Observational and Prospective Study to Develop Predictive and Prognostic Tools for Optimizing Therapy With Bevacizumab Frontline Cancer Therapy in Patients With Metastatic HER 2-Negative and Aggressive Disease Criteria
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche

 
Official Title: 
 
OBSERVATIONAL AND PROSPECTIVE STUDY TO DEVELOP 
PREDICTIVE AND PROGNOSTIC TOOLS FOR OPTIMIZING 
THERAPY WITH BEVACIZUMAB FRONTLINE CANCER 
THERAPY IN PATIENTS WITH METASTATIC HER 2-NEGATIVE 
AND AGGRESSIVE DISEASE CRITERIA.  
ARGO STUDY. 16th DECEMBER 2016  
NCT Number: 
NCT02613208 
Document Date: 
Protocol Version 2: 01-February-2017 
 
 

TITLE: 
OBSERVATIONAL AND PROSPECTIVE STUDY TO 
DEVELOP PREDICTIVE AND PROGNOSTIC TOOLS 
FOR OPTIMIZING THERAPY WITH BEVACIZUMAB 
FRONTLINE CANCER THERAPY IN PATIENTS 
WITH METASTATIC HER 2-NEGATIVE AND 
AGGRESSIVE DISEASE CRITERIA.  
ARGO STUDY. 16TH DECEMBER 2016 
PROTOCOL NUMBER: 
ML29756 /ROC-BEV-2015-01 
VERSION NUMBER: 
2 
DATE OF LAST VERSION: 
16TH December 2016 
MEDICINAL PRODUCT{S}: 
Paclitaxel-Bevacizumab 
SPONSOR: 
Roche Farma S.A. 
DATE FINAL: 
16TH December 2016 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics 
Committee or Institutional Review Board.  It is understood that this information will not be disclosed to 
others without written authorization from Roche except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
Paclitaxel-bevacizumab—F. Hoffmann-La Roche Ltd 
Protocol ML29756, Version 2 (16th December 2016) 

PROTOCOL ACCEPTANCE FORM 
TITLE: 
OBSERVATIONAL AND PROSPECTIVE STUDY TO 
DEVELOP PREDICTIVE AND PROGNOSTIC 
TOOLS FOR OPTIMIZING THERAPY WITH 
BEVACIZUMAB FRONTLINE CANCER THERAPY 
IN PATIENTS WITH METASTATIC HER 2-
NEGATIVE AND AGGRESSIVE DISEASE 
CRITERIA. ARGO STUDY. 16TH DECEMBER 2016 
PROTOCOL NUMBER: 
ML29756 /ROC-BEV-2015-01 
VERSION NUMBER: 
2 
MEDICINAL PRODUCT{S}: 
Paclitaxel-Bevacizumab  
SPONSOR: 
Roche Farma S.A. 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
Date 
 
 
 
Please return the signed original of this form  to the contact provided below.  Please 
retain a copy for your study files. 
  
Roche Farma. C/Eucalipto 33. 28035 Madrid.  
 
 
 
Paclitaxel-Bevacizumab—F. Hoffmann-La Roche Ltd 
Protocol ML29756, Version 1(16th December 2016) 

PROTOCOL AMENDMENT, VERSION 2: 
JUSTIFICATION 
 
The ML29756 study protocol has been modified in order to extend the recruitment period, 
until March 2017, as the inclusion period initially established in the protocol, and that 
finished one year after the inclusion of the first patient (9th December 2016), has not 
allowed us to reach the study’s sample size.  
At the same time, patients’ follow up period has been reduced from 12 to 6 months after 
completing the treatment period in order not to delay the obtainment of clinical 
conclusions in the timelines initially set, due to the extension of the recruitment period, 
as the duration of the follow up period does not affect any of the study objectives. 
To improve the quality and consistence, other minor changes have been performed to 
the protocol. Due to a mistake in the previous version, the definition of Clinical Benefit 
Rate has been modified. The significant information that has been added appears 
tracked in the version document in italics. This amendment shows the changes added to 
the original protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Paclitaxel-Bevacizumab—F. Hoffmann-La Roche Ltd 
Protocol ML29756, Version 1(16th December 2016) 
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Milestones 
Study milestones are given in the following table. 
Milestone 
Planned Date 
Start of data collection 
Q42015 
End of data collection 
Q42018 Q22018 
Final report of study results 
Q42019 Q22019 
 
 
 
Medicine 
…The expected bevacizumab dose will be 10 mg/m2 kg day 1 and 15 every four weeks. 
 
 
 
SECTION 5: MILESTONES 
 
Milestone 
Planned Date 
Start of data collection 
Q42015 
End of data collection 
Q42018 Q22018 
Final report of study results 
Q42019 Q22019 
 
 
SECTION 7.2: OBJECTIVES  
Effectiveness Objectives 
To determine the predictive capacity of early CTCs monitoring predefined as sensitive 
(<5 CTCs after cycle 2) and resistant (>5 CTCs after cycle 2) in terms of Clinical Benefit 
Rate (defined as patients achieving partial or complete response as well as tumor 
stabilization < ≥  24 weeks) 
SECTION 8.1.: STUDY DESIGN 
…The development of the study involves the prospective collection of data for 24 18  
months after initiation of therapy. 
SECTION 8.1.1: OVERVIEW OF STUDY DESIGN 
…The development of the study involves the prospective collection of data for 24 18   
months after initiation of therapy. The total duration of the study comprise approximately 
36 33 months.  Approximately, the inclusion will start in October 2015 and will end in 
October 2016 March 2017. The last patient last visit is planned in October 2018 October 
2019. These dates may vary due to the approval process. 
… The expected bevacizumab dose will be 10 mg/m2 kg day 1 and 15 every four weeks. 
…All patients will be followed for up to 24 18 months from the start of treatment 
(including those who discontinue study treatment for any reason other than PD). 
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SECTION 8.1.4.: Rationale for Study Design 
… A prospective design is chosen where the CTC levels are obtained according the 
clinical practice before the initiation of first line treatment and patients are followed for 24 
18 months to evaluate the treatment response.  
SECTION 8.2.: POPULATION 
…Approximately, the inclusion will start in October 2015 and will end in October 2016 
March 2017.  
 
SECTION 8.2.2.: Dosis, Administración, y Cumplimiento 
…The expected bevacizumab dose will be 10 mg/m2 kg day 1 and 15 every four weeks. 
SECTION 8.3.1.: Primary Effectiveness Variable 
The primary variable is the clinical benefit rate during the study follow-up which will be 
assessed according to CTC levels. Clinical benefit rate is defined as patients achieving 
partial or complete response as well as tumor stabilization < ≥ 24 weeks…. 
SECTION 8.4.4: Data Collected During Follow-Up 
The follow up period cover one year approximately 6 months after the last dose of study 
treatment. 
 
SECTION 8.6.5.: Sample Size Justification 
The calculation of sample size was based on the determination of the main objective: " 
To determine the predictive capacity of early CTCs monitoring predefined as sensitive 
(<5 CTCs after cycle 2) and resistant (>5 CTCs after cycle 2) in terms of Clinical Benefit 
Rate (defined as patients achieving partial or complete response as well as tumor 
stabilization < ≥ 24 weeks)…. 
SECTION 8.8.3.: Administrative Structure 
, Roche Farma S.A. 
. Statistician 
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Protocol ML29756, Version 1(16th December 2016) 
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TABLE OF CONTENTS 
PROTOCOL FINALIZATION SIGNATURE PAGE ............................................... 2 
PROTOCOL ACCEPTANCE FORM .................................................................... 3 
1. 
LIST OF ABBREVIATIONS ......................................................................... 13 
2. 
RESPONSIBLE PARTIES .......................................................................... 16 
3. 
SYNOPSIS .................................................................................................. 17 
4. 
PROTOCOL AMENDMENTS AND UPDATES ........................................... 26 
5. 
MILESTONES ............................................................................................. 26 
6. 
RATIONALE AND BACKGROUND............................................................. 27 
6.1 
Background on metastatic breast cancer............................... 27 
6.2 
Background on paclitaxel-bevacizumab ................................ 27 
6.3 
Study Rationale ..................................................................... 29 
7. 
RESEARCH QUESTION AND OBJECTIVES ............................................. 30 
7.1 
Research Question ................................................................ 30 
7.2 
Objectives .............................................................................. 31 
8. 
RESEARCH METHODS ............................................................................. 32 
8.1 
Study Design ......................................................................... 32 
8.1.1 
Overview of Study Design ..................................................... 32 
8.1.2 
Number of Patients Observed in the Study ............................ 33 
8.1.3 
Centers .................................................................................. 33 
8.1.4 
Rationale for Study Design .................................................... 33 
8.1.5 
Rationale for Patient Population and Analysis 
Groups 
33 
8.2 
Population .............................................................................. 33 
8.2.1 
Concomitant Medication and Treatment ................................ 35 
8.2.2 
Dosage, Administration, and Compliance .............................. 35 
8.3 
Variables ................................................................................ 35 
8.3.1 
Primary Effectiveness Variable. ............................................. 35 
8.3.2 
Secondary Effectiveness Variables ....................................... 36 
8.3.3 
Safety Variables .................................................................... 36 
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8.3.4 
Other Variables of Interest ..................................................... 36 
8.4 
Treatment efficacy evaluation Data Collection ....................... 37 
8.4.1 
Collection of Data on the CRF ............................................... 37 
8.4.2 
Data Collected during the Observation Period ....................... 37 
8.4.3 
Data Collected at Study Completion/Early 
Termination Visit ...................................................................................... 39 
8.4.4 
Data Collected during Follow-Up ........................................... 40 
8.4.5 
Safety Data Collection ........................................................... 40 
8.4.6 
Retrospective Data Collection ............................................... 41 
8.5 
Patient, Study, and Site Discontinuation ................................ 41 
8.5.1 
Patient Discontinuation .......................................................... 41 
8.5.2 
Discontinuation from Treatment with Medicinal 
Product 
41 
8.5.3 
Withdrawal from Study........................................................... 41 
8.5.4 
Study and Site Discontinuation .............................................. 42 
8.6 
Statistical Considerations ...................................................... 42 
8.6.1 
General Considerations ......................................................... 42 
8.6.2 
Analysis Populations ............................................................. 42 
8.6.3 
Analysis Methods .................................................................. 42 
8.6.3.1 Primary Effectiveness Analysis ............................................ 43 
8.6.3.2 Secondary Effectiveness Analysis........................................ 43 
8.6.3.3 Safety Analysis ..................................................................... 43 
8.6.3.4 Other Analyses ..................................................................... 44 
8.6.4 
Interim Analyses .................................................................... 44 
8.6.5 
Sample Size Justification ....................................................... 44 
8.7 
Data Management ................................................................. 44 
8.7.1 
Data Quality Assurance ......................................................... 44 
8.7.2 
Electronic Case Report Forms ............................................... 45 
8.7.3 
Source Data Documentation .................................................. 45 
8.7.4 
Use of Computerized Systems .............................................. 46 
8.7.5 
Retention of Records ............................................................. 46 
8.8 
Study Documentation, Monitoring, and 
Administration ........................................................................ 46 
8.8.1 
Study Documentation ............................................................ 46 
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8.8.2 
Site Audits and Inspections ................................................... 47 
8.8.3 
Administrative Structure......................................................... 47 
8.9 
Limitations of the Research Method ...................................... 47 
8.10 
Other Aspects ........................................................................ 47 
9. 
PROTECTION OF HUMAN SUBJECTS/ETHICAL 
CONSIDERATIONS .................................................................................... 47 
9.1 
Compliance with Laws and Regulations ................................ 47 
9.2 
Informed Consent .................................................................. 47 
9.3 
Institutional Review Board or Ethics Committee .................... 48 
9.4 
Confidentiality ........................................................................ 49 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ 
ADVERSE REACTIONS ............................................................................. 49 
10.1 
Safety Parameters and Definitions ........................................ 49 
10.1.1 
Adverse Events ..................................................................... 49 
10.1.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ........................................................................................ 50 
10.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ................................................ 51 
10.1.4 
Non-Serious Adverse Events other than Adverse 
Events of Special Interest ........................................................................ 51 
10.2 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 51 
10.2.1 
Adverse Event Reporting Period ........................................... 52 
10.2.2 
Assessment of Severity of Adverse Events ........................... 52 
10.2.3 
Assessment of Causality of Adverse Events ......................... 53 
10.2.4 
Procedures for Recording Adverse Events ............................ 54 
10.2.4.1 Infusion-Related or Injection Reactions .............................. 54 
10.2.4.2 Diagnosis versus Signs and Symptoms ............................. 54 
10.2.4.3 Adverse Events Occurring Secondary to 
Other Events ...................................................................................... 54 
10.2.4.4 Persistent or Recurrent Adverse Events ............................ 55 
10.2.4.5 Abnormal Laboratory Values .............................................. 55 
10.2.4.6 Abnormal Vital Sign Values ................................................ 56 
10.2.4.7 Abnormal Liver Function Tests ........................................... 57 
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10.2.4.8 Deaths ................................................................................ 57 
10.2.4.9 Preexisting Medical Conditions .......................................... 57 
10.2.4.10 Lack of Therapeutic Efficacy or Worsening of 
Metastatic Breast Cancer ................................................................... 58 
10.2.4.11 Hospitalization or Prolonged Hospitalization .................... 58 
10.2.4.12 Overdoses, Misuses, Abuses, Off-Label Use, 
Occupational Exposure, or Medication Error ...................................... 58 
10.3 
Reporting Requirements from Physician 
to Sponsor ............................................................................. 59 
10.3.1 
Immediate Reporting Requirements from 
Physician to Sponsor ............................................................................... 59 
10.3.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of Special Interest .................. 59 
10.3.3 
Reporting Requirements for Non-Serious 
Adverse Drug Reactions .......................................................................... 60 
10.3.4 
Reporting Requirements for 
Pregnancies/Breastfeeding ...................................................................... 60 
10.3.4.1 Pregnancies/Breastfeeding in Female Patients .................. 60 
10.3.4.2 Pregnancies in Female Partners of Male 
Patients 60 
10.3.4.3 Abortions ............................................................................ 61 
10.3.4.4 Congenital Anomalies/Birth Defects ................................... 61 
10.4 
Follow-Up of Patients after Adverse Events .......................... 61 
10.4.1 
Physician Follow-Up .............................................................. 61 
10.4.2 
Sponsor Follow-Up ................................................................ 61 
10.5 
Post-Study Adverse Events ................................................... 62 
10.6 
Expedited Reporting to Health Authorities, 
physicianS, Institutional Review Boards, and 
Ethics Committees ................................................................. 62 
10.7 
IF EDC system is temporarily unavailable or not 
used ....................................................................................... 62 
11. PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS ................................................................................................... 63 
12. REFERENCES ........................................................................................... 64 
 
 
 
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LIST OF TABLES 
Table 1. Adverse Event Severity Grading Scale ............................................................ 53 
 
 
LIST OF APPENDICES 
Appendix 1 List of Stand-Alone Documents Not Included in the Protocol, 65 
Appendix 2 Data Collection Overview (as per Standard of Care, 66 
Appendix 3 Procedures of extraction, processing and shipment of samples of 
Circulating Tumor Cells (CTCs), 68 
 
 
 
 
 
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1. 
LIST OF ABBREVIATIONS 
Abbreviation Definition 
AE 
Adverse Event. 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin 
Time 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen  
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CR 
Complete Response 
CRO 
Contract Research Organization 
CTC 
Circulating Tumor Cells 
CTCAE 
Common Terminology Criteria for 
Adverse Events 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology 
Group  
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
ENCePP 
European Network of Centers for 
Pharmacoepidemiology and 
Pharmacovigilance 
ePRO 
Electronic Patient-Reported 
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Abbreviation Definition 
Outcome 
ER 
Estrogen Receptor 
FDA 
Food and Drug Administration 
FPFV 
First Patient First Visit 
GPP 
Good Pharmacoepidemiological 
Practice 
HER 2 
Human Epidermal Growth Factor 
Receptor-Type2 
IARC 
International Agency for Research 
on Cancer  
ICH 
International Conference on 
Harmonisation 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISPE 
International Society of 
Pharmacoepidemiology 
LDH 
Lactate Dehydrogenase  
LPLA 
Last Patient Last Assessment 
LPLV 
Last Patient Last Visit 
MBC 
Metastatic Breast Cancer 
NCI 
National Cancer Institute 
NPV 
Negative Predictive Value  
OR 
Overall Response 
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Abbreviation Definition 
OS  
Overall Survival 
P 
Progression 
PDS 
Pharma Development Safety 
PFS 
Progression-free Survival 
PPV 
Positive Predictive Value  
PR 
Partial Response 
PR 
Progesterone Receptor 
QPPV 
Qualified Person for 
Pharmacovigilance 
RBC 
Red blood cell 
ROC 
Receiver Operating Curve  
SAE 
Serious Adverse Event 
SD  
Stable Disease 
SDV 
Source Data Verification 
SPC 
Summary of Product 
Characteristics 
SPSS 
Statistical Package for the Social 
Sciences  
STIAMP 
Suspected Transmission of 
Infectious Agent by Medicinal 
Product 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
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2. 
RESPONSIBLE PARTIES 
 
, Roche Farma S.A. 
 
Main Authors: 
  Dr. 
 
. Tfno: 
 
 
Dr. 
 
 
. Tfno: 
 
 
Dr. 
 
. Tfno: 
 
 
Dr. 
 
. Tfno: 
 
  
 
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3. 
SYNOPSIS 
TITLE: 
OBSERVATIONAL AND PROSPECTIVE STUDY TO 
DEVELOP PREDICTIVE AND PROGNOSTIC TOOLS 
FOR OPTIMIZING THERAPY WITH BEVACIZUMAB 
FRONTLINE CANCER THERAPY IN PATIENTS WITH 
METASTATIC HER 2-NEGATIVE AND AGGRESSIVE 
DISEASE CRITERIA
PROTOCOL NUMBER: 
ML29756 /ROC-BEV-2015-01 
VERSION NUMBER: 
2 
DATE OF PROTOCOL: 
16th December 2016 
MEDICINAL PRODUCT: 
Paclitaxel-Bevacizumab  
INTERNATIONAL 
MEDICAL LEADER: 
 
MAIN AUTHOR: 
Dr. 
 
Dr. 
 
Dr. 
 
Dr. 
  
PHASE: 
IV, non-interventional study 
INDICATION: 
Metastasic breast cancer  
SPONSOR: 
Roche Farma S.A. 
Rationale and Background 
Bevacizumab is a humanized antibody directed against VEGF-A, a potent 
angiogenic agent shown to be a determinant in the growth and spread of cancer 
in humans. The use of the combination of different cytotoxic agents with 
bevacizumab in advanced breast cancer has shown consistent benefits in 
Progression Free Survival (PFS) and response rates. However, no trial or meta-
analysis has identified a benefit in overall survival for the bevacizumab 
combinations. The absence of global survival before the IMELDA study data 
may have limited the incorporation of this active agent in clinical practice. 
The IMELDA study (Gligorov et al. 2014), one of the second-generation clinical 
trials on breast cancer with bevacizumab as first line treatment, has explored an 
original argument. All MBC patients received docetaxel plus bevacizumab as 
first line therapy (winning arm of the AVADO (Miles DW, et al. 2010) study) for a 
total of six cycles [in the absence of progression]). Patients underwent a 
response evaluation after the sixth cycle; and those that did not present 
progression criteria (stable disease or response) were randomized to 
maintenance with bevacizumab or to bevacizumab in combination with a second 
cytostatic (capecitabine), until disease progression or toxicity. The study shows 
a dramatic benefit in PFS (PFS: 4.3 vs. 11.9 months; Hazard ratio 0.38; p 
<.0001) and Overall Survival (OS) (median OS 23.7 vs 39.0 months; Hazard 
ratio 0.43; p= 0.0003) in favor of the combination. This study optimizes the 
efficacy of bevacizumab, confirming its synergic effect with chemotherapy. 
Therefore, prolonging low intensity chemotherapy with capecitabine plus 
bevacizumab in sensitive patients achieves survival benefits similar to those 
reported with trastuzumab in the HER2-positive population. 
The main limitation of this study is that fails in making an early detection of the 
patients who do not benefit from the treatment with bevacizumab. Since the 
absence of efficacy was defined as progression within the first six cycles of 
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chemotherapy, it did not limit the administration of bevacizumab to truly 
sensitive patients. The IMELDA study stresses the need for an early detection of 
tumor resistance to the combination.  
These data globally concur with an observation made by another clinical study 
(unpublished and blinded data). This study included over 2.200 patients treated 
first line with a bevacizumab-containing regimen, and it showed that overall 
survival maintained a close correlation with the efficacy of the first line treatment. 
Patients with a CR(n = 204; Median OS not achieved, but >40 months), partial 
objective response (n = 1.022; OS 27.4 months) or SD for more than 24 weeks 
(n = 507, OS 26.8 months) obtained higher survival figures than the patients 
who displayed progression before 24 weeks (n = 435, OS 11.3 months). In total, 
20% patients did not reach clinical benefit criteria (progression within 24 weeks) 
to the first line treatment (figure 1). 
Interestingly, when we compare the OS figures from this study and IMELDA, the 
median OS for the control "sensitive" arm (maintaining bevacizumab after six CT 
cycles) moves to 27.2 months (23.7 and median treatment duration on the initial 
phase is 3.5 months); similar to the 27.8 months from the non-resistant group 
(SD >24 weeks + PR + CR; n = 1,733) 
Figure 1. Correlation between overall survival according to best 
response to bevacizumab first line treatment. Total sample analysis 
(N=2264) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*96 patients are excluded. Their responses were not evaluated in the study. 
** The median survival was not estimated because the survival probability 
in CR group is higher than 50%. 
CR: Complete response, PR: Partial response, SD: Stable Disease, PD: 
Progressive disease, 95%CI: 95% confidence interval. 
 
The determination of Circulating Tumor Cells (CTCs) in blood of Metastatic 
Breast Cancer (MBC) patients is a well-established prognostic and predictive 
marker of efficacy/resistance. An initial determination of CTCs superior to 5 
CTCs/ 7.5 ml confers a worse PFS and OS rates to first line chemotherapy 
compared to lower CTC values indicating that it works both as an early marker 
for treatment resistance and survival. Additionally, the persistence of values ≥ 5 
CTCs/ 7.5 ml after the first cycle/weeks of chemotherapy is an early marker for 
resistance (Cristofanilli M et al. 2004). 
 
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R e c e ntl y, t h e S W O G S 0 5 0 0 st u d y ( S m er a g e J B et al. 2 0 1 4) st u d y h a s e x pl or e d 
t h e  a bilit y  of  C T C s  a s  pr o g n o sti c  a n d  pr e di ct or  m ar k ers t o l e a d  t o e arl y 
tr e at m e nt c h a n g e s i n p ati e nt s wit h r e si st a nt crit eri a t u m or s. T h e st u d y c o nfir m e d 
t h e p o s si bilit y  of  m o nit ori n g  C T C s  t o  pr e di cti v e  e arl y  s e n siti vit y  t o  t h e  fir st  li n e 
tr e at m e nt a s w ell a s pr o g n o si s. H o w e v er, it f ail e d i n t h e pri m ar y st u d y o bj e cti v e 
of  t h e  st u d y,  a s  n o  diff er e n c e  i n  P F S  or  O S  w a s  o b s er v e d  w h e n  p ati e nt s w h o 
m ai nt ai n e d ≥ 5  C T C s  aft er  3 -5  w e e k s  o n  t h er a p y  w er e  r a n d o mi z e d  t o  eit h er  
m ai nt ai n t h e fir st li n e t h er a p y ( n = 6 2; P F S/ O S 3. 5 a n d 1 0. 7 m o nt h s) or c h a n g e d  
t o a n o n-cr o s s -r e si st a nt r e gi m e n ( n = 6 0; 4. 6 a n d 1 2. 5 m o nt h s).  
H o w e v er, t h e S W O G S 0 5 0 0 st u d y all o w e d  f or 
t h e e x p e ct e d p att er n s of p o p ul ati o n wit h b a s al 
C T C s < 5 a n d ≥ 5 t o b e e st a bli s h e d, a s w ell a s 
t h o s e of t h e p o p ul ati o n s wit h n or m ali z ati o n / n o-
n or m ali z ati o n o n t h e 3 -5 w e e k s d et er mi n ati o n.  
% 
P ati e nt s  
P F S  
O S  
B a s al C T C s < 5  
4 5 -4 9 %  1 1, 1  
3 5  
B a s al C T C s ≥ 5 a n d s u b s e q u e nt < 5  
2 9 -3 2 %  
8. 9  
2 3  
B a s al a n d s u b s e q u e nt ≥ 5 C T C s  
2 2 %  
4. 9  
1 3  
 
D u e  t o  t h e  af or e m e nti o n e d,  o ur  h y p ot h e si s  s u p p ort s  t h at  a n  e arl y  C T C 
m o nit ori n g; b a s al  a n d aft er s e c o n d c y cl e i n p ati e nt s i niti ati n g fir st li n e p a clit a x el 
pl u s  b e v a ci z u m a b  c h e m ot h er a p y;  will  i d e ntif y  t w o  p o p ul ati o n s  wit h  a  v er y 
diff er e nt  P F S  r e s ult s;  t h e  p o p ul ati o n  wit h  m ai nt ai n e d  hi g h  C T C  l e v el s (≥ 5 
C T C s  i n  b ot h  d et er mi n ati o n s)  will pr o gr e s s  s h ortl y  e x p e ct i n g a  m e di a n  P F S  of 
4. 0 m o nt h s, w hil e t h o s e wit h a l o w C T C d et er mi n ati o n ( b a s al or aft er t h e s e c o n d 
c y cl e) will a c hi e v e m e di a n P F S  i n t h e r a n g e of  1 3 m o nt h s.  
 
T h e  C T C  m o nit ori n g  c o ul d  b e c o m e  a  u s ef ul  t o ol  f or  e arl y  pr e di cti o n  of 
s e n siti vit y/r e si st a n c e  t o  b e v a ci z u m a b  r e gi m e n s.  T h e  S W O G  S 0 5 0 0  tri al h a s 
c o nfir m e d  t h at  t h er e  i s  n o  b e n efit  fr o m  c h a n gi n g  t h e  c yt ot o xi c  a g e nt  or 
c o m bi n ati o n  f or  p ati e nt s  wit h  a  r e si st a nt  C T C  pr ofil e  t o  t h e  fir st  r e gi m e n.  S e e n 
fr o m  a  diff er e nt  p oi nt  of  vi e w,  it  m a k e s  s e n s e  t h at  f or  p ati e nt s  wit h  n o  C T C 
n or m ali z ati o n  f oll o wi n g  t h e  fir st  c y cl e s t h er e  i s  littl e  m ar gi n al  b e n efit  fr o m 
m ai nt ai ni n g b e v a ci z u m a b i n st e a d of m o vi n g t h e p ati e nt t o si n gl e a g e nt p a clit a x el.  
T hi s st u d y will i d e ntif y a p o w erf ul a n d e a s y pr e di cti v e/ pr o g n o sti c m ar k er t o dri v e 
p ati e nt s u n d er b e v a ci z u m a b.  
 
R e s e ar c h Q u e sti o n a n d O bj e cti v e s  
Eff e cti v e n e s s O bj e cti v e s  
T h e pri m ar y eff e cti v e n e s s o bj e cti v e of t hi s st u d y i s a s f oll o w s: 
•  T o d et er mi n e t h e pr e di cti v e c a p a cit y of e arl y C T C s m o nit ori n g pr e d efi n e d a s 
s e n siti v e  ( < 5  C T C s  aft er  c y cl e  2)  a n d  r e si st a nt  ( > 5  C T C s  aft er  c y cl e  2)  i n 
t er m s  of  Cli ni c al  B e n efit  R at e  ( d efi n e d  a s  p ati e nt s  a c hi e vi n g  p arti al  or 
c o m pl et e  r e s p o n s e  a s  w ell  a s  t u m or  st a bili z ati o n ≥ 2 4  w e e k s)  f or  p ati e nt s 
wit h  H E R 2 -n e g ati v e  a g gr e s si v e  m et a st ati c  br e a st  c a n c er  tr e at e d  wit h 
st a n d ar d fir st li n e c h e m ot h er a p y wit h p a clit a x el -b e v a ci z u m a b .  
T h e s e c o n d ar y eff e cti v e n e s s o bj e cti v e s of t hi s st u d y ar e a s f oll o w s : 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
1 9  

 
•  T o  e v al u at e  t h e  v ali dit y  of  e arl y  C T C s  m o nit ori n g,  a s  pr e di ct or  of  o v er all 
r e s p o n s e ( O R) pr o gr e s si o n fr e e s ur vi v al ( P F S) a n d o v er all s ur vi v al ( O S) a n d 
t o xi cit y  gr a di n g  ( 3-4) ( b y  C o m m o n T er mi n ol o g y Crit eri a f or  A d v er s e  E v e nt s 
[ C T C A E] v 4 crit eri a)  
•  T o  e sti m at e  t h e  o pti m al  c ut -off  of  C T C s  i n  s a m pl e  d at a  f or  C B R,  O R,  P F S 
a n d to  c o m p ar e  g o o d  a n d  p o or  pr o g n o sti c  gr o u p s  i n  P F S  a n d  tr e at m e nt 
r e s p o n s e. 
•  T o c orr el at e C E A a n d C A 1 5. 3 wit h C T C l e v el s  
•  T o  e v al u at e  t h e  i n ci d e n c e  of  a d v er s e  e v e nt s,  s eri o u s  a d v er s e  e v e nt s  a n d 
e v e n t s  of  s p e ci al  i nt er e st  i n  t w o  pr o g n o sti c  gr o u p s  a n d  t h e  t ot al  s a m pl e  i n 
r o uti n e cli ni c al pr a cti c e. 
 
S af et y O bj e cti v e s  
T h e s af et y o bj e cti v e s f or t hi s st u d y ar e a s f oll o w s:  
•  T o e v al u at e t h e i n ci d e n c e of a d v er s e e v e nt s, s eri o u s a d v er s e e v e nt s , e v e nt s 
of  s p e ci al  i nt er e st  a n d  e v e nt s  t h at  l e a d  t o  tr e at m e nt  di s c o nti n u ati o n i n  t w o 
pr o g n o sti c gr o u p s a n d t h e t ot al s a m pl e 
•  T o  e v al u at e  t h e  v ali dit y  of  < 5  C T C s/  7. 5  m L  aft er s e c o n d  c h e m ot h er a p y 
c y cl e a s pr e di cti v e f a ct or of t o xi cit y gr a d i n g ( 3-4) ( b y C T C A E v 4 crit eri a)  
•  T o  e sti m at e  t h e  o pti m al  c ut -off  of C T C s  i n  s a m pl e  d at a  f or  t o xi cit y  gr a d i n g 
( 3-4)  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
2 0  

 
St u d y D e si g n  
D e s cri pti o n of St u d y  
T hi s i s a m ulti c e nt er, o b s er v ati o n al, pr o s p e cti v e st u d y i n p ati e nt s wit h m et a st ati c 
br e a st c a n c er w h o i niti at e st a n d ar d tr e at m e nt wit h b e v a ci z u m a b i n c o m bi n ati o n 
wit h p a clit a x el. T h e d e v el o p m e nt of t h e st u d y i n v ol v e s t h e pr o s p e cti v e c oll e cti o n 
of  d at a  f or 1 8  m o nt h s  aft er  i niti ati o n  of  t h er a p y.  T h e  d e ci si o n  of  tr e at m e nt  i s 
i n d e p e n d e nt of t h e i n cl u si o n a n d i n n o c a s e s h all b e s u bj e ct b y t h e i n cl u si o n of 
t h e p ati e nt i n t h e st u d y. T h e vi sit s c oi n ci d e wit h t h e p ati e nt p erf or m r e g ul arl y t o 
m o nit or y o ur c o n diti o n, wit h o ut i nt erf eri n g i n a n y w a y wit h t h e cli ni c al pr a cti c e of 
t h e r e s e ar c h er. 
T o e n s ur e t h e o b s er v ati o n al n at ur e of it, t h e s e d at a s h o ul d al w a y s b e c oll e ct e d 
a n d  w h e n  a v ail a bl e  i n  t h e  m e di c al  r e c or d  or  m a y  b e  o bt ai n e d  d uri n g  t h e 
i nt er vi e w wit h t h e s a m e i n s u c h vi sit s d o n ot a p pl y a n y di a g n o sti c or t h er a p e uti c 
i nt er v e nti o n. 
F or t h e pri m ar y o bj e cti v e t w o C T C s d et er mi n ati o n s will b e  p erf or m e d a s f oll o w s:  
1.  D et er mi n ati o n of b a s al C T C s d et er mi n ati o n ( wit hi n t h e 2 1 d a y s pri or t o d a y 1 
/ c y cl e  1  tr e at m e nt)  will  b e  d o n e  i n  eli gi bl e  p ati e nt s  aft er  t h e  si g n  of  t h e 
i nf or m e d c o n s e nt  
2.  A s e c o n d d et er mi n ati o n of C T C s i n t h e 7 d a y s pri or t o d a y 1/ c y cl e 3 ( b ef or e 
a n y tr e at m e nt a d mi ni str ati o n of c y cl e 3)  
  P a clit a x el a n d b e v a ci z u m a b will b e a d mi ni st er e d a s p er cli ni c al pr ot o c ol i n e a c h 
i n stit uti o n. T h e e x p e ct e d b e v a ci z u m a b d o s e will b e  1 0 m g/ k g d a y 1 a n d 1 5 e v er y 
f o ur  w e e k s.    It  i s  r e c o m m e n d e d  t o  m ai nt ai n  b e v a ci z u m a b  u ntil  c o nfir m ati o n  of 
t u m or pr o gr e s si o n or u n a c c e pt a bl e t o xi cit y. All p ati e nt s will b e f oll o w e d f or u p t o 
1 8  m o nt h s  fr o m  t h e  st art  of  tr e at m e nt  (i n cl u di n g  t h o s e  w h o  di s c o nti n u e  st u d y 
tr e at m e nt f or a n y r e a s o n ot h er t h a n P D). 
St art D at e of St u d y  
T h e  st u d y  st art  d at e  will  b e  t h e  d at e  of  t h e  fir st  d at a  c oll e cti o n:  t h e  d at e  fr o m 
w hi c h i nf or m ati o n o n t h e fir st st u d y s u bj e ct i s r e c or d e d i n t h e st u d y d at a b a s e or, 
i n t h e c a s e of s e c o n d ar y u s e of d at a, t h e d at e fr o m w hi c h d at a e xtr a cti o n st art s .  
E n d of St u d y  
T h e e n d of t h e st u d y will b e t h e d at e fr o m w hi c h t h e l a st i nf or m ati o n of t h e l a st 
s u bj e ct i s r e c or d e d i n t h e st u d y d at a b a s e  a c c or di n g t o st a n d ar d cli ni c al pr a cti c e . 
 
P o p ul ati o n  
I n  t hi s  st u d y, d o c u m e nt ati o n  of  p ati e nt s  w h o  ar e  tr e at e d  a c c or di n g  t o  t h e  l o c al 
S m P C  will b e c oll e ct e d . D o c u m e nt ati o n of p ati e nt s tr e at e d “ off-l a b el” i s t h er ef or e 
e x cl u d e d.  
P ati e nt s m u st m e et t h e f oll o wi n g crit eri a f or st u d y e ntr y:  
•  P ati e nt s a g e d ≥ 1 8 y e ar s   
•  P ati e nt s  wit h  H E R 2 -n e g ati v e  M B C.  M a n d at or y  t o  h a v e  t h e  H E R 2/ e str o g e n 
r e c e pt or( E R)/ pr o g e st er o n e r e c e pt or ( P R) st at u s  
•  P ati e nt  w h o  m et  crit eri a  f or  fir st -li n e  tr e at m e nt  wit h  c h e m ot h er a p y  pl u s 
b e v a ci z u m a b  ( st a n d ar d  d o s e s)  b y  l o c al,  r e gi o n al  or n ati o n al  g ui d eli n e s  or  
a ut h oriti e s . 
•  P ati e nt s wit h m e a s ur a bl e di s e a s e ( R E CI S T crit eri a v 1. 1) or p ati e nt s wit h n o 
m e a s ur a bl e b ut a s s e s s a bl e di s e a s e.  
•  M ol e c ul ar p h e n ot y p e:  
•  Tri pl e n e g ati v e m et a st ati c br e a st c a n c er  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
2 1  

 
•  E R[ +] t u m or s n e e d t o f ulfill at l e a st o n e of t h e t w o cli ni c al crit eri a:  
•  E n d o cri n e  r e si st a n c e  crit eri a: 
M et a st ati c  r el a p s e  o n  a dj u v a nt 
e n d o cri n e  t h er a p y  or  pr o gr e s si o n  t o  at  l e a st  o n e  pri or  li n e  of 
e n d o cri n e t h er a p y f or a d v a n c e d di s e a s e  or  
•  A g gr e s si v e di s e a s e crit eri a ( at l e a st t w o crit eri a):  
o  T a x a n e b a s e d r e gi m e n i n t h e ( n e o) a dj u v a nt s etti n g.  
o  M et a st ati c  r el a p s e  wit hi n  2  y e ar s  fr o m  t h e  e n d  of  c h e m ot h er a p y 
f or e arl y br e a st c a n c er.  
o  Li v er m et a st a si s.  
o  T hr e e or m or e or g a n s wit h m et a st ati c i n v ol v e m e nt ( s ki n - l y m p h - 
br e a st or s oft ti s s u e ar e all c o n si d er e d a si n gl e o n e).  
o  S y m pt o m ati c  vi s c er al  di s e a s e  ( p ati e nt  n ot  s uit a bl e  f or  e n d o cri n e 
t h er a p y). 
•  E C O G 0 -2  
•  Si g n e d i nf or m e d c o n s e nt  f or m 
 
P ati e nt s w h o m e et a n y of t h e f oll o wi n g crit eri a will b e e x cl u d e d fr o m st u d y e ntr y:  
•  P ati e nt h a s r e c ei v e d pri or c h e m ot h er a p y f or m et a st ati c di s e a s e  
•  P ati e nt  r e q uiri n g  m aj or/ mi n or  s ur g er y  wit hi n  3  w e e k s  pri or  t o  a d mi ni str ati o n 
of t h e fir st d o s e of st u d y tr e at m e nt  
•  P ati e nt h a s r e c ei v e d a n i n v e sti g ati o n al t h er a p y wit hi n 4 w e e k s pri or t o st u d y 
e ntr y  
•  P ati e nt h a s k n o w n s y m pt o m ati c br ai n m et a s t a s e s. 
•  P ati e nt wit h n o n m e a s ur a bl e or a s s e s s a bl e di s e a s e:  
•  E x cl u si v e bl a sti c b o n e di s e a s e . 
•  Pl e ur al, p eri c ar di al or a b d o mi n al eff u si o n a s o nl y e vi d e n c e of di s e a s e . 
 
•  P ati e nt i n c hr o ni c d ail y tr e at m e nt wit h c orti c o st er oi d s ( d o s e s > 1 0 m g / d a y of 
m et h yl pr e d ni s ol o n e or e q ui v al e nt), e x c e pt i n h al e d st er oi d s  
•  Pr e g n a nt or br e a stf e e di n g p ati e nt. A s er u m pr e g n a n c y t e st will b e t a k e n u p 
t o 7 d a y s pri or t o st u d y tr e at m e nt, or u p t o 1 4 d a y s pri or t o st u d y tr e at m e nt 
(i n t h e l att er c a s e a n ot h er uri n e t e st will b e t a k e n wit hi n 7 d a y s pri or t o st u d y 
tr e at m e nt t o c o nfir m t h e r e s ult) 
•  W o m e n  of  c hil d b e ari n g  p ot e nti al  ( d efi n e d  a s  t h o s e  w h o  h a v e  h a d  t h eir  l a st 
m e n str u al  p eri o d  < 2  y e ar s  a n d  ar e  n ot  s ur gi c all y  st erili z e d)  w h o  ar e  n ot 
u si n g  h or m o n al  c o ntr a c e pti v e s  or  hi g hl y  eff e cti v e  birt h  c o ntr ol  ( e. g. 
i ntr a ut eri n e d e vi c e) d uri n g t h e st u d y  
•  P ati e nt  h a s  a n  a cti v e,  u n c o ntr oll e d  b a ct eri al,  vir al,  or  f u n g al  i nf e cti o n( s) 
r e q uiri n g s y st e mi c t h er a p y 
•  P ati e nt  wit h  si g nifi c a nt  r e n al,  h e m at ol o gi c al  or  li v er  f u n cti o n  alt er ati o n 
a c c or d i n g t o i n v e sti g at or’ s crit eri a 
•  P ati e nt  h a s  s eri o u s  m e di c al  ri s k  f a ct or s  i n v ol vi n g  a n y  of  t h e  m aj or  or g a n 
s y st e m s 
 
V ari a bl e s  
O nl y v ari a bl e s, o bt ai n e d a c c or di n g t o r o uti n e cli ni c al pr ati c e c a n a n d s h o ul d b e 
d o c u m e nt e d i n t hi s st u d y.  
Pri m ar y Eff e cti v e n e s s V ar i a bl e 
T h e pri m ar y eff e cti v e n e s s v ari a bl e  i n t hi s st u d y i s a s f oll o w s:  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
2 2  

 
•  T h e  pri m ar y  v ari a bl e  i s  t h e  cli ni c al  b e n efit  r at e  d uri n g  t h e  st u d y  f oll o w -u p 
w hi c h  will  b e  a s s e s s e d  a c c or di n g  t o  C T C  l e v el s. Cli ni c al  b e n efit  r at e  i s 
d efi n e d a s p ati e nt s a c hi e vi n g p arti al or c o m pl et e r e s p o n s e a s w ell a s t u m or 
st a bili z ati o n ≥ 2 4  w e e k s . It  will  b e  c o m p ar e d  cli ni c al  b e n efit  r at e s  b et w e e n 
C T C  s e n siti v e  gr o u p  ( < 5  C T C s  i n  o n e  of  t h e  t w o  d et er mi n ati o n s)  a n d 
r e si st a n c e gr o u p ( ≥ 5 C T C s i n t h e t w o d et er mi n ati o n s) 
 
S e c o n d ar y Eff e cti v e n e s s  V ari a bl e   
T h e eff e cti v e n e s s  v ari a bl e s  of  t hi s st u d y ar e a s f oll o w s: 
•  L e v el s of C T C  
•  M e di c al hi st or y.  
•  Tr e at m e nt s f or m et a st ati c br e a st c a n c er  
•  C o n c o mit a nt m e di c ati o n.  
•  V ari a bl e s r el at e d wit h tr e at m e nt r e s p o n s e.  
•  Bi o m ar k er s ( C E A a n d C A 1 5. 3) 
•  Pr o gr e s si o n fr e e s ur vi v al  a n d O S.  
 
S af et y V ari a bl e s  
•  C oll e cti o n  of  a d v er s e  e v e nt s,  s eri o u s  a d v er s e  e v e nt s,  e v e nt s  of  s p e ci al 
i nt er e st,  e v e nt s  w hi c h  l e a d  t o  tr e at m e nt  or  st u d y  di s c o nti n u ati o n  a n d 
l a b or at or y p ar a m et er s. 
 
Ot h er V ari a bl e s of  I nt er e st  
Ot h er v ari a bl e s of i nt er e st ar e d e pi ct e d i n t h e pr ot o c ol.  
D at a S o ur c e s  
T h e  i n v e sti g at or  will  u s e  t h e  el e ctr o ni c  c a s e  r e p ort  f or m  ( e C R F)  wit h  t h e  a s si g n e d 
p ati e nt n u m b er t o e nt er m e di c all y r el e v a nt d at a c oll e ct e d fr o m m e di c al c h art s d uri n g 
t h e st u d y vi sit s. M e di c al r e c or d s will al s o b e u s e d t o c a pt ur e a d diti o n al i nf or m ati o n. 
 
St u d y Si z e  
T h e  e nr oll m e nt of 1 1 0 p ati e nt s i s pl a n n e d f or t h e st u d y i n v ol vi n g 3 0 sit e s t hr o u g h o ut 
t h e c o u ntr y. 
St ati sti c al C o n si d er ati o n s  
T h e  pr o p o s e d  m et h o d s of  st ati sti c al  a n al y si s  s h o w n  b el o w  c o n stit ut e  a s u m m ar y  of 
t h e  m et h o d s  t o  b e  u s e d  f or  t h e  d at a  c oll e ct e d  i n  or d er  t o  a d dr e s s  t h e  o bj e cti v e s  of 
t h e st u d y. 
D e s cri pti v e st ati sti c s a n d st ati sti c al pl ot s will b e  u s e d t o d e s cri b e all d at a. C at e g ori c al 
v ari a bl e s  will  b e  s u m m ari z e d  wit h  n u m b er  of  mi s si n g  v al u e s,  fr e q u e n ci e s  a n d 
p er c e nt a g e s  a n d e x a ct  bi n o mi al  ( Cl o p p er -P e ar s o n)  c o nfi d e n c e  i nt er v al  9 5 %  ( w h e n 
n e c e s s ar y). C o nti n u o u s  v ari a bl e s  will  b e  s u m m ari z e d  wit h  t h e  n u m b er  of " n o n-
mi s si n g" o b s er v ati o n s,  t h e  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  i nt er q u artil e  r a n g e, 
mi ni m u m,  m a xi m u m  a n d  9 5 %  c o nfi d e n c e  i nt er v al  ( w h e n  n e c e s s ar y).  Ti m e  t o  e v e nt 
v ari a bl e s  will  b e  s u m m ari z e d  wit h  r at e s  a n d  9 5 %  c o nfi d e n c e  i nt er v al ( w h e n e v er 
n e c e s s ar y).  
G e n er all y s p e a ki n g, t h er e ar e n o pl a n s t o all o c at e u n a v ail a bl e d at a, w hi c h will si m pl y 
b e d e s cri b e d a s mi s si n g d at a. I n a d diti o n, t h er e ar e n o pl a n s t o c o n d u ct a s e n siti vit y 
a n al y si s.  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
2 3  

 
Analysis Methods 
Primary Effectiveness Analysis 
For the analysis of the primary objective we will compare CBR rates between CTC 
sensitive and resistance groups. The estimation will be performed with a Chi-square 
test for two independent proportions and presented together with 95% exact 
binomial (Clopper-Pearson) confidence intervals.  
 
Secondary Effectiveness Analysis 
We will estimate the positive predictive value (PPV), negative predictive value (NPV), 
sensibility and specificity of the prognostic value of CTC levels (two cut-offs points: 
<5 CTCs/7.5 ml and optimal cuts-off point) to detect patients who are either alive, 
without progression, with complete response or with objective response. The 
estimation will be performed with exact binomial (Clopper-Pearson) confidence 
interval 95% for proportions.   
We will estimate the optimal cut off point for CTCs level with sample data for 
detecting patients who are either alive, without progression, with complete response 
or with objective response. Logistic regression models and receiver operating curve 
(ROC) procedures will be used.  
We will estimate the differences between good and poor prognostic groups (defined 
by two cut-offs point: <5 CTC and optimal for sample) in overall survival, progression 
free survival and time to best response. Analysis will be adjusted by baseline 
prognostic factors. Cox regression models and time dependent ROC will be used. 
 
Safety Analysis 
Summary measures will be performed on the adverse events (adverse event, events 
of special interest, those which lead to a study or treatment discontinuation, SAEs 
and AEs grade ≥3)laboratory parameters and other security parameters. The 
incidence and the 95% CI of every event will be calculated and will be expressed 
with the primary system-organ class and the preferred term according to MedDRA 
version 17.1.  
We will estimate the positive predictive value (PPV), negative predictive value (NPV), 
sensibility and specificity of the prognostic value of CTC levels (two cut-offs: <5 
CTCs/7.5 ml and optimal cuts-off) to detect toxicities grade (3-4). The estimation will 
be performed with exact binomial (Clopper-Pearson) confidence interval 95% for 
proportions.  
We will estimate the optimal cut off for CTCs level with sample data for detecting 
objective response and toxicities grade (3-4). Logistic regression models and 
receiver operating curve (ROC) procedures will be used. 
 
Other Analyses 
For the biomarkers correlation with the CTC levels, correlation coefficients (Pearson 
or Spearman depending on variable distribution) will be analyzed.  
 
Interim Analyses  
No interim analyses are planned. 
 
Sample Size Justification 
The calculation of sample size was based on the determination of the main objective: 
"To determine the predictive capacity of early CTCs monitoring predefined as 
sensitive (<5 CTCs after cycle 2) and resistant (>5 CTCs after cycle 2) in terms of 
Clinical Benefit Rate (defined as patients achieving partial or complete response as 
well as tumor stabilization ≥ 24 weeks) for patients with HER2-negative aggressive 
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metastatic breast cancer treated with standard first line chemotherapy with 
paclitaxel-bevacizumab”. The precision values, power, etc., of the other secondary 
objectives are achieved, accordingly, depending on the size determined by the 
primary endpoint. 
 
The primary endpoint is the clinical benefit rate at follow-up study. The investigator’s 
hypothesis is that clinical benefit rate will be 35% and 70% for CTC-resistance and 
sensitive groups, respectively. We assume the ratio between CTC-Resistance and 
CTC sensitive group will be 1:4. We accept an alpha risk of 0.05 two-sided and a 
beta risk of 0.2. We anticipate a drop-out rate of 10%. We will analyze the data with 
a Chi-square test for two independent proportions.  
 
Finally, 22 subjects in CTC-Resistance group and 88 subjects in CTC-sensitive 
group are estimated. Therefore a total of 110 patients are needed. Sample size has 
been estimated with the GRANMO V7.12 April 2012 program. 
 
Milestones 
Study milestones are given in the following table. 
Milestone 
Planned Date 
Start of data collection 
Q42015 
End of data collection 
Q22018 
Final report of study results 
Q22019 
 
 
 
Medicine 
Paclitaxel and bevacizumab will be administered as per clinical protocol in each 
institution. The expected bevacizumab dose will be 10 mg/kg day 1 and 15 every 
four weeks 
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4. 
PROTOCOL AMENDMENTS AND UPDATES 
Any protocol amendments will be prepared by the Sponsor or designee.   
Protocol amendments will be submitted to the Institutional Review Board 
(IRB)/Ethics Committee (EC) and to regulatory authorities in accordance with local 
regulatory requirements. 
 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes that involve 
logistical or administrative aspects only (e.g., change in Study Monitor or contact 
information). 
 
5. 
MILESTONES 
Milestone 
Planned Date 
Start of data collection 
Q42015 
End of data collection 
Q22018 
Final report of study results 
Q22019 
 
 
 
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6. 
RATIONALE AND BACKGROUND 
6.1 
BACKGROUND ON METASTATIC BREAST CANCER  
Breast cancer is by far the most common female malignancy worldwide, with the 
highest rates reported in Europe and North America. (Parkin, D.M. et al. 2005)  
GLOBOCAN is a recent published report performed by the International Agency for 
Research on Cancer (IARC) the specialized bureau on cancer of World Health 
Organization. It states that breast cancer is the most frequent in women also in Spain 
(29% incidence and 40.8% prevalence), and the fourth most common type of cancer 
throughout the whole population (Fergay J, et al. 2012)  
Breast cancer is increasingly being diagnosed at an early stage due to improved 
awareness and widespread screening programmes. In Spain, the 82.8% will survive 
after 5 years after diagnosis (Eurocare -4). The outlook for patients with metastatic 
breast cancer (MBC) is poor and the disease is generally not considered curable 
(National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: 
Breast cancer v.2.2008). Median OS is around 24 months and the 5-year survival 
rate is low, at just 26 % (Jemal, A. et al, 2007). 
6.2 
BACKGROUND ON PACLITAXEL-BEVACIZUMAB 
Bevacizumab is a humanized antibody directed against VEGF-A, a potent angiogenic 
agent shown to be a determinant in the growth and spread of cancer in humans. The 
use of the combination of different cytotoxic agents with bevacizumab in advanced 
breast cancer has shown consistent benefits in PFS and response rates. However, 
no trial or meta-analysis has identified a benefit in overall survival for the 
bevacizumab combinations. The absence of global survival before the IMELDA study 
data may have limited the incorporation of this active agent in clinical practice. 
The use of bevacizumab in combination with paclitaxel was supported by the phase 
III clinical trial E2100 (Miller et al, 2007). This trial enrolled a total of 722 patients who 
were randomly assigned to receive 90 mg of paclitaxel per square meter of body-
surface area on days 1, 8, and 15 every 4 weeks, either on its own or with 10 mg of 
bevacizumab per kilogram of body weight on days 1 and 15. The primary endpoint 
was PFS; OS was a secondary endpoint. Paclitaxel plus bevacizumab significantly 
prolonged PFS, compared with paclitaxel on its own (median 11.8 vs. 5.9 months; 
hazard ratio for progression 0.60; P<0.001) and increased the objective response 
rate (36.9% vs. 21.2%, p<0.001). The OS rate, however, was similar in the two 
groups (median 26.7 vs. 25.2 months; hazard ratio 0.88; p = 0.16). 
The IMELDA study (Gligorov et al. 2014), one of the second-generation clinical trials 
on breast cancer with bevacizumab as first line treatment, has explored an original 
argument. All MBC patients received docetaxel plus bevacizumab as first line therapy 
(winning arm of the AVADO (Miles DW, et al. 2010) study) for a total of six cycles [in 
the absence of progression]). Patients underwent a response evaluation after the 
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sixth cycle; and those that did not present progression criteria (stable disease or 
response) were randomized to maintenance with bevacizumab or to bevacizumab in 
combination with a second cytostatic (capecitabine), until disease progression or 
toxicity. The study shows a dramatic benefit in PFS (PFS: 4.3 vs. 11.9 months; 
Hazard ratio 0.38; p <.0001) and OS (median OS 23.7 vs 39.0 months; Hazard ratio 
0.43; p= 0.0003)  in favor of the combination. This study optimizes the efficacy of 
bevacizumab, confirming its synergic effect with chemotherapy. Therefore, 
prolonging low intensity chemotherapy with capecitabine plus bevacizumab in 
sensitive patients achieves survival benefits similar to those reported with 
trastuzumab in the HER2-positive population. 
The main limitation of this study is that fails in making an early detection of the 
patients who do not benefit from the treatment with bevacizumab. Since the absence 
of efficacy was defined as progression within the first six cycles of chemotherapy, it 
did not limit the administration of bevacizumab to truly sensitive patients. The 
IMELDA study stresses the need for an early detection of tumor resistance to the 
combination.  
These data globally concur with an observation made by another clinical study 
(unpublished and blinded data). This study included over 2.200 patients treated first 
line with a bevacizumab-containing regimen, and it showed that overall survival 
maintained a close correlation with the efficacy of the first line treatment. Patients 
with a CR(n = 204; Median OS not achieved, but >40 months), partial objective 
response (n = 1.022; OS 27.4 months) or SD for more than 24 weeks (n: 507, OS 
26.8 months) obtained higher survival figures than the patients who displayed 
progression before 24 weeks (n = 435, OS 11.3 months). In total, 20% patients did 
not reach clinical benefit criteria (progression within 24 weeks) to the first line 
treatment (figure 1). 
Interestingly, when we compare the OS figures from this study and IMELDA, the 
median OS for the control "sensitive" arm (maintaining bevacizumab after six CT 
cycles) moves to 27.2 months (23.7 and median treatment duration on the initial 
phase is 3.5 months); similar to the 27.8 months from the non-resistant group 
(SD >24 weeks + PR + CR; n = 1,733) 
 
 
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Figure 1. Correlation between overall survival according to best response to 
bevacizumab first line treatment. Total sample analysis (N=2264) 
 
*96 patients are excluded. Their responses were not evaluated in the study. 
** The median survival was not estimated because the survival probability in CR group is 
higher than 50%. 
CR: Complete response, PR: Partial response, SD: Stable Disease, PD: Progressive 
disease, 95%CI: 95% confidence interval. 
6.3 
STUDY RATIONALE  
The determination of Circulating Tumor Cells (CTCs) in blood of Metastatic Breast 
Cancer (MBC) patients is a well-established prognostic and predictive marker of 
efficacy/resistance. An initial determination of CTCs superior to 5 CTCs/ 7.5 ml 
confers a worse PFS and OS rates to first line chemotherapy compared to lower CTC 
values indicating that it works both as an early marker for treatment resistance and 
survival. Additionally, the persistence of values ≥ 5 CTCs/ 7.5 ml after the first 
cycle/weeks of chemotherapy is an early marker for resistance (Cristofanilli M et al. 
2004). 
Recently, the SWOG S0500 (Smerage JB, et al. 2014) study has explored the ability 
of CTCs as prognostic and predictor markers leading to early treatment changes in 
patients with resistant criteria tumors. The study confirmed the ability of monitoring 
CTCs to predict early sensitivity to the first line treatment as well as prognosis. 
However, it failed in the primary objective of the study, as no difference in PFS or OS 
was observed when patients maintaining ≥ 5 CTCs after 3-5 weeks on therapy were 
randomized to maintain the first line therapy (n = 62; PFS/OS 3.5 and 10.7 months) 
or change to a non-cross-resistant regimen (n = 60; 4.6 and 12.5 months).  
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However, the SWOG S0500 study allows for the expected patterns of population with 
basal CTCs < 5 and ≥ 5 to be established, as well as those of the populations with 
normalization / no-normalization on the 3-5 weeks determination. The distribution 
was: 
% 
Patients PFS OS 
Basall CTCs <5  
45-49% 
11,1 35 
Basal CTCs ≥ 5 and subsequent <5  
29-32% 
8.9 
23 
Basal and subsequent ≥ 5CTCs 
22% 
4.9 
13 
 
The recently published work of Giuliano et al. (Giuliano et al. 2014) explores the path 
of the use of the CTCs value to predict the risk of tumor dissemination. This group 
has a dilated experience in the CTC levels investigation; in their retrospective study 
the data of 492 patients with advanced breast cancer who had the CTC count 
assessed levels prior to the new line treatment were analyzed. Their results suggest 
a new potential role of the CTC as an early predictor of the tumor’s metastatic 
potential. Specifically, a pretreatment CTC level of ≥5 CTCs/7.5 ml was associated 
with an increment in metastatic locations in comparison with <5 CTCs/7.5 ml levels 
(p=0.0077). Furthermore, at treatment failure, the patients with ≥5 CTCs/7.5 ml 
developed new metastatic lesions more frequently and in new locations in 
comparison with those with <5 CTCs/7.5 ml (development of new lesions, p=0.0002; 
lesions in new location, p=0.0031).  
7. 
RESEARCH QUESTION AND OBJECTIVES 
7.1 
RESEARCH QUESTION  
CTC 
monitoring 
could 
become 
a 
useful 
tool 
for 
early 
prediction 
of 
sensitivity/resistance to bevacizumab regimens. The SWOG 0500 trial has confirmed 
that there is no benefit from changing the cytotoxic agent or combination regimen for 
patients with a resistant CTC profile to the first regimen. Seen from a different point 
of view, it makes sense that for patients with no CTC normalization following the first 
cycles, there is little marginal benefit from maintaining Bevacizumab instead of 
moving the patient to single agent paclitaxel. Furthermore, the recent works of 
Giuliano also state the predictive potential of the CTCs levels in tumor dissemination 
that has a high relation to the target of treatments such as bevacizumab.  
Due to the aforementioned, our hypothesis is that early CTC monitoring, basal and 
after second cycle in patients initiating first line paclitaxel plus bevacizumab 
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c h e m ot h er a p y,  will  i d e ntif y  t w o  p o p ul ati o n s  wit h  v er y  diff er e nt  pr o gr e s si o n  fr e e 
s ur vi v al  r e s ult s;  t h e  p o p ul ati o n  wit h  m ai nt ai n e d  hi g h  C T C  l e v el s  ( ≥ 5  C T C s  i n  b ot h 
d et er mi n ati o n s) will pr o gr e s s s h ortl y, e x p e cti n g  a m e di a n P F S of 4 m o nt h s, w hil e t h e 
p o p ul ati o n  wit h  a  l o w  C T C  d et er mi n ati o n  ( b a s al or  aft er  t h e s e c o n d c y cl e)  will 
a c hi e v e m e di a n P F S i n t h e r a n g e of  1 3 m o nt h s.  
T hi s st u d y will i d e ntif y a p o w erf ul a n d e a s y pr e di cti v e/ pr o g n o sti c m ar k er t o u s e wit h 
p ati e nt s u n d er b e v a ci z u m a b. T h e cli ni c al i m pli c ati o n s of t h e I M E L D A st u d y  will al s o 
h el p t o i n cr e a s e t h e diff er e n c e s b et w e e n b ot h gr o u p s. F or t h e st u d y i n v e sti g at or s it i s 
i m p ort a nt  t o  st at e  t h at  t hi s  t o ol  will  o pti mi z e  t h e  tr e at m e nt  wit h  t h e  p a clit a x el-
b e v a ci z u m a b  c o m bi n ati o n,  a n d  t hi s  h a s  i m p ort a nt  i m pli c ati o n s  n ot  o nl y  i n  p ati e nt 
m a n a g e m e nt b ut i n e c o n o mi c r e s o ur c e s.  
7. 2  
O B J E C TI V E S  
Eff e cti v e n e s s  O bj e cti v e s  
T h e pri m ar y eff e cti v e n e s s o bj e cti v e of  t hi s st u d y i s a s f oll o w s: 
•  
T o  d et er mi n e  t h e  pr e di cti v e c a p a cit y of  e arl y  C T C s  m o nit ori n g  pr e d efi n e d  a s 
s e n siti v e ( < 5 C T C s aft er c y cl e 2) a n d r e si st a nt ( > 5 C T C s aft er c y cl e 2) i n t er m s 
of  Cli ni c al  B e n efit  R at e  ( d efi n e d  a s  p ati e nt s  a c hi e vi n g  p arti al  or  c o m pl et e 
r e s p o n s e  a s  w ell  a s  t u m or  st a bili z ati o n ≥ 2 4  w e e k s)  f or  p ati e nt s  wit h  H E R 2 -
n e g ati v e  a g gr e s si v e  m et a st ati c  br e a st  c a n c er  tr e at e d  wit h  st a n d ar d  fir st  li n e 
c h e m ot h er a p y wit h p a clit a x el -b e v a ci z u m a b  
T h e s e c o n d ar y eff e cti v e n e s s o bj e cti v e s of t hi s st u d y ar e a s f oll o w s: 
•  
T o  e v al u at e  t h e  v ali dit y  of  e arl y  C T C s  m o nit ori n g,  a s  pr e di ct or  of  o v er all 
r e s p o n s e  ( O R)  pr o gr e s si o n  fr e e  s ur vi v al  ( P F S)  a n d  o v er all  s ur vi v al  ( O S)  a n d 
t o xi cit y  gr a di n g  ( 3-4)  ( b y  C o m m o n  T er mi n ol o g y  Crit eri a  f or  A d v er s e  E v e nt s 
[ C T C A E] v 4 crit eri a). 
•  
T o e sti m at e t h e o pti m al c ut -off of C T C s i n s a m pl e d at a f or C B R, O R, P F S a n d t o 
c o m p ar e g o o d a n d p o or pr o g n o sti c gr o u p s i n P F S a n d tr e at m e nt r e s p o n s e.  
•  
T o c orr el at e C E A a n d C A 1 5. 3 wit h C T C l e v el s  
•  
T o e v al u at e t h e i n ci d e n c e of a d v er s e e v e nt s, s eri o u s a d v er s e e v e nt s a n d e v e nt s 
of  s p e ci al  i nt er e st  i n  t w o  pr o g n o sti c  gr o u p s  a n d  t h e  t ot al  s a m pl e  i n  r o uti n e 
cli ni c al pr a cti c e.  
 
S af et y O bj e cti v e s  
T h e s af et y o bj e cti v e s of t hi s st u d y ar e a s f oll o w s: 
•  
T o e v al u at e t h e i n ci d e n c e of a d v er s e e v e nt s, s eri o u s a d v er s e e v e nt s, e v e nt s of 
s p e ci al  i nt er e st  a n d  e v e nt s  t h at  l e a d  t o  tr e at m e nt  di s c o nti n u ati o n  i n  t w o 
pr o g n o sti c gr o u p s a n d t h e t ot al s a m pl e  
•  
T o e v al u at e t h e v ali dit y of < 5 C T C s/ 7. 5 m L aft er s e c o n d c h e m ot h er a p y  c y cl e a s 
pr e di cti v e f a ct or of t o xi cit y gr a di n g ( 3 -4) ( b y C T C A E v 4 crit eri a)  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 1  

 
•  
T o e sti m at e t h e o pti m al c ut -off o f C T C s i n s a m pl e d at a f or t o xi cit y gr a di n g ( 3-4)  
 
8.  
R E S E A R C H M E T H O D S  
8. 1  
S T U D Y D E SI G N  
T hi s  i s  a  m ulti c e nt er,  o b s er v ati o n al,  pr o s p e cti v e  st u d y  i n  p ati e nt s  wit h  M B C  w h o 
i niti at e  st a n d ar d  tr e at m e nt  wit h  b e v a ci z u m a b  i n  c o m bi n ati o n  wit h  p a clit a x el.  T h e 
d e v el o p m e nt  of  t h e  st u d y  i n v ol v e s  t h e  pr o s p e cti v e  c oll e cti o n  of  d at a  f or 1 8  m o nt h s 
aft er  i niti ati o n  of  t h er a p y.  T h e  tr e at m e nt  d e ci si o n  i s  i n d e p e n d e nt  t o  st u d y  i n cl u si o n 
a n d i n n o c a s e s h all b e s u bj e ct t o t h e p ati e nt’ s i n cl u si o n i n t h e st u d y. T h e vi sit s will 
c oi n ci d e p ati e nt’ s r e g ul ar vi sit s m a d e t o m o nit or hi s/ h er c o n diti o n, wit h o ut i nt erf eri n g 
i n a n y w a y wit h t h e r e s e ar c h er’ s cli ni c al pr a cti c e. 
T o  e n s ur e  t h e  o b s er v ati o n al  n at ur e  of  t h e  st u d y,  t h e s e  d at a  s h o ul d  al w a y s  b e 
c oll e ct e d,  w h e n  a v ail a bl e,  fr o m  t h e  m e di c al  r e c or d  or  t h e y  m a y  b e  o bt ai n e d  d uri n g 
t h e  i nt er vi e w  wit h  t h e  s u bj e ct  i n  t h eir  r e g ul ar  vi sit,  wit h o ut  a n y  di a g n o sti c  or 
t h er a p e uti c i nt er v e nti o n s. 
8. 1. 1  
O v er vi e w of St u d y  D e si g n  
T h e s c o p e of t h e st u d y c o v er s t h e p ati e nt s w h o ar e g oi n g t o st art a fir st li n e tr e at m e nt 
wit h  a  c o m bi n ati o n  of  p a clit a x el  a n d  b e v a ci z u m a b.  B y  t hi s  t h er e  ar e  t w o m e di ci n e s  
u n d er o b s er v ati o n, p a clit a x el a n d b e v a ci z u m a b. I n b ot h c a s e s, t h e m e di ci n e s  will b e 
u s e d a c c or di n g t o n ati o n al l a b eli n g a n d l o c al st a n d ar d of c ar e will b e o b s er v e d. T h e 
d e v el o p m e nt  of  t h e  st u d y  i n v ol v e s  t h e  pr o s p e cti v e  c oll e cti o n  of  d at a  f or 1 8  m o nt h s 
aft er i niti ati o n of t h er a p y. T h e t ot al d ur ati o n of t h e st u d y c o m pri s e a p pr o xi m a t el y 3 3  
m o nt h s.  A p pr o xi m at el y, t h e i n cl u si o n will st art i n O ct o b er 2 0 1 5 a n d will e n d i n M ar c h 
2 0 1 7 .  T h e  l a st  p ati e nt  l a st  vi sit  i s  pl a n n e d  i n  O ct o b er 2 0 1 9 . T h e s e  d at e s  m a y  v ar y 
d u e t o t h e a p pr o v al pr o c e s s.  
It i s pl a n n e d t o r e cr uit a t ot al of 1 1 0 p ati e nt s fr o m 3 0 S p a ni s h sit e s. 
F or t h e pri m ar y o bj e cti v e t w o C T C s d et er mi n ati o n s  will b e p erf or m e d a s f oll o w s:  
 
1.  B a s al  C T C s  d et er mi n ati o n  ( wit hi n  t h e  2 1  d a y s  pri or  t o  d a y  1  /  c y cl e  1 
tr e at m e nt)  will  b e  d o n e  i n  eli gi bl e  p ati e nt s  aft er  t h e  si g n  of  t h e  i nf or m e d 
c o n s e nt  
2.    A  s e c o n d  d et er mi n ati o n  of  C T C s (*),i n  t h e  7  d a y s  pri or  t o  d a y  1/ c y cl e  3 
( b ef or e a n y tr e at m e nt a d mi ni str ati o n of c y cl e 3) 
P a clit a x el  a n d  b e v a ci z u m a b  will  b e  a d mi ni st er e d  a s  p er  cli ni c al  pr ot o c ol  i n  e a c h 
i n stit uti o n. T h e e x p e ct e d b e v a ci z u m a b d o s e will b e 1 0 m g/ k g d a y 1 a n d 1 5 e v er y f o ur 
w e e k s. It  i s  r e c o m m e n d e d  t o  m ai nt ai n  b e v a ci z u m a b  u ntil  c o nfir m ati o n  of t u m or 
pr o gr e s si o n or u n a c c e pt a bl e t o xi cit y. All p ati e nt s will b e f oll o w e d f or u p t o 1 8  m o nt h s 
fr o m t h e st art of tr e at m e nt (i n cl u di n g t h o s e w h o di s c o nti n u e st u d y tr e at m e nt f or a n y 
r e a s o n ot h er t h a n P D). 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 2  

 
A d at a c oll e cti o n o v er vi e w i s pr o vi d e d i n A p p e n di x 2. 
8. 1. 2  
N u m b er of P ati e nt s  O b s er v e d i n t h e St u d y 
It i s pl a n n e d t o c o n s e c uti v el y r e cr uit a t ot al of 1 1 0 p ati e nt s.  
8. 1. 3  
C e nt er s  
T hi s st u d y will b e c o n d u ct e d at  a p pr o xi m at el y  3 0  c e nt er s i n S p ai n . 
A d diti o n al  c e nt er s m a y b e a d d e d or s u b stit ut e d if u n d er p erf or mi n g.  
8. 1. 4  
R ati o n al e f or St u d y D e si g n  
T h e pr e s e nt st u d y a s s e s s e s t h e pr e di cti v e c a p a cit y of t h e C T C l e v el s i n t h e r e s p o n s e 
t o p a clit a x el-b e v a ci z u m a b tr e at m e nt. A pr o s p e cti v e d e si g n i s c h o s e n w h er e t h e C T C 
l e v el s  ar e  o bt ai n e d  a c c or di n g  t h e  cli ni c al  pr a cti c e  b ef or e  t h e  i niti ati o n  of  fir st  li n e 
tr e at m e nt a n d p ati e nt s ar e f oll o w e d f or 1 8  m o nt h s t o  e v al u at e t h e tr e at m e nt r e s p o n s e.  
T h e di s e a s e i s e v al u at e d a c c or di n g t o cli ni c al pr a cti c e  a n d t h e r e s p o n s e t o tr e at m e nt 
i s a s s e s s e d u si n g t h e R E CI S T crit eri a v 1. 1, t h e g ol d st a n d ar d of effi c a c y a s s e s s m e nt 
i n  br e a st  c a n c er.  Cli ni c al  b e n efit,  o v er all  r e s p o n s e,  c o m pl et e  r e s p o n s e,  p arti al 
r e s p o n s e, st a bl e di s e a s e a n d pr o gr e s si o n will b e c al c ul at e d.  
8. 1. 5  
R ati o n al e f or P ati e nt P o p ul ati o n a n d A n al y si s Gr o u p s  
D u e t o t h e pri m ar y o bj e cti v e of t h e st u d y, it i s n e c e s s ar y t o i n cl u d e p ati e nt s w h o h a v e 
n ot  y et  r e c ei v e d  fir st  li n e  tr e at m e nt  t o p erf or m  t h e  C T C  b a s al  d et er mi n ati o n  b ef or e 
a n y fir st li n e dr u g a d mi ni str ati o n. T h e a n al y si s gr o u p s will b e cr e at e d a c c or di n g t o t h e 
C T C l e v el s ( 5 C T C s/ 7. 5 m L ) a n d u si n g a R e c ei v er O p er ati n g C ur v e ( R O C ) cur v e f or 
t h e s e c o n d ar y o bj e cti v e).  
8. 2  
P O P U L A TI O N  
P ati e nt s  wit h  M B C  r e c ei vi n g  a  c o m bi n ati o n  tr e at m e nt  of  p a clit a x el -b e v a ci z u m a b 
a c c or di n g  t o  st a n d ar d  of  c ar e  a n d  i n  li n e  wit h  t h e  c urr e nt  s u m m ar y  of  pr o d u ct 
c h ar a ct eri sti c s  ( S P C)/l o c al  l a b eli n g  a n d  w h o  h a v e  n o c o ntr ai n di c ati o n  t o  p a clit a x el -
b e v a ci z u m a b t h er a p y a s p er t h e l o c al l a b el, ar e eli gi bl e f or o b s er v ati o n i n t hi s c o h ort 
if  t h e  f oll o wi n g  a p pli e s. T h e  writt e n  i nf or m e d  c o n s e nt  f or m  h a s  t o  b e  si g n e d  b ef or e 
a n y st u d y pr o c e d ur e.  A p pr o xi m at el y,  t h e i n cl u si o n will st art i n O ct o b er 2 0 1 5 a n d will 
e n d i n M ar c h 2 0 1 7. P ati e nt s will b e r e cr uit e d fr o m h o s pit al s.  
P ati e nt s m u st m e et t h e f oll o wi n g crit eri a f or st u d y e ntr y:  
•  P ati e nt s a g e d ≥ 1 8 y e ar s  
•  P ati e nt s  wit h  H E R 2 -n e g ati v e  M B C.  M a n d at or y  t o  h a v e  t h e  H E R 2/ e str o g e n 
r e c e ptor( E R)/ pr o g e st er o n e r e c e pt or ( P R) st at u s  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 3  

 
•  P ati e nt  w h o  m et  crit eri a  f or  fir st -li n e  tr e at m e nt  wit h  c h e m ot h er a p y  pl u s 
b e v a ci z u m a b  ( st a n d ar d  d o s e s) b y  l o c al,  r e gi o n al  or  n ati o n al  g ui d eli n e s  or 
a ut h oriti e s . 
•  P ati e nt s  wit h  m e a s ur a bl e  di s e a s e  ( R E CI S T  crit eri a  v 1. 1)  or  p ati e nt s  wit h  n o 
m e a s ur a bl e b ut a s s e s s a bl e di s e a s e.   
•  M ol e c ul ar p h e n ot y p e:  
 
Tri pl e n e g ati v e m et a st ati c br e a st c a n c er  
 
E R[ +] t u m or s n e e d t o f ulfill at l e a st o n e of t h e t w o cli ni c al crit eri a:  
 E n d o cri n e  r e si st a n c e  crit eri a: M et a st ati c  r el a p s e  o n  a dj u v a nt  e n d o cri n e 
t h er a p y or pr o gr e s si o n t o at l e a st o n e pri or li n e of e n d o cri n e t h er a p y f or 
a d v a n c e d di s e a s e  or  
 A g gr e s si v e di s e a s e crit eri a ( at l e a st t w o crit eri a):  
o  T a x a n e b a s e d r e gi m e n i n t h e ( n e o) a dj u v a nt s etti n g  
o  M et a st ati c r el a p s e wit hi n 2 y e ar s fr o m t h e e n d of c h e m ot h er a p y 
f or e arl y br e a st c a n c er  
o  Li v er m et a st a si s  
o  T hr e e or m or e or g a n s wit h m et a st ati c i n v ol v em e nt  ( s ki n - l y m p h - 
br e a st or s oft ti s s u e ar e all c o n si d er e d a si n gl e o n e)  
o  S y m pt o m ati c vi s c er al di s e a s e ( p ati e nt n ot s uit a bl e f or e n d o cri n e 
t h er a p y) 
•  E C O G 0 - 2.  
•  Si g n e d i nf or m e d c o n s e nt f or m  
P ati e nt s w h o m e et a n y of t h e f oll o wi n g crit eri a will b e e x cl u d e d fr o m st u d y e ntr y:  
•  P ati e nt h a s r e c ei v e d pri or c h e m ot h er a p y f or m et a st ati c di s e a s e  
•  P ati e nt  r e q uiri n g  m aj or/ mi n or  s ur g er y  wit hi n  3  w e e k s  pri or  t o a d mi ni str ati o n  of  t h e 
fir st d o s e of st u d y tr e at m e nt 
•  P ati e nt h a s r e c ei v e d a n i n v e sti g ati o n al t h er a p y wit hi n 4 w e e k s pri or t o st u d y e ntr y  
•  P ati e nt h a s k n o w n s y m pt o m ati c br ai n m et a st a s e s  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 4  

 
•  P ati e nt wit h n o n m e a s ur a bl e or a s s e s s a bl e di s e a s e : 
•  E x cl u si v e bl a sti c b o n e  di s e a s e  
•  Pl e ur al, p eri c ar di al or a b d o mi n al eff u si o n a s o nl y e vi d e n c e of di s e a s e  
•  P ati e nt  i n  c hr o ni c  d ail y  tr e at m e nt  wit h  c orti c o st er oi d s  ( d o s e s >  1 0  m g  /  d a y  of 
m et h yl pr e d ni s ol o n e or e q ui v al e nt), e x c e pt i n h al e d st er oi d s  
•  Pr e g n a nt  or  br e a stf e e di n g  p ati e nt.  A  s er u m  pr e g n a n c y  t e st  will  b e  t a k e n  u p  t o  7 
d a y s pri or t o st u d y tr e at m e nt, or u p t o 1 4 d a y s pri or t o st u d y tr e at m e nt (i n t h e l att er 
c a s e a n ot h er uri n e t e st will b e t a k e n wit hi n 7 d a y s pri or t o st u d y tr e at m e nt t o c o nfir m 
t h e r e s ult) 
•  W o m e n  of  c hil d b e ari n g  p ot e nti al  ( d efi n e d  a s  t h o s e  w h o  h a v e  h a d  t h eir  l a st 
m e n str u al  p eri o d  < 2  y e ar s  a n d  ar e  n ot  s ur gi c all y  st erili z e d)  w h o  ar e  n ot  u si n g 
h or m o n al  c o ntr a c e pti v e s  or  hi g hl y  eff e cti v e  birt h  c o ntr ol  ( e. g.  i ntr a ut eri n e  d e vi c e) 
d uri n g t h e st u d y  
•  P ati e nt  h a s  a n  a cti v e,  u n c o ntr oll e d  b a ct eri al,  vir al,  or  f u n g al  i nf e cti o n( s)  r e q uiri n g 
s y st e mi c t h er a p y  
•  P ati e nt  wit h  si g nifi c a nt  r e n al,  h e m at ol o gi c al  or  li v er  f u n cti o n  alt er ati o n  a c c or di n g  t o 
i n v e sti g at or’ s crit eri a 
•  P ati e nt h a s s eri o u s m e di c al ri s k f a ct or s i n v ol vi n g a n y of t h e m aj or or g a n s y st e m s  
8. 2. 1  
C o n c o mit a nt M e di c ati o n a n d Tr e at m e nt  
C o n c o mit a nt  m e di c ati o n  pr e s cri b e d  f or  c o n c o mit a nt  di s e a s e s  of  s p e ci al  i nt er e st  a n d 
tr e at m e nt  f or  M B C  at  t h e  b e gi n ni n g  of  t h e  o b s er v ati o n  p eri o d  or  i ntr o d u c e d  d uri n g  t h e 
o b s er v ati o n  p eri o d  will  b e  d o c u m e n t e d  i n  t h e e C R F  fr o m  t h e st art  of  t h er a p y  wit h 
p a clit a x el -b e v a ci z u m a b u ntil t h e e n d of t h e f oll o w u p if a p pli c a bl e. 
8. 2. 2  
D o s a g e, A d mi ni str ati o n, a n d C o m pli a n c e  
D o si n g a n d tr e at m e nt d ur ati o n of t h e p a clit a x el -b e v a ci z u m a b  ar e at t h e di s cr eti o n of t h e 
i n v e sti g at or i n a c c or d a n c e wit h l o c al cli ni c al pr a cti c e a n d l o c al l a b eli n g. 
P a clit a x el  a n d  b e v a ci z u m a b  will  b e  a d mi ni st er e d  a s  p er  cli ni c al  pr ot o c ol  i n  e a c h 
i n stit uti o n.  T h e  e x p e ct e d  b e v a ci z u m a b  d o s e  will  b e  1 0  m g/k g d a y  1  a n d  1 5  e v er y  f o ur 
w e e k s.  
8. 3  
V A RI A B L E S  
8. 3. 1  
Pri m ar y Ef f e cti v e n e s s V ari a bl e . 
T h e pri m ar y eff e cti v e n e s s v ari a bl e i n t hi s st u d y i s a s f oll o w s:  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 5  

 
T h e  pri m ar y  v ari a bl e  i s  t h e  cli ni c al  b e n efit r at e  d uri n g  t h e  st u d y f oll o w -u p  w hi c h  will  b e 
a s s e s s e d a c c or di n g t o C T C l e v el s. Cli ni c al b e n efit r at e i s d efi n e d a s p ati e nt s a c hi e vi n g 
p arti al  or  c o m pl et e  r e s p o n s e  a s  w ell  a s  t u m or  st a bili z ati o n ≥ 2 4  w e e k s.  It  will  b e 
c o m p ar e d cli ni c al b e n efit r at e s b et w e e n C T C s e n siti v e gr o u p ( < 5 C T C s i n o n e of t h e t w o 
d et er mi n ati o n s) a n d r e si st a n c e gr o u p ( ≥ 5 C T C s i n t h e t w o d et er mi n ati o n s)  
8. 3. 2  
S e c o n d ar y E ff e cti v e n e s s V ari a bl e s  
T h e eff e cti v e n e s s v ari a bl e s of t hi s st u d y ar e a s f oll o w s:  
 
•  L e v el s of C T C  
•  M e di c al hi st or y.  
•  Tr e at m e nt s f or m et a st ati c br e a st c a n c er  
•  C o n c o mit a nt m e di c ati o n.  
•  V ari a bl e s r el at e d wit h tr e at m e nt r e s p o n s e.  
•  Bi o m ar k er s ( C E A a n d C A 1 5. 3)  
•  Pr o gr e s si o n fr e e s ur vi v al a n d O S.  
 
8. 3. 3  
S af et y V ari a bl e s  
•  C oll e cti o n  of  a d v er s e  e v e nt s,  s eri o u s  a d v er s e  e v e nt s,  e v e nt s  of  s p e ci al  i nt er e st, 
e v e nt s w hi c h l e a d t o tr e at m e nt or st u d y di s c o nti n u ati o n a n d l a b or at or y p ar a m et er s  
8. 3. 4  
Ot h er V ari a bl e s  of I nt er e st  
•  Cli ni c al a n d p at h ol o gi c al v ari a bl e s: a g e, pr e/ p o st m e n o p a u si c al st at u s, t u m or st at u s, 
hi st ol o g y,  h or m o n e  r e c e pt or  a n d  H E R 2  st at u s,  c o n c o mit a nt  m e di c ati o n s ,  E C O G 
f u n cti o n al st at u s, w ei g ht, h ei g ht,  c h e m ot h er a p y ( d o s e s a n d s c h e m e), r a di ot h er a p y 
or s ur g er y t o tr e at  c a n c er di s e a s e a n d m e di c al hi st or y, a n d t o xi citi e s t h at m a y o c c ur 
d uri n g t h e st u d y p eri o d  
•  C T C d et er mi n ati o n s. 
•  L a b or at or y a s s e s s m e nt ( p er u s u al cli ni c al pr a cti c e) u s u all y c o nt ai n s:  
•  H a e m at ol o g y:  h a e m o gl o bi n,  h e m at o crit,  pl at el et  c o u nt,  r e d  bl o o d  c ell  ( R B C)  
c o u nt,  w hit e  bl o o d  c ell  ( W B C)  c o u nt,  a b s ol ut e  diff er e nti al  c o u nt  ( n e utr o p hil s, 
e o si n o p hil s, l y m p h o c yt e s, m o n o c yt e s, b a s o p hil s, ot h er c ell s)  
•  S er u m  c h e mi str y:  s o di u m,  p ot a s si u m,  c hl ori d e,  bl o o d  gl u c o s e,  bl o o d  ur e a 
nitr o g e n  ( B U N)  or  ur e a,  cr e ati ni n e,  c al ci u m,  t ot al  bilir u bi n,  t ot al  pr ot ei n  or 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 6  

 
al b u mi n,  al a ni n e  a mi n otr a n sf er a s e  ( A L T),  a s p art at e  a mi n otr a n sf er a s e  ( A S T), 
al k ali n e p h o s p h at a s e ( A L P), l a ct at e d e h y dr o g e n a s e ( L D H)  
•  C o a g ul ati o n:  I nt er n ati o n al  N or m ali z e d  R ati o  (I N R)  a n d  a cti v at e d  p arti al 
t hr o m b o pl a sti n ti m e ( a P T T) 
•  Uri n al y si s: b y di p sti c k t e st  
•  Pr e g n a n c y t e st  
•  Ti m e  v ari a bl e s  a s  f or  e x a m pl e:  d at e  of  fir st  br e a st  c a n c er  di a g n o si s,  d at e  of 
m et a st ati c di s e a s e, st art d at e of t h e fir st li n e tr e at m e nt, d at e of pr o gr e s si o n a n d d at e 
of d e at h (if h a p p e n s d uri n g t h e st u d y)  
8. 4  
T R E A T M E N T E F FI C A C Y E V A L U A TI O N D A T A C O L L E C TI O N   
8. 4. 1  
C oll e cti o n of D at a o n t h e C R F  
P ati e nt s’ m e di c al r e c or d s will b e t h e s o ur c e of all d at a t h at will b e r e c or d e d in t h e C R F s.  
T h er ef or e,  o nl y  d at a  a v ail a bl e  a n d  alr e a d y  e xi sti n g  i n  p a ti e nt’ s  fil e s  will  b e r e c or d e d  in 
C R F s.  T h e d e gr e e of d et ail a n d c o m pl et e n e s s of d at a c oll e ct e d i s d e p e n d e nt o n w h at i s 
r e c or d e d i n t h e p ati e nt c h art s.  D at a fr o m p ati e nt n ot e s s h o ul d b e e nt er e d in t h e C R F a s 
s o o n a s t h e y b e c o m e a v ail a bl e.  
8. 4. 2  
D at a C oll e ct e d d uri n g t h e O b s er v ati o n  P eri o d  
D uri n g  t h er a p y  wit h  p a clit a x el -b e v a ci z u m a b,  l a b or at or y  a s s e s s m e nt s  r o uti n el y 
p erf or m e d  i n  a c c or d a n c e  wit h  c urr e nt  g ui d eli n e s  a n d  l o c al  st a n d ar d  of  c ar e.  W h e n 
p erf or m e d  d uri n g  t h e  o b s er v ati o n al  p eri o d,  a v ail a bl e  r e s ult s  fr o m  t h e  r a n g e  of 
a s s e s s m e nt s d e s cri b e d  b el o w  will  b e  d o c u m e nt e d  o n  t h e  C R F.  M o st  d at a  will  b e 
d o c u m e nt e d ar o u n d t h e tr e at m e nt p eri o d a n d s o m e of t h e m i n t h e f oll o w u p p eri o d. T h e 
pr o p o s e d  
a s s e s s m e nt s  
a n d  
s u g g e st e d  ti mi n g s  f or  
a s s e s s m e nt s  i n  t h e 
pr ot o c ol/ o b s er v ati o n al  pl a n  ar e  n ot  m a n d at or y.    It  i s  u p  t o  t h e  tr e ati n g  p h y si ci a n  t o 
p erf or m a n d d o c u m e nt t h e a s s e s s m e nt s a s p erf or m e d i n t h e r e al cli ni c al s etti n g.  
I n t h e r o uti n e c ar e s etti n g, p ati e nt s ar e s e e n r e g ul arl y b y t h eir tr e ati n g p h y si ci a n s eit h er 
f or tr e at m e nt or f or r e g ul ar a s s e s s me nt aft er tr e at m e nt.  T h u s , n o st u d y-s p e cifi c vi sit s or 
e v al u ati o n s ar e r e q uir e d b y t hi s pr ot o c ol . 
B a s eli n e vi sit  
•  R e vi si o n of t h e s el e cti o n crit eri a  
•  I nf or m e d c o n s e nt 
•  Cli ni c al a n d p at h ol o gi c al v ari a bl e s: a g e, pr e/ p o st m e n o p a u si c al st at u s, t u m or st at u s, 
hi st ol o g y,  h or m o n e  r e c e pt or  a n d  H E R 2  st at u s,  c o n c o mit a nt  m e di c ati o n s,  E C O G 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 7  

 
f u n cti o n al  st at u s,  w ei g ht,  h ei g ht,  c h e m ot h er a p y  ( d o s e s  a n d  s c h e m e),  r a di ot h er a p y 
or s ur g er y t o tr e at c a n c er di s e a s e a n d m e di c al hi st or y.  
•  C T C d et er mi n ati o n ( b a s eli n e d et er mi n ati o n)  
•   La b or at or y a s s e s s m e nt ( p er u s u al cli ni c al pr a cti c e) u s u all y c o nt ai n s:  
•  H a e m at ol o g y:  h a e m o gl o bi n,  h e m at o crit,  pl at el et  c o u nt,  r e d  bl o o d  c ell  ( R B C) 
c o u nt,  w hit e  bl o o d  c ell  ( W B C)  c o u nt,  a b s ol ut e  diff er e nti al  c o u nt  ( n e utr o p hil s, 
e o si n o p hil s, l y m p h o c yt e s, m o n o c y t e s, b a s o p hil s, ot h er c ell s) 
•  S er u m  c h e mi str y:  s o di u m,  p ot a s si u m,  c hl ori d e,  bl o o d  gl u c o s e,  bl o o d  ur e a 
nitr o g e n  ( B U N)  or  ur e a,  cr e ati ni n e,  c al ci u m,  t ot al  bilir u bi n,  t ot al  pr ot ei n  or 
al b u mi n,  al a ni n e  a mi n otr a n sf er a s e  ( A L T),  a s p art at e  a mi n otr a n sf er a s e  ( A S T), 
a l k ali n e p h o s p h at a s e ( A L P), l a ct at e d e h y dr o g e n a s e ( L D H)  
•  C o a g ul ati o n:  I nt er n ati o n al  N or m ali z e d  R ati o  (I N R)  a n d  a cti v at e d  p arti al 
t hr o m b o pl a sti n ti m e ( a P T T) 
•  Uri n al y si s: b y di p sti c k t e st  
•  Pr e g n a n c y t e st  
•  Ti m e  v ari a bl e s  a s  f or  e x a m pl e:  d at e  of  fir st  br e a st  c a n c er  di a g n o si s,  d at e  of 
m et a st ati c di s e a s e, st art d at e of t h e fir st li n e tr e at m e nt, d at e of pr o gr e s si o n a n d d at e 
of d e at h (if h a p p e n s d uri n g t h e st u d y) . 
•  Tr e at m e nt effi c a c y e v al u ati o n.  
Tr e at m e nt vi sit s  
T h e s e  vi sit s  will  c oi n ci d e  wit h  a  p ati e nt  cli ni c al a p p oi nt m e nt  a n d  ar e  e x p e ct e d  t o  b e 
a p pr o xi m at el y e a c h 9- 1 2  w e e k s  
•  Cli ni c al  a n d  p at h ol o gi c al  v ari a bl e s:  c o n c o mit a nt  m e di c ati o n s,  E C O G  f u n cti o n al 
st at u s, w ei g ht, fir st li n e t h er a p y a n d t o xi citi e s t h at m a y o c c ur d uri n g t h e st u d y p eri o d  
•  C T C  d et er mi n ati o n  ( a  s e c o n d  d et er mi n ati o n  of  C T C s,i n  t h e  7  d a y s  pri or  t o  d a y 
1/ c y cl e 3 ( b ef or e a n y tr e at m e nt a d mi ni str ati o n of c y cl e 3). ) 
•  L a b or at or y a s s e s s m e nt ( p er u s u al cli ni c al pr a cti c e) u s u all y c o nt ai n s:  
•  H a e m at ol o g y:  h a e m o gl o bi n,  h e m at o crit,  pl at el et  c o u nt,  r e d  bl o o d  c ell  ( R B C) 
c o u nt,  w hit e  bl o o d  c ell  ( W B C)  c o u nt,  a b s ol ut e  diff er e nti al  c o u nt  ( n e utr o p hil s, 
e o si n o p hil s, l y m p h o c yt e s, m o n o c yt e s, b a s o p hil s, ot h er c ell s)  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 8  

 
•  S er u m  c h e mi str y:  s o di u m,  p ot a s si u m,  c hl ori d e,  bl o o d  gl u c o s e,  bl o o d  ur e a 
nitr o g e n  ( B U N)  or  ur e a,  cr e ati ni n e,  c al ci u m,  t ot al  bilir u bi n,  t ot al  pr ot ei n  or 
al b u mi n,  al a ni n e  a mi n otr a n sf er a s e  ( A L T),  a s p art at e  a mi n otr a n sf er a s e  ( A S T), 
al k ali n e p h o s p h at a s e ( A L P), l a ct at e d e h y dr o g e n a s e ( L D H)  
•  Uri n al y si s: b y di p sti c k t e st  
•  Pr e g n a n c y t e st  
•  Ti m e  v ari a bl e s  a s  f or  e x a m pl e:  d at e  of  fir st  br e a st  c a n c er  di a g n o si s,  d at e  of 
m et a st ati c di s e a s e, st art d at e of t h e fir st li n e tr e at m e nt, d at e of pr o gr e s si o n a n d d at e 
of d e at h (if h a p p e n s d uri n g t h e st u d y)  
Tr e at m e nt  effi c a c y  e v al u ati o n.  Pl e a s e  s e e  A p p e n di x  2  f or t h e d at a c oll e cti o n o v er vi e w 
( a s p er st a n d ar d of c ar e)  
8. 4. 3  
D at a C oll e ct e d  at St u d y C o m pl eti o n/ E arl y T er mi n ati o n Vi sit  
F or  p ati e nt s  w h o  c o m pl et e  t h e  st u d y,  i n cl u di n g  e arl y  t er mi n ati o n, t h e st u d y  c o m pl eti o n 
vi sit s h o ul d b e d o c u m e nt e d . 
St u d y c o m pl eti o n vi sit  
•  Cli ni c al  a n d  p at h ol o gi c al  v ari a bl e s:  c o n c o mit a nt  m e di c ati o n s,  E C O G  f u n cti o n al 
st at u s, w ei g ht, fir st li n e t h er a p y a n d t o xi citi e s t h at m a y o c c ur d uri n g t h e st u d y p eri o d  
•  L a b or at or y a s s e s s m e nt ( p er u s u al cli ni c al pr a cti c e) u s u all y c o nt ai n s:  
•  H a e m at ol o g y:  h a e m o gl o bi n,  h e m at o crit,  pl at el et  c o u nt,  r e d  bl o o d  c ell  ( R B C) 
c o u nt,  w hit e  bl o o d  c ell  ( W B C)  c o u nt,  a b s ol ut e  diff er e nti al  c o u nt  ( n e utr o p hil s, 
e o si n o p hil s, l y m p h o c yt e s, m o n o c yt e s, b a s o p hil s, ot h er c ell s)  
•  S er u m  c h e mi str y:  s o di u m,  p ot a s si u m,  c hl ori d e,  bl o o d  gl u c o s e,  bl o o d  ur e a 
nitr o g e n  ( B U N)  or  ur e a,  cr e ati ni n e,  c al ci u m,  t ot al  bilir u bi n,  t ot al  pr ot ei n  or 
al b u mi n,  al a ni n e  a mi n otr a n sf er a s e  ( A L T),  a s p art at e  a mi n otr a n sf er a s e  ( A S T), 
al k ali n e p h o s p h at a s e ( A L P), l a ct at e d e h y dr o g e n a s e ( L D H)  
•  Uri n al y si s: b y di p sti c k t e st  
•  Pr e g n a n c y t e st  
•  Ti m e v ari a bl e s  a s  f or  e x a m pl e:  d at e  of  fir st  br e a st  c a n c er  di a g n o si s,  d at e  of 
m et a st ati c di s e a s e, st art d at e of t h e fir st li n e tr e at m e nt, d at e of pr o gr e s si o n a n d d at e 
of d e at h (if h a p p e n s d uri n g t h e st u d y)  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
3 9  

 
Tr e at m e nt effi c a c y e v al u ati o n pl e a s e  s e e A p p e n di x 2  f or t h e d at a c oll e cti o n o v er vi e w  at 
t h e tr e at m e nt c o m pl eti o n vi sit if a v ail a bl e. 
8. 4. 4  
D at a C oll e ct e d d uri n g F oll o w -U p  
T h e f oll o w u p p eri o d c o v er a p pr o xi m at el y 6 m o nt h s aft er t h e l a st d o s e of st u d y tr e at m e nt. 
T h e vi sit s will c oi n ci d e wit h a p ati e nt cli ni c al a p p oi nt m e nt. T h e f oll o wi n g i nf or m ati o n will 
b e c oll e ct e d:  
F oll o w u p vi sit  
F oll o w u p vi sit s will b e p erf or m e d aft er tr e at m e nt di s c o nti n u ati o n, d u e t o pr o gr e s si o n or 
t o ot h er r e a s o n ( p ati e nt/ p h y si ci a n d e ci si o n, t o xi cit y, et c. ). T h e s e vi sit s will c oi n ci d e wit h 
a p ati e nt cli ni c al a p p oi nt m e nt a n d ar e e x p e ct e d t o b e a p pr o xi m at el y e a c h 9 -1 2 w e e k s  
•  Cli ni c al  a n d  p at h ol o gi c al  v ari a bl e s:  c o n c o mit a nt  m e di c ati o n s,  E C O G  f u n cti o n al 
st at u s, w ei g ht, a n d t o xi citi e s t h at m a y o c c ur d uri n g t h e st u d y p eri o d  
•  L a b or at or y a s s e s s m e nt  ( p er u s u al cli ni c al pr a cti c e) u s u all y c o nt ai n s:  
•  H a e m at ol o g y:  h a e m o gl o bi n,  h e m at o crit,  pl at el et  c o u nt,  r e d  bl o o d  c ell  ( R B C) 
c o u nt,  w hit e  bl o o d  c ell  ( W B C)  c o u nt,  a b s ol ut e  diff er e nti al  c o u nt  ( n e utr o p hil s, 
e o si n o p hil s, l y m p h o c yt e s, m o n o c yt e s, b a s o p hil s, ot h e r c ell s) 
•  S er u m  c h e mi str y:  s o di u m,  p ot a s si u m,  c hl ori d e,  bl o o d  gl u c o s e,  bl o o d  ur e a 
nitr o g e n  ( B U N)  or  ur e a,  cr e ati ni n e,  c al ci u m,  t ot al  bilir u bi n,  t ot al  pr ot ei n  or 
al b u mi n,  al a ni n e  a mi n otr a n sf er a s e  ( A L T),  a s p art at e  a mi n otr a n sf er a s e  ( A S T), 
al k ali n e p h o s p h at a s e ( A L P), l a ct at e d e h y dr o g e n a s e ( L D H)  
•  Uri n al y si s: b y di p sti c k t e st  
•  Pr e g n a n c y t e st  
•  Ti m e  v ari a bl e s  a s  f or  e x a m pl e:  d at e  of  fir st  br e a st  c a n c er  di a g n o si s,  d at e  of 
m et a st ati c di s e a s e, st art d at e of t h e fir st li n e tr e at m e nt, d at e of pr o gr e s si o n a n d d at e 
of d e at h (if h a p p e n s d uri n g t h e st u d y) . 
•  Tr e at m e nt effi c a c y e v al u ati o n.  
Aft er  t h e  st u d y  c o m pl eti o n/ e arl y  t er mi n ati o n  vi sit, a d v er s e  e v e nt s  ( A E s) s h o ul d  b e 
f oll o w e d a s o utli n e d i n S e cti o n  1 0. 5 . 
Pl e a s e s e e  A p p e n di x 2 f or t h e d at a c oll e cti o n o v er vi e w d uri n g f oll o w-u p.  
 
8. 4. 5  
S af e t y D at a C oll e cti o n  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
4 0  

 
Cli ni c al  A E s,  s eri o u s  a n d  n o n -s eri o u s,  will  b e  r e c or d e d i n t h e C R F  t hr o u g h o ut  all  t h e 
o b s er v ati o n p eri o d, wit h p h y si ci a n’ s a s s e s s m e nt of s e v erit y ( mil d, m o d er at e, s e v er e or i n 
o n c ol o g y st u di e s u si n g t h e N ati o n al C a n c er I n stit ut e [N CI ] C o m m o n T er mi n ol o g y Crit eri a 
f or  A d v er s e  E v e nt s [C T C A E ])  a n d r el ati o n s hi p  t o  t h er a p y  (i. e., r el at e d  or  u nr el at e d) a s 
d e s cri b e d i n S e cti o n  1 0 . 
8. 4. 6  
R etr o s p e cti v e D at a C oll e cti o n  
N ot a p pli c a bl e  
8. 5  
P A TI E N T, S T U D Y, A N D SI T E DI S C O N TI N U A TI O N  
8. 5. 1  
P ati e nt Di s c o nti n u ati o n  
A s  t h e  d e ci si o n  f or  tr e at m e nt  li e s  wit h  t h e  tr e ati n g  p h y si ci a n  a n d  i s  n ot  b o u n d  t o  t h e 
p arti ci p ati o n  of  a  p ati e nt  i n  t h e  st u d y,  t h e  p h y si ci a n  h a s  t h e  ri g ht  t o  wit h dr a w  a  p ati e nt 
fr o m  t h e  st u d y  at  a n y  ti m e.  I n  a d diti o n,  p ati e nt s  h a v e  t h e  ri g ht  t o  v ol u nt aril y  wit h dr a w 
fr o m t h e st ud y at a n y ti m e f or a n y r e a s o n.  R e a s o n s f or di s c o nti n u ati o n of tr e at m e nt wit h 
t h e m e di ci n al  pr o d u ct  or  wit h dr a w al  fr o m  t h e  st u d y  m a y  i n cl u d e,  b ut  ar e  n ot  li mit e d  t o, 
t h e f oll o wi n g: 
•  
P ati e nt wit h dr a w al of c o n s e nt at a n y ti m e  
•  
P h y si ci a n or S p o n s or j u d g e s di s c o nti n u ati o n i s i n t h e p ati e nt’ s b e st i nt er e st  
•  
P ati e nt i s l o st t o f oll o w -u p . 
•  
T o xi cit y  
•  
Pr o gr e s si o n .  
 
 
 
8. 5. 2  
Di s c o nti n u ati o n fr o m Tr e at m e nt wit h M e di ci n al Pr o d u ct  
T h e  d e ci si o n  f or  di s c o nti n u ati o n  fr o m  tr e at m e nt  li e s  wit h  t h e  tr e ati n g  p h y si ci a n in 
a c c or d a n c e  wit h  t h e  S m P C  a n d  i n  a gr e e m e nt  wit h  t h e  p ati e nt’ s  d e ci si o n  a n d  i s  n ot 
r e g ul at e d b y t hi s pr ot o c ol.  
 
T h e  e arl y  t er mi n ati o n  vi sit  s h o ul d  b e  c o m pl et e d  b y p ati e nt s  w h o  di s c o nti n u e tr e at m e nt 
wit h p a clit a x el or b e v a ci z u m a b  e arli er t h a n pl a n n e d a c c or di n g t o l a b eli n g.  T h e pri m ar y 
r e a s o n  f or 
e arl y  tr e at m e nt  
di s c o nti n u ati o n  s h o ul d  b e  d o c u m e nt e d  o n  t h e 
a p pr o pri at e  C R F  p a g e . E v er y  eff ort  s h o ul d  b e  m a d e  t o  o bt ai n  i nf or m ati o n  o n  p ati e nt s 
w h o di s c o nti n u e tr e at m e nt . 
8. 5. 3  
Wit h dr a w al fr o m S t u d y 
E v er y  eff ort  s h o ul d  b e  m a d e  t o  o bt ai n  i nf or m ati o n  o n  p ati e nt s  w h o  wit h dr a w  fr o m  t h e 
st u d y.  T h e pri m ar y r e a s o n f or wit h dr a w al fr o m t h e st u d y s h o ul d b e d o c u m e nt e d o n t h e 
a p pr o pri at e C R F  p a g e .  P ati e nt s  will  n ot  b e  f oll o w e d  f or  a n y  r e a s o n  aft er  c o n s e nt  h a s 
b e e n wit h dr a w n.  P ati e nt s w h o wit h dr a w fr o m t h e st u d y will  n ot b e r e pl a c e d.    
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
4 1  

 
8. 5. 4  
St u d y a n d Sit e Di s c o nti n u ati o n  
T h e S p o n s or h a s t h e ri g ht t o t er mi n at e t hi s st u d y at a n y ti m e.  R e a s o n s f or t er mi n ati n g 
t h e st u d y m a y i n cl u d e, b ut ar e n ot li mit e d to, t h e f oll o wi n g:  
•  
P ati e nt e nr oll m e nt i s u n s ati sf a ct or y  
T h e  S p o n s or  will  n otif y  t h e p h y si ci a n if  t h e  st u d y  i s  pl a c e d  o n  h ol d,  or  if  t h e  S p o n s or 
d e ci d e s t o di s c o nti n u e t h e  st u d y.  
T h e S p o n s or h a s t h e ri g ht t o r e pl a c e a sit e at a n y ti m e. R e a s o n s f or r e pl a ci n g a sit e m a y 
i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g: 
•  
E x c e s si v el y sl o w r e cr uit m e nt  
•  
P o or pr ot o c ol a d h er e n c e  
•  
I n a c c ur at e or i n c o m pl et e d at a r e c or di n g 
•  
N o n -c o m pli a n c e  wit h  t h e G ui d eli n e s  f or  G o o d  P h ar m a c o e pi d e mi ol o gi c al  Pr a cti c e s 
( G P P) or a n y ot h er p erti n e nt l o c al l a w or g ui d eli n e 
 
8. 6  
S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 6. 1  
G e n er al C o n si d er ati o n s  
U p o n st u d y c o m pl eti o n, aft er t h e d at a f or t h e fi n al st u d y p ati e nt h a v e b e e n r e c or d e d, t h e 
d at a b a s e  will  b e  cl o s e d  a n d  tr a n sf err e d  t o  t h e  Bi o m etri c s  D e p art m e nt  f or  st ati sti c al 
a n al y si s.  
T h e pr o p o s e d m et h o d s of st ati sti c al a n al y si s s h o w n b el o w c o n stit ut e a s u m m ar y of t h e 
m et h o d s t o b e u s e d f or t h e d at a c oll e ct e d i n or d er t o a d dr e s s t h e o bj e cti v e s of t h e st u d y.  
D e s cri pti v e  st ati sti c s  a n d  st ati sti c al  pl ot s  will  b e  u s e d  t o  d e s cri b e  all  d at a.  C at e g ori c al 
v ari a bl e s will b e s u m m ari z e d wit h n u m b er of mi s si n g v al u e s, fr e q u e n ci e s  e x a ct bi n o mi al 
( Cl o p p er-P e ar s o n) c o nfi d e n c e i nt er v al 9 5 % ( w h e n n e c e s s ar y) . C o nti n u o u s v ari a bl e s will 
b e  s u m m ari z e d  wit h  t h e  n u m b er  of  " n o n -mi s si n g"  o b s er v ati o n s, t h e  m e a n,  st a n d ar d 
d e vi ati o n, m e di a n, i nt er q u artil e r a n g e, mi ni m u m, m a xi m u m a n d 9 5 % c o nfi d e n c e i nt er v al 
( w h e n  n e c e s s ar y).  Ti m e  t o  e v e nt  v ari a bl e s  will  b e  s u m m ari z e d  wit h  r at e s  a n d  9 5 % 
c o nfi d e n c e i nt er v al ( w h e n e v er n e c e s s ar y).  
G e n er all y s p e a ki n g, t h er e ar e  n o pl a n s t o all o c at e u n a v ail a bl e d at a, w hi c h will si m pl y b e 
d e s cri b e d  a s  mi s si n g  d at a.  I n  a d diti o n,  t h er e  ar e  n o  pl a n s  t o  c o n d u ct  a  s e n siti vit y 
a n al y si s.  
8. 6. 2  
A n al y si s P o p ul ati o n s   
Eff e cti v e n e s s a n al y s e s will b e b a s e d o n all e nr oll e d p ati e nt s w h o m e et s el e cti o n crit eri a. 
S af et y a n al y s e s will i n cl u d e all p ati e nt s w h o r e c ei v e d at l e a st o n e d o s e of p a clit a x el or 
b e v a ci z u m a b.  
8. 6. 3  
A n al y s i s M et h o d s 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
4 2  

 
The proposed methods of statistical analysis shown below constitute a summary of the 
methods to be used for the data collected in order to address the objectives of the study. 
Descriptive statistics and statistical plots will be used to describe all data. Categorical 
variables will be summarized with number of missing values, frequencies and 
percentages and confidence interval 95% (when necessary). Continuous variables will 
be summarized with the number of "non-missing" observations, the mean, standard 
deviation, median, interquartile range, minimum, maximum and 95% confidence interval 
(when necessary). Time to event variables will be summarized with rates and 95% 
confidence interval (whenever necessary).  
8.6.3.1 
Primary Effectiveness Analysis 
For the analysis of the primary objective an estimation using the Chi square for 
independent proportions and the 95% CI for each estimation of a group will be used and 
presented together with 95% exact binomial (Clopper-Pearson) confidence intervals. As 
a part of a secondary analysis the predictive values will be estimated to a new possible 
cutpoint.  
8.6.3.2 
Secondary Effectiveness Analysis 
Secondary Effectiveness Analysis 
We will estimate the positive predictive value (PPV), negative predictive value (NPV), 
sensibility and specificity of the prognostic value of CTC levels (two cut-offs points: <5 
CTCs/7.5 ml and optimal cuts-off point) to detect patients who are either alive, without 
progression, with complete response or with objective response. The estimation will be 
performed 
with exact 
binomial 
(Clopper-Pearson) confidence 
interval 
95% 
for 
proportions. 
We will estimate the optimal cut off point for CTCs level with sample data for detecting 
patients who are either alive, without progression, with complete response or with 
objective response. Logistic regression models and ROC procedures will be used.  
We will estimate the differences between good and poor prognostic groups (defined by 
two cut-offs point: <5 CTC and optimal for sample) in overall survival, progression free 
survival and time to best response. Analysis will be adjusted by baseline prognostic 
factors. Cox regression models and time dependent ROC will be used. 
8.6.3.3 
Safety Analysis 
Summary measures will be performed on the adverse events (adverse event, events of 
special interest, those which lead to a study or treatment discontinuation, SAEs and AEs 
grade ≥3) laboratory parameters and other security parameters. The incidence and the 
95% CI of every event will be calculated and will be expressed with the primary system-
organ class and the preferred term according to MedDRA version 17.1.  
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We will estimate the positive predictive value (PPV), negative predictive value (NPV), 
sensibility and specificity of the prognostic value of CTC levels (two cut-offs: <5 
CTCs/7.5 ml and optimal cuts-off) to detect toxicities grade (3-4). The estimation will be 
performed with exact binomial (Clopper-Pearson) confidence interval 95% for 
proportions. 
We will estimate the optimal cut off for CTCs level with sample data for detecting 
objective response and toxicities grade (3-4). Logistic regression models and ROC 
procedures will be used. 
8.6.3.4 
Other Analyses  
For the biomarkers correlation with the CTC levels, correlation coefficients (Pearson or 
Spearman depending on variable distribution) will be analyzed.  
8.6.4 
Interim Analyses  
No interim analyses are planned. 
8.6.5 
Sample Size Justification 
The calculation of sample size was based on the determination of the main objective: " 
To determine the predictive capacity of early CTCs monitoring predefined as sensitive 
(<5 CTCs after cycle 2) and resistant (>5 CTCs after cycle 2) in terms of Clinical Benefit 
Rate (defined as patients achieving partial or complete response as well as tumor 
stabilization ≥ 24 weeks) for patients with HER2-negative aggressive metastatic breast 
cancer treated with standard first line chemotherapy with paclitaxel-bevacizumab”. The 
precision values, power, etc., of the other secondary objectives are achieved, 
accordingly, depending on the size determined by the primary endpoint. 
The primary endpoint is the clinical benefit rate at follow-up study. The investigator’s 
hypothesis is that CBR will be 35% and 70% for CTC-resistance and sensitive groups, 
respectively. We assume the ratio between CTC-Resistance and CTC sensitive group 
will be 1:4. We accept an alpha risk of 0.05 two-sided and a beta risk of 0.2. We 
anticipate a drop-out rate of 10%. We will analyze the data with a Chi-square test for two 
independent proportions.  
Finally, 22 subjects in CTC-Resistance group and 88 subjects in CTC-sensitive group 
are estimated. Therefore a total of 110 patients are needed. Sample size has been 
estimated with the GRANMO V7.12 April 2012 program. 
8.7 
DATA MANAGEMENT 
8.7.1 
Data Quality Assurance 
The Sponsor will supply CRF specifications for this study.  A contract research 
organization (CRO) will be responsible for data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC using 
CRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
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discrepant data, the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor 
standard procedures will be used to handle and process the electronic transfer of these 
data. 
CRFs and correction documentation will be maintained in the EDC system audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO standard procedures. 
8.7.2 
Electronic Case Report Forms 
CRFs are to be completed using a Sponsor-designated electronic data capture (EDC) 
system.  Sites will receive training and have access to a manual for appropriate CRF 
completion.  CRFs will be submitted electronically to the Sponsor and should be handled 
in accordance with instructions from the Sponsor.  
All CRFs should be completed by designated trained site staff.  CRFs should be 
reviewed and electronically signed and dated by the physician or a designee. 
At the end of the study, the physician will receive the data related to patients from his or 
her site in an electronically readable format (e.g., on a compact disc [CD]).  Data must 
be kept with the study records.  Acknowledgement of receipt of the data is required. 
8.7.3 
Source Data Documentation 
Study monitors will perform ongoing SDV as defined in the Trial Monitoring Plan to 
confirm that critical protocol data (i.e., source data) entered in the CRF by authorized 
site personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
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Before study initiation, the types of source documents that contain study-relevant 
information will be clearly defined in the Trial Monitoring Plan.  This includes any 
protocol data to be entered directly into the CRF (i.e., no prior written or electronic record 
of the data) and considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered in the CRF must not be obliterated or destroyed and must be retained per the 
policy for retention of records described in Section 8.7.5. 
To facilitate SDV, the physicians and institutions must provide the Sponsor direct access 
to applicable source documents and reports for trial-related monitoring, Sponsor audits, 
and IRB/EC review.  The participating sites must also allow inspection by applicable 
health authorities. 
8.7.4 
Use of Computerized Systems 
When clinical observations are entered directly into a participating site's computerized 
medical record system (i.e., in lieu of original hardcopy records), the electronic record 
can serve as the source document if the system has been validated in accordance with 
health authority requirements pertaining to computerized systems used in clinical 
research.  An acceptable computerized data collection system allows preservation of the 
original entry of data.  If original data are modified, the system should maintain a 
viewable audit trail that shows the original data as well as the reason for the change, 
name of the person making the change, and date of the change. 
 
8.7.5 
Retention of Records 
Records and documents pertaining to the conduct of this study, including CRFs and 
Informed Consent Forms, must be retained by the Physician for at least 15 years after 
completion or discontinuation of the study, or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8.8 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
8.8.1 
Study Documentation 
The physician must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the physician will receive 
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the patient data, which include an audit trail containing a complete record of all changes 
to data. 
8.8.2 
Site Audits and Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for audit of 
study data, patients’ medical records, and CRFs.   
The physician will also permit national and local health authorities to inspect facilities 
and records relevant to this study. 
8.8.3 
Administrative Structure 
Main Authors: 
Dr. 
, MD. 
.  
Dr. 
, MD. 
.  
Dr. 
, MD. 
.  
Dr. 
, MD. 
. 
. 
, Roche Farma S.A. 
.  
 
8.9 
LIMITATIONS OF THE RESEARCH METHOD 
Apart from those belonging to the design of the observational studies, no further 
potential limitations are detected. 
8.10 
OTHER ASPECTS 
No other aspects are worth to mention. 
9. 
PROTECTION OF HUMAN SUBJECTS/ETHICAL CONSIDERATIONS 
9.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the Guidelines for GPP published 
by the International Society of Pharmacoepidemiology (ISPE) and the laws and 
regulations of the country in which the research is conducted. 
9.2 
INFORMED CONSENT  
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site. If applicable, it will be provided in a certified translation of the 
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local language. The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate Consent 
Forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final Consent Forms approved by the IRB/EC must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
By signing the form, the patient confirms that he/she has been informed about the study 
and agrees to pseudonymous data collection, pooling of data with similar scientific data 
(if applicable), and the possibility of monitoring activities.  It is the responsibility of the 
physician to obtain written informed consent from each patient participating in the study, 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study.  The physician must also explain that the patient is completely free 
to refuse to enter the study or to withdraw from it at any time, for any reason and without 
losing the benefit of any medical care to which the patient is entitled or is presently 
receiving. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
9.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Lead 
Scientific Responsible and reviewed and approved by the IRB/EC before the study is 
initiated. In addition, any patient recruitment materials must be approved by the IRB/EC. 
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The Lead Scientific Responsible is responsible for providing written summaries of the 
status of the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Physicians are also 
responsible for promptly informing the IRB/EC of any protocol amendments. 
In addition to the requirements for collecting all AEs in the CRF and reporting all 
suspected ADRs (including causality unknown or not provided), adverse events of 
special interest, and SAEs to the Sponsor, physicians must comply with requirements for 
AE reporting to the local health authority and IRB/EC. 
9.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in datasets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
10. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ 
ADVERSE REACTIONS 
10.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording SAEs and non-serious AEs 
(including AEs of special interest), performing safety laboratory assessments, measuring 
vital signs, and conducting other tests that are deemed critical to the safety evaluation of 
the study as per standard medical practice.  For details of the monitoring and recording 
of AEs, please see Sections 10.2 and 10.3. Situations requiring safety reporting possibly 
without an associated AE are outlined in Section 10.3.4. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 10.3. 
10.1.1 
Adverse Events 
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A c c or di n g t o t h e I nt er n ati o n al C o nf er e n c e of H ar m o ni s ati o n (I C H) , a n A E i s a n y 
u nt o w ar d m e di c al o c c urr e n c e i n a p ati e nt or cli ni c al i n v e sti g ati o n s u bj e ct a d mi ni st er e d a 
p h ar m a c e uti c al pr o d u ct, r e g ar dl e s s of c a u s al attri b uti o n.  A n A E c a n t h er ef or e b e a n y of 
t h e f oll o wi n g: 
•  
A n y u nf a v or a bl e a n d u ni nt e n d e d si g n (i n cl u di n g a n a b n or m al l a b or at or y fi n di n g), 
s y m pt o m, or di s e a s e t e m p or all y a s s o ci at e d wit h t h e u s e of a m e di ci n al pr o d u ct, 
w h et h er or n ot c o n si d er e d r el at e d t o t h e m e di ci n al pr o d u ct  
•  
A n y n e w di s e a s e or e x a c er b ati o n of a n e xi sti n g di s e a s e ( a w or s e ni n g i n t h e 
c h ar a ct er, fr e q u e n c y, or s e v erit y of a k n o w n c o n diti o n), e x c e pt  a s d e s cri b e d i n 
S e cti o n  1 0. 2. 4. 1 0 . 
•  
R e c urr e n c e of a n i nt er mitt e nt m e di c al c o n diti o n ( e. g., h e a d a c h e) n ot pr e s e nt at 
b a s eli n e  
•  
A n y d et eri or ati o n i n a l a b or at or y v al u e or ot h er cli ni c al t e st ( e. g., el e ctr o c ar di o gr a m 
[E C G ], X-r a y) t h at i s a s s o ci at e d wit h s y m pt o m s or l e a d s t o a c h a n g e i n st u d y 
tr e at m e nt or c o n c o mit a nt tr e at m e nt or di s c o nti n u ati o n fr o m st u d y m e di ci n e . 
 
1 0. 1. 2  
S eri o u s A d v er s e E v e nt s (I m m e di at el y R e p ort a bl e t o t h e S p o n s or ) 
A n S A E  i s a n y A E t h at m e et s a n y of t h e f oll o wi n g crit eri a: 
•  
I s fat al (i. e., t h e A E a ct u all y c a u s e s or l e a d s t o d e at h)  
•  
I s lif e-t hr e at e ni n g ( N O T E:  Th e t er m “lif e-t hr e at e ni n g” r ef er s t o a n e v e nt i n w hi c h t h e 
p ati e nt w a s at i m m e di at e ri s k of d e at h at t h e ti m e of t h e e v e nt; it d o e s n ot r ef er t o a n 
e v e nt t h at h y p ot h eti c all y mi g ht h a v e c a u s e d d e at h if it w er e m or e s e v er e. ) 
•  
R e q uir e s or pr ol o n g s i n p ati e nt h o s p it ali z ati o n ( s e e S e cti o n 1 0. 2. 4. 1 1 ) 
•  
R e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y/i n c a p a cit y (i. e., t h e A E r e s ult s i n 
s u b st a nti al di sr u pti o n of t h e p ati e nt’ s a bilit y t o c o n d u ct n or m al lif e f u n cti o n s)  
•  
I s a c o n g e nit al a n o m al y/ birt h d ef e ct i n a n e o n at e/i nf a nt b or n  t o a m ot h er e x p o s e d t o 
st u d y m e di ci n e  
•  
I s a si g nifi c a nt m e di c al e v e nt i n t h e p h y si ci a n’ s j u d g m e nt ( e. g., m a y j e o p ar di z e t h e 
p ati e nt or m a y r e q uir e m e di c al/ s ur gi c al i nt er v e nti o n t o pr e v e nt o n e of t h e o ut c o m e s 
li st e d a b o v e) 
 
T h e t er m s “ s e v er e” a n d “ s eri o u s” ar e n ot  s y n o n y m o u s.  S e v erit y r ef er s t o t h e i nt e n sit y of 
a n A E (e. g., r at e d a s mil d, m o d er at e, or s e v er e, or a c c or di n g t o NCI  C T C A E crit eri a; s e e  
S e cti o n  1 0. 2. 2 ); t h e e v e nt it s elf m a y b e of r el ati v el y mi n or m e di c al si g nifi c a n c e ( s u c h a s 
s e v er e h e a d a c h e wit h o ut a n y f urt h er fi n di n g s).  
S e v erit y a n d s eri o u s n e s s n e e d t o b e i n d e p e n d e ntl y a s s e s s e d f or e a c h A E r e c or d e d o n 
t h e C R F . 
S A E s  ar e r e q uir e d t o b e r e p ort e d b y t h e p h y si ci a n t o t h e S p o n s or i m m e di at el y (i. e., n o 
m or e t h a n 2 4 h o ur s aft er l e ar ni n g of t h e e v e nt ; s e e S e cti o n  1 0. 3. 1  a n d S e cti o n  1 0. 3. 2  f or 
r e p orti n g i n str u cti o n s). 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 0  

 
1 0. 1. 3  
N o n -S eri o u s A d v er s e E v e nt s of S p e ci al I nt er e st (I m m e di at el y 
R e p ort a bl e t o t h e S p o n s or )  
N o n -s eri o u s A E s of s p e ci al i nt er e st ar e r e q uir e d t o b e r e p ort e d b y t h e p h y si ci a n t o t h e 
S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s aft er l e ar ni n g of t h e e v e nt; s e e 
S e cti o n  1 0. 3. 1  a n d  S e cti o n  1 0. 3. 2  for r e p orti n g i n str u cti o n s).  A E s of s p e ci al i nt er e st f or 
t hi s st u d y i n cl u d e t h e f oll o wi n g: 
•  
C a s e s of p ot e nti al m e di ci n e -i n d u c e d li v er i nj ur y t h at i n cl u d e a n el e v at e d A L T or A S T 
i n c o m bi n ati o n wit h eit h er a n el e v at e d bilir u bi n or cli ni c al j a u n di c e, a s d efi n e d b y 
H y' s l a w ( s e e S e cti o n  1 0. 2. 4. 7 ).  
•  
S u s p e ct e d tr a n s mi s si o n of a n i nf e cti o u s a g e nt b y t h e st u d y m e di ci n e , a s d efi n e d  
b el o w:  
A n y or g a ni s m, vir u s, or i nf e cti o u s p arti cl e ( e. g., pri o n pr ot ei n tr a n s mitti n g 
tr a n s mi s si bl e s p o n gif or m e n c e p h al o p at h y), p at h o g e ni c or n o n-p at h o g e ni c, i s 
c o n si d er e d a n i nf e cti o u s a g e nt.  A tr a n s mi s si o n of a n i nf e cti o u s a g e nt m a y b e 
s u s p e ct e d fr o m cl i ni c al s y m pt o m s or l a b or at or y fi n di n g s t h at i n di c at e a n i nf e cti o n i n 
a p ati e nt e x p o s e d t o a m e di ci n al pr o d u ct.  T hi s t er m o nl y  a p pli e s w h e n a 
c o nt a mi n ati o n of t h e st u d y m e di ci n e i s s u s p e ct e d. 
•  
H y p ert e n si o n ≥ gr a d e 3  
•  
Pr ot ei n uri a ≥ gr a d e 3  
•  
GI p erf or ati o n, a b s c e s s e s a n d fi st ul a e ( a n y gr a d e)  
•  
W o u n d h e ali n g c o m pli c ati o n s ≥ gr a d e 3  
•  
H a e m orr h a g e ≥ gr a d e 3 ( a n y gr a d e C N S bl e e di n g; ≥ gr a d e 2 h a e m o pt y si s)  
•  
Art eri al t hr o m b o e m b oli c e v e nt s ( a n y gr a d e)  
•  
V e n o u s t hr o m b o e m b oli c e v e nt s ≥ gr a d e 3  
•  
P R E S ( or R P L S; a n y gr a d e)  
•  
C o n g e sti v e h e art f ail ur e ≥ gr a d e 3  
•  
N o n -GI fi st ul a or a b s c e s s ≥ gr a d e 2 Art eri al t hr o m b o e m b oli c e v e nt s, c o n g e sti v e 
h e art f ail ur e, i nt er stiti al l u n g di s e a s e, o st e o n e cr o si s of j a w  
 
1 0. 1. 4  
N o n -S eri o u s A d v er s e E v e nt s ot h er t h a n A d v er s e E v e nt s of S p e ci al 
I nt er e st 
All n o n -s eri o u s A E s (i n a d diti o n t o A E s of s p e ci al i nt er e st) will b e c oll e ct e d f or t hi s st u d y.  
 
1 0. 2  
M E T H O D S A N D TI MI N G F O R C A P T U RI N G A N D A S S E S SI N G 
S A F E T Y  P A R A M E T E R S  
T h e p h y si ci a n i s r e s p o n si bl e f or e n s uri n g t h at all A E s ( s e e S e cti o n  1 0. 1. 1  f or d efi niti o n) 
ar e r e c o r d e d o n t h e A E C R F  a n d r e p ort e d t o  t h e S p o n s or i n a c c or d a n c e wit h 
i n str u cti o n s pr o vi d e d i n t hi s s e cti o n a n d i n S e cti o n 1 0. 3 −S e cti o n  1 0. 5 . 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 1  

 
For each AE recorded on the AE CRF, the physician will make an assessment of 
seriousness (see Section 10.1.2 for seriousness criteria), severity (see Section 10.2.2), 
and causality (see Section 10.2.3). 
10.2.1 
Adverse Event Reporting Period 
Physicians will seek information on AEs at each patient contact.  All AEs subject to the 
collecting and reporting requirements outlined in this protocol, whether reported by the 
patient or noted by study personnel, will be recorded in the patient’s medical record and 
on the AE CRF. 
After initiation of the study, all protocol-defined AEs will be reported from the time a 
patient enters the study until the end of his or her observation period.  After this period, 
the physician is not required to actively monitor patients for AEs; however, the Sponsor 
should be notified if the physician becomes aware of any AEs, SAEs, AESIs or non-
serious AEs of special interest related to the study medicine (see Section 10.5). 
10.2.2 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v 4.0) will be used for assessing AE 
severity.  The table below will be used for assessing severity for AEs that are not 
specifically listed in the NCI CTCAE. 
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T a bl e  1 
A d v er s e E v e nt S e v erit y Gr a di n g S c al e  
Gr a d e  
S e v erit y  
1  
Mil d; a s y m pt o m ati c or mil d s y m pt o m s; cli ni c al or di a g n o sti c 
o b s er v ati o n s o nl y; or i nt er v e nti o n n ot i n di c at e d  
2  
M o d er at e; mi ni m al, l o c al, or n o n -i n v a si v e i nt er v e nti o n i n di c at e d; or 
li miti n g a g e-a p pr o pri at e i n str u m e nt al a cti viti e s of d ail y li vi n g  a 
3 
S e v er e or m e di c all y si g nifi c a nt, b ut n ot i m m e di at el y lif e-t hr e at e ni n g; 
h o s pit ali z ati o n or pr ol o n g ati o n of h o s pit ali z ati o n i n di c at e d; di s a bli n g; or 
li miti n g s elf -c ar e a cti viti e s of d ail y li vi n g  b,  c 
4  
Lif e -t hr e at e ni n g c o n s e q u e n c e s or ur g e nt i nt er v e nti o n i n di c at e d d  
5  
D e at h r el at e d t o A E  d  
N ot e:   B a s e d o n t h e N CI C T C A E ( v  4. 0), w hi c h c a n b e f o u n d at: 
htt p:// ct e p. c a n c er. g o v/ pr ot o c ol D e v el o p m e nt/ el e ctr o ni c a p pli c ati o n s/ ct c. ht m  
 
a  I n str u m e nt al a cti viti e s of d ail y li vi n g r ef er t o pr e p ari n g m e al s, s h o p pi n g f or gr o c eri e s 
or cl ot h e s, u si n g t h e t el e p h o n e, m a n a gi n g m o n e y, et c.  
b  E x a m pl e s of s elf -c ar e a cti viti e s of d ail y li vi n g i n cl u d e b at hi n g, dr e s si n g a n d 
u n dr e s si n g, f e e di n g o n e s elf, u si n g t h e t oil et, a n d t a ki n g m e di c ati o n s, a s p erf or m e d 
b y p ati e nt s w h o ar e n ot b e dri d d e n.  
c If a n e v e nt i s a s s e s s e d a s a “ si g nifi c a nt m e di c al e v e nt,” it m u st b e r e p ort e d a s a n 
S A E ( s e e S e cti o n  1 0. 3. 2  f or r e p orti n g i n str u cti o n s), p er t h e d efi niti o n of S A E i n 
S e cti o n  1 0. 1. 2 . 
d  Gr a d e 4 a n d 5  e v e nt s m u st b e r e p ort e d a s S A E s ( s e e S e cti o n  1 0. 3. 2  f or r e p orti n g 
i n str u cti o n s), p er t h e d efi niti o n of S A E i n S e cti o n  1 0. 1. 2 . 
 
1 0. 2. 3  
A s s e s s m e nt of C a u s alit y of A d v er s e E v e nt s  
P h y si ci a n s s h o ul d u s e t h eir k n o wl e d g e of t h e p ati e nt, t h e cir c u m st a n c e s s urr o u n di n g t h e 
e v e nt, a n d a n e v al u ati o n of a n y p ot e nti al alt er n ati v e c a u s e s t o d et er mi n e w h et h er or n ot 
a n A E  i s c o n si d er e d t o b e r el at e d t o t h e st u d y m e di ci n e , i n di c ati n g “y e s ” or “n o ” 
a c c or di n gl y.  T h e f oll o wi n g g ui d a n c e s h o ul d b e t a k e n i nt o c o n si d er ati o n:  
•  
T e m p or al r el ati o n s hi p of e v e nt o n s et t o t h e i niti ati o n of st u d y m e di ci n e  
•  
C o ur s e of t h e e v e nt, c o n si d eri n g e s p e ci all y t h e eff e ct s of d o s e r e d u cti o n, 
di s c o nti n u ati o n of st u d y m e di ci n e , or r ei ntr o d u cti o n of st u d y m e di ci n e ( w h en 
a p pli c a bl e)  
•  
K n o w n a s s o ci ati o n of t h e e v e nt wit h t h e st u d y m e di ci n e or wit h si mil ar tr e at m e nt s  
•  
K n o w n a s s o ci ati o n of t h e e v e nt wit h t h e di s e a s e u n d er st u d y  
•  
Pr e s e n c e of ri s k f a ct or s i n t h e p ati e nt or u s e of c o n c o mit a nt m e di c ati o n s k n o w n t o 
i n cr e a s e t h e o c c urr e n c e of t h e e v e nt 
•  
Pr e s e n c e of n o n -tr e at m e nt-r el at e d f a ct or s t h at ar e k n o w n t o b e a s s o ci at e d wit h t h e 
o c c urr e n c e of t h e e v e nt  
F or p ati e nt s r e c ei vi n g c o m bi n ati o n t h er a p y, c a u s alit y will b e a s s e s s e d i n di vi d u all y f or 
e a c h of t h e m e di ci n al pr o d u ct . 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 3  

 
1 0. 2. 4  
Pr o c e d ur e s f or R e c or di n g A d v er s e  E v e nt s  
P h y si ci a n s s h o ul d u s e c orr e ct m e di c al t er mi n ol o g y/ c o n c e pt s w h e n r e c or di n g A E s i n t h e 
A E  s e cti o n  of t h e C R F .  Coll o q ui ali s m s a n d a b br e vi ati o n s  s h o ul d b e a v oi d e d . 
O nl y o n e A E  t er m s h o ul d b e r e c or d e d i n t h e e v e nt fi el d of t h e C R F . 
1 0. 2. 4. 1  
I nf u si o n-R el at e d  or  I nj e cti o n R e a cti o n s 
A E s t h at o c c ur d uri n g or wit hi n 2 4 h o ur s aft er st u d y m e di ci n e a d mi ni str ati o n a n d ar e 
j u d g e d t o b e r el at e d t o st u d y m e di ci n e i nf u si o n or  i nj e cti o n s h o ul d b e c a pt ur e d a s a 
di a g n o si s ( e. g., i nf u si o n -r el at e d r e a cti o n or  i nj e cti o n-sit e r e a cti o n  or a n a p h yl a cti c 
r e a cti o n) in t h e A E s e cti o n of t h e C R F.  If p o s si bl e, a v oi d a m bi g u o u s t er m s s u c h a s 
" s y st e mi c r e a cti o n."  A s s o ci at e d si g n s a n d s y m pt o m s s h o ul d b e r e c or d e d o n t h e 
d e di c at e d i nf u si o n-r el at e d r e a cti o n or i nj e cti o n r e a cti o n C R F.  If a p ati e nt e x p eri e n c e s 
b ot h a l o c al a n d s y st e mi c r e a cti o n t o t h e s a m e d o s e of st u d y m e di ci n e , e a c h r e a cti o n 
s h o ul d b e r e c or d e d s e p ar at el y in t h e A E  s e cti o n of t h e C R F, wit h si g n s a n d s y m pt o m s 
al s o r e c or d e d s e p ar at el y o n t h e d e di c at e d  i nf u si o n-r el at e d r e a cti o n or  i nj e cti o n r e a cti o n 
C R F.  
1 0. 2. 4. 2  
Di a g n o si s v er s u s Si g n s a n d S y m pt o m s  
F or A E s ot h er t h a n i nf u si o n -r el at e d or i nj e cti o n r e a cti o n s ( s e e S e cti o n 1 0. 2. 4. 1 ), a 
di a g n o si s (if k n o w n) s h o ul d b e r e c or d e d i n t h e A E  s e cti o n of t h e C R F  r at h er t h a n 
i n di vi d u al si g n s a n d s y m pt o m s ( e. g., r e c or d o nl y li v er f ail ur e or h e p atiti s r at h er t h a n 
j a u n dic e, a st eri xi s , a n d el e v at e d tr a n s a mi n a s e s).  H o w e v er, if a c o n st ell ati o n of si g n s 
a n d/ or s y m pt o m s c a n n ot b e m e di c all y c h ar a ct eri z e d a s a si n gl e di a g n o si s or s y n dr o m e 
at t h e ti m e of r e p orti n g, e a c h i n di vi d u al e v e nt s h o ul d b e r e c or d e d i n t h e A E  s e cti o n of 
t h e C R F . If a di a g n o si s i s s u b s e q u e ntl y e st a bli s h e d, all pr e vi o u sl y r e p ort e d A E s b a s e d 
o n si g n s a n d s y m pt o m s s h o ul d b e n ullifi e d a n d r e pl a c e d b y o n e A E  r e p ort b a s e d o n t h e 
si n gl e di a g n o si s, wit h a st arti n g d at e t h at c orr e s p o n d s t o t h e st arti n g d at e of t h e fir st 
s y m pt o m of t h e e v e nt u al  di a g n o si s.  
1 0. 2. 4. 3  
A d v er s e E v e nt s O c c urri n g S e c o n d ar y t o Ot h er  E v e nt s  
I n g e n er al, A E s t h at ar e s e c o n d ar y t o ot h er e v e nt s ( e. g., c a s c a d e e v e nt s or cli ni c al 
s e q u el a e ) s h o ul d b e i d e ntifi e d b y t h eir pri m ar y c a u s e, wit h t h e e x c epti o n of s e v e r e or 
s eri o u s s e c o n d ar y e v e nt s.   A m e di c all y si g nifi c a nt s e c o n d ar y A E  t h at i s s e p ar at e d i n 
ti m e fr o m t h e i niti ati n g e v e nt s h o ul d b e r e c or d e d a s a n i n d e p e n d e nt e v e nt i n t h e A E  
s e cti o n of t h e C R F .  F or e x a m pl e:  
•  
If v o miti n g r e s ult s i n mil d d e h y dr ati o n wit h n o a d diti o n al tr e at m e nt i n a h e alt h y a d ult, 
o nl y v o miti n g s h o ul d b e r e p ort e d o n t h e C R F . 
•  
If v o miti n g r e s ult s i n s e v er e d e h y dr ati o n, b ot h e v e nt s s h o ul d b e r e p ort e d s e p ar at el y 
o n t h e C R F . 
•  
If a s e v er e g a str oi nt e sti n al h e m orr h a g e l e a d s t o r e n al f ail ur e, b ot h e v e nt s s h o ul d b e 
r e p ort e d s e p ar at el y o n t h e C R F . 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 4  

 
•  
If di z zi n e s s l e a d s t o a f all a n d s u b s e q u e nt fr a ct ur e, all t hr e e e v e nt s s h o ul d b e 
r e p ort e d s e p ar at el y o n t h e C R F . 
•  
If n e utr o p e ni a i s a c c o m p a ni e d b y a n i nf e cti o n, b ot h e v e nt s s h o ul d b e r e p ort e d 
s e p ar at el y o n t h e C R F . 
 
All A E s s h o ul d b e r e c or d e d s e p ar at el y in t h e A E  s e cti o n of t h e C R F  if it i s u n cl e ar a s t o 
w h et h er t h e e v e nt s ar e a s s o ci at e d.  
1 0. 2. 4. 4  
P er si st e nt or R e c urr e nt A d v er s e E v e nt s  
A p er si st e nt A E  i s o n e t h at e xt e n d s c o nti n u o u sl y, wit h o ut r e s ol uti o n, b et w e e n p ati e nt 
e v al u ati o n ti m e p oi nt s .  S u c h e v e nt s s h o ul d o nl y b e r e c or d e d o n c e in t h e A E  s e cti o n of 
t h e C R F.  T h e i niti al s e v erit y (i nt e n sit y or gr a d e) of t h e e v e nt will b e r e c or d e d at t h e ti m e 
t h e e v e nt i s fir st r e p ort e d.  If a p er si st e nt A E  b e c o m e s m or e s e v er e, t h e m o st e xtr e m e 
s e v erit y s h o ul d al s o b e r e c or d e d i n t h e A E s e cti o n of t h e C R F .  If t h e e v e nt b e c o m e s 
s eri o u s, it s h o ul d b e r e p ort e d t o t h e S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s 
aft er l e ar ni n g t h at t h e e v e nt b e c a m e s eri o u s; s e e S e cti o n 1 0. 3. 1 a n d S e cti o n  1 0. 3 . 2 f or 
r e p orti n g i n str u cti o n s).  T h e A E s e cti o n of t h e C R F s h o ul d b e u p d at e d b y  c h a n gi n g t h e 
e v e nt fr o m " n o n -s eri o u s" t o " s eri o u s," pr o vi di n g t h e d at e t h at t h e e v e nt b e c a m e s eri o u s, 
a n d c o m pl eti n g all d at a fi el d s r el at e d t o S A E s. 
A r e c urr e nt A E  i s o n e t h at r e s ol v e s b et w e e n p ati e nt e v al u ati o n ti m e p oi nts a n d 
s u b s e q u e ntl y r e c ur s.  E a c h r e c urr e n c e of a n A E  s h o ul d b e r e c or d e d s e p ar at el y i n t h e 
A E  s e cti o n of t h e C R F . 
1 0. 2. 4. 5  
A b n or m al L a b or at or y V al u e s  
N ot e v er y l a b or at or y a b n or m alit y q u alifi e s a s a n A E .  A l a b or at or y t e st r e s ult m u st b e 
r e p ort e d a s a n A E  if it m e et s a n y of t h e f oll o wi n g crit eri a: 
•  
I s ac c o m p a ni e d b y cli ni c al s y m pt o m s  
•  
R e s ult s i n a c h a n g e i n st u d y tr e at m e nt ( e. g., d o s a g e m o difi c ati o n, tr e at m e nt 
i nt err u pti o n, or tr e at m e nt di s c o nti n u ati o n) 
•  
R e s ult s i n a m e di c al i nt er v e nti o n ( e. g., p ot a s si u m s u p pl e m e nt ati o n f or h y p o k al e mi a) 
or  a c h a n g e i n c o n c o mit a nt t h er a p y  
•  
I s cli ni c all y si g nifi c a nt i n t h e p h y si ci a n’ s j u d g m e nt  
 
It i s t h e p h y si ci a n’ s r e s p o n si bilit y t o re vi e w all l a b or at or y fi n di n g s.  M e di c al a n d s ci e ntifi c 
j u d g m e nt s h o ul d b e e x er ci s e d i n d e ci di n g w h et h er a n i s ol at e d l a b or at or y a b n or m alit y 
s h o ul d b e cl a s sifi e d a s a n A E . 
If a cli ni c all y si g nifi c a nt l a b or at or y a b n or m alit y i s a si g n of a di s e a s e or s y n dr o m e 
( e. g., al k ali n e p h o s p h at a s e a n d bilir u bi n 5  ×  t h e u p p er li mit of n or m al [U L N ] a s s o ci at e d 
wit h c h ol e st a si s ), o nl y t h e di a g n o si s (i. e., c h ol e st a si s ) s h o ul d b e r e c or d e d in t h e A E  
s e cti o n of t h e C R F . 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 5  

 
If a cli ni c all y si g nifi c a nt l a b or at or y a b n or m alit y i s n ot a si g n of a di s e a s e or s y n dr o m e, 
t h e a b n or m alit y it s elf s h o ul d b e r e c or d e d in t h e A E  s e cti o n of t h e C R F , al o n g wit h a 
d e s cri pt or i n di c ati n g if t h e t e st r e s ult i s a b o v e or b el o w t h e n or m al r a n g e ( e. g., “el e v at e d 
p ot a s si u m ,” a s o p p o s e d t o “a b n or m al p ot a s si u m ”).  If t h e l a b or at or y a b n or m alit y c a n b e 
c h ar a ct eri z e d b y a pr e ci s e cli ni c al t er m p er st a n d ar d d efi nit i o n s, t h e cli ni c al t er m s h o ul d 
b e  r e c or d e d a s t h e A E .  F or e x a m pl e, a n  el e v at e d s er u m p ot a s si u m l e v el of 7. 0 m E q/ L 
s h o ul d b e r e c or d e d a s “h y p er k al e mi a .” 
O b s er v ati o n s of t h e s a m e cli ni c all y si g nifi c a nt l a b or at or y a b n or m alit y fr o m vi sit t o vi sit 
s h o ul d o nl y b e r e c or d e d o n c e in t h e A E  s e cti o n of t h e C R F ( s e e S e cti o n  1 0. 2. 4. 4 f or 
d et ail s o n r e c or di n g p er si st e nt A E s) . 
1 0. 2. 4. 6  
A b n or m al Vit al Si g n V al u e s  
N ot e v er y vit al si g n a b n or m alit y q u alifi e s a s a n A E .  A vit al si g n r e s ult m u st b e r e p ort e d 
a s a n A E  if it m e et s a n y of t h e f oll o wi n g crit eri a: 
•  
I s ac c o m p a ni e d b y cli ni c al s y m pt o m s  
•  
R e s ult s i n a c h a n g e i n st u d y tr e at m e nt ( e. g., d o s a g e m o difi c ati o n, tr e at m e nt 
i nt err u pti o n, or tr e at m e nt di s c o nti n u ati o n) 
•  
R e s ult s i n a m e di c al i nt er v e nti o n or a c h a n g e i n c o n c o mit a nt t h er a p y  
•  
I s cli ni c all y si g nifi c a nt i n t h e p h y si ci a n ’ s j u d g m e nt  
 
It i s t h e p h y si ci a n’ s r e s p o n si bilit y t o re vi e w all vit al si g n fi n di n g s.   M e di c al a n d s ci e ntifi c 
j u d g m e nt s h o ul d b e e x er ci s e d i n d e ci di n g w h et h er a n i s ol at e d vit al si g n a b n or m alit y 
s h o ul d b e cl a s sifi e d a s a n A E . 
If a cli ni c all y si g nifi c a nt vit al si g n a b n or m alit y i s a si g n of a di s e a s e or s y n dr o m e 
( e. g., hi g h bl o o d pr e s s ur e), o nl y t h e di a g n o si s (i. e.,  h y p ert e n si o n) s h o ul d b e r e c or d e d in 
t h e A E  s e cti o n of t h e C R F . 
O b s er v ati o n s of t h e s a m e cli ni c all y si g nifi c a nt vit al si g n a b n or m alit y fr o m vi sit t o vi sit 
s h o ul d o nl y b e r e c or d e d o n c e in t h e A E  s e cti o n of t h e C R F ( s e e S e cti o n  1 0. 2. 4. 4 f or 
d et ail s o n r e c or di n g p er si st e nt A E s) . 
 
 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 6  

 
 
1 0. 2. 4. 7  
A b n or m al Li v er F u n cti o n T e st s   
T h e fi n di n g of a n el e v at e d A L T or A S T ( >  3 ×  t h e U L N) i n c o m bi n ati o n wit h eit h er a n 
el e v at e d t ot al bilir u bi n ( >  2 ×  t h e U L N) or cli ni c al j a u n di c e i n t h e a b s e n c e of c h ol e st a si s 
or ot h er c a u s e s of h y p er bilir u bi n e mi a i s c o n si d er e d t o b e a n i n di c at or of s e v er e li v er 
i nj ur y.  T h er ef or e, p h y si ci a n s m u st r e p ort a s a n A E  t h e o c c urr e n c e of eit h er of t h e 
f oll o wi n g: 
•  
Tr e at m e nt -e m er g e nt A L T or A S T >  3 ×  U L N i n c o m bi n ati o n wit h t ot al bilir u bi n >  2 ×  
t h e U L N  
•  
Tr e at m e nt -e m er g e nt A L T or A S T >  3 ×  U L N i n c o m bi n ati o n wit h cli ni c al j a u n di c e  
 
T h e m o st a p pr o pri at e di a g n o si s or (if a  di a g n o si s c a n n ot b e e st a bli s h e d) t h e a b n or m al 
l a b or at or y v al u e s s h o ul d b e r e c or d e d in t h e A E  s e cti o n of t h e C R F  ( s e e S e cti o n  1 0. 2. 4. 2 ) 
a n d r e p ort e d t o t h e S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4  h o ur s aft er l e ar ni n g of 
t h e e v e nt) eit h er a s an S A E  or a n o n -s eri o u s A E  of s p e ci al i nt er e st ( s e e S e cti o n 1 0. 3. 1 
a n d S e cti o n  1 0. 3. 2 ). 
1 0. 2. 4. 8  
D e at h s  
All d e at h s t h at o c c ur d uri n g t h e pr ot o c ol -s p e cifi e d A E r e p orti n g p eri o d ( s e e 
S e cti o n  1 0. 2. 1 ), r e g ar dl e s s of r el ati o n s hi p t o st u d y m e di ci n e , m u st b e r e c or d e d i n t h e 
A E  s e cti o n of t h e C R F  a n d i m m e di at el y r e p ort e d t o  t h e S p o n s or ( s e e S e cti o n  1 0. 3. 1 a n d 
S e cti o n  1 0. 3. 2 ). 
D e at h s h o ul d b e c o n si d er e d a n o ut c o m e a n d n ot a di sti n ct e v e nt.  T h e e v e nt or c o n diti o n 
t h at c a u s e d or c o ntri b ut e d t o t h e f at al o ut c o m e s h o ul d b e r e c or d e d a s t h e si n gl e m e di c al 
c o n c e pt o n t h e A E s e cti o n of t h e C R F .  G e n er all y, o nl y o n e s u c h e v e nt s h o ul d b e 
r e p ort e d.  T h e t er m “ s u d d e n d e at h ”  s h o ul d o nl y b e u s e d f or t h e o c c urr e n c e of a n 
a br u pt a n d u n e x p e ct e d d e at h d u e t o pr e s u m e d c ar di a c c a u s e s i n a p ati e nt wit h or 
wit h o ut pr e e xi sti n g h e art di s e a s e, wit hi n 1 h o ur aft er  t h e o n s et of a c ut e s y m pt o m s or, i n 
t h e c a s e of a n u n wit n e s s e d d e at h, wit hi n 2 4 h o ur s aft er t h e p ati e nt w a s l a st s e e n ali v e 
a n d st a bl e. If t h e c a u s e of d e at h i s u n k n o w n a n d c a n n ot b e a s c ert ai n e d at t h e ti m e of 
r e p orti n g, “ u n e x pl ai n e d d e at h ”  s h o ul d b e r e c or d e d o n t h e A E s e cti o n of t h e C R F . If t h e 
c a u s e of d e at h l at er b e c o m e s a v ail a bl e ( e. g., aft er a ut o p s y), “u n e x pl ai n e d d e at h ” s h o ul d 
b e r e pl a c e d b y t h e e st a bli s h e d c a u s e of d e at h.  
1 0. 2. 4. 9  
Pr e e xi sti n g M e di c al C o n diti o n s   
A pr e e xi sti n g m e di c al c o n diti o n i s o n e t h at i s pr e s e nt at t h e s cr e e ni n g vi sit f or t hi s st u d y.  
S u c h c o n diti o n s s h o ul d b e r e c or d e d o n t h e G e n er al M e di c al Hi st or y a n d B a s eli n e 
C o n diti o n s s e cti o n of t h e C R F.  
A pr e e xi sti n g m e di c al c o n diti o n s h o ul d b e r e c or d e d a s a n A E o nl y  if t h e fr e q u e n c y, 
s e v erit y, or c h ar a ct er of t h e c o n diti o n w or s e n s d uri n g t h e st u d y.  W h e n r e c or di n g s u c h 
e v e nt s in t h e A E s e cti o n of t h e C R F, it i s i m p ort a nt t o c o n v e y t h e c o n c e pt t h at t h e 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 7  

 
pr e e xi sti n g c o n diti o n h a s c h a n g e d b y i n cl u di n g a p pli c a bl e d e s cri pt or s ( e. g., “ m or e 
fr e q u e nt h e a d a c h e s”). 
1 0. 2. 4. 1 0  
L a c k of T h er a p e uti c  Effi c a c y or W or s e ni n g of M et a st ati c Br e a st 
C a n c er  
E v e nt s t h at ar e cl e arl y c o n si st e nt wit h t h e e x p e ct e d p att er n of pr o gr e s si o n of t h e 
u n d erl yi n g di s e a s e s h o ul d n ot  b e r e c or d e d a s A E s.  T h e s e d at a will b e c a pt ur e d a s  
eff e cti v e n e s s  a s s e s s m e nt d at a o nl y.  I n m o st c a s e s, t h e e x p e ct e d p att er n of pr o gr e s si o n 
will b e b a s e d o n R E CI S T crit eri a . I n r ar e c a s e s, t h e d et er mi n ati o n of cli ni c al pr o gr e s si o n 
will b e b a s e d o n s y m pt o m ati c d et eri or ati o n.  H o w e v er, e v er y eff ort s h o ul d b e m a d e t o 
d o c u m e nt pr o gr e s si o n t hr o u g h u s e of o bj e cti v e crit eri a.   If t h er e i s a n y u n c ert ai nt y a s t o 
w h et h er a n e v e nt i s d u e t o di s e a s e pr o gr e s si o n, it s h o ul d b e r e p ort e d a s a n A E . T hi s 
e x c e pti o n fr o m r e p orti n g i n cl u d e s e v e nt s of di s e a s e pr o gr e s si o n wit h a f at al o ut c o m e 
w hi c h ar e cl e arl y attri b ut a bl e t o di s e a s e pr o gr e s si o n.  
1 0. 2. 4. 1 1  
H o s pit ali z ati o n or Pr ol o n g e d H o s pit ali z ati o n  
A n y A E  t h at r e s ult s i n h o s pit ali z ati o n or pr ol o n g e d h o s pit ali z ati o n s h o ul d b e d o c u m e nt e d 
a n d r e p ort e d a s a n S A E  ( p er t h e d efi niti o n of S A E  i n S e cti o n  1 0. 1. 2 ), e x c e pt a s o utli n e d 
b el o w.  
T h e f oll o wi n g h o s pit ali z ati o n s c e n ari o s ar e n ot  c o n si d er e d t o b e S A E s: 
•  
H o s pit ali z ati o n f or r e s pit e c ar e  
•  
H o s pit ali z ati o n f or a pr e e xi sti n g c o n diti o n, pr o vi d e d t h at all of t h e f oll o wi n g crit eri a 
ar e m et:  
–  T h e h o s pit ali z ati o n w a s pl a n n e d pri or t o t h e st u d y or w a s s c h e d ul e d d uri n g t h e 
st u d y w h e n el e cti v e s ur g er y b e c a m e n e c e s s ar y b e c a u s e  of t h e e x p e ct e d n or m al 
pr o gr e s si o n of t h e di s e a s e . 
–  T h e p ati e nt h a s n ot s uff er e d a n A E . 
•  
H o s pit ali z ati o n d u e s ol el y t o pr o gr e s si o n of t h e u n d erl yi n g c a n c er   
 
T h e f oll o wi n g h o s pit ali z ati o n s c e n ari o s ar e n ot c o n si d er e d t o b e S A E s b ut s h o ul d b e 
r e p ort e d a s A E s  i n st e a d:  
•  
H o s pit ali z ati o n t h at w a s n e c e s s ar y b e c a u s e of p ati e nt r e q uir e m e nt f or o ut p ati e nt 
c ar e o ut si d e of n or m al o ut p ati e nt cli ni c o p er ati n g h o ur s  
 
1 0. 2. 4. 1 2  
O v er d o s e s , Mi s u s e s , A b u s e s, Off -L a b el U s e, O c c u p ati o n al E x p o s ur e, 
or M e di c ati o n Err or  
A n y o v er d o s e, mi s u s e, a b u s e, off -l a b el u s e, o c c u p ati o n al e x p o s ur e, m e di c ati o n err or, or 
a n y ot h er i n c orr e ct a d mi ni str ati o n of m e di ci n e u n d er o b s er v ati o n s h o ul d b e n ot e d o n t h e 
Dr u g A d mi ni str ati o n s e cti o n of t h e C R F .  An y o v er d o s e, a b u s e,  mi s u s e, 
i n a d v ert e nt/ err o n e o u s a dmi ni str ati o n, m e di c ati o n err or , or o c c u p ati o n al e x p o s ur e r e p ort s 
m u st b e f or w ar d e d t o t h e s p o n s or wit h or wit h o ut a n A E.  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 8  

 
R e p ort s wit h or wit h o ut a n A E s h o ul d b e f or w ar de d  t o t h e S p o n s or a s p er n o n -s eri o u s 
ti m eli n e s.  If t h e a s s o ci at e d A E f ulfill s t h e s eri o u s n e s s crit eri a , t h e e v e nt s h o ul d b e 
r e p ort e d t o t h e S p o n s or i m m e di at el y ( i. e., n o m or e t h a n 2 4 h o ur s aft er l e ar ni n g of t h e 
e v e nt, s e e S e cti o n  1 0. 3. 1  a n d S e cti o n 1 0. 3. 2 ). 
F or t h e p ur p o s e of r e p orti n g c a s e s of s u s p e ct e d a d v er s e r e a cti o n s, a n o c c u p ati o n al  
e x p o s ur e t o a m e di ci n e m e a n s a n e x p o s ur e t o a m e di ci n e a s a r e s ult of o n e’ s 
pr of e s si o n al or n o n -pr of e s si o n al o c c u p ati o n.  
1 0. 3  
R E P O R TI N G R E Q UI R E M E N T S F R O M P H Y SI CI A N  T O  S P O N S O R  
1 0. 3. 1  
I m me di at e R e p orti n g R e q uir e m e nt s fr o m P h y si ci a n  t o S p o n s or  
C ert ai n e v e nt s r e q uir e i m m e di at e r e p orti n g t o all o w t h e S p o n s or / M ar k eti n g A ut h ori z ati o n 
H ol d er a n d t h e r e g ul at or y a ut h oriti e s  t o t a k e a p pr o pri at e m e a s ur e s t o a d dr e s s p ot e nti al 
n e w ri s k s a s s o ci at e d wit h t h e u s e of t h e m e di ci n e .  T h e p h y si ci a n m u st r e p ort s u c h 
e v e nt s t o t h e S p o n s or i m m e di at el y; u n d er n o cir c u m st a n c e s s h o ul d r e p orti n g t a k e pl a c e 
m or e t h a n 2 4 h o ur s aft er t h e p h y si ci a n  l e ar n s of t h e e v e nt.  T h e f oll o wi n g i s a li st of 
e v e nt s t h at t h e p h y si ci a n  m u st r e p ort t o t h e S p o n s or wit hi n 2 4 h o ur s aft er l e ar ni n g of t h e 
e v e nt, r e g ar dl e s s of r el ati o n s hi p t o st u d y m e di ci n e : 
•  
S A E s  
•  
N o n -s eri o u s A E s of s p e ci al i nt er e st  
•  
Pr e g n a n ci e s  
T h e p h y si ci a n  m u st r e p ort n e w si g nifi c a nt f oll o w -u p i nf or m ati o n f or t h e s e e v e nt s t o t h e 
S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s aft er b e c o mi n g a w ar e of t h e 
i nf or m ati o n). N e w si g nifi c a nt i nf or m ati o n i n cl u d e s t h e f oll o wi n g:  
•  
N e w si g n s or s y m pt o m s or a c h a n g e i n t h e di a g n o si s  
•  
Si g nifi c a nt n e w di a g n o sti c t e st r e s ult s  
•  
C h a n g e i n c a u s alit y b a s e d o n n e w i nf or m ati o n  
•  
C h a n g e i n t h e e v e nt’ s o ut c o m e, i n cl u di n g r e c o v er y  
•  
A d diti o n al n arr ati v e i nf or m ati o n o n t h e cli ni c al c o ur s e of t h e e v e nt  
 
P h y si ci a n s  m u st al s o c o m pl y wit h l o c al r e q uir e m e nt s f or r e p orti n g S A E s t o t h e l o c al 
h e alt h a u t h orit y a n d I R B/ E C. 
1 0. 3. 2  
R e p orti n g R e q uir e m e nt s f or S eri o u s A d v er s e E v e nt s a n d 
N o n -S eri o u s A d v er s e E v e nt s of S p e ci al I nt er e st  
F or r e p ort s of S A E s  a n d n o n -s eri o u s A E s  of s p e ci al i nt er e st, p h y si ci a n s  s h o ul d r e c or d all 
c a s e d et ail s t h at c a n b e g at h er e d i m m e di at el y (i. e., wit hi n 2 4 h o ur s) in t h e A E  p a g e of 
t h e C R F  a n d s u b mit t h e r e p ort vi a t h e E D C s y st e m.   A r e p ort will b e g e n er at e d a n d s e nt 
t o R o c h e S af et y Ri s k M a n a g e m e nt b y t h e E D C s y st e m. 
I n t h e e v e nt t h at t h e E D C s y st e m i s t e m p or aril y u n a v ail a bl e, pl e a s e r ef er t o Se cti o n 1 0. 7.  
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
5 9  

 
10.3.3 
Reporting Requirements for Non-Serious Adverse Drug Reactions 
For non-serious AEs considered related to any study medicine (including AEs for which 
causality is unknown or not assessed),  physicians must record all case details that can 
be gathered within 30 calendar days of learning of the event on the AE section of the 
CRF and submit the report via the EDC system.  A report will be generated and sent to 
Roche Safety Risk Management to allow appropriate reporting to relevant competent 
authorities. 
In the event that the EDC system is temporarily unavailable, please refer to Section 10.7. 
Non-serious AEs that are suspected to be related only to medicinal products other than 
the studied medicine should be reported by the physician/consumer to the marketing 
authorization holder of the suspected medicinal product, or to the concerned competent 
authorities via the national spontaneous reporting system. 
10.3.4 
Reporting Requirements for Pregnancies/Breastfeeding  
10.3.4.1 
Pregnancies/Breastfeeding in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
physician if they become pregnant during the study or within 90 days after the end of the 
treatment after the last dose of medicine.  A Pregnancy Report CRF (if available) should 
be completed by the physician immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  A pregnancy report will 
automatically be generated and sent to Roche Safety Risk Management.  Pregnancy 
should not be recorded on the AE CRF.  The physician should discontinue the medicine 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any SAEs associated with the pregnancy (e.g., an event in the fetus, an event in the 
mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) 
should be reported on the AE section of the CRF.  
In the event that the EDC system is temporarily unavailable please refer to Section 10.7. 
Suspected adverse reactions that occur in infants following exposure to a medicinal 
product from breast milk should be reported to Roche Safety Risk Management. 
10.3.4.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the physician if their partner becomes pregnant during the study or within within 
174 days after the end of the treatment  after the last dose of study medicine.  A 
Pregnancy Report CRF should be completed by the physician immediately (i.e., no more 
than 24 hours after learning of the pregnancy) and submitted via the EDC system.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study medicine.  The pregnant 
partner will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Paclitaxel-Bevacizumab—F. Hoffmann-La Roche Ltd 
Protocol ML29756, Version 2 (16th December 2016) 
60 

 
Information to allow for follow-up on her pregnancy.  Once the authorization has been 
signed, the physician will update the Pregnancy Report CRF with additional information 
on the course and outcome of the pregnancy.  An physician who is contacted by the 
male patient or his pregnant partner may provide information on the risks of the 
pregnancy and the possible effects on the fetus, to support an informed decision in 
cooperation with the treating physician and/or obstetrician. 
In the event that the EDC system is temporarily unavailable, please refer to Section 10.7. 
10.3.4.3 
Abortions 
Any abortion should be classified as an SAE (as the Sponsor considers abortions to be 
medically significant), recorded in the AE section of the CRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 10.3.1 and Section 10.3.2).  
10.3.4.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to the 
medicine or the female partner of a male patient exposed to the medicine  should be 
classified as an SAE, recorded in the AE section of the CRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 10.3.1 and Section 10.3.2). 
10.4 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
10.4.1 
Physician Follow-Up 
The physician should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the physician, the patient is lost to follow-up, 
or the patient withdraws consent.  Every effort should be made to follow all SAEs 
considered to be related to study medicine or trial-related procedures until a final 
outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented in the AE 
section of the CRF and in the patient’s medical record to facilitate SDV. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 10.7. 
10.4.2 
Sponsor Follow-Up 
For SAEs, non-serious AEs of special interest , and pregnancies , the Sponsor or a 
designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
Paclitaxel-Bevacizumab—F. Hoffmann-La Roche Ltd 
Protocol ML29756, Version 2 (16th December 2016) 
61 

 
1 0. 5  
P O S T -S T U D Y A D V E R S E E V E N T S  
At t h e st u d y c o m pl eti o n/ e arl y t er mi n ati o n vi sit, t h e p h y si ci a n  s h o ul d i n str u ct e a c h p ati e nt 
t o r e p ort t o t h e p h y si ci a n  a n y s u b s e q u e nt A E s t h at c o ul d b e r el at e d or n ot t o t h e 
m e di ci n e .  T h e p h y si ci a n  s h o ul d n otif y t h e S p o n s or of a n y d e at h, S A E, A E s or n o n -
s eri o u s A E of s p e ci al i nt er e st r el at e d t o t h e m e di ci n al pr o d u ct o c c urri n g at a n y ti m e aft er 
a p ati e nt h a s di s c o nti n u e d st u d y p arti ci p ati o n.  T h e S p o n s or s h o ul d al s o b e n otifi e d if t h e 
p h y si ci a n  b e c o m e s a w ar e of t h e d e v el o p m e nt of c a n c er or a c o n g e nit al a n o m al y/ birt h 
d ef e ct i n a s u b s e q u e ntl y c o n c ei v e d off s pri n g of a p ati e nt t h at p arti ci p at e d i n t hi s st u d y.  
T h e p h y si ci a n  d o e s n ot n e e d t o a cti v el y m o nit or p ati e nt s  f or A E s o n c e t h e tri al h a s 
e n d e d.  
T h e p h y si ci a n  s h o ul d r e p ort t h e s e e v e nt s dir e ctl y t o R o c h e or it s d e si g n e e, eit h er b y 
f a xi n g or b y s c a n ni n g a n d e m aili n g t h e S eri o u s A d v er s e E v e nt / A d v er s e E v e nt of 
S p e ci al I nt er e st R e p orti n g F or m u si n g  t h e f a x n u m b er or e m ail a d dr e s s pr o vi d e d t o 
p h y si ci a n s . 
1 0. 6  
E X P E DI T E D R E P O R TI N G T O H E A L T H A U T H O RI TI E S, P H Y SI CI A N S , 
I N S TI T U TI O N A L R E VI E W B O A R D S, A N D E T HI C S C O M MI T T E E S  
T h e S p o n s or will pr o m ptl y e v al u at e all S A E s a n d n o n -s eri o u s A E s of s p e ci al i nt er e st 
a g ai n st c u m ul ati v e pr o d u ct e x p eri e n c e t o i d e ntif y a n d e x p e diti o u sl y c o m m u ni c at e 
p o s si bl e n e w s af et y fi n di n g s t o p h y si ci a n s, I R B s, E C s, a n d a p pli c a bl e h e alt h a ut h oriti e s 
b a s e d o n a p pli c a bl e l e gi sl ati o n.  
T o d et er mi n e r e p orti n g r e q uir e m e nt s f or si n gl e A E  c a s e s, t h e S p o n s or will a s s e s s t h e 
e x p e ct e d n e s s of t h e s e e v e nt s u si n g t h e f oll o wi n g r ef er e n c e d o c u m e nt s: 
•  
L o c al pr e s cri bi n g i nf or m ati o n f or p a clit a x el a n d b e v a ci z u m a b  
•  
P a clit a x el a n d b e v a ci z u m a b C or e D at a S h e et   
 
T h e S p o n s or will c o m p ar e t h e s e v erit y of e a c h e v e nt a n d t h e c u m ul ati v e e v e nt 
fr e q u e n c y r e p ort e d f or t h e st u d y wit h t h e s e v erit y a n d fr e q u e n c y r e p ort e d i n t h e 
a p pli c a bl e r ef er e n c e d o c u m e nt.  
R e p orti n g r e q uir e m e nt s will al s o b e b a s e d o n t h e p h y si ci a n ’s a s s e s s m e nt of c a u s alit y 
a n d s eri o u s n e s s, wit h all o w a n c e f or u p gr a di n g b y t h e S p o n s or a s n e e d e d.  
C ert ai n A E s ar e a nti ci p at e d t o o c c ur i n t h e st u d y p o p ul ati o n at s o m e fr e q u e n c y 
i n d e p e n d e nt of e x p o s ur e t o t h e m e di ci n e  a n d will b e e x cl u d e d fr o m e x p e dit e d r e p orti n g.  
T h e s e a nti ci p at e d e v e nt s i n cl u d e  di s e a s e pr o gr e s si o n a s i s d e s cri b e d i n 1 0. 2. 4. 1 0 . 
 
1 0. 7  
I F E D C S Y S T E M I S T E MP O R A RI L Y U N A V AI L A B L E  O R N O T U S E D  
I n t h e e v e nt t h at t h e E D C s y st e m i s t e m p or aril y u n a v ail a bl e, a c o m pl et e d p a p er 
r e p orti n g f or m ( g c p _f or 0 0 3 0 0 8) a n d f a x c o v er s h e et s h o ul d b e f a x e d/ s c a n n e d t o R o c h e 
S af et y Ri s k M a n a g e m e nt or it s d e si g n e e i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s aft er 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
6 2  

 
learning of the event) or within 30 days for non-serious ADRs if not AEs of special 
interest, using the fax number or email address provided to physicians.  
In the event that the EDC system is temporarily unavailable, the Clinical Trial Pregnancy 
Reporting Form (gcp_for000023) provided to physicians should be completed and 
submitted to Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy). 
Once the system is available again, all information should additionally be entered and 
submitted via the EDC system.  
11. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the physician must agree to submit all manuscripts or abstracts to the Sponsor 
prior to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the physician. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating physician will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors’ authorship requirements. Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the physician and the appropriate 
Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
To ensure the equitable site representativeness, the authors order will be according the 
number patients recruited in each centre.  
The manuscript will included the maximum number of authors permitted by the Journal.  
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12. 
REFERENCES 
1. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease 
progression, and survival in metastatic breast cancer. The New England journal 
of medicine 2004;351:781-791 
2. Cristofanilli M, Hayes DF, Budd GT, et al: Circulating tumor cells: a novel 
prognostic factor for newly diagnosed metastatic breast cancer. J Clin 
Oncol 2005, 23:1420-1430.A published erratum appears in J Clin 
Oncol 2005, 23:4808 
3. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer 
Incidence and Mortality Worldwide: IARC. 
4. Giuliano M, Giordano A, Jackson S, et al. Circulating tumor cells as early 
predictors of metastatic spread in breast cancer patients with limited metastatic 
dissemination. BCR 2014;16:440 
5. Gligorov J, Doval D, Bines J, et al. Maintenance capecitabine and bevacizumab 
versus bevacizumab alone after initial first-line bevacizumab and docetaxel for 
patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, 
open-label, phase 3 trial. The Lancet Oncology 2014; 
6. Jemal, A. et al. Cancer statistics, 2007. CA Cancer J Clin 57, 43-66 (2007). 
7. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel 
compared with placebo plus docetaxel for the first-line treatment of human 
epidermal growth factor receptor 2-negative metastatic breast cancer. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 
2010;28:3239-3247 
8. National Comprehensive Cancer Network. Clinical Practice Guidelines in 
Oncology: Breast cancer v.2.2008. 
http://www.nccn.org/professionals/physician gls/PDF/breast.pdf. (2008). 
9. Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating Tumor Cells and 
Response to Chemotherapy in Metastatic Breast Cancer: SWOG S0500. Journal 
of clinical oncology: official journal of the American Society of Clinical Oncology 
2014. 
10. Parkin,D.M., Bray,F., Ferlay,J. et al. Global cancer statistics, 2002. CA Cancer J. 
Clin. 55, 74-108 (2005). 
 
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A p p e n di x  1   
Li st of St a n d -Al o n e D o c u m e nt s N ot I n cl u d e d i n t h e Pr ot o c ol  
•   
Li st of c o nt a ct d et ail s of r e s p o n si bl e p arti e s a n d all p h y si ci a n s  
 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 1( 2 3 t h O ct o b er  2 0 1 5 ) 
6 5  

 
Appendix 2  
Data Collection Overview (as per Standard of Care) 
Data Collection 
Basal 
Data 
Collected 
during 
Treatment 
Period  
(every 9-12 
weeks) 
Data 
Collected at 
Study 
Completion/ 
Early 
Termination 
Visit 
Data 
Collected 
during 
Follow-
Up  
(every 9-
12 weeks) 
(available data 
will be collected; 
no additional 
diagnostic or 
monitoring 
procedures shall 
be applied to the 
patients outside 
of routine clinical 
practice) 
(the 
screening 
and the 
first 
observation 
visit can 
coincide) 
Selection criteria 
x 
  
  
  
Informed consent 
a 
x 
  
  
  
Demographic 
data 
x 
xb  
xb  
xb  
Vital signsc 
x 
x  
x  
x  
Medical historyd  
x 
Physical 
exploratione 
x 
x  
x  
x  
Concomitant 
medicationsf 
x 
x  
x  
x  
Cancer related 
data   
x 
x  
x  
x  
CTC 
determinationg 
x 
x  
  
  
Haematology 
x 
x  
x  
x  
Serum chemistry 
x 
x  
x  
x  
Coagulation 
x 
  
  
  
Urinalysis 
x 
x  
x  
x  
Pregnancy testh 
x 
x  
x  
  
Biomarkers 
statusi 
x 
  
  
 
Treatment 
efficacy 
evaluation 
  
x 
x  
x 
Adverse events 
  
x 
x  
x 
a Written informed consent must be obtained before any data collection. 
b Only weight. 
c Include measurements of systolic and diastolic blood pressure while the patient is in a 
seated position. 
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d Medical history includes clinically significant diseases surgeries, smoking history, use 
of alcohol and drugs of abuse, any abnormality. Any relevant change in the medical 
history during the follow up will be considered as an adverse event.   
e Include an evaluation of the head, eye, ear, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, GI, genitourinary, and neurological systems. 
Any relevant change during the follow up will be considered as an adverse event.   
f Include all medications (e.g. prescription medicines, over-the-counter medicines, 
herbal/homeopathic remedies, nutritional supplements) used by the patient; and 
changes from the initial in the follow up visits. 
g CTC determinations: within the 21 days prior to day 1/ cycle 1 treatment and in the 7 
days prior to day 1/cycle 3 (before any treatment administration of cycle 3). 
h Only in premenopausical women 
i Included CEA and CA 15.3. 
 
 
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67 

 
A p p e n di x  3 Pr o c e d ur e s of e xtr a cti o n, pr o c e s si n g a n d s hi p m e nt of s a m pl e s of 
Cir c ul ati n g T u m or C ell s ( C T C s)  
T h e C T C s d et er mi n ati o n will b e p erf or m e d b y C ell S e ar c h  s y st e m. D uri n g t h e st art u p 
vi sit a n d al o n g t h e st u d y, it will b e gi v e n s p e cifi c t u b e s t o t h e sit e s f or t h e s a m pl e s f or 
C T C s d et er mi n ati o n. T h e bl o o d dr a wi n g h a v e t o  b e E X C L U SI V E L Y m a d e i n t h e C ell 
S a v e t u b e s gi v e n. N e v er h a v e t o b e u s e d ot h er t y p e s of t u b e s.  
T h e t u b e  f or C T C s i s of 1 0 ml. T o p erf or m t h e dr a w i s m u st b e a mi ni m u m bl o o d 
v ol u m e of 7 .5 ml. U s u all y, if t h er e i s n ot a n y pr o bl e m, a v ol u m e of a p pr o xi m at el y 
8. 5 ml i s t a k e n. If t h e bl o o d dr a wi n g i s c o m pli c at e d, it c a n bl e n d t h e v ol u m e fr o m 
s o m e t u b e s, u p t o 7. 5 ml.  
 
If bl o o d s a m pl e  i s t a k e n i n a m ulti-s a m pl e t u b e h ol d er ( V a c ut ai n er, et c.) t h e C ell S a v e 
t u b e N E V E R H A V E T O B E T H E FI R S T I N B E R E FI L L E D . R efill ot h er s b ef or e t h e C ell 
S a v e t u b e. If o nl y i s g oi n g t o b e t a k e n t h e s a m pl e f or t h e C T C s, r ul e o ut, i n ot h er t u b e, 
t h e fir st 3-4 ml of t h e s a m pl e.  
 
O n c e t h e s a m pl e i s t a k e n, i s m u st b e s e nt ( wit h o ut b e c e ntrif u g e d or b e c o ol e d) t o t h e 
r ef er e n c e l a b or at or y or l o c al ( o nl y if t h e sit e h a s t h e C ell S e ar c h s y st e m) 
 
T h e s a m pl e s m u st b e s e nt b y c o uri er s er vi c e, a s s o o n a s p o s si bl e, b e c a u s e h a v e t o b e 
pr o c e s s e d i n a m a xi m u m of 9 6 h o ur s aft er t h e dr a w ( e xtr a cti o n s o n Fri d a y m u st b e 
a v oi d)  
 
T h e s a m pl e s will b e s e nt t o t h e r ef er e n c e l a b or at ori e s, b y n o ur g e nt c o uri er s er vi c e. 
C o nt a ct d at a will b e pr o vi d e d at st art u p vi sit.  
 
I m p ort a nt i nf or m ati o n: 
•  
T h e e C R F m u st r e gi str y if t h e s a m pl e h a v e b e e n dr a w u si n g a c e ntr al or 
p eri p h er al  vi a.  
•  
T h e C ell S e ar c h t u b e s gi v e n t o t h e sit e s will h a v e a r ef err al n ot e wit h a p h o n e 
n u m b er f or c o n s ult a n c y, if t h e p er s o n w h o m a k e s t h e e xtr a cti o n h a s a n y d o u bt.  
•  
I n t h e t u b e s m u st b e write d o w n t h e p ati e nt c o d e gi v e s b y  t h e e C R F.  
T h e d et er mi n ati o n will b e c arri e d o ut  i n t w o r ef er e n c e l a b or at ori e s (
 
) t o m a n a g e t h e n u m b er of 
r e c ei v e d s a m pl e s a n d h a v e t h e m o st h o m o g e n o u s  r e s ult s.  
 
All c o st s d eri v e d b y st u d y d et er mi n ati o n s ar e d efr a y e d b y t h e st u d y s p o n s or.  
 
 
P a clit a x el -B e v a ci z u m a b — F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol M L 2 9 7 5 6 , V er si o n 2 (1 6 t h D e c e m b er 2 0 1 6 ) 
6 8