A Randomized Phase II Study Evaluating Different Schedules of Nab-Paclitaxel in Metastatic Breast Cancer (SNAP Trial)
Phase: PHASE2
Conditions: Metastatic Breastcancer
Sponsor: ETOP IBCSG Partners Foundation

IBCSG 42-12/BIG 2-12 Schedules of nab-Paclitaxel (SNAP) 
Amendment 2 v3.0 06Jan15 
 
Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
 
 
 
 
A randomized phase II study evaluating different schedules 
of nab-Paclitaxel in metastatic breast cancer 
 
 
Amendment 2 
 
EudraCT Number:  
2012-003058-10 
NCT Number:  
NCT01746225 
 
Coordinating Group and Sponsor: International Breast Cancer Study Group 
(IBCSG) 
 
IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 389 93 91 
Fax: +41 31 389 93 92 
 
 
 
 
 
 
 
 
 
 
 
 
INTERNATIONAL BREAST CANCER 
STUDY GROUP 
IBCSG 42-12/BIG 2-12 
SNAP 
Schedules of nab-Paclitaxel 
 
 
 
 
 

IBCSG 42-12/BIG 2-12 Schedules of nab-Paclitaxel (SNAP)  
2 
Amendment 2 v3.0 06Jan15 
 
                 
              Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
 
Trial Specific Contacts 
 
Study Chair 
Alessandra Gennari, MD 
Division of Medical Oncology 
E.O. Galliera 
Genoa, Italy 
Email: alessandra.gennari@galliera.it 
Tel: +39 0105634502 
Fax: +39 01057481321 
 
 
 
Study Co-Chair 
Guy Jerusalem MD, PhD 
CHU Sart Tilman and University of 
Liège 
Liège, Belgium 
Email: g.jerusalem@chu.ulg.ac.be 
Tel: +32 43667801 
 
(or +32 43667664) 
Fax: +32 43667448  
 
 
 
IBCSG Statistical Center 
Trial Statistician 
Zhuoxin Sun, PhD 
 
Email: zhuoxin@jimmy.harvard.edu 
Tel: +1 617-632-2458 
Fax: +1 617-632-2444 
 
 
 
IBCSG Data Management Center  
Trial Data Managers 
 
 
 
Lead Trial Coordinator 
Trial Coordinator 
Theresa Zielinski 
Jocelyn Swick-Jemison 
Sandra Lippert 
 
 
Holly Shaw 
Colleen King 
Email: ibcsg42_SNAP@fstrf.org 
Tel : +1 716-898-7500 (general) 
Fax : +1 716-836-6097 
Tel : +1 716-898-7384  
Tel : +1 716-898-7254 
Tel : +1 716-898-7355  
Tel: +1-716-898-7227 
 
 
 
IBCSG Central Pathology Office 
Rosita Kammler 
Stefania Andrighetto/Elvira Benini        
 
pathology.ibcsg@ieo.it 
Tel : +39 0257 489 928 
 
 
 
IBCSG Quality of Life Office 
Karin Ribi, PhD 
Jürg Bernhard, PhD 
Email: karin.ribi@ibcsg.org 
juerg.bernhard@ibcsg.org 
Tel: + 41 31 389 93 88 
Fax: +41 31 389 92 39 
 
 
 
 
 
 

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             Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
IBCSG Contacts 
 
Coordinating Center 
 
 
Anita Hiltbrunner 
Dr. Barbara Ruepp 
Dr. Manuela Rabaglio 
Dr. Rudolf Maibach 
Linda Fritzsche/Sabrina Ribeli 
Rosita Kammler 
IBCSG Coordinating Center 
Effingerstrasse 40 
CH-3008  Bern, Switzerland 
Email: anita.hiltbrunner@ibcsg.org  
Email: regulatoryoffice@ibcsg.org   
Email: medical.affairs@ibcsg.org  
Email: rudolf.maibach@ibcsg.org  
Email: drugsupply@ibcsg.org 
Email: rosita.kammler@ibscg.org 
 
Tel: +41 31 389 9391 
Fax: +41 31 389 9392 
 
 
 
Data Management Center 
Lynette Blacher 
Tara Scolese 
Karolyn Scott 
FSTRF 
4033 Maple Rd.  
Amherst, NY  14226  USA 
Email: blacher.lynette@fstrf.org 
Email: scolese.tara@fstrf.org 
Email: scott.karolyn@fstrf.org 
Tel: +1 716 834 0900 
Fax: +1 716 836 6097 
 
 
 
Statistical Center 
Prof. Richard D. Gelber 
Dr. Meredith M. Regan 
Dept. of Biostatistics and 
Computational Biology 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215  USA 
Email: gelber@jimmy.harvard.edu 
Email: mregan@jimmy.harvard.edu 
Tel: +1 617-632-3012 
Fax: +1 617-632-2444 
 
 
 
 
 
 
Central Pathology Office 
Prof. Giuseppe Viale 
University of Milan & European 
Institute of Oncology 
Via Ripamonti 435 
20141 Milan, Italy 
Tel: +39 02 5748 9419 
Fax: +39 02 5748 9417 
E-mail: giuseppe.viale@ieo.it 
pathology.ibcsg@ieo.it 
 
 
 
 
Scientific Committee Chairs 
Prof. Aron Goldhirsch 
European Institute of Oncology 
Milan, Italy 
Ospedale ltaliano 
Lugano-Viganello, Switzerland 
 
Tel: +39-02-57489439 
Fax: +39-02-94379273 
Email: aron.goldhirsch@ibcsg.org 
 
Prof. Alan Coates 
NSW  
Australia 
 
Tel: +61 2 9331 3521 
Fax: +61 2 9380 8233 
Email: alan.coates@ibcsg.org 
 
Dr. Marco Colleoni  
European Institute of Oncology 
Milan, Italy 
Tel: +39 02 574 89 439 
Fax: +39 02 574 89 581 
Email: marco.colleoni@ieo.it 
 
 
 
Biological Protocols Working 
Group 
Prof. Barry Gusterson 
Emeritus Professor of Pathology 
University of Glasgow 
Tel: +44-1372720559  
E-mail: barry.gusterson@glasgow.ac.uk 
 

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Amendment 2 v3.0 06Jan15 
 
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Protocol Amendment 2 Signature Page 
 
IBCSG 42-12/BIG 2-12 
Schedules of nab-Paclitaxel - SNAP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Dr. Meredith M. Regan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Approved by: 
Director, International Breast Cancer Study Group 
Anita Hiltbrunner 
 
 
 

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5 
Amendment 2 v3.0 06Jan15 
 
             Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
Protocol Amendment 1 Signature Page 
 
IBCSG 42-12/BIG 2-12 
Schedules of nab-Paclitaxel - SNAP 
 
 
 
 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Dr. Meredith M. Regan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Approved by: 
Director, International Breast Cancer Study Group 
Anita Hiltbrunner 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 

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6 
Amendment 2 v3.0 06Jan15 
 
             Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
Protocol Signature Page 
 
IBCSG 42-12/BIG 2-12 
Schedules of nab-Paclitaxel - SNAP 
 
 
 
 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Dr. Meredith M. Regan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Approved by: 
Director, International Breast Cancer Study Group 
Anita Hiltbrunner 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 

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Amendment 2 v3.0 06Jan15 
 
             Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
Principal Investigator Protocol Amendment 2 Signature Page 
 
IBCSG 42-12/BIG 2-12 
Schedules of nab-Paclitaxel - SNAP 
 
I have read the amended protocol and agree that it contains all necessary details for 
conducting this study. I will conduct the study as outlined in the following protocol and in 
compliance with GCP. I will provide copies of the amended protocol and all drug 
information relating to pre-clinical and prior clinical experience furnished to me by IBCSG, 
to all physicians responsible to me who participate in this study. I will discuss this 
material with them to assure that they are fully informed regarding the drug and the 
conduct of the study. I agree to keep records on all patient information, drug shipment and 
return forms, and all other information collected during the study for a minimum period of 
15 years. 
 
Name of Principal Investigator:  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
 

IBCSG 42-12/BIG 2-12 Schedules of nab-Paclitaxel (SNAP)  
8 
Amendment 2 v3.0 06Jan15 
 
             Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
Principal Investigator Protocol Amendment 1 Signature Page 
 
IBCSG 42-12/BIG 2-12 
Schedules of nab-Paclitaxel - SNAP 
 
I have read the amended protocol and agree that it contains all necessary details for 
conducting this study. I will conduct the study as outlined in the following protocol and in 
compliance with GCP. I will provide copies of the amended protocol and all drug 
information relating to pre-clinical and prior clinical experience furnished to me by IBCSG, 
to all physicians responsible to me who participate in this study. I will discuss this 
material with them to assure that they are fully informed regarding the drug and the 
conduct of the study. I agree to keep records on all patient information, drug shipment and 
return forms, and all other information collected during the study for a minimum period of 
15 years. 
 
Name of Principal Investigator:  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 

IBCSG 42-12/BIG 2-12 Schedules of nab-Paclitaxel (SNAP)  
9 
Amendment 2 v3.0 06Jan15 
 
             Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
Principal Investigator Protocol Signature Page 
 
IBCSG 42-12/BIG 2-12 
Schedules of nab-Paclitaxel - SNAP 
 
I have read the protocol and agree that it contains all necessary details for conducting this 
study. I will conduct the study as outlined in the following protocol and in compliance with 
GCP. I will provide copies of the protocol and all drug information relating to pre-clinical 
and prior clinical experience furnished to me by IBCSG, to all physicians responsible to me 
who participate in this study. I will discuss this material with them to assure that they 
are fully informed regarding the drug and the conduct of the study. I agree to keep records 
on all patient information, drug shipment and return forms, and all other information 
collected during the study for a minimum period of 15 years. 
 
Name of Principal Investigator:  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 

IBCSG 42-12/BIG 2-12 Schedules of nab-Paclitaxel (SNAP)  
10 
Amendment 2 v3.0 06Jan15 
 
             Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 
Schedules of nab-Paclitaxel - SNAP 
Protocol Summary and Schema 
A randomized phase II study evaluating different schedules of nab-Paclitaxel 
in metastatic breast cancer 
TITLE A randomized phase II study evaluating different schedules of nab-Paclitaxel in 
metastatic breast cancer (SNAP Trial) 
SPONSOR International Breast Cancer Study Group (IBCSG) 
PHARMA PARTNER Celgene 
POPULATION Patients with histologically or cytologically confirmed HER2-negative metastatic (stage IV) 
breast cancer who have not received chemotherapy for metastatic breast cancer. 
STUDY SCHEMA  
 Schedule of nab-Paclitaxel administration:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue treatment until progressive disease (PD) or unacceptable toxicity. 
RANDOMIZATION Patients will be randomized (using a 1:1:1 allocation) to one of three treatment arms.  
 
 
=150 mg/m2 
=75 mg/m2 
=100mg/m2 
=125 mg/m2 
Legend: 
R
A
N
D
O
M
I
Z
E 
nab-Paclitaxel  
125 mg/m2  
days 1,8,15 
3 cycles (28-day)  
nab-Paclitaxel 150 mg/m2 days 1, 15 
nab-Paclitaxel 100 mg/m2 days 1,8,15 
nab-Paclitaxel 75 mg/m2 days 1,8,15,22 
A
B
C
A
B
C

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RATIONALE Longer first line chemotherapy duration has recently been associated with a modest, but 
significant improvement in overall survival and a clinically meaningful and statistically 
significant improvement in progression-free survival, in metastatic breast cancer patients 
(1). Prolonging chemotherapy until disease progression, however, must be weighed 
against the detrimental effects of continuous chemotherapy delivery. The SNAP trial seeks 
to improve the tolerability of prolonged chemotherapy administration strategy by 
studying alternative treatment schedules, while preserving and possibly improving 
treatment efficacy in this disease setting.  
The availability of a new nanoparticle albumin-bound taxane, nab-Paclitaxel (Abraxane®), 
represents an opportunity to test this hypothesis. Nab-Paclitaxel has been developed in 
an attempt to reduce the toxicity associated with standard taxane administration (caused 
by the use of chemical solvents) while increasing antitumor efficacy. FDA and EMEA 
approval was based on a Phase III study (N=454) reporting that patients treated with nab-
Paclitaxel (260 mg/m2 every 3 weeks) achieved significantly higher response rates and 
longer PFS compared with standard 3-weekly paclitaxel (2). More recently, a randomized 
study in first-line metastatic breast cancer demonstrated superior efficacy and safety of 
nab-Paclitaxel 150 mg/m2 on a weekly schedule, compared with docetaxel 100 mg/m2 
every 21 days, with a statistically and clinically significant prolongation of PFS and OS. 
Toxicity increased, however, particularly in terms of neutropenia and neurotoxicity, and 
only 50% of the patients were able to receive the planned chemotherapy cycles. 
Conversely, the weekly 100 mg/m2 nab-Paclitaxel schedule showed a good tolerability 
profile with a moderate incidence of grade 3 peripheral neuropathy and, as evaluated by 
the independent reviewers, also significantly prolonged PFS (> 5 months) compared with 
docetaxel (3,4). 
The SNAP randomized phase II trial evaluates three schedules of nab-Paclitaxel as 
prolonged chemotherapy administration strategy. Each of three arms will be compared to 
a historical reference of seven-month median PFS based on the most recent trial with 
docetaxel as control arm (3) to determine whether any of the three arms are worthy of 
further investigation. 
In the original design of this phase II trial, patients will receive three cycles of nab-
Paclitaxel 150 mg/m2 days 1, 8, 15 every 28 days during induction phase. Following the 
first safety review of 48 treated patients, it was decided to modify the dose in the 
induction phase to 125 mg/m².  
QUALITY OF LIFE/ 
TRANSLATIONAL 
RESEARCH 
Quality-of-life assessments will be conducted to explore the change in QL over time until 
treatment discontinuation by LASA scales for physical well-being, mood, coping effort, 
overall treatment burden, appetite, tiredness, hair loss and feeling sick (nausea/vomiting). 
Sensory neuropathy will be assessed by the 4-item subscale of the FACT/GOG-Ntx. 
Translational research will investigate the prognostic role of putative markers SPARC and 
caveolin determined in FFPE tumor tissue. 
ELIGIBILITY Inclusion criteria 
 
Histologically or cytologically confirmed HER2-negative metastatic (stage IV) breast 
cancer. 
 
Measurable or non-measurable, but radiologically evaluable, disease according to 
RECIST 1.1 criteria.  

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 
Female aged 18 years or older. 
 
Life expectancy > 3 months. 
 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.  
 
Either ER-positive or ER-negative disease. Patients with ER-positive disease must be 
endocrine resistant, defined as having failed at least one prior endocrine therapy for 
breast cancer, or must be candidates for first-line chemotherapy. 
 
If previously treated with a taxane or anthracycline in the neoadjuvant or adjuvant 
setting, the period from end of treatment to disease recurrence must have been > 12 
months (> 365 days). 
 
Radiation therapy, if given and regardless of site, must be completed at least 2 weeks 
prior to randomization. 
 
Normal hematologic status. Must meet all criteria: absolute neutrophil count ≥ 
1500/mm3 (1.5 x 109/L), platelets ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL (≥ 90 g/L)). 
 
Normal renal function (serum creatinine ≤ 1.5 ULN or calculated creatinine clearance 
≥ 50mL/min according to the Cockcroft and Gault formula). 
 
Normal liver function. Must meet all criteria: ALT (SGPT) and AST (SGOT) ≤ 3 × upper 
limit of normal (ULN) (without liver metastases; total bilirubin ≤ 1.5 mg/dL;. 
Exceptions: If the patient has liver metastases, ALT (SGPT) and AST (SGOT) must be ≤ 
5 × ULN; total bilirubin ≤ 1.5 mg/dL. If the patient has Gilbert’s disease higher 
bilirubin is acceptable (≤ 3 mg/dL) 
 
Normal cardiac function defined as left ventricular ejection fraction within the 
institutional range of normal as measured by MUGA or echocardiogram. 
 
Women of child bearing potential must have documented negative pregnancy test 
within 2 weeks prior to randomization and agree to acceptable birth control during 
the duration of the trial therapy and for a period of 6 months following the last 
administration of study drug. If for any reason the administration of first dose of trial 
treatment is not within 2 weeks of the pregnancy test, a second pregnancy test 
should be performed within two weeks of day 1 of cycle 1. 
 
Written Informed Consent (IC) must be signed and dated by the patient and the 
Investigator prior to randomization.  
 
Completed baseline Quality of Life Form. 
 
The patient has been informed of and agrees to data transfer and handling, in 
accordance with national data protection guidelines. 
 
Availability of an FFPE block from the primary tumor (breast lesion) for submission to 
central pathology review and for translational research. 
 
Written consent to pathology material submission, indicating the patient has been 
informed of and agrees to tissue material use, transfer and handling, must be signed 
and dated by the patient and the Investigator prior to randomization. 
 
Exclusion criteria 
 
Any prior chemotherapy for metastatic breast cancer. 
 
Presence of CNS metastasis. 
 
Peripheral neuropathy grade 2 or higher (CTCAE version 4). 
 
Significant uncontrolled cardiac disease (i.e. unstable angina, recent myocardial 
infarction within prior 6 months), patients classified as having a New York Heart 
Association (NYHA) class III or IV congestive heart failure. 
 
Pregnant or lactating. 

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 
Prior history of non-breast malignancy (except for adequately controlled basal cell 
carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the 
bladder).  
 
Any concurrent condition which in the Investigator’s opinion makes it inappropriate 
for the patient to participate in the trial or which would jeopardize compliance with 
the protocol.  
 
Contraindications or known hypersensitivity to the study medication or excipients.  
 
The use of any anti-cancer investigational agents within 30 days prior to expected 
start of trial treatment.  
 
Inability or unwillingness to abide by the study protocol or cooperate fully with the 
Investigator.  
STUDY 
OBJECTIVES AND 
ENDPOINTS  
Primary objective 
To evaluate the efficacy of three different schedules of nab-Paclitaxel administration, as 
measured by progression-free survival (PFS), using the historical reference of PFS of 
docetaxel for first-line treatment of metastatic breast cancer.  
Secondary objectives 
 To evaluate: 
 Tolerability 
 Feasibility  
 Disease response according to RECIST criteria, including disease control rate  
 Overall survival 
 To explore the changes in quality of life (QL) over time until treatment discontinuation. 
 To investigate the prognostic role of putative markers (SPARC and caveolin) and assess 
any change in the expression of SPARC and caveolin between primary and the 
metastatic sites. 
Primary endpoint 
 Progression-free survival (PFS): time from randomization to documented progressive 
disease according to RECIST criteria or death, whichever occurs first. 
Secondary endpoints 
 Tolerability: adverse events according to CTCAE v4 
 Feasibility: completing treatment according to the protocol for at least 24 weeks 
 Disease control: overall response or stable disease (or non-CR/non-PD for patients 
with non-measurable disease) or better (i.e., partial or complete response) according 
to RECIST criteria for a duration of ≥24 weeks  
 Overall survival: time from randomization to death from any cause 
 QL: primary endpoint physical well-being 
 Prognostic markers: SPARC and caveolin expression 
STRATIFICATION Stratification will be performed according to: 
 ER Status (positive or negative) 
 Prior adjuvant taxanes (yes or no) 
 Measurable or non-measurable only disease according to RECIST criteria 
Dynamic institution balancing will be done in order to balance randomized assignments 
within institution. 
 
 

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STATISTICAL 
CONSIDERATIONS 
The primary efficacy endpoint of PFS will be evaluated among each of the three 
treatment arms separately, in three independent tests, and compared to the historic PFS 
of first-line docetaxel.  Assuming the median PFS of docetaxel is 7 months and the 
median PFS of a new regimen is 10 months, with 76 patients in an arm, and an accrual 
rate of 8 patients per month for an accrual period of 30 months plus an additional 16 to 
18 months of follow up to reach the target number of events, the study will have 88% 
power to detect an improvement in PFS in a new regimen relative to docetaxel, using a 
one-sample log-rank test at the one-sided significance level of 0.05. The target number of 
events per group is 63. Assuming a 12% drop out rate and those patients do not 
contribute events, the sample size is increased to 86 patients per arm. 
Randomized patients who received at least one dose of the trial treatment will be 
included in the PFS analysis.  For each arm separately, PFS distributions will be 
summarized using the method of Kaplan-Meier and the two-sided 90% confidence 
interval (CI) for the median PFS will be provided.  
The toxicities and feasibility of each of the three treatment arms will be assessed. OS, 
disease control rate and other measures of disease response will be evaluated for each 
treatment arm separately.  
The primary quality of life endpoint is physical well-being. The change in QL over time 
until treatment discontinuation for patients on each arm will be explored using repeated 
measures modeling.  
In translational research, on FFPE material from the primary tumor and metastatic sites 
separately, it will be evaluated whether SPARC and caveolin are prognostic markers for 
PFS in women with metastatic breast cancer using log-rank tests and Cox regression 
analysis. 
NUMBER OF 
PATIENTS 
258 patients will be enrolled.  
(Arm A: 86, Arm B: 86, Arm C: 86) 
STUDY 
DURATION 
Randomization of 258 patients during approximately 24 to 26 months, with an additional 
16 to 18 months of follow up after the last patient is entered, to reach the target number 
of events. 
REFERENCES 
FOR SYNOPSIS 
1. Gennari A, Stockler M, Puntoni M, et al. Duration of chemotherapy for metastatic breast 
cancer: A systematic review and meta-analysis of randomized clinical trials. J Clin Oncol 29: 
2144-2149, 2011.  
2. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound 
paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast 
cancer. J Clin Oncol 23: 7794-7803, 2005. 
3. Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly longer progression-free survival 
with nab-Paclitaxel compared with docetaxel as first-line therapy for metastatic breast 
cancer. J Clin Oncol 27:3611-3619, 2009. 
4. Gradishar WJ, Krasnojon D, Cheporov S, et al. Phase II Trial of Nab-Paclitaxel Compared With 
Docetaxel as First-Line Chemotherapy in Patients With Metastatic Breast Cancer: Final 
Analysis of Overall Survival. Clin Breast Cancer. 2012 Oct; 12(5):313-21. 
 

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Trial Schedule 
Within 14 
days prior 
to rando 
Induction Cycle 
1  
(28 days) 
Induction 
Cycle 2 
(28 days) 
Induction 
Cycle 3 
(28 days) 
Maintenance Cycles 4 
and up  
(to PD or stop tx) 
Within 30 
days after 
end of tx 
Follow 
up to PD 
Follow 
after PD 
Days during cycle 
 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
22 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Vital signs 1) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
MUGA or echocardiogram 
X14) 
 
 
 
X14) 
 
 
X14) 
 
 
X14) 
 
 
 
 X14) 
 
 
HER2 / ER / PgR status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B & C 
X 
C 
X 
 
 
Biochemistry 3) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Baseline symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X13) 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Pregnancy test 
X 
X4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility  criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QL self-assessment 5) 
X 7) 
X7) 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Tumor evaluation 6) 
X  
 ………every 12 weeks until progression ……… 
X 8) 
X 8) 
 
FFPE sample from primary tumor9) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FFPE sample metastatic biopsy 9) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nab-paclitaxel administration 10) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B & C 
X 
C 
 
 
 
Adverse events 11) 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 12) 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
B = required for arm B; C = required for arm C 
1) 
Blood pressure and pulse rate after 5 minutes in sitting position; body temp.; body weight; respiratory rate 
2) 
Hemoglobin, ANC, platelets 
3) 
ALT (SGPT), AST (SGOT), total bilirubin, serum creatinine or calculated creatinine clearance acc. Cockcroft and Gault 
4) 
Pregnancy test (in case of childbearing potential) to be repeated prior to cycle 1 if more than 14 days from pre-randomization test to date of first dose of cycle 1. 
5) 
Complete QL at baseline (after informed consent and prior to randomization) and on day 1 of the first 12 cycles, before any diagnostic or treatment intervention; or until treatment discontinuation, 
whichever occurs first. 
6) 
Tumor evaluation to be done according to RECIST 1.1 criteria every 12 weeks (see Section 10.4). For bone scans see note c) in “Notes for Sections 10.1.-10.4.” in section 10.4.  
7) 
May be within 28 days prior to randomization  If the baseline QL was completed within 14 days prior to treatment start, no QL form is required at day 1 of cycle one. 
8) 
If PD not documented, tumor evaluation must be repeated at end of treatment visit and every 12 weeks (+/- 2 weeks) until PD 
9) 
Availability of FFPE block from primary tumor is eligibility criterion;  in case of metastatic biopsy FFPE block to be submitted (see section 13.2) 
10) For dosing of nab-Paclitaxel, see section 7.1.3 
11) Adverse events must be reported for the cycle in which they occur 
12) Adverse events must be recorded during and up to 30 days after stop of treatment 
13) Concomitant medication eCRFs should be completed continuously as medications are started or re-started. 
14) Baseline MUGA/echo can be done up to 6 months prior to randomization if patient is clinically cardiac compensated with no heart symptoms. During and at end of treatment, repeat if clinically 
indicated. 

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TABLE OF CONTENTS 
 
1. 
Background and rationale ................................................................................... 19 
1.1. 
Disease background ............................................................................................. 19 
1.2. 
Nab-Paclitaxel ...................................................................................................... 19 
1.3. 
Nab-Paclitaxel clinical data .................................................................................. 21 
1.4. 
Trial rationale ....................................................................................................... 22 
2. 
Trial objectives .................................................................................................... 23 
2.1. 
Primary objective ................................................................................................. 23 
2.2. 
Primary endpoint ................................................................................................. 23 
2.3. 
Secondary objectives ........................................................................................... 23 
2.4. 
Secondary endpoints ........................................................................................... 24 
3. 
Trial design and duration .................................................................................... 24 
3.1. 
Trial schema ......................................................................................................... 24 
3.2. 
Trial duration ....................................................................................................... 24 
4. 
Patient selection: criteria for patient eligibility/ineligibility ............................... 25 
4.1. 
Inclusion criteria .................................................................................................. 25 
4.2. 
Exclusion criteria .................................................................................................. 26 
5. 
Randomization and Stratification ....................................................................... 26 
5.1. 
Randomization procedures ................................................................................. 27 
5.2. 
Randomization help desk .................................................................................... 27 
5.3. 
Randomization assignment ................................................................................. 27 
5.4. 
Stratification ........................................................................................................ 28 
6. 
Study drugs formulation and handling ............................................................... 28 
6.1. 
nab-Paclitaxel ...................................................................................................... 28 
6.2. 
Packaging and labeling ........................................................................................ 28 
6.3. 
Storage and Handling .......................................................................................... 29 
6.4. 
Receipt of the drug .............................................................................................. 29 
6.5. 
Unused study drug supplies ................................................................................ 29 
7. 
Treatments .......................................................................................................... 30 
7.1. 
Treatment schedules ........................................................................................... 30 
7.2. 
Dose modifications and delays for toxicity ......................................................... 31 
7.3. 
Duration of trial treatment .................................................................................. 32 
7.4. 
Removal from the trial......................................................................................... 33 
7.5. 
Concomitant medication ..................................................................................... 33 
8. 
Safety, adverse events and reporting ................................................................. 34 
8.1. 
Adverse effects of nab-Paclitaxel ........................................................................ 34 
8.2. 
Adverse event reporting ...................................................................................... 36 
8.3. 
Targeted adverse events ..................................................................................... 38 
8.4. 
Rare AEs to be reported ...................................................................................... 38 
8.5. 
Abnormal Laboratory Values ............................................................................... 38 
8.6. 
Serious adverse event (SAE) reporting ................................................................ 39 
8.7. 
Pregnancy ............................................................................................................ 41 
8.8. 
Safety review of nab-Paclitaxel ........................................................................... 41 
9. 
Disease assessment, response and progression (RECIST 1.1) ............................ 41 
9.1. 
Introduction ......................................................................................................... 41 
9.2. 
Methods of assessment ....................................................................................... 41 

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9.3. 
Measurability of tumor at baseline ..................................................................... 42 
9.4. 
Selection of target lesions ................................................................................... 43 
9.5. 
Selection of non-target lesions ............................................................................ 43 
9.6. 
Evaluation of target lesions (measurable disease) .............................................. 44 
9.7. 
Evaluation of non-target lesions (measurable or non-measurable disease) ...... 44 
9.8. 
Determination of new lesions ............................................................................. 45 
9.9. 
Additional considerations .................................................................................... 45 
9.10. 
Determination of time point response ................................................................ 45 
9.11. 
Determination of best overall response and response duration ........................ 46 
9.12. 
Progression-free survival ..................................................................................... 46 
10. 
Clinical and laboratory evaluations ..................................................................... 47 
10.1. 
Prior to randomization ........................................................................................ 47 
10.2. 
During induction nab-Paclitaxel .......................................................................... 47 
10.3. 
During maintenance nab-Paclitaxel..................................................................... 48 
10.4. 
After discontinuation of trial treatment .............................................................. 48 
10.5. 
Follow-up ............................................................................................................. 49 
11. 
Data submission .................................................................................................. 49 
11.1. 
Case report forms schedule ................................................................................. 50 
11.2. 
Signing and submitting forms .............................................................................. 51 
11.3. 
Data management ............................................................................................... 51 
11.4. 
Investigator’s file ................................................................................................. 51 
11.5. 
Authorization log ................................................................................................. 52 
11.6. 
Patient identification log ..................................................................................... 52 
12. 
Statistical considerations .................................................................................... 53 
12.1. 
Primary endpoint ................................................................................................. 53 
12.2. 
Secondary objectives ........................................................................................... 54 
12.3. 
Interim analyses ................................................................................................... 55 
12.4. 
Accrual ................................................................................................................. 56 
12.5. 
Data and Safety Monitoring Committee (DSMC) ................................................ 56 
13. 
Pathology and Translational Research ................................................................ 56 
13.1. 
Central pathology assessment............................................................................. 56 
13.2. 
Submitting biological material to IBCSG .............................................................. 57 
13.3. 
Banking biological material ................................................................................. 57 
13.4. 
Translational research ......................................................................................... 57 
14. 
Quality of Life ...................................................................................................... 59 
14.1. 
Introduction ......................................................................................................... 59 
14.2. 
Objectives ............................................................................................................ 59 
14.3. 
Patient selection .................................................................................................. 60 
14.4. 
QL design ............................................................................................................. 60 
14.5. 
QL assessment ..................................................................................................... 60 
14.6. 
Statistical considerations ..................................................................................... 60 
14.7. 
Timing requirements ........................................................................................... 61 
14.8. 
Data collection and local data management ....................................................... 62 
15. 
Ethical aspects, regulatory approval, and patient informed consent ................ 62 
15.1. 
Ethical Review Board/Ethics Committee ............................................................. 62 
15.2. 
Regulatory approval procedures ......................................................................... 63 
15.3. 
Protection of human subjects ............................................................................. 63 

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15.4. 
Informed consent ................................................................................................ 63 
15.5. 
Premature withdrawal ......................................................................................... 64 
16. 
Governance and Administrative Considerations ................................................ 64 
16.1. 
Insurance ............................................................................................................. 64 
16.2. 
Steering Committee ............................................................................................. 64 
16.3. 
Premature discontinuation of the trial ................................................................ 65 
16.4. 
Quality assurance and monitoring ...................................................................... 65 
16.5. 
Data protection .................................................................................................... 65 
16.6. 
Record retention .................................................................................................. 66 
16.7. 
Confidentiality ..................................................................................................... 66 
17. 
References........................................................................................................... 66 
18. 
List of abbreviations ............................................................................................ 70 
 
 
LIST OF TABLES 
Table 1 – Dose Levels for Induction Cycles 1 – 3 ........................................................................................ 31 
Table 2 – Induction Phase: Cycles 1-3 ......................................................................................................... 31 
Table 3 – Dose Levels for Maintenance Cycles >4 ...................................................................................... 32 
Table 4 – Maintenance Phase: Cycles ≥4 .................................................................................................... 32 
Table 5 – Measurable Disease - Overall Response ..................................................................................... 45 
Table 6 – Non-Measurable Disease - Overall Response ............................................................................. 46 
Table 7 – Evaluations Prior to Randomization.............................................................................................. 47 
Table 8 – Evaluations During Induction ........................................................................................................ 47 
Table 9 – Evaluations During Maintenance .................................................................................................. 48 
Table 10 – Evaluations After Discontinuation ............................................................................................... 48 
Table 11 – Confidence Intervals (CI) for AE Rates (%) ................................................................................ 54 
Table 12 – Detectable Hazard Ratio SPARC Analysis ................................................................................. 58 
Table 13 – Detectable Hazard Ratio Caveolin Analysis ............................................................................... 59 
Table 14 – Effect Sizes by Statistical Power ................................................................................................ 61 
 
 
APPENDICES  
 
I. Requirements for Informed Consent  
II. NCI Common Terminology Criteria for Adverse Events v4 [available from the internet 
at:  http://evs.nci.nih.gov/ftp1/CTCAE/About.html] 
 

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1. 
Background and rationale 
1.1. 
Disease background 
Metastatic breast cancer is an incurable disease, but can be successfully managed with 
appropriate treatment strategies (1,2,3,4). The aims of therapy in this setting include 
prolongation of survival with good quality of life and symptom palliation. Because of the 
chemosensitivity of this disease, the large majority of patients are, or eventually become, 
candidates for chemotherapy, either upfront in endocrine-insensitive or after failure of 
hormone therapy in endocrine-sensitive disease.  
Although the selection of chemotherapy is generally affected by patient and disease-
related factors, as well as patient/physician preferences, controversy remains about how 
long chemotherapy should be continued, and the number of administered cycles is 
generally based on patient responsiveness and individual tolerability as well as physician 
preferences.   
During the last three decades, a number of randomized clinical trials have addressed the 
value of maintenance first-line chemotherapy in metastatic breast cancer. These studies 
indicated that prolonged treatment results in a longer time to progression and improved 
quality of life, but failed to show a consistent benefit in terms of overall survival (OS) for 
patients who continued chemotherapy. However, some of these early studies were 
plagued by a number of limitations, such as insufficient sample size, limited chemotherapy 
duration in control arms, and/or drugs and schedules that, based on today standards, can 
be considered obsolete (5).  
A recently published systematic review including 11 randomized controlled trials 
(6,7,8,9,10,11,12,13,14,15,16), comparing shorter with longer chemotherapy duration, 
showed that longer duration is associated with a modest, but significant improvement in 
OS and a clinically meaningful and statistically significant improvement in progression-free 
survival (PFS) (17). The formal demonstration of a survival advantage associated with 
longer chemotherapy use has clinical and scientific consequences. From a clinical 
viewpoint, prolonged chemotherapy administration may now be justified on the basis of 
the possibility of an appreciable survival benefit for some patients. From a scientific 
perspective, this finding supports further research on maintenance therapy in metastatic 
breast cancer.  
In this disease setting, where palliation is the primary goal of treatment and life expectancy 
is limited, toxicity and quality of life become important factors when deciding on 
therapeutic agents and schedules. In particular, in an attempt to improve the tolerability of 
prolonged chemotherapy administration, while maintaining and possibly improving 
treatment efficacy, alternative chemotherapy schedules, with lower dosages, could be 
explored in this disease setting. 
1.2. 
Nab-Paclitaxel 
The availability of a new nanoparticle albumin-bound taxane, nab-Paclitaxel (Abraxane®), 
represents an opportunity to test this hypothesis. 
Nab-Paclitaxel has been developed in an attempt to reduce the toxicity associated with 
standard taxane administration (caused by the use of chemical solvents) while increasing 

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antitumor efficacy. Conventional taxane formulations use solvents (e.g., Cremophor EL 
(polyoxyethylated castor oil) for paclitaxel and Tween 80 for docetaxel) to overcome the 
insolubility of the drug molecules. These solvents are associated with increased toxicity as 
hypersensitivity reactions, neurotoxicity and additional myelosuppression, and may also 
hinder the ability of circulating drug to cross the endothelial barrier and accumulate in 
tumors, reducing antitumor activity and increasing the risk of systemic toxicity. The first 
attempt to overcome the limitations imposed by solvent use was the development of 
albumin-bound (nab)-paclitaxel. With nab-Paclitaxel, the reversible binding of albumin to 
paclitaxel permits exploitation of endogenous albumin pathways to enhance delivery of 
the drug to tumors. Albumin is a natural carrier for hydrophobic molecules (18,19) and 
binds to the gp60 receptor on endothelial cells, signaling the formation of vesicles 
(caveolae) in the membrane that carry the albumin complex across the endothelial 
membrane (transcytosis) and into surrounding tissue. The entry and retention of albumin 
complexes in tumor tissue are facilitated by the enhanced permeation and retention 
effect, i.e., the accumulation of albumin complexes and other macromolecules in the 
tumor interstitium via leaky tumor vasculature coupled with reduced release back into 
blood vessels due to impaired lymphatic drainage in tumor tissue. The preferential 
accumulation of albumin-bound drug in the tumor interstitium results in high 
concentrations of active drug being in contact with tumor cells. This process appears to be 
facilitated by the albumin-binding activity of secreted protein acidic and rich in cysteine 
(SPARC, also known as osteonectin) (20), a protein with multiple biologic activities 
including roles in embryonic development, wound repair and tissue remodeling. SPARCs 
are overexpressed in many tumor types including breast cancer, and high SPARC 
expression is associated with a significantly poorer outcome in breast cancer (21). 
The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of nab-
Paclitaxel at dose levels of 80 to 375 mg/m2 were determined in clinical studies. The 
paclitaxel exposure (AUC) increased linearly from 2653 to 16736 μg·h/mL following dosing 
from 80 to 300 mg/m2. Following intravenous administration of nab-Paclitaxel to patients 
with metastatic breast cancer at the recommended clinical dose of 260 mg/m2, paclitaxel 
plasma concentrations declined in a multiphasic manner. The mean Cmax of paclitaxel, 
which occurred at the end of the infusion, was 18.7 μg/mL. The mean total clearance was 
15 L/h/m2. The terminal half-life was about 27 hours. The mean volume of distribution was 
632 L/m2; the large volume of distribution indicates extensive extravascular distribution 
and/or tissue binding of paclitaxel.  
In a study in patients with advanced solid tumors, the pharmacokinetic characteristics of 
paclitaxel following nab-Paclitaxel administered intravenously at 260 mg/m2 over 30 
minutes were compared with those following 175 mg/m2 of the solvent-based paclitaxel 
injection administered over 3 hours. The clearance of paclitaxel with nab-Paclitaxel was 
larger (43%) than that following a solvent-based paclitaxel injection and its volume of 
distribution was also higher (53%). Differences in Cmax and Cmax corrected for dose reflected 
differences in total dose and rate of infusion. There were no differences in terminal half-
lives.  
In a repeat dose study with 12 patients receiving nab-Paclitaxel administered intravenously 
at the approved dose, intrapatient variability in systemic paclitaxel exposure (AUCinf) was 
19% (range = 3.21%-27.70%). There was no evidence for accumulation of paclitaxel with 
multiple treatment courses. An analysis of patient exposure (AUCinf) against bodyweight 

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indicated a trend toward reduced AUC at 260 mg/m2 nab-Paclitaxel, with decreased body 
weight. Patients weighing 50 kg had paclitaxel AUC approximately 25% lower than those 
weighing 75 kg. The clinical relevance of this finding is uncertain.  
The protein binding of paclitaxel following nab-Paclitaxel was evaluated by ultrafiltration. 
The fraction of free paclitaxel was significantly higher with nab-Paclitaxel (6.2%) than with 
solvent-based paclitaxel (2.3%), resulting in significantly higher exposure to unbound 
paclitaxel with nab-Paclitaxel compared with solvent-based paclitaxel, even though the 
total exposure is comparable. This higher exposure is possibly due to paclitaxel not being 
trapped in Cremophor EL micelles as with solvent-based paclitaxel. Based on the published 
literature, in vitro studies of binding to human serum proteins, (using paclitaxel at 6μM) 
the presence of ranitidine, dexamethasone, or diphenhydramine did not affect protein 
binding of paclitaxel (22,23).  
1.3. 
Nab-Paclitaxel clinical data 
A phase I clinical study by Ibrahim (24) conducted on 19 patients with solid tumors 
including breast cancer, showed a maximum tolerated dose of nab-Paclitaxel about 70% 
higher than that of solvent-based paclitaxel formulation (300 mg/m2 for an every 3 weeks 
regimen). Dose-limiting toxicities were sensory neuropathy, stomatitis and ocular toxicity 
(superficial keratopathy and blurred vision at a dose of 375 mg/m2). No patients 
experienced hypersensitivity reactions. Nab-paclitaxel was administered intravenously 
with no premedication, in a relatively short infusion period (30 minutes versus 3 hours for 
solvent- based paclitaxel) and with a standard infusion device. Moreover, pharmacokinetic 
parameters showed a linear trend. A Phase II trial confirmed that nab-Paclitaxel has 
important antitumor activity in patients with metastatic breast cancer. The overall 
response rate (at a dose of 300 mg/m2 every 3 weeks) was 48% for all patients and 64% for 
patients in first-line therapy. Median time to tumor progression was 26.6 weeks for all 
patients and 48.1 weeks for patients with confirmed tumor responses; median OS was 63.6 
weeks. No severe ocular events were noted, and other common taxane-associated 
toxicities were less frequent and less severe (e.g., myelosuppression, peripheral 
neuropathy, nausea, vomiting, fatigue, arthralgia, myalgia, alopecia) (25). In a phase III 
trial, 460 women with measurable metastatic breast cancer who had no prior taxane 
therapy for metastatic disease were randomized to receive either conventional paclitaxel 
(175 mg/m2 every 3 weeks via 3-hour infusion; N=225) with standard premedication with 
dexamethasone and antihistamines or nab-Paclitaxel (260 mg/m2 q3w via 30-minute 
infusion; N=229) with no standard premedication (26). Approximately three quarters of 
patients had received prior anthracycline therapy, and more than half of patients had 
received at least one prior treatment for metastatic disease. The response rate was 33% 
with nab-Paclitaxel versus 19% with paclitaxel (P= 0.001). The time to disease progression 
(TTP) was significantly prolonged with nab-Paclitaxel, from a median of 16.9 weeks to 23 
weeks (Hazard Ratio= 0.75; P= 0.006). There was no significant difference between groups 
with regard to OS among all patients (65.0 vs 55.7 weeks; P= 0.374).  
With regard to toxicities, nab-Paclitaxel was associated with a significantly reduced 
frequency of grade 3-4 neutropenia. Sensory neuropathy of any grade was significantly 
more common with nab-Paclitaxel. Of 24 patients with grade 3 neuropathy; 14 had 
documented rapid improvement (median 22 days) with 10 of these patients resuming 
treatment at a reduced dose. Overall, 6 of 233 patients (3%) discontinued nab-Paclitaxel 

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due to sensory neuropathy; there were no cases of severe motor neuropathy. Despite the 
absence of premedication in the nab-Paclitaxel group, hypersensitivity reactions were 
virtually absent (grade 2 in less than 1% of patients). Overall adverse event rates in each 
group did not differ from patients aged < 65 years and those aged ≥ 65 years, raising no 
additional safety concerns about the use of nab-Paclitaxel in older patients. Similar findings 
were recently reported in a Chinese trial comparing solvent-based paclitaxel (175 mg/m2) 
and nab-Paclitaxel (260 mg/m2 q3w) in 210 patients with metastatic breast cancer (27).  
In a trial comparing weekly nab-Paclitaxel, every three-weekly (q3w) nab-Paclitaxel and 
conventional docetaxel in first-line treatment for metastatic breast cancer, 302 patients 
were randomized to receive 300 mg/m2 of nab-Paclitaxel q3w (N=76), 100 mg/m2 of nab-
Paclitaxel weekly 3 of 4 weeks (N= 76), 150 mg/m2 weekly 3 of 4 weeks (N= 74) or 100 
mg/m2 of docetaxel q3w (N=74) (28,29). The objectives of the trial were to obtain 
comparative toxicity and preliminary antitumor response data for nab-Paclitaxel versus 
docetaxel, weekly versus q3w nab-Paclitaxel, and higher dose versus lower dose weekly 
nab-Paclitaxel. Nab-paclitaxel 150 mg/m2 weekly demonstrated significantly longer PFS 
than docetaxel by both independent radiologist assessment (12.9 v 7.5 months, 
respectively; P=0.0065) and Investigator assessment (14.6 v 7.8 months, respectively; 
P=0.012). It should be noted that the weekly 100 mg/m2 nab-Paclitaxel schedule, as 
evaluated by the independent reviewers, also significantly prolonged PFS (> 5 months) 
compared with docetaxel. With regard to toxicity, Grade 3 or 4 fatigue, neutropenia, and 
febrile neutropenia were less frequent in all nab-paclitaxel arms, with the nab-Paclitaxel 
100 mg/m2 weekly regimen being associated with a significantly lower rate than the nab-
Paclitaxel q3w regimen. The frequency and grade of peripheral neuropathy were similar in 
all arms. Febrile neutropenia occurred in 1% of each of the nab-Paclitaxel groups compared 
with 8% of the docetaxel group. Rates of neutropenia were significantly higher with q3w 
nab-Paclitaxel and the 150mg/m2 weekly dose compared with the 100mg/m2 weekly 
dose. The rate of peripheral neuropathy was significantly lower in the 100mg/m2 weekly 
nab-Paclitaxel group than in the other nab-Paclitaxel groups. The median time to 
improvement of peripheral neuropathy was 16 days in the nab-Paclitaxel q3w group, 22 
days in the 100mg/m2 weekly nab-Paclitaxel group, 23 days in the 150mg/m2 weekly nab-
Paclitaxel group and 41 days in the docetaxel group. This trial showed that in first-line 
treatment two regimens of nab-Paclitaxel (150 mg/m2 weekly and 300 mg/m2 q3w) 
increase PFS compared with docetaxel with an improved safety profile. 
Moreover, the 150 mg/m2 weekly schedule proved to be superior to docetaxel in terms of 
overall survival (28). 
Based on this most-recent trial with docetaxel as the control arm (28), a seven-month 
median PFS was selected as a historical reference to which each of the three different 
schedules of nab-Paclitaxel administration will be compared in the SNAP trial to determine 
whether any of the three schedules are worthy of further investigation.  
1.4. 
Trial rationale 
With these premises, we designed a phase II randomized clinical trial evaluating three 
treatment schedules, each consisting of an induction and a maintenance phase of nab-
Paclitaxel, for the strategy of prolonged administration of first-line chemotherapy for 
metastatic breast cancer. The aim of the alternative schedules is to improve the tolerability 

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of prolonged chemotherapy administration while preserving and possibly improving 
treatment efficacy.  
Patients will be randomized to one of three treatment arms and continue treatment until 
disease progression or unacceptable toxicity. 
In the original design, in the induction phase, the schedules each begin with 3 cycles of 
nab-Paclitaxel 150 mg/m2 days 1, 8, 15 every 28 days. The 150mg/m2 regimen has 
demonstrated a survival advantage compared with conventional docetaxel (28). However, 
by limiting its administration to 3 cycles, this should improve tolerability and ability to 
continue treatment, as most cumulative toxicity leading to treatment discontinuation 
occurred after 3-4 cycles (28).  The first safety review of the induction phase of the 
regimen, conducted in March 2014 on 48 patients, revealed however, that few patients 
completed the three cycles of induction regimen without dose modification. The median of 
actually administered doses corresponds to a dose level of about 125 mg/m² given 3 out of 
4 weeks. It was therefore decided to modify the dose in the induction phase to 125 mg/m² 
days 1, 8, 15 every 28 days. 
The schedules continue into a maintenance phase from cycle 4 and through subsequent 
cycles using one of three alternative dose densities using lower dosages which each give a 
cumulative dose of 300 mg/m2 over 28 days (schema, Section 3.1).  
Because the aim of the treatment schedules is prolonged treatment, during the first 3 
cycles and during all subsequent cycles, the protocol provides strict dose-reduction criteria 
in case of thrombocytopenia, neutropenia, anemia, febrile neutropenia, neurotoxicity, and 
other grade 3-4 toxicities. 
2. 
Trial objectives 
2.1. 
Primary objective 
To evaluate the efficacy of three different schedules of nab-Paclitaxel administration, as 
measured by progression-free survival (PFS), using the historical reference of PFS of 
docetaxel for first-line treatment of metastatic breast cancer.  
2.2. 
Primary endpoint 
Progression-free survival (PFS) is defined as time from randomization to documented 
progressive disease according to RECIST criteria (Section 9) or death, whichever occurs 
first. A detailed definition is given in section 9.12. 
2.3. 
Secondary objectives 
 To evaluate: 
 Tolerability 
 Feasibility  
 Disease response according to RECIST criteria (Section 9), including disease control 
rate (DCR) 
 Overall survival (OS) 
 To explore the changes in quality of life (QL) over time until treatment discontinuation. 
 To investigate the prognostic role of putative markers (SPARC and caveolin) and assess 
any change in the expression of SPARC and caveolin between the primary and the 
metastatic sites. 

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2.4. 
Secondary endpoints 
 Tolerability: adverse events according to CTCAE version 4 
 Feasibility: completing treatment according to the protocol for at least 24 weeks 
 Disease control: overall response of stable disease (or non-CR/non-PD for patients with 
non-measurable disease) or better (i.e., partial or complete response) according to 
RECIST criteria for a duration of ≥24 weeks  
 Overall survival: time from randomization to death from any cause 
 QL endpoints (see Section 14.2) 
 Prognostic marker endpoints (see Section 13.4) 
3. 
Trial design and duration  
3.1. 
Trial schema 
 
 
 
 
 
 
 
 
 
Randomization allocation 1:1:1 
 nab-Paclitaxel administered in 28-day cycles 
 Continue treatment until progressive disease (PD) or unacceptable toxicity. 
 258 (Arm A 86, Arm B 86, Arm C 86) patients will be randomized.  
 Tumor evaluations will be required every 12 weeks.  
3.2. 
Trial duration 
The randomization of 258 patients is expected to occur over approximately 24 to 26 
months, with an additional 16 to 18 months of follow up after the last patient is 
randomized. The end of the trial therefore will be approximately 4 years after 
randomization of the first patient. 
All patients will be followed up until approximately 18 months following the enrollment of 
the last patient to reach the target number of events (maximum of 42 months, minimum 
of approximately 18 months).  
If at the end of the trial a patient has not progressed and wants to continue nab-Paclitaxel, 
the agent will be provided until progressive disease. In this case, adverse events, serious 
adverse events, treatment, and concomitant medications will continue to be collected. 
 
R
A
N
D
O
M
I
Z
E 
nab-Paclitaxel  
125 mg/m2  
days 1,8,15 
3 cycles (28-day)  
nab-Paclitaxel 150 mg/m2 days 1, 15 
nab-Paclitaxel 100 mg/m2 days 1,8,15 
nab-Paclitaxel 75 mg/m2 days 1,8,15,22 
A
B
C
A
B
C

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4. 
Patient selection: criteria for patient eligibility/ineligibility 
4.1. 
Inclusion criteria  
4.1.1. 
Histologically or cytologically confirmed HER2-negative metastatic (stage IV) 
breast cancer. 
4.1.2. 
Measurable or non-measurable, but radiologically evaluable, disease according to 
RECIST 1.1 criteria.  
4.1.3. 
Female aged 18 years or older. 
4.1.4. 
Life expectancy > 3 months. 
4.1.5. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.  
4.1.6. 
Either ER-positive or ER-negative disease. Patients with ER-positive disease must 
be endocrine resistant, defined as having failed at least one prior endocrine 
therapy for breast cancer, or must be candidates for first-line chemotherapy. 
4.1.7. 
If previously treated with a taxane or anthracycline in the neoadjuvant or adjuvant 
setting, the period from end of treatment to disease recurrence must have been > 
12 months (> 365 days). 
4.1.8. 
Radiation therapy, if given and regardless of site, must be completed at least 2 
weeks prior to randomization. 
4.1.9. 
Normal hematologic status. Must meet all criteria: absolute neutrophil count 
(ANC) ≥ 1500/mm3 (1.5 x 109/L), platelets ≥ 100 x 109/L and hemoglobin (Hgb) ≥ 9 
g/dL (≥ 90 g/L). 
4.1.10. Normal renal function (serum creatinine ≤ 1.5 ULN or calculated creatinine 
clearance ≥ 50mL/min according to the Cockcroft and Gault formula). 
4.1.11. Normal liver function. Must meet all criteria: ALT (SGPT) and AST (SGOT) ≤ 3 × 
upper limit of normal (ULN)(without liver metastases); total bilirubin ≤ 1.5 mg/dL. 
Exceptions: If the patient has liver metastases, ALT (SGPT) and AST (SGOT) must 
be ≤ 5 × ULN; total bilirubin ≤ 1.5 mg/dL. If the patient has Gilbert’s disease higher 
bilirubin is acceptable (≤ 3 mg/dL).  
4.1.12. Normal cardiac function defined as left ventricular ejection fraction within the 
institutional range of normal as measured by MUGA or echocardiogram 
4.1.13. Women of child bearing potential must have documented negative pregnancy test 
within 2 weeks prior to randomization and agree to acceptable birth control 
during the duration of the trial therapy and for a period of 6 months following the 
last administration of study drug. If for any reason the administration of first dose 
of trial treatment is not within 2 weeks of the pregnancy test, a second pregnancy 
test should be performed within two weeks of day 1 of cycle 1. 
4.1.14. Written Informed Consent (IC) must be signed and dated by the patient and the 
Investigator prior to randomization.  
4.1.15. Completed baseline Quality of Life Form. 

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4.1.16. The patient has been informed of and agrees to data transfer and handling, in 
accordance with national data protection guidelines. 
4.1.17. Availability of an FFPE block from the primary tumor (breast lesion) for submission 
to central pathology review and for translational research. 
4.1.18. Written consent to pathology material submission, indicating the patient has been 
informed of and agrees to tissue material use, transfer and handling, must be 
signed and dated by the patient and the Investigator prior to randomization. 
4.2. 
Exclusion criteria 
4.2.1. 
Any prior chemotherapy for metastatic breast cancer. 
4.2.2. 
Presence of CNS metastasis. 
4.2.3. 
Peripheral neuropathy grade 2 or higher (CTCAE version 4). 
4.2.4. 
Significant uncontrolled cardiac disease (i.e., unstable angina, recent myocardial 
infarction within prior 6 months), patients classified as having a New York Heart 
Association (NYHA) class III or IV congestive heart failure. 
4.2.5. 
Pregnant or lactating. 
4.2.6. 
Prior history of non-breast malignancy (except for adequately controlled basal cell 
carcinoma of the skin, carcinoma in situ of the cervix, in situ carcinoma of the 
bladder).  
4.2.7. 
Any concurrent condition which in the Investigator’s opinion makes it 
inappropriate for the patient to participate in the trial or which would jeopardize 
compliance with the protocol.  
4.2.8. 
Contraindications or known hypersensitivity to the study medication or excipients.  
4.2.9. 
The use of any anti-cancer investigational agents within 30 days prior to expected 
start of trial treatment.  
4.2.10. Inability or unwillingness to abide by the study protocol or cooperate fully with 
the Investigator.  
5. 
Randomization and Stratification 
This trial will use the web-based IBCSG Registration/Randomization System. Each 
Participating Group will determine how its Participating Centers will access the IBCSG 
Registration/Randomization system, either through a Group Randomization Center, or 
directly from the Participating Center.  The following procedures should be used in either 
case. Country- or Group-specific details for registering/randomizing can be found in the 
“IBCSG Group/Country Specific Logistical Information,” which is available from IBCSG.  
 
 

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5.1. 
Randomization procedures 
Complete the following steps to randomize a patient on this trial. 
5.1.1. 
Verify eligibility 
5.1.2. 
Obtain written informed consent both for the clinical trial and the pathology 
material submission, signed and dated by the patient and Investigator. Informed consent 
must be obtained prior to any trial-specific screening procedure or intervention.  
5.1.3. 
Directly access the IBCSG Registration/Randomization System and provide the 
requested information as indicated on the Confirmation of Registration (42-A) Form.  The 
date the Informed Consent Form was signed by the patient and the date signed by the 
Investigator are both required to complete randomization 
The Randomization System will provide the following information via e-mail: 
 Patient ID (randomization number)  
 Treatment assignment 
 Date of randomization  
5.1.4. 
Submit the Confirmation of Randomization (42-A) electronic case report form 
(eCRF) via iDataFax. The patient binder of eCRFs will be available in iDataFax within 24 
hours of successful randomization.  
5.2. 
Randomization help desk  
The IBCSG Data Management Center located at Frontier Science and Research Technology 
Foundation (FSTRF) is responsible for developing and maintaining the IBCSG 
Registration/Randomization System. The Randomization Help Desk includes technical 
personnel and administrators of the randomization programs at the Data Management 
Center in Amherst, NY, USA. 
Business Hours:  00:00 (midnight) to 18:00 US Eastern Time Monday through Friday 
FSTRF Randomization Help Desk 
Frontier Science & Technology Research Foundation (FSTRF) 
4033 Maple Rd, Amherst, NY 14226 USA 
Phone: +1 716 898 7301 
Fax: +1 716 898 7082  
Email: bc.helpdesk@fstrf.org 
This telephone information may also be used after business hours for urgent issues. 
5.3. 
Randomization assignment 
Randomization is performed prior to starting any nab-Paclitaxel. Patients are assigned 
randomly to one of 3 treatment schedules in a ratio of 1:1:1.  
All three treatment schedules begin with the same chemotherapy dosing schedule: 
A, B, C: nab-Paclitaxel 125 mg/m2 days 1, 8, 15 
every 28 days for 3 cycles 
And during the fourth and subsequent cycles continue treatment with an alternative 
maintenance dosing schedule: 

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A: nab-Paclitaxel 150 mg/m2 days 1,     15 
every 28 days 
B: nab-Paclitaxel 100 mg/m2 days 1, 8, 15  
every 28 days 
C: nab-Paclitaxel   75 mg/m2 days 1, 8, 15, 22 every 28 days 
5.4. 
Stratification 
For randomization, patients will be stratified by 
 ER status (ER-negative or ER-positive) based on metastatic biopsy if available or 
otherwise the primary tumor 
 Prior adjuvant taxanes in the neoadjuvant or adjuvant setting (yes or no) 
 Measurable or non-measurable only disease according to RECIST criteria. 
Dynamic institution balancing will be done in order to balance randomized assignments 
within institutions. 
6. 
Study drugs formulation and handling 
Nab-Paclitaxel is the investigational drug used in this trial. Celgene Corporation will supply 
nab-Paclitaxel for the entire duration of the study. Please consult the Drug Supply Manual 
for further details on initial supply and resupply procedures. 
Complete details of the study drug logistics, distribution, packaging, labeling and handling 
are described in a separate drug supply manual. 
6.1. 
nab-Paclitaxel 
6.1.1. 
Product characterization 
Nab-Paclitaxel is a solvent-free, protein-bound particle form of paclitaxel injection with a 
mean particle size of approximately 130 nanometers. Nab-Paclitaxel is supplied as a white-
to-yellow, sterile, lyophilized cake containing 100 mg of paclitaxel and approximately 
900mg (800 mg theoretical) of human albumin solution as a stabilizer in a 50-mL vial. Each 
vial of the lyophilized product is reconstituted with 20 mL of 0.9% Sodium Chloride 
Injection (USP) to create a suspension. Each mL of reconstituted suspension contains 5 mg 
of paclitaxel. Vials of nab-Paclitaxel provided for clinical trials are labeled according to 
country-specific regulatory requirements for labeling of investigational products. Nab-
Paclitaxel contains paclitaxel, a taxane with the Anatomical Therapeutic Chemical (ATC) 
code L01C D01. 
6.1.2. 
Pharmaceutical form 
Nab-Paclitaxel - powder for suspension for infusion - will be supplied in vials and each vial 
contains 100 mg of paclitaxel (as paclitaxel albumin).  
After reconstitution, each mL of suspension contains 5 mg of paclitaxel (as paclitaxel 
albumin).  
Excipients: the reconstituted medicinal product contains approximately 425 mg sodium per 
dose. 
6.2. 
Packaging and labeling  
Nab-Paclitaxel is supplied as a sterile, lyophilized powder for reconstitution before use. 
Both the box label and vial label will fulfill all requirements specified by governing 
regulations.  

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All drugs will be stored as per the current version of the products SPC’s (Summary of 
Product Characteristics) and the standard hospital procedures. Unopened vials do not 
require any special temperature storage conditions (Store the vials in original cartons to 
protect from light, below 25°C). Pharmacy will maintain temperature logs of all storage 
conditions as per hospital pharmacy standard operating procedures.  
Celgene will ship the investigational product to the pharmacy at each study site. Each vial 
will be packed into a white cardboard carton. Both the vial and carton will be labeled and 
the kit will be closed with tamper seals so that the site can confirm no interference upon 
receipt. Keep the vial in the outer carton in order to protect it from light. The number of 
kits to be shipped to each site for the initial and resupply shipment will be determined 
between Celgene and IBCSG and will be documented in the drug supply manual. 
6.3. 
Storage and Handling 
Nab-Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic paclitaxel 
compounds, caution should be exercised in handling nab-Paclitaxel. The use of gloves is 
recommended. Procedures for proper handling and disposal of anticancer drugs should be 
followed. Several guidelines on this subject are available (Clinical Oncological Society of 
Australia, Jones, American Medical Association, American Society of Hospital Pharmacists, 
Occupational Safety and Health Administration, Jeffrey). There is no general agreement 
that all of the procedures recommended in these guidelines are necessary or appropriate. 
However, according to the Active Pharmaceutical Ingredient manufacturer’s safety data for 
paclitaxel, the product should not be released into the environment even though it is a 
natural, biodegradable product. It is recommended that the material be recovered, if 
possible, and incinerated under controlled conditions in compliance with the current local 
and national regulations. 
Stability of reconstituted suspension in the vial: From a microbiological point of view, the 
reconstituted suspension in the vial should be filled into an infusion bag immediately. If not 
filled immediately, storage times and conditions are the responsibility of the user and 
should not normally be longer than 8 hours at 2−8°C (36−46°F). If not used immediately, 
each vial of reconstituted suspension should be replaced in the original carton to protect it 
from bright light. Stability of the reconstituted suspension in the infusion bag: From a 
microbiological point of view, the reconstituted suspension in the infusion bag should be 
used immediately. If not used immediately, in-use storage times and conditions prior to 
administration are the responsibility of the user and should not normally be longer than 8 
hours at ambient temperature (approximately 25°C [77°F]) and lighting conditions. 
6.4. 
Receipt of the drug  
The Investigator or designee is responsible for taking an inventory of each shipment of 
study drug received and comparing it with the accompanying study drug accountability 
form. The Investigator will verify the accuracy of the information on the form, sign and 
date it, retain a copy in the study file, and return a copy to Celgene or its representative. 
6.5. 
Unused study drug supplies 
Unused study drug will be destroyed locally in compliance with local pharmacy destruction 
procedures and drug disposition must be appropriately documented in the study file. The 

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destruction documents will be shipped to Celgene. If any study drug is lost or damaged, its 
disposition should be documented in the source documents. 
7. 
Treatments 
Patients will be randomized to one of three treatment schedules, which will continue until 
progressive disease or unacceptable toxicity. Ideally, trial treatment should begin within 5 
working days of randomization. A treatment cycle is defined as 28 days. 
The Investigator has to change the dose of the chemotherapy if there is an increase or 
decrease of ≥ 10% in a patient’s body weight. The body surface area does not need to be 
recalculated if the weight change is less than 10%. 
7.1. 
Treatment schedules 
7.1.1. 
Induction nab-Paclitaxel 
During the induction phase, all patients initiate treatment with 3 cycles of nab-Paclitaxel:  
Arm A: nab-Paclitaxel 125 mg/m2 days 1, 8, 15 every 28 days 
Arm B: nab-Paclitaxel 125 mg/m2 days 1, 8, 15 every 28 days 
Arm C: nab-Paclitaxel 125 mg/m2 days 1, 8, 15 every 28 days 
7.1.2. 
Maintenance nab-Paclitaxel 
During the maintenance phase, patients continue treatment with one of three 
maintenance schedules until disease progression: 
Arm A: nab-Paclitaxel 150 mg/m2 days 1,     15 
every 28 days 
Arm B: nab-Paclitaxel 100 mg/m2 days 1, 8, 15  
every 28 days 
Arm C: nab-Paclitaxel   75 mg/m2 days 1, 8, 15, 22 every 28 days 
7.1.3. 
Dosage, administration and schedule  
Administer reconstituted nab-Paclitaxel suspension intravenously using an infusion set 
incorporating a 15 μm filter. 
During the induction phase, patients receive for 3 cycles: 
Arm A: nab-Paclitaxel 125 mg/m2 i.v. infusion over 30 minutes, days 1, 8, 15 every 28 days  
Arm B: nab-Paclitaxel 125 mg/m2 i.v. infusion over 30 minutes, days 1, 8, 15 every 28 days  
Arm C: nab-Paclitaxel 125 mg/m2 i.v. infusion over 30 minutes, days 1, 8, 15 every 28 days  
In the absence of progressive disease, patients continue to the maintenance phase and 
receive:  
Arm A: nab-Paclitaxel 150 mg/m2 i.v. infusion over 30 minutes on days 1 and 15 every 28 
days 
Arm B: nab-Paclitaxel 100 mg/m2 i.v. infusion over 30 minutes on days 1, 8 and 15 every 28 
days 
Arm C: nab-Paclitaxel   75 mg/m2 i.v. infusion over 30 minutes on days 1, 8, 15 and 22 
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7.2. 
Dose modifications and delays for toxicity 
7.2.1. 
Hypersensitivity  
Rare occurrences of severe hypersensitivity reactions, including very rare events of 
anaphylactic reactions with fatal outcome, have been reported. If a severe hypersensitivity 
reaction occurs, the medicinal product should be discontinued immediately, symptomatic 
treatment should be initiated, and the patient should not be rechallenged with paclitaxel. 
7.2.2. 
Induction phase 
In case of toxicities of lower grade or not described below in Table 2, dose reductions 
following the dose levels in Table 1 may be done according to Investigators’ medical 
judgment. 
Table 1 – Dose Levels for Induction Cycles 1 – 3 
Dose Level  
Induction 
Days 1, 8, 15 
Starting dose 
125 mg/m2 
Reduction - 1 dose level  
100 mg/m2 
 
Table 2 – Induction Phase: Cycles 1-3 
AE  
Grade/count 
Required nab-Paclitaxel dose reduction  
Platelet count 
decreased 
< 75 x 109/L  
Hold until improvement to ≥ 100 x109/L.  
Reintroduce at  -1 dose level (100 mg/m2) 
Neutrophil count 
decreased 
< 1.5 x109/L  
Hold until improvement to ≥ 1.5 x109/L.  
Reintroduce at -1 dose level (100 mg/m2).  
G-CSF use as a secondary prophylaxis  at the discretion of 
the Investigator 
Anemia 
Hgb < 9.0g/dL 
Hold until improvement to ≥ 9.0 g/dL.  
Reintroduce at -1 dose level (100 mg/m2).  
Febrile neutropenia  
3, 4  
Hold until improvement of neutrophils to ≥ 1.5 x109/L 
and no fever.  
Reintroduce at -1 dose level (100 mg/m2).  
G-CSF use as a secondary prophylaxis  at the discretion of 
the Investigators 
Peripheral sensory 
neuropathy  
2, 3  
Hold until improvement to grade 1 or less.  
Reintroduce at -1 dose level (100 mg/m2).  
Other toxicities  
(except specific AEs 
above)  
3, 4  
 
Hold until symptoms improve to grade ≤ 1.  
Reintroduce at -1 dose level (100 mg/m2). 
  
Note: Physicians should manage patients according to their medical judgment based on the 
particular clinical circumstances.  
7.2.3. 
Maintenance phase: cycles ≥ 4 
For patients randomized to arm A: The maintenance phase needs to start at the assigned 
starting dose (150 mg/m2 days 1 and 15), regardless of whether the dose in the induction 
phase was kept at 125 mg/m2 or had to be reduced to 100 mg/m2. 

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In case of toxicities of lower grade or not described below in Table 4, dose reductions 
following the dose levels in Table 3 may be done according to Investigators’ medical 
judgment. 
Table 3 – Dose Levels for Maintenance Cycles >4 
Dose Level  
Maintenance 
Arm A 
Days 1, 15 
Maintenance 
Arm B 
Days 1, 8, 15 
Maintenance 
Arm C 
Days 1, 8, 15, 22 
Starting dose 
150 mg/m2 
100 mg/m2 
75 mg/m2 
Reduction - 1 dose level  
125 mg/m2 
75 mg/m2 
60 mg/m2 
Reduction - 2 dose levels 
100 mg/m2 
Remain at 75 mg/m2 
Remain at 60 mg/m2 
 
Table 4 – Maintenance Phase: Cycles ≥4 
AE  
Grade/count 
Required nab-Paclitaxel dose reduction  
Platelet count decreased 
< 75 x 109/L  
Hold until improvement to ≥ 75 x109/L.  
Reintroduce at next lower dose level. 
Neutrophil count 
decreased 
<1.5 x 109/L  
Hold until improvement to ≥ 1.5 x 109/L.  
Reintroduce at next lower dose level.  
G-CSF use as a secondary prophylaxis  at the discretion 
of the Investigator 
Anemia  
Hgb <9.0 g/dL 
Hold until improvement to ≥ 9.0 g/dL.  
Consider reducing to next lower dose level. 
Febrile neutropenia  
3, 4  
Hold until improvement of neutrophils to ≥ 1.5 x 109/L 
and no fever.  
Reintroduce at the next lower dose level.  
G-CSF use as a secondary prophylaxis at the discretion 
of the Investigators. 
Peripheral sensory 
neuropathy 
2, 3  
Hold until improvement to grade 1 or less.  
Reintroduce at next lower dose level. 
Other toxicities  
(except specific AEs 
above)  
3, 4  
 
Hold until symptoms improve to grade ≤ 1.  
Reintroduce at the next lower dose level. 
  
Note: Physicians should manage patients according to their medical judgment based on the 
particular clinical circumstances.  
 
7.2.4. 
Treatment delay or discontinuation 
Continuing treatment with nab-paclitaxel for as long as possible is the hypothesis 
underlying the SNAP protocol. Therefore, dose reductions are preferred, rather than delays 
or discontinuations. If the treating physician feels it is in the best interest of the patient to 
discontinue SNAP treatment, contact IBCSG (ibcsg42_SNAP@fstrf.org) before treatment 
discontinuation to discuss next steps.  
7.3. 
Duration of trial treatment 
Duration of therapy will depend on individual response, evidence of disease progression 
and tolerance. The treatment of the individual patient will be discontinued in case of: 
 Objective disease progression 

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 Unacceptable adverse event(s) 
 Intercurrent illness that prevents further administration of trial treatment 
 Patient demonstrates an inability or unwillingness to comply with the treatment 
regimen and/or study requirements 
 Patient declines further trial treatment 
 General or specific changes in the patient’s condition which render her 
unacceptable for further treatment in the opinion of the treating Investigator 
Patients who discontinue treatment for any reason other than objective disease 
progression will continue to be followed until documented disease progression on the 
same schedule, as per Section 10.5 and have an end of treatment visit as per section 10.4.  
7.4. 
Removal from the trial  
After a patient has been randomized, she becomes part of the clinical trial population and 
cannot be removed from the trial for any reason other than a decision by the patient to 
decline any further participation in the study requirements and/or to decline further 
collection of data (see Section 15.5). If the patient discontinues treatment for any of the 
reasons listed in the prior subsection, she should continue to be followed according to 
protocol and eCRFs should be completed as expected as described in Section 11.1.  
7.5. 
Concomitant medication 
The following agents may not be taken at any time during trial treatment: 
 Chemotherapy, antiangiogenic drugs including bevacizumab  
 Investigational anti-cancer treatments 
Concomitant medications are any prescription medications or over-the-counter 
preparations used by the patient from 2 weeks before the start of trial treatment until the 
completion of trial treatment. All concomitant medications will be recorded in the eCRF 
(Form 42-CCM) with indication and dates of administration. The following may be 
administered during trial treatment: 
 Continuation of previously started LHRH agonists 
 Bisphosphonates  
 Denosumab 
 Antiemetics  
 G-CSF, epoetin  
 Steroid prophylaxis  
 
The metabolism of paclitaxel is catalyzed, in part, by cytochrome P450 isoenzymes CYP2C8 
and CYP3A4. Therefore, caution should be exercised when administering paclitaxel 
concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole 
antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, 
indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, 
nevirapine) either CYP2C8 or CYP3A4. 

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8. 
Safety, adverse events and reporting 
8.1. 
Adverse effects of nab-Paclitaxel 
The following adverse reactions have been reported:  
Very common (≥ 10%):  
Blood and lymphatic system: Neutropenia, anemia, thrombocytopenia, lymphopenia, bone 
marrow suppression  
Metabolism and nutrition system: Anorexia, hypokalemia, dehydration, decreased appetite 
Nervous system disorders: Peripheral neuropathy, neuropathy, hypoesthesia, paresthesia, 
dizziness, dysgeusia, headache 
Psychiatric disorders: Insomnia, depression 
Respiratory, thoracic and mediastical disorders: Epistaxis, cough, dyspnea. 
Gastrointestinal disorders: Nausea, diarrhea, vomiting, constipation, stomatitis, abdominal 
pain, abdominal pain upper  
Skin and subcutaneous tissue disorders: Alopecia, rash, nail disorder, pruritus  
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, pain in extremity  
General disorders: Fatigue, asthenia, pyrexia, chills  
Investigations: Increased alanine aminotransferase, decreased weight 
Common (1 – 10%):  
Infection: Sepsis, urinary tract infection, folliculitis, upper respiratory tract infection, 
candidiasis, sinusitis, nail infection, oral candidiasis, pneumonia, bronchitis 
Blood and lymphatic system: Febrile neutropenia, pancytopenia  
Metabolism and nutrition system: decreased appetite 
Psychiatric disorders: Anxiety  
Nervous system disorders: Ataxia, sensory disturbance, somnolence.  
Eye disorders: Increased lacrimation, blurred vision, dry eye, keratoconjunctivitis sicca, 
madarosis, visual impairment  
Ear and labyrinth disorders: Vertigo  
Cardiac disorders: Cardiac failure congestive, tachycardia, palpitations 
Vascular disorders: Deep vein thrombosis, hot flushes, hypertension, lymphedema, 
hypotension  
Respiratory, thoracic and mediastinal disorders: Pneumonitis, oropharyngeal pain, 
pharyngolaryngeal pain, nasal congestion 
Gastrointestinal disorders: Colitis, intestinal obstruction, small intestinal obstruction, 
abdominal distension, dyspepsia, gastroesophageal reflux disease, oral hypesthesia, dry 
mouth  

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Hepatobiliary Disorders: Cholangitis, hyperbilirubinaemia 
Skin and subcutaneous tissue disorders: dry skin, erythema, nail pigmentation/ 
discoloration, skin hyperpigmentation, onycholysis, nail changes, erythema, palmar-plantar 
erythrodysesthesia syndrome 
Musculoskeletal and connective tissue disorders: bone pain, back pain, muscle cramps, limb 
pain, muscular weakness 
Renal and urinary disorders: Acute renal failure, hematuria 
General disorders: Peripheral edema, mucosal inflammation, pain, rigors, edema, 
weakness, decreased performance status, chest pain, influenza-like illness, malaise, 
lethargy, hyperpyrexia, infusion site reaction  
Investigations: Increased aspartate aminotransferase, decreased hematocrit, decreased 
red blood cell count, increased body temperature, increased gamma-glutamyltransferase, 
increased blood alkaline phosphatase, increased blood creatinine 
Uncommon (0.1 – 1%):  
Infection: Nasopharyngitis, cellulitis, herpes simplex, viral infection, pneumonia, catheter-
related infection, fungal infection, herpes zoster, injection site infection  
Blood and lymphatic system: Thrombotic thrombocytopenic purpura 
Immune system disorders: Hypersensitivity  
Metabolism and nutrition system: Hypophosphatemia, fluid retention, hypoalbuminemia, 
polydipsia, hyperglycemia, hypocalcemia, hypoglycemia, hyponatremia  
Psychiatric disorders: Restlessness  
Nervous system disorders: VIIth nerve paralysis, polyneuropathy, areflexia, dyskinesia, 
hyporeflexia, neuralgia, sensory loss, syncope, postural dizziness, neuropathic pain, 
tremor, facial palsy  
Eye disorders: Eye irritation, eye pain, abnormal vision, reduced visual acuity, conjunctivitis, 
visual disturbance, eye pruritus, keratitis, cystoid macular edema, maculopathy 
Ear and labyrinth disorders: Ear pain, tinnitus  
Cardiac disorders: Atrioventricular block, hypotension, peripheral coldness, orthostatic 
hypotension 
Respiratory, thoracic and mediastical disorders: Productive cough, exertional dyspnea, 
sinus congestion, decreased breath sounds, pleural effusion, allergic rhinitis, hoarseness, 
nasal 
congestion, 
nasal 
dryness, 
wheezing, 
pulmonary 
emboli, 
pulmonary 
thromboembolism, dry throat 
Gastrointestinal disorders: Dysphagia, flatulence, glossodynia, dry mouth, gingival pain, 
loose stools, esophagitis, lower abdominal pain, mouth ulceration, oral pain, rectal 
hemorrhage  
Skin and subcutaneous tissue disorders: Nail bed tenderness, urticaria, skin pain, 
photosensitivity reaction, pigmentation disorder, pruritic rash, skin disorder, hyperhidrosis, 
onychomadesis, erythematous rash, neutropenia rash, dermatitis, night sweats, maculo-

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papular rash, vitiligo, hypotrichosis, nail discomfort, generalized pruritus, macular rash, 
skin lesion, swollen face, erythema multiforme  
Musculoskeletal and connective tissue disorders: Chest wall pain, neck pain, groin pain, 
muscle spasms, musculoskeletal pain, flank pain, limb discomfort 
Renal and urinary disorders: Hemolytic-uremic syndrome, dysuria, pollakiuria, nocturia, 
polyuria, urinary incontinence 
Reproductive system and breast disorders: Breast pain  
General disorders: Chest discomfort, abnormal gait, swelling, injection site reaction  
Investigations: Increased blood pressure, increased weight, increased blood lactate 
dehydrogenase, increased blood glucose, increased blood phosphorus, decreased blood 
potassium 
Injury, poisoning and procedural complications: Contusion  
Rare (0.01 – 0.1%):  
Blood and lymphatic system: Pancytopenia 
Immune system disorders: Severe hypersensitivity  
Cardiac disorders: Bradycardia, cardiac arrest, left ventricular dysfunction 
Vascular disorders: Thrombosis 
Respiratory, thoracic and mediastinal disorders: Interstitial pneumonitis  
General disorders and administration site conditions: Extravasation 
Injury, poisoning and procedural complications: Radiation recall phenomenon, radiation 
pneumonitis   
Very Rare (< 0.01 %): 
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal 
necrolysis 
8.2. 
Adverse event reporting 
The main criterion for tolerability is the occurrence of toxicities and adverse events.  The 
severity and causality will be classified according to the NCI CTCAE Version 4. The CTCAE is 
available for downloading on the internet (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
An interactive version can be found at http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx.  
An adverse event is defined as any untoward medical occurrence that occurs from the first 
dose of study medication until 30 days after the final dose, regardless of whether it is 
considered related to a medication. 
In addition, any known untoward event that occurs subsequent to the adverse event 
reporting period that the Investigator assesses as possibly related to the trial treatment 
should be considered an adverse event. 
Symptoms of the targeted cancer (if applicable) should not be reported as adverse events. 

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An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE.  If an overdose is associated with an AE, the overdose and adverse event should be 
reported as separate terms. 
8.2.1. 
Severity / intensity 
The adverse event severity grade provides a qualitative assessment of the extent or 
intensity of an adverse event, as determined by the Investigator or as reported by the 
subject.  The severity grade does not reflect the clinical seriousness of the event, only the 
degree or extent of the affliction or occurrence (e.g., severe nausea, mild seizure), and 
does not reflect the relationship to study drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
 Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
 Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may 
be needed; no or minimal medical intervention/therapy required 
 Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 
 Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable 
 Grade 5 = Death – the event results in death 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache).  This criterion is not the same as 
“serious” which is based on subject/event outcome or action criteria associated with 
events that pose a threat to a subject’s life or functioning.   
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
8.2.2. 
Causality  
The Investigator must determine the relationship between the administration of nab-
Paclitaxel and the occurrence of an adverse event (AE) or serious adverse event (SAE) as 
“not suspected” or “suspected” as defined below: 
Not suspected: 
The temporal relationship of the adverse event to nab-
Paclitaxel administration makes a causal relationship unlikely or 
remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the 
observed event. 
Suspected: 
The temporal relationship of the adverse event to nab-
Paclitaxel administration makes a causal relationship possible, 
and 
other 
medications, 
therapeutic 
interventions, 
or 
underlying conditions do not provide a sufficient explanation 
for the observed event. 

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8.2.3. 
Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of 
the event. 
8.2.4. 
Action taken 
The Investigator will report the action taken with nab-Paclitaxel as a result of an AE or SAE, 
as applicable (e.g., discontinuation or reduction of nab-Paclitaxel, as appropriate) and 
report if concomitant and/or additional treatments were given for the event. 
8.3. 
Targeted adverse events 
The presence or absence of the following AEs must be indicated on each required AE form 
(Form 42-AE): 
 Peripheral sensory neuropathy 
 Neutrophil count decreased 
 Febrile neutropenia 
 Anemia 
 Platelet count decreased   
 Nausea  
 Vomiting  
 Diarrhea  
 Cardiac disorders: 
 Ventricular arrhythmia 
 Sinus tachycardia 
 Heart failure 
 Left ventricular systolic dysfunction  
 Recurrent laryngeal nerve palsies  
 Allergic reaction 
 Blood antidiuretic hormone abnormal 
 Pneumonitis 
8.4. 
Rare AEs to be reported 
The following AEs have been very rarely observed; their occurrence should be reported on 
the adverse event form (Form 42-AE) under “other, specify”: 
 Vocal cord paresis 
 Macular edema 
 Blindness, uni- or bilateral 
8.5. 
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if any of the following apply: 
 Results in discontinuation from the study 
 Requires treatment, modification/ interruption of nab-Paclitaxel dose, or any other 
therapeutic intervention 
 Is judged to be of significant clinical importance 

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Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness 
criterion need to be documented as a SAE. 
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, if it is a targeted AE or another AE grade 3 or higher. 
8.6. 
Serious adverse event (SAE) reporting 
8.6.1. 
Definition 
An SAE is defined in general as any undesirable medical occurrence/adverse drug 
experience that occurs during or within 30 days after stopping trial treatment that, at any 
dose, results in any of the following:  
 Fatal (any cause except progression of disease) 
 Life-threatening 
 Requires or prolongs inpatient hospitalization 
 Persistent or significant disability/incapacity 
 Congenital anomaly or birth defect 
 Secondary (non-breast) malignancy 
 Constitutes an “important medical event”:  
Important medical events are defined as those occurrences that may not be immediately 
life threatening or result in death, hospitalization, or disability, but may jeopardize the 
patient or require medical or surgical intervention to prevent one of the other outcomes 
listed above.   
Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. 
All SAEs must also be reported for the period in which the trial protocol interferes with the 
standard medical treatment given to the patient.  After completion of trial treatments, 
report all SAEs that are considered at least possibly related to previous trial treatment. 
Second (non-breast) malignancies and congenital anomalies should be regarded as SAEs, 
regardless of whether they occur during or after study treatment. These events should be 
reported on the SAE eCRFs (42-SAE-A and 42-SAE-B). 
SAE also includes any other event that the Investigator or the IBCSG Safety Office judges to 
be serious or which is defined as serious by the regulatory agency in the country in which 
the event occurred. 
An unexpected adverse event is one that is not listed as a known toxicity of the 
investigational drug in the summary of product characteristics. 
A related adverse event is one for which the Investigator assesses that there is a 
reasonable possibility that the event is related to the investigational drug. All adverse 
events judged as having a reasonable suspected causal relationship to the trial medication 
qualify as adverse reactions. 

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8.6.2. 
Exceptions to the definition 
Hospitalizations occurring under the following circumstances are not considered to be 
SAEs:  
 Elective surgery 
 Occur on an outpatient basis and do not result in admission (hospitalization < 24 h) 
 Are part of the normal treatment or monitoring of the studied treatment 
 Progression of disease (by convention, clinical events related to the primary cancer 
being studied or to the primary cancer progression are not to be reported as SAEs, 
even if they meet any of the seriousness criteria from the standard SAE definition, 
unless the event is more severe than expected and therefore the Investigator 
considers that their clinical significance deserves reporting). Progression of disease 
is to be reported on Form 42-TEV and not as an SAE. 
8.6.3. 
Reporting SAEs  
Any SAE occurring in a patient after providing informed consent must be reported. 
Information about all SAEs will be collected and recorded on the IBCSG Serious Adverse 
Event eCRFs (42-SAE-A and 42-SAE-B). 
To ensure patient safety, the IBCSG must be informed of each SAE using the procedures 
described below: 
 The Investigator/MD responsible for the patient must complete a Serious Adverse 
Event (SAE-A) eCRF in English within 24 hours via iDataFax.  A copy is automatically 
forwarded to the IBCSG Safety Office for medical review. 
 Follow-up information should be completed, via iDataFax, on the Serious Adverse 
Event (SAE-B) eCRF within 15 days of the initial report, even if the event reported in 
the SAE-A eCRF is not yet resolved.  If the event is not resolved within 15 days, 
revise the original Serious Adverse Event (SAE-B) eCRF in iDataFax to report the 
final resolution. 
 All SAEs that have not resolved upon discontinuation of the subject’s participation 
in the trial must be followed until recovered, recovered with sequelae, not 
recovered (death due to another cause) or death (due to the SAE). 
 If a non-serious adverse event becomes serious, this and other relevant follow-up 
information must also be provided within 24 hours. 
 Photocopies of all examinations carried out with the dates on which these 
examinations were performed should be sent by fax into the DataFax system. Care 
should be taken to ensure that the patient's identity is protected and the patient’s 
Randomization ID Number is properly included on ALL pages of any reports. For 
laboratory results, include the laboratory normal ranges. 
 In the event the eCRF system is not working, the SAE Forms can be sent via fax into 
the DataFax system. 
If the original SAE (42-SAE-A and 42-SAE-B) was submitted by fax, the original forms and 
the fax confirmation sheet(s) must be kept at the Participating Center. 
The IBCSG will inform Celgene and other appropriate persons about all SAEs within 24 
hours of receipt at the IBCSG Safety Office.  

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The IBCSG will record the SAE and prepare a monthly SAE report. Principal Investigators 
will receive the summary report on a monthly basis, and these reports can be found on the 
IBCSG website (www.ibcsg.org ). 
8.7. 
Pregnancy 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a patient occurring during trial treatment, or within 30 days of the 
last dose of nab-Paclitaxel, should be reported within 24 hours of having knowledge of the 
event. Nab-Paclitaxel is to be discontinued immediately. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported, using the pregnancy eCRF (42-
PREG), to the IBCSG who will inform Celgene immediately. 
The patient should be referred to an obstetrician-gynecologist, preferably one experienced 
in reproductive toxicity for further evaluation and counseling.   
The Investigator will follow the patient until completion of the pregnancy, and must notify 
IBCSG immediately about the outcome of the pregnancy by completing the corresponding 
section on the pregnancy form (42-PREG). 
All neonatal deaths that occur within 28 days of birth should be reported as SAEs, without 
regard to causality.  In addition, any infant death after 28 days that the Investigator 
suspects is related to the in utero exposure to nab-Paclitaxel should also be reported 
within 24 hours of the Investigator’s knowledge of the event using the eCRFs (42-SAE-A 
and 42-SAE-B). 
8.8. 
Safety review of nab-Paclitaxel 
Every six months, the reported AEs will be summarized in a safety report, according to 
randomized treatment assignment; separate tabulations will include those events reported 
during the first 3 cycles of induction therapy, those AEs reported during subsequent 
maintenance cycles, and those reported at any time. Investigators should document 
treatment and AEs immediately at the end of each cycle by completing the appropriate 
eCRFs.  
The safety reports will be reviewed by the Data and Safety Monitoring Committee (see 
section 12.5). 
9. 
Disease assessment, response and progression (RECIST 1.1)  
9.1. 
Introduction 
All randomized patients will be evaluated for disease response and progression according 
to the revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) (30). In this 
trial, patients may have measurable or non-measurable disease (see definitions below). 
Patients will be re-evaluated every 12 weeks. 
9.2. 
Methods of assessment 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 

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evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment. CT scan should generally be performed using a ≤ 5 mm 
contiguous reconstruction algorithm. MRI is acceptable for certain situations, e.g., body 
scans. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules) and ≥10 mm. In the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended. 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT scan is preferable. 
Ultrasound is not useful in assessment of lesion size and is not accepted as a method of 
assessment. 
FDG-PET is not foreseen for regular response assessments. It may, however, be used to 
detect or confirm the appearance of new lesions. Attenuation correction CT scans 
performed as part of a PET/CT scan frequently show lower resolution; therefore, dedicated 
CT scans are preferred. However, if the site can demonstrate that the CT scan performed 
as part of a PET/CT is of the same diagnostic quality as a diagnostic CT scan (with i.v. and 
oral contrast), then the CT scan portion of the PET/CT can be used for RECIST 
measurements. 
9.3. 
Measurability of tumor at baseline 
9.3.1  Measurable disease 
Measurable disease is defined as the presence of at least one measurable lesion. 
Measurable lesions: 
 Tumor lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5mm) 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Reminder: A lesion in a previously irradiated area is not eligible for 
measurable disease. 
 Malignant lymph nodes: to be considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in short axis when assessed by CT scan, assuming 
the slice thickness is ≤ 5 mm. At baseline and in follow-up, only the short axis will be 
measured. 
9.3.2 Non-measurable disease 
Non-measurable disease is defined as lesions or sites of disease that cannot be measured.  
Non-measurable lesions/sites of disease and special considerations:  

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 Small non-nodal lesions (longest diameter < 10 mm in CT scan) 
 Small lymph nodes (short axis ≥ 10 and < 15 mm). Lymph nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or 
followed as measurable or non-measurable disease. 
 Bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 
 Leptomeningeal disease 
 Ascites 
 Pleural or pericardial effusion 
 Inflammatory breast disease 
 Lymphangitic involvement of skin or lung 
 Cystic lesions. Cystic lesions thought to represent cystic metastases may be 
considered as measurable lesions. However, if non-cystic lesions are present, these 
are preferred as target lesions. 
 Tumor lesions situated in a previously irradiated area, or subjected to other 
locoregional therapy. Such lesions may be considered measurable if there has been 
demonstrated progression in the lesion. 
 Abdominal masses/abdominal organomegaly identified by physical exam that are 
not measurable by reproducible imaging techniques 
9.4. 
Selection of target lesions 
For patients with measurable disease, target lesions should be identified, measured and 
recorded at baseline (Form 42-TEV-B). At baseline, there can be up to a maximum of 5 
lesions representative of all involved organs, and up to 2 per organ. Target lesions should 
be selected on the basis of their size and their suitability for accurate repetitive 
measurements. A sum of diameters for all target lesions will be calculated and reported as 
the baseline sum of diameters. Lymph nodes selected as target lesions should always have 
the short axis recorded. All other lesions should always have their longest diameters 
recorded. The sum of diameters will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
9.5. 
Selection of non-target lesions  
For patients with measurable or non-measurable disease, non-target lesions should be 
identified. For patients with measurable disease, all other lesions (or sites of disease) not 
identified as target lesions should also be recorded as non-target lesions at baseline.  
For patients with non-measurable disease, non-target lesions or sites of disease must be 
identified and recorded at baseline (Form 42-TEV-B). These non-target sites will be 
followed for tumor evaluation (Form 42-TEV). 
For non-target lesions, measurements are not required, but the presence or absence of 
each should be noted throughout follow-up (Form 42-TEV). It is possible to record multiple 
non-target lesions as a single item on the eCRF (e.g., "multiple liver metastases"). 

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9.6. 
Evaluation of target lesions (measurable disease) 
All target lesions will be measured at each tumor assessment, and the sum of their 
diameters will be compared to previous assessments in order to assign the response status 
as specified below. 
 Complete Response (CR): Disappearance of all target lesions. Lymph nodes selected 
as target lesions must each have reduction in the short axis to < 10 mm in order for 
the response to be considered complete. In this case, the sum of diameters may be 
> 0. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions taking as reference the baseline sum of diameters. 
 Progression (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum recorded on study. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. The appearance of one or more new lesions (see section 9.8) denotes disease 
progression. 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters 
recorded on study. 
Note: All target lesions, including lymph nodes, should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). If the 
radiologist does not feel comfortable assigning an exact measure and reports a lesion as 
"too small to measure", a default value of 5 mm should be recorded. If a target lesion is 
thought likely to have disappeared, use "0 mm." 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case 
of PD. 
9.7. 
Evaluation of non-target lesions (measurable or non-measurable disease) 
 Complete Response (CR): Disappearance of all non-target lesions; lymph nodes 
selected as non-target lesions must be non-pathological in size (< 10 mm). 
 Non-CR/non-PD: Persistence of one or more non-target lesions (non-CR). 
 Progression (PD): unequivocal progression of existing non-target lesions. 
Unequivocal means: comparable in magnitude to the increase that would be 
required to declare PD for measurable disease or an overall substantial increase in 
tumor burden that merits treatment discontinuation. 
When no imaging is done at all at a particular time point, the patient is not evaluable (NE) 
at that time point. If only a subset of lesions are evaluated at an assessment, usually the 
case is also considered NE at that time point, unless a convincing argument can be made 
that the contribution of the individual missing lesion(s) would not change the assigned 
time point response. This would be most likely to happen in the case of PD. 

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9.8. 
Determination of new lesions 
The appearance of any new malignant lesions denotes disease progression. The finding of a 
new lesion should be unequivocal, i.e., not attributable to differences in scanning 
technique or findings thought to represent something other than tumor. If a new lesion is 
equivocal, e.g., because of its small size, the patient will stay on treatment (if the decision 
on PD is based on this lesion only). If the repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the previous scan when the 
lesion was discovered. 
Lesions or sites of disease found in a new location not included in the baseline scan (e.g., 
brain metastases) are considered new lesions. 
Note: The "re-appearance" of a previously "disappeared" target or non-target lesion does 
not in itself necessarily qualify as PD; this is the case only if the overall evaluation meets 
the PD criteria, or if the patient was previously in CR. 
9.9. 
Additional considerations 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
9.10. Determination of time point response 
Based on the responses of target lesions, non-target lesions, and the presence or absence 
of new lesions, the overall response will be determined at each tumor evaluation time 
point, according to the table below. 
9.10.1. For patients with measurable disease 
Table 5 – Measurable Disease - Overall Response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD* 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any  
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes  
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  

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9.10.2. For patients with non-measurable disease only 
Table 6 – Non-Measurable Disease - Overall Response 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD* 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
9.11. Determination of best overall response and response duration 
Best overall response is defined as best response recorded from the start of treatment 
across all time points until disease progression. Confirmation of partial or complete 
response by an additional scan is not requested in this trial. Best overall response will be 
determined by a team consisting of the study chair, co-chair and IBCSG Head of Medical 
Affairs.  
Among patients with measurable disease, the duration of response is defined as the time 
from which the criteria for partial or complete response are first met until disease 
progression. Among patients with non-measurable disease, the duration of response is 
defined as the time from which the criteria for CR are first met until disease progression.   
9.12. Progression-free survival 
Progression-free survival (PFS) is defined as time from randomization until objective 
disease progression or death, whichever occurs first.  
Patients with new non-breast cancer malignancy must continue to be followed for 
progression of the original breast cancer. For patients without progression, follow-up will 
be censored at the date of last disease assessment without progression, unless death 
occurs within a short period of time (12 weeks) following the date last known progression-
free, in which case the death will be counted as a PFS event.  
Patients who discontinue treatment prior to documented disease progression (see Section 
7.4), including those who initiate non-protocol therapy prior to progression, will be 
followed for disease progression. 
 
 

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10. 
Clinical and laboratory evaluations 
10.1. Prior to randomization 
Table 7 – Evaluations Prior to Randomization 
Investigation 
Timing 
Patient informed consent 
Prior to randomization 
Medical history (including height) & physical exam 
Within 14 days prior to randomization 
ECOG performance status and life expectancy 
Within 14 days prior to randomization 
Vital signs (Blood pressure and pulse rate after 5 minutes 
in sitting position; body temperature; body weight; 
respiratory rate) 
Within 14 days prior to randomization 
MUGA or echocardiogram 
Within 14 days prior to randomization. If the 
patient is clinically cardiac compensated with 
no heart symptoms, these can be done up to 6 
months prior to randomization 
Hematology (ANC, hemoglobin, platelets) 
Within 14 days prior to randomization 
Biochemistry (ALT (SGPT), AST (SGOT), total bilirubin, 
serum creatinine or calculated creatinine clearance 
acc. Cockcroft and Gault) 
Within 14 days prior to randomization 
Concomitant medications 
Medications used within 14 days prior to 
randomization 
Pregnancy test (for patients with child-bearing 
potential) 
Within 14 days prior to randomization; Must be 
repeated if time from pregnancy test today 1 of 
cycle 1 exceeds 14 days. 
Verify all inclusion/exclusion criteria 
Prior to randomization 
Baseline symptoms 
Observed within 14 days prior to treatment 
QL self-assessment 
Within 28 days prior to randomization, after 
patient informed consent 
Tumor evaluation (RECIST 1.1) 
Within 28 days prior to randomization, after 
patient informed consent 
HER2 analysis 
Prior to randomization 
ER and PgR status 
Prior to randomization 
Menopausal status 
Prior to randomization 
FFPE tumor tissue sample from primary tumor (breast 
lesion) and if available from metastatic biopsy 
Prior to randomization 
10.2. During induction nab-Paclitaxel 
Table 8 – Evaluations During Induction 
Investigation 
Prior to treatment, each of 3 cycles 
 
Day 1 
Day 8 
Day 15 
Physical exam 
X 
 
 
Vital signs 
X 
 
 
MUGA or echocardiogram only if clinically indicated 
X 
 
 
Hematology 
X 
X 
X 
Biochemistry 
X 
 
 
Concomitant medications 
Continuously as started or re-started 
Performance status 
X 
 
 
QL self-assessment 
If baseline QL was within 14 days prior to treatment start, 
no QL form has to be completed  at day 1 of cycle 1 
X 
 
 
AEs 
At the end of each cycle 
Tumor evaluation (RECIST 1.1) 
12 weeks from day of randomization. If 
evaluation shows progression, stop trial 
treatment. 

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10.3. During maintenance nab-Paclitaxel 
Table 9 – Evaluations During Maintenance 
Investigation 
Prior to treatment, each cycle 
 
Day 1 
Day 8 
(Arms B&C) 
only 
Day 15 
Day 22 
(Arm C only) 
Physical exam 
X 
 
 
 
Vital signs 
X 
 
 
 
MUGA or echocardiogram only if 
clinically indicated 
X 
 
 
 
Hematology 
X 
X 
X 
X 
Biochemistry 
X 
 
 
 
Concomitant medications 
continuously 
Performance status 
X 
 
 
 
QL self-assessment 
X 
 
 
 
AEs 
X 
At the end of each cycle 
Tumor evaluation (RECIST 1.1) 
Every 12 weeks. If evaluation shows progression, stop trial 
treatment 
10.4. After discontinuation of trial treatment 
Table 10 – Evaluations After Discontinuation 
Investigation 
 
End of treatment visit within 30 days 
after stop of trial treatment  
 
Record last dose of trial treatment and document 
reason for stopping treatment 
 
Physical exam, vital signs, performance status 
 
Hematology, blood chemistry  
 
Adverse events and concomitant medications up 
to 30 days after last dose of trial treatment 
 
Quality of life self-assessment form 
Tumor evaluation (RECIST 1.1) 
If progression is not documented at last routine tumor 
evaluation then tumor evaluation must be continued 
on the same schedule (every 12 weeks +/- 2 weeks) 
until progression is documented.   
Post-treatment follow-up 
Patients will be followed for survival status. Follow up 
continues until end of trial (approx. 18 months after 
randomization of the last patient; see Section 3.2) 
Notes for Sections 10.1-10.4 
(a) Adverse events (AE) should be graded using the NCI CTCAE version 4 (Appendix II).  
Targeted adverse events occurring during and up to 30 days after discontinuation of trial 
treatment should be recorded on the eCRF (42-AE). 
(b) Quality of Life (QL) self-assessment forms should be completed on day 1 of each of the 
first 12 cycles, prior to any diagnostic procedures (or communication of diagnostic 
information) or receiving chemotherapy. If baseline QL was within 14 days prior to 
treatment start, no QL form has to be completed at day 1 of cycle 1. QL forms must be 
completed and submitted according to guidelines in Section 14. Because they are 
completed by the patient, QL Forms cannot be completed in iDataFax and must instead be 
faxed into the DataFax System.  
(c) Tumor evaluation: CT/MRI scans of the chest, abdomen and pelvis must be available at 
screening (i.e., within the 28 days between signing the informed consent form and 

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randomization of the patient) and will be performed every 12 weeks from the day of 
randomization until documented disease progression.  
Bone scans should be performed at baseline in patients with known bone metastases and 
where there is clinical suspicion of previously unknown bone metastasis. Bone scan (if 
clinically indicated) are acceptable ≤ 8 weeks before randomization. In case of a positive 
bone scan, correlative conventional imaging as defined by RECIST 1.1 of the respective 
lesion(s) should be performed. These areas should have repeat conventional imaging at 
every scheduled imaging time point. Subsequent imaging with bone scans after baseline 
should be based on clinical indication, at the discretion of the Investigator. For example, 
when complete response is identified in target disease or when progression in bone is 
suspected (to confirm the presence or disappearance of bone lesions). 
(d) Section 11 (Data Submission) provides details on eCRF schedule and submission.   
10.5. Follow-up 
Patients should be followed through the end of the trial (approximately 18 months after 
the last patient is randomized) or death, whichever occurs first. Patients who discontinue 
treatment with documented disease progression will be followed for survival status. 
Patients who discontinue treatment without disease progression will be followed with 
continued tumor evaluations on the same schedule (every 12 weeks +/- 2 weeks) until 
progression is documented. Other treatments prior to progression should be reported; 
after progression patients will be followed for survival status only. 
11. 
Data submission 
We will conduct the trial according to the ICH Good Clinical Practice (GCP) guidelines.  
Keeping accurate and consistent records is essential to a cooperative study.  Timeliness of 
data submission and quality of data will result in fewer queries to the Center.   
Case Report Forms should be completed electronically (eCRF) in iDataFax (with the 
exception of QL self-assessment Forms, Pathology Reports, SAE related reports and 
possibly laboratory reports, which must be faxed to the DataFax system) by either the 
Principal Investigator or designee, according to the Authorization Log. The following 
eCRFs/data are to be submitted at the indicated times by the Participating Centers for each 
patient.

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11.1. Case report forms schedule  
Forms 
Description/Name 
Forms Submission 
Registration/Randomization  
ALL data should be submitted in iDataFax (iDF) (unless otherwise 
specified) 
Informed 
Consent 
Form 
Consent to participation in clinical trial 
Obtain before randomization and keep with patient records as 
documentation (hard copy only). 
42-A 
Confirmation of Registration Form 
Complete in iDF after you or your Randomization Center has 
randomized the patient in the IBCSG Registration/Randomization 
System.  
42-QLC 
Quality of Life 
Complete prior to randomization and submit to DataFax via fax or 
DFSend.  
Baseline  
42-H 
History Form 
Complete in iDF within 1 week of randomization. 
Path. 
report 
Pathology Report 
Submit Report to DataFax, via fax or DFSend, within 1 week of 
randomization. 
42-BS 
Baseline Symptoms Form 
Complete in iDF within 1 week of randomization.   
42-CCM 
Concomitant Medications Form  
Complete in iDF each time a medication is started, amended, or 
ended, including medications taken within 14 days prior to start of 
treatment. 
42-TEV-B 
Baseline Tumor Evaluation Form 
Complete in iDF within 1 week of randomization.  
During trial treatment 
42-AE 
Adverse Events Form 
Complete in iDF at the end of each cycle of chemotherapy = day 1 
of next cycle. 
42-TEV 
Tumor Evaluation Form 
Complete in iDF after every tumor evaluation (every 12 weeks). 
42-CCM 
Concomitant Medications Form 
Review the original CCM Form at the end of each cycle.  Update in 
iDF any current medications if needed and add new medications 
taken. 
42-QLC 
Quality of Life (self-assessment)  Form 
Submit to DataFax, via fax or DFSend, after completion, day 1 of 
each of the first 12 cycles.  If baseline QL was within 14 days prior 
to day 1 of cycle 1, no QL form has to be completed at day 1 of 
cycle 1. 
42-CT 
Chemotherapy Form (including lab 
values) 
Complete in iDF at the end of each cycle. 
Follow Up (after discontinuation of trial treatment) 
42-TC 
Treatment Completion Form 
Complete in iDF within 30 days of trial treatment stop. 
42-QLC 
Quality of Life self-assessment form 
Submit to DataFax, via fax or DFSend, after completion at end-of-
treatment visit. 
42-E 
Follow up Form 
Complete in iDF every 3 months after trial treatment is 
discontinued. 
42-TEV 
Tumor Evaluation Form 
Complete in iDF at end of treatment and every 12 weeks until 
progression, only if patient discontinued trial treatment prior to 
documented progression.  
42-AE 
Adverse Events Form 
Complete in iDF 30 days after the last dose of trial treatment.  
Event Driven  
 
42-SAE-A 
Serious Adverse Event initial report 
Complete within 24 hours of the SAE in iDF. If iDF is not available, 
fax the form within 24 hours to DataFax. 
42-SAE-B 
Serious Adverse Event B follow-up 
report 
Complete in iDF within 15 days of completion of initial report (42-
SAE-A). If event is not resolved in 15 days, complete 42-SAE-B 
again at the time of resolution. 
42-PREG 
Pregnancy Form 
Complete in iDF if a patient becomes pregnant on trial treatment.  
Complete the second section of the form at the end of pregnancy. 
42-COC 
Change of Consent Form 
Complete in iDF if there is any change in patient's consent to 
participate in the trial, see Section 15.5.2. 
42-E-
Death 
Death Form 
Complete in iDF if a patient dies. 

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If at the end of the trial a patient has not progressed and wants to continue nab-Paclitaxel, 
the drug will be provided until progressive disease. In this case, adverse events, serious 
adverse events, treatment, and concomitant medications will continue to be collected. 
The Data Managers’ Manual for this trial contains instructions for completing forms.  
Please note that we expect forms submission, unless the patient has explicitly declined any 
further participation in the study requirements and/or explicitly declined further collection 
of data.  For instructions on forms submission in these cases, please contact the IBCSG 
Data Management Center at ibcsg42_SNAP@fstrf.org . 
11.2. Signing and submitting forms 
All forms should be signed by the Principal Investigator or designee.  An Authorization Log 
should be completed at each Participating Center. Instructions for completing the 
Authorization Log can be found in the Authorization Log Manual, available on the IBCSG 
website (www.ibcsg.org ). 
CRFs, including SAE Forms, should be completed electronically in iDataFax. Reports (lab, 
pathology, etc.) and any other non-eCRF data (such as QL forms) must be faxed into the 
DataFax system.  Any patient identification on such reports (name, date of birth, hospital 
number) should be carefully blacked out and every page identified by the Patient 
Identification Number (ID) assigned by the IBCSG Registration/ Randomization System. Full 
instructions on submitting forms will be distributed to each Participating Center and are 
available on the IBCSG website (www.ibcsg.org ). Also available on the website is the “Data 
Fax toll free numbers” document. 
For Centers participating through a Group: Please consult your Participating Group 
Specific Logistical Information for special instructions about how to submit data. 
11.3. Data management 
Data collected in this trial will be submitted to the IBCSG Data Management Center in 
Amherst, NY USA.  The Data Management Center will process the data and will generate 
Quality Control (QC) Reports, which contain queries and forms requests.  The IBCSG 
Coordinating Center in Bern, Switzerland will provide medical review and summaries of 
SAEs.  The IBCSG Statistical Center in Boston, MA USA will perform the data analysis. 
11.4. Investigator’s file 
Each Participating Center should keep documentation about this trial in an Investigator’s 
File, which should include all of the following documents (ICH GCP essential documents): 
 Protocol activation/distribution letter 
 Protocol and appendices 
 Amendments 
 Signed Protocol Signature Pages 
 Sample CRFs including blank SAE Forms 
 Data Managers’ Manual 
 Obvious Corrections Documents and Signature Pages 
 Randomization Manual 
 Instructions for Using the DataFax System 

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 iDataFax User Manual 
 Drug Supply Manual 
 Participating Group/Country Specific Logistical Information 
 Patient information and Informed Consent templates approved by Ethics 
Committee 
 Investigator's Brochure and updates 
 Ethics Committee approval of protocol, Patient Information Sheet and IC, 
amendments 
 Ethics Committee review of SAE, Investigators' alert, and other documents 
 Correspondence with Ethics Committee 
 Agreement with IBCSG 
 Clinical trial insurance policy 
 Center Activation e-mail from the Data Management Center 
 Correspondence with IBCSG  
 SAE reports from IBCSG  
 Accrual reports from IBCSG 
 Normal laboratory values/reference ranges 
 Laboratory Certifications 
 CV of Principal Investigator and Co-Investigators (including GCP training certificate) 
 Authorization Log (see below) 
 Patient identification log (see below) 
 Drug accountability log (including certificates of destruction if applicable)   
 ICH GCP guidelines/Declaration of Helsinki and updates 
 Audit certificates 
 IBCSG Training certificates  
 Monitoring reports 
 IBCSG and/or trial newsletters 
 Other Reports from IBCSG (Biostatistician Report, Data Safety Monitoring 
Committee minutes, Annual Safety Reports, IBCSG EC Approval) 
11.5. Authorization log 
The Principal Investigator should identify the other members of the Clinical Trial Team who 
are supervised by the Principal Investigator and approved to provide information in CRFs, 
queries, etc. A manual for completing the Authorization Log is available on the IBCSG 
website.   
11.6. Patient identification log 
As per GCP, patients have the right to confidentiality.  Therefore, no patients’ names 
should be used in CRFs or any other documentation transmitted to IBCSG central offices. 
The only item that is used to identify a patient is the Patient ID (randomization number 
assigned by the Randomization System). It is therefore imperative that the local Data 
Manager keeps an identification log for all patients entered in this trial including: 
 Patient's name 
 Patient ID (randomization number) 
 Date of birth 

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Other items that could be included are treatment assignment and date of randomization. 
12. 
Statistical considerations  
The primary objective of this randomized phase II trial is to evaluate the efficacy of three 
different schedules of nab-Paclitaxel administration. Efficacy is measured by progression-
free survival (PFS), using a historical reference of PFS of docetaxel for first-line treatment of 
metastatic breast cancer (28), assumed as median of 7 months. A total of 258 patients will 
be stratified as described in section 5.4 and randomized in a 1:1:1 allocation, which will 
result in approximately 86 patients in each arm.  
In the original design of this phase II trial, patients will receive three cycles of nab-Paclitaxel 
150 mg/m2 days 1, 8, 15 every 28 days during induction phase. Following the first safety 
review of 48 treated patients, it was decided to modify the dose in the induction phase to 
125 mg/m².  
12.1. Primary endpoint 
The primary efficacy endpoint of PFS will be evaluated among three treatment arms. The 
definition of PFS is given in Section 9.12. For each arm separately, in three independent 
tests, PFS will be compared to the historic PFS of first-line docetaxel. For each of the tests, 
the type I error will be controlled at one-sided 0.05. 
12.1.1. Sample size justification 
Assuming the median PFS of docetaxel is 7 months and the median PFS of a nab-Paclitaxel 
treatment schedule is 10 months, with 76 patients in an arm, and an accrual rate of 8 
patients per month for an accrual period of 30 months plus an additional 12 months of 
follow up to reach the target number of events, the study will have 88% power to detect 
an improvement in PFS in a nab-Paclitaxel treatment schedule relative to docetaxel, using a 
one-sample log-rank test at a one-sided significance level of 0.05.  The target number of 
events per arm is 63. Assuming a 12% drop out rate and those patients do not contribute 
events, the sample size is increased to 86 patients per arm. Exponential failures were 
assumed for the sample size calculations (31), which were carried out using a locally-
maintained library in R (R Foundation for Statistical Computing, Vienna, Austria).  
A higher than expected drop out rate was observed during trial conduct, and based on 
recommendations from the IBCSG DSMC the sample size was increased. As of November 
2014, 9 drop outs who will not contribute events had been documented. Considering the 
subset of patients enrolled prior to April 2014 who had longer follow-up, the drop out rate 
was 9.2% (8 of 87 patients). Thus as longer follow-up accumulates, the drop out rate was 
anticipated to rise to as much as 12%. To obtain the originally planned power, the accrual 
per arm was increased to 86 patients (76/0.88 = 86.4). 
To reach the target number of events, the design assumed accrual duration of 30 months 
and 12 months of additional follow-up. As of the fourth quarter of 2014, an accrual 
duration of 24 to 26 months is anticipated. An additional follow up of 16 to 18 months, 
resulting in the same anticipated maximum follow up of 42 months and end of trial 
approximately 4 years after randomization of the first patient, will reach the target number 
of events. 

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12.1.2. Analysis of the primary endpoint 
Randomized patients who received at least one dose of the trial treatment will be included 
in the PFS analysis. For each arm separately, PFS will be compared to the historic PFS of 
first-line docetaxel using a one-sample log-rank test. PFS distributions will be summarized 
using the method of Kaplan-Meier and the two-sided 90% confidence interval (CI) for the 
median PFS will be provided.  
For each arm, PFS distribution will also be summarized separately by different starting dose 
in induction (150 mg/m2 and 125 mg/m2). 
Subgroup analyses according to age groups and ER status as defined for the stratification 
will be performed as exploratory analyses. 
12.2. Secondary objectives 
12.2.1. Tolerability 
Tolerability will be evaluated in each of the three treatment arms separately. The 
frequencies of adverse events (AE) while on treatment will be summarized and tabulated 
by arm; separate tabulations will include those AEs reported during the induction phase, 
those events reported during the maintenance phase, and those reported at any time. 
These tabulations will also be done separately by different starting dose in induction (150 
mg/m2 and 125 mg/m2). Randomized patients who received at least one dose of the trial 
treatment will be included in the tolerability analyses. Two frequently-observed AEs in 
patients receiving nab-Paclitaxel were neutropenia and sensory neuropathy (28). The two-
sided 90% CIs of grade 3-4 neutropenia and grade ≥ 2 sensory neuropathy will be provided 
by arm. With 86 patients in each arm, the width of the two-sided exact binomial 90% CI for 
the rate of grade 3-4 neutropenia (or grade ≥ 2 sensory neuropathy) will be no wider than 
19%, as summarized in Table 11. 
Table 11 shows the width of a two-sided exact binomial 90% CI for a range of possible true 
AE rates, for a sample size of 86 patients in a treatment arm. 
Table 11 – Confidence Intervals (CI) for AE Rates (%) 
True AE rate (%) 
5% 
10% 
20% 
30% 
40% 
50% 
90% CI width 
8.7 
11.4 
15.1 
17.1 
18.3 
18.9 
For each arm, the two-sided 90% CIs of grade 3-4 neutropenia and grade ≥ 2 peripheral 
sensory neuropathy will also be provided separately by different starting dose in induction 
(150 mg/m2 and 125 mg/m2). 
12.2.2. Feasibility  
Feasibility will be evaluated in each of the three treatment arms separately. Feasibility is 
defined as the percentage of patients who complete treatment according to the protocol 
for at least 24 weeks. Randomized patients who received at least one dose of the trial 
treatment will be included in the analysis. The percentages will be summarized by arm with 
two-sided 90% CI. In each arm, the width of the two-sided exact binomial 90% CI will be no 
wider than 19% (similarly as in Table 11). The percentages of the feasibility will also be 
summarized for each arm separately by different starting dose in induction (150 mg/m2 
and 125 mg/m2). In addition, the cumulative amount of nab-Paclitaxel administered and 
the total duration of therapy will all be summarized; dose modifications, dose 

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interruptions, reason for treatment discontinuation will also be summarized by treatment 
arm and different starting dose in induction (150 mg/m2 and 125 mg/m2). 
12.2.3. Disease Response 
The primary measure is the Disease Control Rate (DCR). The definition of disease control is 
given in section 2.4. Randomized patients who received at least one dose of the trial 
treatment will be included in the analysis. The DCR and two-sided 90% CI of DCR will be 
assessed for each arm separately.  
Additional measures that will be characterized similarly are the best overall response 
(defined in section 9.11) and the overall response at the first restaging after the 3 cycles of 
induction therapy (as defined in section 9.10).  
Among the patients who experience a CR or PR, the distribution of duration of response (as 
defined in section 9.11) will be summarized using the method of Kaplan-Meier for each 
arm separately. The timing at which response is achieved (i.e., of the start of the duration 
of response interval) will be summarized descriptively. 
DCR, best overall response, the overall response after the 3 cycles of induction therapy, 
and duration of response will also be summarized for each arm separately by different 
starting dose in induction (150 mg/m2 and 125 mg/m2). 
12.2.4. Overall Survival (OS) 
The definition of OS is given in section 2.4. Randomized patients who received at least one 
dose of the trial treatment will be included in the analysis. OS distributions will be 
summarized using the method of Kaplan-Meier and the two-sided 90% CI for the median 
OS will be provided for each treatment arm separately, and also be summarized for each 
arm separately by different starting dose in induction (150 mg/m2 and 125 mg/m2). 
12.2.5. Quality of Life (QL) 
The QL study is described in Section 14.  
12.2.6. Translational Research 
The translational research studies are described in Section 13.4.  
12.3. Interim analyses 
No interim efficacy analyses are planned.  Accrual, accumulation of PFS events and adverse 
events will be monitored throughout the trial and presented to the IBCSG Data and Safety 
Monitoring Committee (DSMC) approximately every six months.  
We prospectively plan two focused safety reviews of dose-reductions and treatment 
discontinuations because of toxicity (as described in Section 7.3) during the induction 
phase with nab-Paclitaxel 150 mg/m2 days 1,8,15 every 28 days for 3 cycles. The reviews 
will be done without regard to randomized treatment assignment because the induction 
phase is the same in each of the three treatment arms. If too few patients are able to 
complete the induction phase without dose reduction or treatment discontinuation 
because of toxicity (“complete”), then a modification of the induction phase treatment 
schedule will be considered.  

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The guidelines for decision-making are based on the principles of a two-stage design. 
Fewer than 80% of patients able to “complete” the induction phase is considered as too 
low, and at least 90% of patients able to “complete” the induction phase is considered as 
high enough. After treating 48 patients, 39 or fewer patients who “complete” would 
suggest that a change be considered, whereas greater than 39 patients who “complete” 
would suggest no change to the induction phase. Assuming the trial continues without 
change, after treating 120 patients, 101 patients is the critical value for decision-making at 
the second review. With these guidelines, if “completion” of the induction phase truly is 
too low, then there is an 0.081 probability of concluding that “completion” is not too low 
(target α=0.10). If “completion” is truly high enough, then there is a 0.064 probability of 
concluding that “completion” is not high enough (target β=0.10). If “completion” of the 
induction phase truly is too low, then there is a 0.649 probability of this conclusion and 
considering a change. 
The population for each of the safety reviews will be the first 48 (20%) and 120 (50%) 
consecutively randomized patients, after excluding any patient who never starts or 
discontinues treatment during the induction phase for a reason that is unrelated to toxicity 
(e.g., objective disease progression); any such patient will be documented as part of the 
review.    
Following the first safety review of 48 treated patients, it was decided to modify the dose 
in the induction phase to 125 mg/m². The second focused safety review as described 
above will not occur since it would come too late to have an impact on patients’ 
induction treatment. Summary of dose reduction and treatment discontinuation will 
continue to be part of regular monitoring throughout the trial that is presented to the 
IBCSG DSMC approximately every six months.  
12.4. Accrual 
The overall accrual goal of this study is 258 patients.  We originally anticipated that the 
accrual rate will be approximately 8 patients per month and the accrual will be completed 
within 30 months. As of the fourth quarter of 2014, an accrual duration of 24 to 26 months 
is anticipated. 
12.5. Data and Safety Monitoring Committee (DSMC) 
The study will be presented for review to the IBCSG DSMC at each of their semi-annual 
meetings. Accrual, safety and accumulation of PFS events will be monitored.  
13. 
Pathology and Translational Research 
13.1. Central pathology assessment 
One formalin fixed, paraffin-embedded (FFPE) block of the primary tumor, representative 
of the invasive component of the tumor (possibly including at least 5 mm invasive tumor 
and a minor component of non-neoplastic breast tissue) must be submitted to the IBCSG 
Central Pathology Office in Milan, Italy.  If a metastatic site was biopsied, an additional 
tumor block from the metastatic site should also be submitted.  
Central Pathology Review will be done on all the primary tumors and the metastatic 
biopsies, and will include histopathological parameters (tumor histology and grade, 

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occurrence of peritumoral vascular invasion), hormone receptors (estrogen and 
progesterone receptors), HER2 status, and proliferation (Ki-67 immunostaining).  
Central pathology review reports will be available to institution pathologists who wish to 
see them.  
13.2. Submitting biological material to IBCSG 
The following items are required for all randomized patients: 
1. One FFPE block of tumor from the primary tumor (breast lesion). This should include 
at least 5mm invasive tumor, and a minor component of normal breast tissue 
(whenever it is available). Availability of such a block is an eligibility criterion. 
And, if a metastatic site has been biopsied,  
2. One FFPE block from the diagnostic biopsy of the metastatic site 
All pathology reports, and FFPE blocks must be marked with the IBCSG patient ID number.  
Refer to the IBCSG website for additional FFPE specimen shipping recommendations, and 
to download the Pro Forma Invoice and IATA certification (“iata650”) templates that 
should be completed for international tissue shipments. 
Mailing address for the FFPE blocks and H&E slides: 
IBCSG Central Pathology Office 
European Institute of Oncology, EIO  
Division of Pathology  
Via Ripamonti 435  
20141 Milano, Italy  
E-mail: pathology.ibcsg@ieo.it 
13.3. Banking biological material  
IBCSG wants to be ready with a suitable tissue bank for assessing the prognostic role of 
putative marker (SPARC and caveolin) and also for unveiling new markers in the very near 
future.  All FFPE blocks will be banked in the IBCSG Tissue Bank, to have available for 
Translational Research.  If the return of the block is requested, cores (2-4 cores, 1mm thick) 
for tissue microarray (TMA) construction and cores (2-3 cores, 1mm thick) for banking for 
future translational research will be taken.  DNA will be extracted. 
All biological material will be logged in the IBCSG Pathology Material Tracking System 
/Translational Research System and banked in the IBCSG Tissue Bank.   
The use of the biological material for unspecified future research will be under the auspices 
of the IBCSG Biological Protocols Working Group and any project has to be approved by the 
IBCSG Ethics Committee.  As part of the informed consent process, patients are asked to 
indicate whether they agree to donate their sample for unspecified future research. The 
patient’s decision is recorded on the IBCSG Confirmation of Registration (A) Form. 
13.4. Translational research  
Based on preliminary results in pancreatic cancer and in breast cancer, we will investigate 
the prognostic role of SPARC and caveolin in the whole series of patients, and on both the 
primary tumor blocks and metastatic biopsies. Immunohistochemistry (IHC) for SPARC 

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requires staining of the samples both with a monoclonal antibody and a polyclonal 
antibody. Caveolin will require a single IHC assay with a monoclonal antibody.  These 
assays are added to the evaluation of the primary tumors to ascertain the actual 
prevalence of their expression in breast cancer.  IBCSG wants to assess any change in the 
expression of these markers between the primary and the metastatic sites, and therefore 
will re-stain all the metastatic samples to compare the results with the corresponding 
primaries (32,33). 
The IBCSG Central Pathology Office will be responsible for cutting and staining the sections, 
evaluation by a board-certified pathologist, quality control of at least 10% of the cases by a 
second board-certified pathologist, adjudication of the equivocal cases; data entry, data 
quality control by a data manager, banking of the slides and paraffin blocks.   
The expression of SPARC and caveolin will be compared between the primary and 
metastatic sites using Wilcoxon signed rank test. Assuming 90 (35% of 258) patients will 
have both primary and metastatic samples available, there will be 82% power to detect an 
effect size of 0.31 with a two-sided significance level 0.05. The effect size is defined as the 
difference in the expression of SPARC (or caveolin) between the primary and metastatic 
sites divided by the standard deviation of the difference. 
For the primary sites and metastatic sites separately, we will examine whether SPARC and 
caveolin are prognostic indicators for women with metastatic breast cancer. Patients will 
be classified by the average z-score algorithm into high-SPARC (average z-score ≥ 0) and 
low-SPARC group (average z-score < 0) (32).  We will compare PFS between the high-SPARC 
patients and low-SPARC patients. It is suspected that patients with high-SPARC have better 
PFS (32). Assume 50% of patients will have SPARC status evaluated and 50% of them are 
high-SPARC. Using two-sided log-rank test and Schoenfeld’s approximation, with all the 
treatment arms combined and with 95 events at the end of the study, we will have 80% 
power to detect 1.78 hazard ratio for low-SPARC / high-SPARC in PFS at a two-sided 
significance level of 0.05. The table below shows the hazard ratio for low-SPARC / high-
SPARC to be detected with at least 80% power based on various percentages of patients 
who will have SPARC analyzed. 
Table 12 – Detectable Hazard Ratio SPARC Analysis 
% of patients have SPARC analyzed  
40% 
(n=103) 
45% 
(n=116) 
50% 
(n=129) 
Hazard ratio (low-SPARC / high-SPARC) to be detected 
with enough power  
1.91 
1.84 
1.78 
For caveolin, the expression will be scored as (++), (+), or (-) according to the proportion of 
positively stained tumor cells (T) and stromal cells (S). The PFS of combined T(++)/S(-) 
status will be compared to others. It is suspected that T(++)/S(-) will be significantly 
correlated with unfavorable outcome (33). Assume 50% of patients will have caveolin 
status evaluated and 5% of them are T(++)/S(-). Using two-sided log-rank test and 
Schoenfeld’s approximation, with all the treatment arms combined and with 95 events at 
the end of the study, we will have 80% power to detect 3.8 hazard ratio for [T(++)/S(-)] 
/others in PFS at two-sided significance level of 0.05. The table below shows the hazard 
ratio for [T(++)/S(-)]/others to be detected with at least 80% power based on various 
percentages of patients who will have caveolin analyzed. 

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Table 13 – Detectable Hazard Ratio Caveolin Analysis 
% of patients have 
caveolin analyzed 
40% 
(n=103) 
45% 
(n=116) 
50% 
(n=129) 
Hazard ratio [T(++)/S(-)]/ 
others could be 
detected with enough 
power 
4.4 
4.0 
3.8 
PFS distributions will be summarized using the method of Kaplan-Meier. Cox regression 
analysis, adjusted by treatment effect, will be used to assess whether SPARC or caveolin is 
an independent predictor for PFS. 
14. 
Quality of Life 
14.1. Introduction 
In patients with HER-2 negative metastatic (stage IV) breast cancer, balancing the trade-
offs between treatment efficacy and side-effects is a key issue. Quality of life (QL) is an 
important outcome in this population, given the limited survival time. Endpoints evaluating 
the net benefit between efficacy and side-effects have commonly been defined as “clinical 
benefit” and have not included QL measures. Recently, these endpoints have been referred 
to as “disease control.” The common definition of disease control in patients with 
metastatic breast cancer is defined as complete (CR) or partial (PR) response, or stable 
disease (SD) for at least 6 months.  
Whether this endpoint could be used as a surrogate measure for patients’ perception of 
treatment effects in clinical trials is an important question. In an earlier trial, patients 
receiving second-line endocrine treatment for metastatic breast cancer differed in the 
perception of their QL from the established disease control endpoint (34). Although the 
groups with CR or PR, and those with SD for at least 6 months had similar times to 
treatment failure, patients with CR or PR reported substantially better QL, suggesting more 
beneficial response to the investigated treatments. This finding has not been replicated. 
14.2. Objectives 
The primary quality of life objective is to explore the change in QL over time until 
treatment discontinuation for patients on each treatment arm. 
 
Secondary objectives are: 
 To compare the change in physical well-being from baseline to 6 months (24 weeks) 
between treatment arms 
 To examine QL in patients with CR/PR as compared to QL in patients who have had 
SD for at least 6 months (or non-CR/non-PD in the case of non-measurable disease) 
 To examine the association between the QL scores at baseline and treatment 
feasibility 
QL endpoints include: physical well-being (primary endpoint), mood, coping effort, overall 
treatment burden, appetite, tiredness, hair loss and feeling sick (nausea/vomiting) as 
measured by linear analog self-assessment (LASA) indicators; sensory neuropathy as 

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measured by 4-item subscale of FACT/GOG-Ntx. Treatment feasibility is defined in Section 
2.4. 
14.3. Patient selection 
All patients randomized into IBCSG Trial 42-12 must complete QL questionnaires. There 
should be no patient selection within Participating Centers. Completion of the baseline 42-
QLC questionnaire is mandatory prior to randomization, and is thus considered an 
eligibility criterion in Section 4.1.  
14.4. QL design 
A monthly longitudinal assessment is used to assess differential effects of the randomized 
treatments on patients’ QL. Patients are asked to complete a QL questionnaire: 
 At baseline (prior to randomization) 
 At day 1 of every cycle for the first 12 cycles on trial treatment, or until treatment 
discontinuation, whichever occurs first. If baseline QL was within 14 days prior to 
treatment start, no QL form has to be completed at day 1 of cycle 1. It is important 
that the QL questionnaire is completed before any procedures or treatment, as 
described in Section 14.7.  
 At the end-of-treatment visit 
14.5. QL assessment 
In these patients, QL may be closely associated with the clinical efficacy of chemotherapy, 
functional status and psychological well-being (35). Key domains will be assessed by global 
linear analogue self-assessment (LASA) indicators: physical well-being defined as the 
primary QL endpoint (36), mood (37,38), coping effort (36,38) and overall treatment 
burden (39). Responses on these global indicators are expected to reflect the summation 
of the individual meaning and importance of various factors to each patient (40). These 
indicators are an alternative to a comprehensive standard assessment, as used for the 
comparison of paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast 
cancer (41); such a comprehensive approach is better suited for less frequent assessments. 
In addition, specific LASA indicators based on the GLQ-8 (42) for appetite, tiredness, hair 
loss and feeling sick (nausea/vomiting) will be included with an adapted wording. Finally, 
sensory neuropathy will be assessed by the 4-item subscale of the FACT/GOG-Ntx (43). This 
subscale is an efficient alternative in measuring this toxicity in clinical trials (44,45). The QL 
indicators are comprised in a one-page questionnaire. Patients need only a few minutes to 
complete it.  The LASA indicators range from 0 to 100. The FACT/GOG-Ntx subscale for 
sensory neuropathy range from 0 to 16. For all QL measures higher scores reflect a better 
condition (e.g., better physical well-being). 
14.6. Statistical considerations   
The QL portion of this trial is designed to assess patient-reported well-being, symptoms 
and side-effects over time for patients treated with three different schedules of nab-
Paclitaxel as first-line therapy in metastatic breast cancer.  The primary QL endpoint is 
physical well-being. We hypothesize that QL changes over time. We will examine this 

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hypothesis using a repeated measures model, controlling for stratification factors. 
Treatment will be included as a within-subject covariate with the identical values 
corresponding to the assessments of the first 3 induction cycles and the actual treatment 
assignment corresponding to the rest of the assessments. A covariate indicating different 
starting dose in induction (150 mg/m2 vs 125 mg/m2) will also be included. All patients with 
at least one QL assessment will be included into the analysis. This model will describe the 
effects of the randomized maintenance treatments on QL over the whole observation 
period. The impact of patients’ age will be explored.  
We suspect that the change in physical well-being from baseline to 6 months (24 weeks) 
after start of treatment differs between treatment arms. We consider statistical power 
based on the Wilcoxon rank sum test for comparing this change between treatment arms. 
Table 14 displays the effect sizes and powers for each pairwise treatment comparison, 
assuming a 25% or 40% missing rate across the treatment arms (i.e., 75% or 60% of 
patients having baseline and 24 week assessments) and a two-sided alpha-level of 0.05. 
Effect size is defined as the difference between two treatments arms of the change in 
physical well-being from baseline to 24 weeks divided by the common standard deviation 
of the two treatment arms. For example, assuming a 40% missing rate, a sample size of 86 
(52 per arm) will achieve 80% statistical power to detect an effect size of 0. 57 between 
two arms using a two-sided 0.05 level Wilcoxon rank sum test. These power calculations do 
not adjust for multiple comparisons. 
Table 14 – Effect Sizes by Statistical Power 
N1 
N2 
Missing rate 
80% Power 
85% Power 
90% Power 
86 
86 
25% 
.51 
.55 
.59 
86 
86 
40% 
.57 
.61 
.66 
 
We hypothesize that QL differs from baseline to 6 months (24 weeks) after start of 
treatment in patients with CR/PR as compared to patients who have had SD for at least 6 
months (or non-CR/non-PD in the case of non-measurable disease). We will test this 
hypothesis for the endpoints, physical well-being, mood and coping effort, using the 
Wilcoxon rank sum test.  In addition, the change in physical well-being from baseline to 6 
months after start of treatment will also be summarized for each treatment arm by 
different starting dose in induction (150 mg/m2 and 125 mg/m2) separately. 
The association between the QL baseline scores and treatment feasibility (completing 
treatment according to the protocol for at least 24 weeks) will be examined by comparing 
QL baseline scores between feasibility groups using the Wilcoxon rank sum test for each 
treatment arm separately. This will also be done for each arm separately by different 
starting dose in induction (150 mg/m2 and 125 mg/m2). 
Missing assessments may be due to stopping treatment, not completing the QL 
assessments, and other reasons. The reasons missing will be collected and reported. 
14.7. Timing requirements  
All QL questionnaires are to be completed during the patients’ visits in the clinic. The 
schedule of QL assessment time points must be followed as closely as possible. Timing 
effects have an impact on patients’ self-estimation of QL (46). It is important that the QL 

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questionnaire is completed before any diagnostic procedures or communication of 
diagnostic information to the patient (exception: baseline assessment) and before any 
administration of treatment. If, for administrative reasons, the form has not been 
presented to the patient, it may be filled in at home and mailed.  
14.8. Data collection and local data management 
For the first assessment, the QL questionnaire must be explained to the patient, with 
particular emphasis on making sure the patient understands both the LASA and the 
categorical response format. All questions must be answered. The completed 
questionnaire is to be checked while the patient is still present. If necessary, the patient 
should be asked to fill in missing answers. If the patient does not complete a scheduled QL 
assessment, an empty QL questionnaire should be faxed with the patient ID number and 
initials, the date the questionnaire was meant to be filled in, and the reason for not 
completing the questionnaire. 
Questions regarding QL assessment may be addressed to the IBCSG QL Office (see contact 
person and address on front page). 
15. 
Ethical aspects, regulatory approval, and patient informed consent 
The Investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual. The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline (January 1997) or with local law if it affords 
greater protection to the patient. For studies conducted in the EU/EEA countries, the 
Investigator will ensure compliance with the EU Clinical Trial Directive (2001/20/EC). 
15.1. Ethical Review Board/Ethics Committee 
All protocols and the patient informed consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The ERB/IRB 
written, signed approval letter/form must contain approval of the designated Investigator, 
the protocol (identifying protocol title and version number), and of the patient informed 
consent. Documentation of Ethics Committee approval(s) must be sent to the IBCSG Data 
Management Center prior to enrollment of the first patient. The IBCSG Ethics Committee 
also approves the protocol and reviews it annually. 
Any modifications made to the protocol will be reviewed by the IBCSG Ethics Committee 
and must also be submitted to the appropriate ERB/IRB for information or approval in 
accordance with local procedures and regulatory requirements and to Health Authorities if 
required.  
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities 
(if required), the Investigator shall implement the protocol modifications. Protocol 
modifications for urgent safety matters may be directly implemented following the 
instructions of IBCSG. 

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15.2. Regulatory approval procedures 
If applicable, in addition to the approval of the Ethics Committee according to national 
legislation, the protocol, other protocol-related documents including patient information 
and informed consent and other documents as required locally must be submitted to and 
be approved by the health authority. Documentation of health authority approval must be 
sent to the IBCSG Data Management Center prior to Participating Center activation. 
15.3. Protection of human subjects 
The IBCSG has an Office for Human Research Protection (OHRP) Federal Wide Assurance 
(FWA00009439) and follows all of the policies and procedures that are part of that 
assurance.  All potential subjects for this trial will receive a full explanation of the trial, its 
purpose, treatments, risks, benefits, and all of the other items listed in Section 15.4. 
Additional institution-specific sections should be added to Appendix I as described in 
Section 15.4. 
The medical record must be available for review by the IBCSG audit team and regulatory 
authorities as described in Section 16.4. 
Serious Adverse Event (SAE) Reports are distributed monthly. In addition they are available 
on the IBCSG website (www.ibcsg.org) for participating Centers. 
15.4. Informed consent  
Informed consent for each patient will be obtained prior to initiating any trial procedures 
in accordance with the “IBCSG Patient Information and Informed Consent" (See Appendix 
I). One signed and dated copy of the informed consent must be given to each patient and 
the original copy must be retained in the Investigator's trial records.  The Informed Consent 
Form must be available in the case of data audits. Verification of signed informed consent 
and the date signed are required for randomization to this trial.   
The "Declaration of Helsinki" recommends that consent be obtained from each potential 
patient in biomedical research trials after the aims, methods, anticipated benefits, and 
potential hazards of the trial, and discomfort it may entail, are explained to the individual 
by the physician (http://www.wma.net/en/30publications/10policies/b3/index.html).  The 
potential patient should also be informed of her right to not participate or to withdraw 
from the trial at any time.  The patient should be told that material from her tumor will be 
stored and potentially used for additional studies not described in this protocol.  
If the patient is in a dependent relationship to the physician or gives consent under duress, 
the informed consent should be obtained by an independent physician.  If the patient is 
legally incompetent (i.e., a minor, or mentally incompetent), informed consent must be 
obtained from the parent, legal guardian, or legal representative in accordance with the 
law of the country in which the trial is to take place.  By signing this protocol, the 
Investigator agrees to conduct the trial in accordance with Good Clinical Practice and the 
"Declaration of Helsinki."  
The IBCSG recognizes that each institution has its own local, national, and international 
guidelines to follow with regard to informed consent.  Therefore, we provide a template 
Information Sheet and Informed Consent Form (Appendix I), which can be downloaded and 
edited to incorporate information specific to your institution (see www.ibcsg.org). The 

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template Patient Information Sheet and Informed Consent has been written according to 
ICH guidelines which state the Informed Consent should adhere to GCP and to the ethical 
principles that have origin in the “Declaration of Helsinki.” The final version should receive 
the Institutional Review Board/ Local Ethics Committee approval in advance of its use. 
Centers should send their locally modified PIS/IC to the IBCSG Data Management Center 
for review and approval before submitting to their Ethics Committee.  
15.5. Premature withdrawal  
15.5.1. Withdrawal from trial treatment 
Patients have the right to refuse further trial treatment at any time during the trial. 
Patients may also be withdrawn at any time from trial treatment at the discretion of the 
Investigator due to an adverse event, or based on any other relevant medical condition. 
Such patients will remain in the trial and will be transferred to the follow-up phase. For the 
patient’s safety, a last examination (end-of-treatment visit) should be performed and 
documented in the corresponding iDataFax forms. 
15.5.2. Withdrawal of consent 
Patients have the right to withdraw consent for further trial participation at any time 
without having to specify the reason. The data recorded up to the timepoint of withdrawal 
will continue to be evaluated in the trial. The Investigator should ask the patient for her 
consent to continue to collect information on her disease and survival status. 
It should be documented in both the medical records and in the eCRF (Form 42-COC) 
whether it is acceptable for the patient to be contacted for survival status updates despite 
her withdrawal of study consent. 
16. 
Governance and Administrative Considerations 
16.1. Insurance 
IBCSG will contract the appropriate liability insurance for this trial. Patients who suffer 
injuries due to the trial should report them immediately to their physician. The local 
Group/Center should report all alleged claims immediately to the IBCSG. 
The IBCSG insurance does NOT cover patients from the United States of America or from 
Canada.   
16.2. Steering Committee 
A Steering Committee will be constituted for this trial. The primary responsibilities of the 
Steering Committee are twofold. First, the Steering Committee is responsible for 
maintaining the scientific integrity of the trial, for example, by recommending changes to 
the protocol in light of emerging clinical or scientific data from other trials. Second, the 
Steering Committee is responsible for translation of recommendations of the IBCSG Data 
and Safety Monitoring Committee into decisions. Membership will include IBCSG officials, 
study chair and co-chairs, trial statisticians, representatives from some participating 
Centers and Groups, and representatives from Celgene. 
General partition of responsibilities: 

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The Steering Committee has the authority to make and implement any final decisions, such 
as substudies of the trial or amendments to the trial protocol, and may recommend the 
termination/early termination of the trial. 
The IBCSG Executive Committee is responsible for the implementation of all final decisions 
taken by the Steering Committee. 
The IBCSG Foundation Council decides on the termination/early termination of the trial. 
16.3. Premature discontinuation of the trial 
The trial may be discontinued early in part or completely if the information on the product 
leads to doubt as to the benefit/risk ratio. 
16.4. Quality assurance and monitoring 
The IBCSG conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The 
Trial IBCSG Data Manager reviews each CRF as it is received. In addition, the IBCSG Medical 
Reviewer reviews each case at specific timepoints.  The IBCSG conducts periodic audit visits 
to ensure proper trial conduct, verify compliance with GCP, and perform source data 
verification. 
The Investigator should ensure that source documents are made available to appropriately 
qualified personnel from IBCSG, Celgene Quality Assurance Group or its designees, or to 
health authority inspectors after appropriate notification. 
At regular intervals during the clinical trial, the Center will be contacted, through 
monitoring visits, letters or telephone calls, by a representative of the Monitoring Team to 
review study progress, Investigator and patient compliance with clinical trial protocol 
requirements and any emergent problems. These monitoring visits will include but not be 
limited to review of the following aspects: patient informed consent, patient recruitment 
and follow-up, SAE documentation and reporting, AEs with pre-specified monitoring 
documentation and reporting, AE documentation, nab-Paclitaxel administration, patient 
compliance with the regimens, drug accountability, concomitant therapy use and quality of 
data. 
16.5. Data protection 
A unique Patient Identification Number (ID) will be attributed by the IBCSG Registration/ 
Randomization System to each patient randomized into the trial. The names of the patients 
will not be disclosed to the IBCSG.  
Only the patient ID will be used to identify the patient on the CRF. Identification of patients 
must be guaranteed at the participating Center. In order to avoid identification errors, 
Centers should keep a Patient Identification Log containing the patients’ name, year of 
birth, hospital number and the ID allocated by IBCSG. 
Regulatory authorities and the pertinent Ethics Committee (ERB/IRB) may have access to 
patient data on-site. IBCSG audit or monitoring personnel will also have access to such data 
on-site. 

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16.6. Record retention 
The Center must retain all essential documents according to ICH GCP. This includes copies 
of the patient trial records, which are considered as source data, patient informed consent 
statement, laboratory printouts, drug inventory and destruction logs, and all other 
information collected during the trial. These documents are to be stored until at least 15 
years after the termination of the trial. IBCSG guarantees access and availability of the data 
entered into iDataFax for at least 15 years after the termination of the trial. 
Longer retention may be required for participating Centers according to national 
regulations. 
In the event that the Principal Investigator retires or changes employment, custody of the 
records may be transferred to another competent person who will accept responsibility for 
those records. Written notice of such transfer has to be given to IBCSG and the local Ethics 
Committee at least one month in advance. 
16.7. Confidentiality 
The protocol, CRFs and other protocol-related documents are confidential and are the 
property of the IBCSG. 
17. 
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18. 
List of abbreviations  
 
ADL 
Activities of daily living 
ATC 
Anatomical therapeutic chemical 
AE 
Adverse event 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
NCI CTCAE National Cancer Institute common toxicity criteria for adverse events 
DCR 
Disease control rate 
DMC 
Data Management Center (IBCSG) 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ER 
Estrogen receptor 
FFPE 
Formalin fixed paraffin embedded 
FSTRF 
Frontier Science and Technology Research Foundation 
GCP 
Good clinical practice 
GI 
Gastro-intestinal 
H&E 
Hematoxylin and eosin 
HER2 
Human epidermal growth factor 2 
HR 
Hazard ratio 
IATA 
International Air Transport Association 
IBCSG 
International Breast Cancer Study Group 
IC 
Informed consent 
ICH 
International conference on harmonization 
iDF 
iDataFax 
LASA 
Linear analog self-assessment 
NYHA 
New York Heart Association 
OS 
Overall survival 
PFS 
Progression-free survival 
PgR 
Progesterone receptor 
PD 
progressive disease 
PR 
Partial response 
QC 
Quality control 
QL 
Quality of life 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SD 
Stable disease 
SPARC 
Secreted protein, acidic, cysteine-rich (osteonectin) 
SPC 
Summary of product characteristics 
TL 
Target lesions 
ULN 
Upper limit of normal 
UN 
Unknown 
USP 
United States pharmacopeial convention