes 
by transcriptional and epigenetic regulations, post-translational modification, signaling pathway, and 
intercellular communication via exosomes. In this study, lncRNA analysis will be carried out to identify 
biomarkers using available RNA-sequencing databases with associated outcomes of interest. Integrative 
RNA-seq analysis will be used to identify 1) differentially expressed lncRNA and 2) presence of lncRNA 

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mutations in the following comparison groups: good vs poor prognosis; pathologic complete response vs. 
minimal response following neoadjuvant therapy; primary vs. metastatic tumors; low vs. high tumor 
infiltrating lymphocytes (starting with 30% cut-off); and BRCA vs. non-BRCA patients. Future work will 
include whole transcriptomic RNA-seq data from neoadjuvant responders vs. non-responders, and 
orthogonal validation of bioinformatic findings by in situ hybridization to analyze key lncRNAs, in a 
separate validation cohort. 
 
9.2. Blood Specimen Processing and Designation 
1.2.1 
Blood Samples 
All blood specimens will be drawn using the following vacutainer tubes: 
Tubes #1-3   – Three 7 ml EDTA (purple-top) tube 
Tube #4        – One 7 ml Paxgene tube 
Tubes #5-6   – Two - 10ml tubes containing EDTA anticoagulant and Cytochex 
preservative 
Timing: 
Pre-chemotherapy:  
 
 
Tubes #: 1-6 
Mid-chemotherapy: 
 
 
Tubes #: 1-6 
Prior to definitive surgery: 
 
Tubes #: 1-6 
Every 6 months x 5 years: 
Tubes #: 1-6 
 
9.2.2. 
Specimen Handling: 
All EDTA tubes (purple top) will be kept on ice.  After centrifugation at 1100 rpm for 10 minutes 
at 4 degrees Celsius, the plasma will be transferred to Eppendorf tubes and centrifuged at 14000 
rpm for 10 minutes at 4 degrees Celsius to separate the WBC fraction.  The plasma will be divided 
into 500 microliter aliquots and stored at –80 degrees Celsius.  The WBC will be washed with a red 
cell lysis buffer, pelleted and stored at –80 degrees Celsius. 
The EDTA tubes will be delivered to the translational research core lab within 1 hour of 
procurement and centrifuged to separate the buffy coat and plasma fractions.  
Tube #4 is a PAXgene tube for stabilization of whole blood and subsequent isolation of cellular 
RNA.  After incubation for 2 hours at ambient temperature, the tube will be stored in a loose wire 
rack at –20 degrees Celsius for up to one year.  The RNA will be extracted following the protocol in 
the PAXgene Blood RNA Kit sold by QIAGEN.  The RNA will be analyzed by real-time PCR or 
micro array.  This tube will be procured for RNA extraction from PMN cells in Dr. Yen’s 
laboratory. 
Tubes # 5-6 will be procured and shipped to the Yen lab, or other collaborator’s laboratory, in 
order to quantitate, isolate, and characterize circulating tumor cells. 
After venipuncture, the initial 1/2 cc of blood will be discarded (or drawn into any pediatric tube, 
which is then discarded) so as not to contaminate the subsequent blood sample with skin epithelial 
cells.   
To test for the presence of tumor-like cells, the blood will be labeled with fluorescent molecules 
marking for Cytokeratin (CK), CD-45 and DAPI antibodies with subsequent processing for 
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Tubes # 1-3: Blood will be collected in the 10ml tubes containing EDTA anticoagulant and 
Cytochex preservative,The blood samples will be split between the involved research laboratories  
(Dr. Wang and others at  COH).  
 
9.2.3. 
Specimen Tracking: 
The date of blood draw will be recorded.  For tracking purposes, the following will also be 
recorded upon receipt to the processing and receiving laboratories: 
 
a. Specimen ID number (all specimens will be anonymized by assigning a unique 
identifier, similarly to the process described under “Tissue specimen handling”, with 
coding provided by Biostatistics. 
b. Number and types of tubes received and date of receipt. 
c. Number of aliquots of plasma and serum (5-6 aliquots per tube expected), freezer 
location(s) stored, and date(s) of initial storage. 
Liquid nitrogen tank location of stored PBMC and date of initial storage will be tracked. 
Upon transfer of specimens to any designated labs, tracking will include: 
a. Specimen ID number 
b. Lab to which specimen was sent 
c. Date of transfer 
Upon return of data from the designated labs, the following will be recorded: 
a. Specimen ID number 
b. Date of run and run number (all specimens will be run in replicate for at least two runs 
in order to evaluate intra-and inter-assay reliability) 
c. Type of assay 
d. Lab performing assay 
e. Assay results 
 
10. 
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 28 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 
 
Wk  
4 
Cycle 
2 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
 
Wk  
4 
 
Mid-
Tx  
Cycle 
3 
Wk 
1 
 
Wk 
2 
 
Wk 
3 
 
Wk 
4 
Cycle 4 
= same 
as Cycles 
1 & 2 
Defi-
nitive 
Surgery 
Visit 
Follow-
upe 
carboplatin 
 
 
Day 
(D) 1 
 
 
 
D 1 
 
 
 
 
D 1 
 
 
 
 
 
 
nab-paclitaxel 
 
 
D 1 
D 8 
D 15 
D 22 
D 1 
D 8 
D 15 
D 22 
 
D 1 
D 8 
D 15 
D 22 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
 
 
   X-----------------------------------------------------------------------------------------------------------------X              
 
 
Physical exam, Height, 
weight 
X 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Vital signs 
X 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Performance Status 
X 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
CBC w/diff, plts 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
Serum chemistrya 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
 
   X------------------------------------------------------------------------------------------------------------------X  
X 
 
Tumor measurements as 
applicable (clinical) 
X 
 
 
Tumor assessments (clinical) are repeated every 4 weeks.  Documentation (radiologic or clinical) must be 
provided for patients removed from study for progressive disease. 
X 
 
Radiologic evaluation 
X 
 
 
Radiological assessment will be carried out at the conclusion of 16 weeks of therapy, as applicable  
(Mammogram, US, MRI, as deemed appropriate by the treatment team). 
X 
Xh 
MUGA/ECHO 
X 
 
 
 
 
 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlatives - Tissue: 
Core Biopsies/Tumor 
Specimens 
 
Xc 
 
 
 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
Xc 
 
 
 
Correlatives - Blood d: 
 
 
X  
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
X 
X  
a:Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT],   sodium. 
b:Serum pregnancy test (women of childbearing potential).  
c: Procurement of pretreatment tumor, core biopsies, and (if feasible) lymph node sample pre-treatment ; the mid-treatment (prior to cycle 3) procurement is optional. See Section 9.1 for complete Tissue instruction 
regarding preparation/submission 
d: Procurement of blood specimens; to occur prior to treatment on Cycle 1, 3, and  Day of  Definitive Surgery, prior to surgery., and each follow up visit. Please see Section 9.2 for complete blood instruction regarding 
preparation/submission 

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e: Follow up to be done every 6 months x5 years or till disease progression. After 5 years, follow up should be as per standard of clinical practice. 
f:Requested as per Standard of Care 

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11. 
Evaluation Criteria/Measurement of Effect 
11.1. 
Response Criteria  
The study endpoint is pathological complete response (pCR), and this will be assessed after 
completion of study therapy, based on assessment of the surgical specimen, by Dr. Sean Lau, non-
treating pathologist/collaborating investigator. Dr. Lau will also assess response scored for residual 
cancer burden (RCB) by applying the Symmans criteria (3). 
12. 
Data Reporting/Protocol Deviations 
12.1. 
Data Reporting 
12.1.2. 
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, and the sponsor City of Hope under the guidelines established by the Federal Privacy Act and 
rules for the protection of human subjects. 
12.1.3. 
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 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 
the sponsor, City of Hope, will be fulfilled. 
12.1.4. 
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.   
12.1.4.1. 
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. 
12.1.4.2. 
Prior Therapy and On-Study Data 
Within a week of registration, the clinical research associate will submit on-study checklist 
form. 
12.1.4.3    Treatment Data 
Within four (4) weeks of completion of each course the following data should be recorded in the 
EDC: 
 
12.1.4.3.1 Treatment and Adverse Events 
 
12.1.4.3.2 Supplemental Data 

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12.1.4.3.3 Flow Sheets 
 
12.1.4.4 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. 
 12.1.4.5 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). 
 
12.2. 
Protocol Deviations 
12.2.2. 
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. 
12.2.3. 
Reporting of Unplanned Deviations 
All unplanned deviations will be reported to the COH DSMB who will forward to the IRB 
following review. 
12.2.4. 
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. 
 
13. 
Statistical Considerations 
13.1. 
Study Design/Endpoints 
13.1.1 Study Design 
This is a Phase II study of neoadjuvant therapy with carboplatin + nab-paclitaxel for triple 
negative locally advanced or inflammatory breast cancer.  
A two stage design followed by an expanded cohort is proposed based on detecting a promising 
pCR rate (using the MD Anderson criteria of lack of evidence of any residual invasive tumor in 
breast and/or regional lymph nodes) or a promising Symmans 0-1 pathological response. The 
design selected will meet our objectives and permits the early termination of the trial in the event 
that the therapy appears inferior to other neoadjuvant regimens.   

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13.2 
Sample Size/Accrual Rate 
13.2.1 Study Size (49 total in two-stage design, 20 in expanded cohort for  69 total study 
patients maximum) 
Study size for the two stage design is based on our therapeutic target of achieving with acceptable 
toxicity either a promising pCR rate or a promising Symmans 0-1 pathological response rate. To 
permit early termination for a discouraging result, we have employed a two-stage design. In the 
first stage, accrual will continue until 22 patients are enrolled, with second stage accrual to 45 
patients during the two-stage design evaluation. 
An expanded cohort of 20 patients (given the promising results in the first 45) will be added to the 
49 patients (see note below) to better evaluate the response rates in specific subsets: basal, 
androgen receptor positive, immunomodulatory subtype, mesenchymal/stem cell like.   This will 
result in a total of 69 total patients.  
Two-stage design considerations: 
Our institutional experience with two neoadjuvant regimens suggests a pCR rate in her2- patients 
of 11-14% (N=75), and in the basal subtype (N=20) of approximately 20%. Other investigators 
have observed higher pCR rates in triple negative patients, although with differing definitions of 
pCR. As a result, a true 20% pCR rate in triple negative patients treated with this regimen would 
be considered a disappointing result, not superior to current approaches to neoadjuvant 
chemotherapy. A true encouraging pCR rate (where we want a small probability of declaring it 
discouraging) is considered 38%.  
Similarly, we observed a Symmans 0-1 response rate of 27-28% in our institutional experience 
(75pts) in her2- patients, and a Symmans 0-1 response rate of 35% in the basal subtype (N=20).  
Due to the paucity of other data on the Symmans response rate in basal subtype, and our limited 
prior experience, we consider a 25% Symmans 0-1 response rate to be discouraging and a 45% 
Symmans response rate to be encouraging.  
Based on these considerations, we have chosen a design that simultaneously discriminates 
between pCR rate of 20% vs 38% and a Symmans response rate of 25% and 45%. 
In particular:  
If no more than four (4) Symmans 0-1 responses are observed and no more than three (3) pCRs 
are observed in the first 22 patients, the study will be terminated early and declared negative. If 
five (5) or more Symmans 0-1 responses or four (4) or more pCRs are observed in the first 22 
patients, an additional 23 patients will be accrued during the second stage of the study. If at least 
17 Symmans 0-1 responses (38%) or at least 14 pCRs are observed in the 45 patients (31%), this 
combination would be considered worthy of further testing in this setting. 
This design yields at least 87% power to detect a true Symmans response rate of at least 45%. It 
yields at least 86% power to detect a true pCR rate of at least 38%. It yields at least .91 probability 
of a negative result if the true pCR response rate is no more than 20% and the Symmans 0-1 
response rate is no more than 25%.  This last probability is calculated assuming that pCR rate and 
the Symmans 0-1 rate are uncorrelated. As they are positively correlated, the probability will be 
higher (type I error less than 9%).  
Note: the initial 45 patients was based on eligible patients starting treatment, but as the response 
rate clearly exceeded the threshold for promising (20 of the first 38 had a pCR) accrual continued 
to 49 to achieve 45 who were treated per protocol for a more thorough evaluable as part of the 
two-stage design.  The added cohort of 20 patients will result in a total of 69 patients. 

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Accrual will be suspended at the end of the first stage pending the interim analysis decision, based 
on the response of the previously accrued patients.  
Expanded Cohort Considerations: 
Given the promising results at 45 evaluable patients (49 total), the expanded cohort  of 20 patients 
will result in a total of 69 patients (~65 evaluable).  This will allow a better exploratory analysis of 
the response rate based on phenotypic and gene array profiling subsets: Approximately 40% are 
expected to be of the basal subtypes (~27 patients), androgen subtype 11% (~7 patients expected), 
tumor 
infiltrating 
lymphocyte/immunomodulatory 
subtype 
25% 
(~17 
patients), 
and 
mesenchymal/mesenchymal/stem cell like ~25% (~17 patients).  With 69 patients, there is a 89% 
chance of having 5 or more patients in even the smallest subset, and as a result, we should observe 
a pCR in all subsets (e.g. 97% chance of observing at least one pCR with 5 patients if the true pCR 
response rate is 50%).  Dramatic reduction/lack of pCR in any subset will help guide future 
development of subset specific treatment additions to the backbone of nab-paclitaxel and 
carboplatin.  For the more common subsets, such as the basal subtype, the 95% CI for the pCR can 
be estimated with a half-width of at most 12% assuming 27 patients in that group.  The confidence 
interval will be larger or smaller depending on the exact number of patients in that group enrolled, 
and these estimates will be made for the pCR rate for all patients who initiated treatment and are 
eligible, along with all patients who were treated per protocol. Symmans response rate will also be 
evaluated similarly. 
Toxicity:  
Previous experience with carboplatin/paclitaxel suggests this is a well-tolerated regimen, 
and prior experience also suggests that carboplatin/nab-paclitaxel should be better 
tolerated. However, toxicity will be monitored and reported to the COH/DSMB every 6 
months as specified in section 7. 
 
13.2.2  Accrual Rate 
Estimated monthly accrual rate is 1-3 patients per month. With a maximum target accrual of 69 
patients, we expect accrual to be completed in approximately 54 months.   
 
13.3 
Stratification Factors 
NA 
 
13.4 
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.  Subset specific analysis is also a secondary endpoint as 
discussed above.  Additionally:  
13.4.1 Overall Survival 
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.  

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13.4.2 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.  
 
13.5 
Reporting and Exclusions 
13.5.1 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with carboplatin + 
nab-paclitaxel. 
13.5.2 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.  Each patient will be assigned a 
Symmans score, and Yes/No on pCR. 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, refused surgery, 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 (inevaluable patients, e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the main basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly reported. 
14. 
Human Subject Issues 
14.1. 
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. 
 
14.2. 
Recruitment of Subjects 
Participants for this study will be recruited from among patients undergoing treatment at City of Hope 
Cancer Center for stage II/III –including inflammatory - breast adenocarcinoma. 
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.  

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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. 
 
14.3. 
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. 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.  Carboplatin, 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.   
   
14.4. 
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 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.   
 

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