Conditions: Pancreatic Cancer
Keywords: Pancreatic cancer Locally advanced Metastatic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 146
Healthy volunteers: no

Brief summary:
This was a quality of life (QOL) study done in the context of a randomized trial in locally advanced or metastatic pancreatic cancer. Eligible patients were randomized to receive either the combination of nab-paclitaxel/gemcitabine or standard gemcitabine monotherapy. The combination regimen of nab-paclitaxel and gemcitabine showed improved efficacy with acceptable toxicity in this disease setting in first-line and was approved for this indication. The study design allowed patients in standard treatment to receive the combination treatment after first tumour progression.

The proposed study explored the impact of treatment on the QOL scores and compared the times to definitive deterioration of the QOL scores using the validated EORTC QLQ-C30 questionnaire. Efficacy and safety were secondary endpoints and were reported descriptively.

Molecular studies will be performed on blood and tissue samples as avaialble and will be reported separately.

Detailed description:

Arms:
arm 1: Nab-paclitaxel - IV - 125 mg/m2 - 3xq4wks Gemcitabine - IV - 1000 mg/m2 - 3xq4wks arm 2: Gemcitabine - IV - 1000 mg/m2 - 3xq4wks

Interventions: intervention 1: Nab-paclitaxel intervention 2: Gemcitabine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Protocol amended version 3.0 – 08/06/2015 
 
Randomized crossover trial to assess the effects and quality of life in 
patients with locally advanced or metastatic pancreatic cancer treated 
with gemcitabine in combination with nab-paclitaxel: QOLINPAC 
 
EudraCT # 2013-004101-75, U.Z. Leuven reference # S56122 
 
Central principal 
investigator:  
Professor Eric Van Cutsem 
U.Z. Leuven 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven, Belgium 
phone: 
    + 32 16 344225 
fax: 
    + 32 16 344419 
e-mail: 
    eric.vancutsem@uzleuven.be 
 
Coordinating 
physician:  
Dr. Gabriela Chiritescu 
U.Z. Leuven 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven, Belgium 
phone: 
    + 32 16 340495 
fax: 
    + 32 16 344419 
e-mail: 
    gabriela.chiritescu@uzleuven.be 
 
Study manager:  
Ms. Kristien Dumon 
U.Z. Leuven 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven, Belgium 
phone: 
    + 32 16 340495 
fax: 
    + 32 16 344419 
e-mail: 
    kristien.dumon@uzleuven.be 
 
 
Academic study 
sponsored by: U.Z. Leuven (University Hospital Leuven) · Herestraat 49 · B -3000 Leuven 
supported by: Celgene International sarl · Route de Perreux 1 · 2017 Boudry · Switzerland · www.celgene.eu  
Celgene IIT code #: AX-CL-PANC-PI-003568 
This study is listed on www.clinicaltrials.gov 
 
CONFIDENTIAL 
This document is the property of U.Z. Leuven, Belgium and may not – in full or part – be passed on, reproduced, 
published or used without the express permission of U.Z. Leuven, Belgium or its representatives. 


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1 
Summary information 
1.1 
Coordinating center 
U.Z. Leuven (University Hospital Leuven) 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven 
Belgium 
1.2 
Participating centers and local investigators 
Belgian medical centers are selected based on experience. Details will be available at the 
time of submissions. 
1.3 
Writing committee 
Dr. Gabriela Chiritescu 
Prof. Dr. Eric Van Cutsem 
Prof. Dr. Chris Verslype 
Prof. Dr. Hans Prenen 
Ms. Kristien Dumon 
1.4 
Patient registration online 
The electronic platform is created by Lambda+: www.lambdaplus.com  
Online registration address: https://www.qolinpac.net 
Instructions are provided in the manual of procedures (MOP) and its appendices or by the 
clinical trial monitor. 
1.5 
Pharmacovigilance 
The pharmacovigilance procedures and regulatory reporting are ensured by the CRO “The 
Clinical Company”: http://www.theclinicalcompany.com 
Instructions for serious adverse event reporting are provided in the protocol, the manual of 
procedures (MOP) and its appendices or by the clinical trial monitor. 
 
 
 
 
 
 
 
 
 
 


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1.6 
Protocol signature sheet 
 
I agree to conduct the study in accordance with the protocol and its amendment and in 
compliance with Good Clinical Practice and applicable regulatory requirements. 
 
 
Central principal investigator: 
Professor Eric Van Cutsem 
U.Z. Leuven 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven, Belgium 
phone: 
     
+ 32 16 344225 
fax:      
 
+ 32 16 344419 
e-mail: 
     
eric.vancutsem@uzleuven.be 
 
 
Date:………………………..  
 
Signature:……………………………………. 
 
 
Main author and coordinator physician U.Z. Leuven: 
Dr. Gabriela Chiritescu 
U.Z. Leuven 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven, Belgium 
phone: 
     
+ 32 16 340495 
fax:      
 
+ 32 16 344419 
e-mail: 
     
gabriela.chiritescu@uzleuven.be 
 
 
Date:………………………..  
 
Signature:……………………………………. 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document has been approved electronically. Additionally, a print-out of the document 
has been signed by the responsible persons and the original archived for regulatory 
purposes. A scanned copy of the signature sheet is attached to the protocol. 


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1.7 
Study administrative structure 
The U.Z. Leuven, Belgium is the sponsor of this investigator initiated clinical study with nab-
paclitaxel. The study will take place under the umbrella of BGDO (Belgian Group of Digestive 
Oncology). Celgene EU is supporting the study by providing the investigational drug (nab-
paclitaxel) and a research grant. 
Selected centers in Belgium will participate. The central principal investigator will be Prof. Dr. E. 
Van Cutsem, U. Z. Leuven, Belgium. 
Study coordination and study management will be performed by the sponsor and delegates. 
Electronic data capture systems and case report forms will be developed by Lambda+ under the 
supervision of the sponsor. 
Data management and statistical analysis of all data gathered in electronic case report forms will be 
performed by the sponsor and delegates. Statistical analysis of translational data will be performed 
by the sponsor. 
Pharmacokinetic evaluations are not foreseen. 
Quality of life parameters will be measured using the EORTC QLQ-C30 core questionnaire. Quality 
of life analysis will be performed by U.Z. Leuven following the EORTC guidelines. 
Under the supervision of the sponsor, the appointed Clinical Research Organisation (CRO) or 
designated representatives will undertake the procedures related to drug safety and the timely 
reporting of Adverse Events (AEs), Serious Adverse Events (SAEs) and Suspected Unexpected 
Serious Adverse Reactions (SUSARs) as required. Safety data from the study will be processed as 
per current guidelines by the sponsor or delegates. All parties (Sponsor, Celgene and investigators) 
will receive and review the safety data on a regular basis as required by law in order to ensure that 
the continuation of the study is not to the detriment of the subjects.  
The study medication will be produced under Good Manufacturing Practice (GMP) conditions. 
Distribution of study medication to all participating centers will be done by Celgene and appointed 
delegates. 
Quality Assurance activities and data monitoring are performed and/or coordinated by the sponsor 
and delegates. 
This study requires a logistical and administrative structure for its efficient execution. Details of 
such structures and associated procedures will be defined in the manual of procedures (MOP) 
prepared by the sponsor.  
The following items will be addressed in the MOP and its appendices: 
 
Randomization and online registration of patients. 
 
Ordering, handling and preparation of study medication. 
 
Guidance for Case Report Form (e-CRF) and questionnaire completion. 
 
Reporting of SAEs. 
 
Translational research procedures: Instructions for collection, processing, storage and 
transportation of biological samples.  
 
Quality Assurance requirements. 
 


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1.8 
Table of contents 
1 
Summary information ................................................................................................................ 2 
1.1 Coordinating center ..................................................................................................................2 
1.2 Participating centers and local investigators ............................................................................2 
1.3 Writing committee ...................................................................................................................2 
1.4 Patient registration online ........................................................................................................2 
1.5 Pharmacovigilance ...................................................................................................................2 
1.6 Protocol signature sheet ...........................................................................................................3 
1.7 Study administrative structure..................................................................................................4 
1.8 Table of contents ......................................................................................................................5 
1.9 List of figures ...........................................................................................................................8 
1.10 
List of tables ........................................................................................................................8 
1.11 
List of appendices ................................................................................................................8 
1.12 
List of abbreviations ............................................................................................................8 
1.13 
Protocol synopsis ...............................................................................................................11 
1.14 
Study overview ..................................................................................................................17 
2 
Background and rationale ....................................................................................................... 18 
2.1 Pancreatic cancer ....................................................................................................................18 
2.2 Response assessments in pancreatic cancer ...........................................................................19 
2.3 Quality of Life measures in pancreatic cancer .......................................................................20 
2.4 Gemcitabine ...........................................................................................................................20 
2.5 Paclitaxel ................................................................................................................................21 
2.6 Paclitaxel albumin-bound particles (nab-paclitaxel, Abraxane®, ABI-007) .........................21 
2.6.1 
Preclinical studies with nab-paclitaxel ..........................................................................21 
2.6.2 
Clinical studies with nab-paclitaxel - efficacy and safety data .....................................22 
2.7 Risk assessment ......................................................................................................................23 
2.8 Study rationale .......................................................................................................................24 
3 
Objectives of the trial ............................................................................................................... 25 
3.1 Primary objective ...................................................................................................................25 
3.2 Secondary objectives ..............................................................................................................25 
4 
Investigational plan .................................................................................................................. 25 
4.1 Overall study design and plan ................................................................................................25 
4.2 Selection of participating centers ...........................................................................................26 
4.3 Selection of study population .................................................................................................26 
4.3.1 
Inclusion criteria ............................................................................................................26 
4.3.2 
Exclusion criteria ...........................................................................................................27 
4.3.3 
Additional eligibility criteria for cross-over ..................................................................27 
4.4 Removal of subjects from the study or study treatment .........................................................28 
4.5 Study termination ...................................................................................................................28 
5 
Treatments ................................................................................................................................ 28 


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5.1 Nab-paclitaxel ........................................................................................................................28 
5.1.1 
Handling, packaging and labelling ................................................................................28 
5.1.2 
Storage, reconstitution and destruction .........................................................................28 
5.1.3 
Administration ...............................................................................................................29 
5.1.4 
General safety information ............................................................................................30 
5.2 Gemcitabine ...........................................................................................................................32 
5.2.1 
Handling ........................................................................................................................32 
5.2.2 
Administration ...............................................................................................................32 
5.2.3 
General safety information ............................................................................................33 
5.3 Dose modifications and treatment alterations ........................................................................34 
5.3.1 
General criteria for dose modifications .........................................................................34 
5.3.2 
Rules for Dose Omissions and Modified Schedules .....................................................38 
5.3.3 
Study treatment discontinuation criteria ........................................................................38 
5.4 Prior and concomitant therapy ...............................................................................................40 
5.5 Treatment compliance ............................................................................................................41 
6 
Methodology and study procedures ........................................................................................ 41 
6.1 Screening ................................................................................................................................41 
6.2 Informed consent ....................................................................................................................42 
6.3 Randomization and allocation of patient number ..................................................................42 
6.4 Baseline ..................................................................................................................................42 
6.5 Baseline blood and tissue samples for translational research.................................................43 
6.6 Cycle 1 ...................................................................................................................................44 
6.6.1 
Infusion visit Day 1 .......................................................................................................44 
6.6.2 
Infusion visits Day 8 and Day 15 ..................................................................................44 
6.6.3 
Infusion visit Day 22 – Arm B only ..............................................................................45 
6.6.4 
Infusion visit Day 29 – Arm B only ..............................................................................45 
6.6.5 
Infusion visits Day 36 and Day 43 – Arm B only .........................................................46 
6.7 Cycle >= 2 ..............................................................................................................................46 
6.7.1 
Infusion visit Day 1 .......................................................................................................46 
6.7.2 
Infusion visit Day 8 and 15 ...........................................................................................47 
6.7.3 
Infusion visit Day 22 .....................................................................................................47 
6.8 Blood samples for translational research during treatment ....................................................47 
6.9 Evaluations at each 8 weekly visit – tumour (response) evaluation visits .............................48 
6.10 
Cross-over – Arm B only ...................................................................................................48 
6.11 
Blood samples for translational research at cross-over ......................................................48 
6.12 
End of Treatment visit .......................................................................................................48 
6.13 
Blood samples for translational research at the “End of Treatment” visit .........................49 
6.14 
Follow up ...........................................................................................................................49 
6.14.1 
First Follow-Up visit .................................................................................................49 
6.14.2 
Subsequent follow up visits ......................................................................................50 
6.15 
Subsequent anti-cancer treatments .....................................................................................55 
7 
Assessment of quality of life .................................................................................................... 55 
7.1 Structure of the questionnaire ................................................................................................55 
7.2 Completion of the questionnaire ............................................................................................56 
7.2.1 
Missing forms ................................................................................................................56 
7.3 QOL data handling .................................................................................................................57 


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Assessment of efficacy .............................................................................................................. 57 
8.1 Disease (tumour) assessments ................................................................................................57 
8.2 Criteria for target and non-target lesions (RECIST) ..............................................................58 
8.2.1 
Target lesions ................................................................................................................58 
8.2.2 
Non-target lesions..........................................................................................................58 
8.3 Response criteria per timepoint ..............................................................................................58 
8.4 Best overall response .............................................................................................................60 
9 
Assessment of safety ................................................................................................................. 61 
9.1 Adverse events .......................................................................................................................61 
9.1.1 
Reference documents ....................................................................................................61 
9.1.2 
Definitions .....................................................................................................................61 
9.1.3 
Methods of recording and assessing adverse events .....................................................63 
9.1.4 
Procedure for reporting Serious Adverse Events ..........................................................64 
9.2 Laboratory safety assessments ...............................................................................................64 
9.3 Vital signs, physical examinations, and other safety assessments .........................................65 
10 
Exploratory translational research ......................................................................................... 66 
10.1 
Background ........................................................................................................................66 
10.2 
Translational research objectives .......................................................................................66 
10.3 
Samples, timepoints, preparation and analyses..................................................................67 
10.3.1 
Blood and blood products .........................................................................................67 
10.3.2 
Tissue ........................................................................................................................68 
11 
Statistics ..................................................................................................................................... 70 
11.1 
Primary variables ...............................................................................................................70 
11.2 
Secondary variables ...........................................................................................................70 
11.2.1 
Efficacy variables ......................................................................................................70 
11.2.2 
Safety variables .........................................................................................................71 
11.3 
Analysis sets ......................................................................................................................72 
11.4 
Statistical design ................................................................................................................73 
11.4.1 
Sample size ...............................................................................................................73 
11.4.2 
Statistical analysis - general considerations ..............................................................73 
11.4.3 
QOL analyses ............................................................................................................74 
11.4.4 
Efficacy analyses.......................................................................................................74 
11.4.5 
Safety analyses ..........................................................................................................74 
11.4.6 
Interim analyses ........................................................................................................75 
11.4.7 
Reporting deviations from the analysis plan .............................................................75 
12 
Study management ................................................................................................................... 75 
12.1 
Electronic case report form ................................................................................................75 
12.2 
Source data and subject files ..............................................................................................76 
12.3 
Investigator Site File, Pharmacy file and archiving ...........................................................76 
12.4 
Monitoring, Quality Assurance and inspection by authorities ...........................................77 
12.5 
Changes to the study protocol ............................................................................................77 
12.6 
Study report and publication policy ...................................................................................77 
13 
Ethical and regulatory aspects ................................................................................................ 78 
13.1 
Responsibilities of the Investigator....................................................................................78 


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13.2 
Subject information ...........................................................................................................78 
13.3 
Subject consent ..................................................................................................................78 
13.3.1 
Informed consent procedures ....................................................................................78 
13.3.2 
Witnessed informed consent .....................................................................................79 
13.4 
Compensation to subjects ..................................................................................................79 
13.5 
Ethics Committee or Institutional Review Board ..............................................................79 
13.6 
Notification to authorities ..................................................................................................80 
14 
Trial sponsorship and financing ............................................................................................. 81 
15 
References ................................................................................................................................. 82 
Investigator signature page .............................................................................................................. 87 
Appendices ......................................................................................................................................... 88 
 
1.9 
List of figures 
Figure 1. Study overview…………………………………………………………………………….17 
Figure 2: Translational research timepoints and logistics – overview………………………………69 
 
1.10 
List of tables 
Table 1: Dose level reductions for patients with adenocarcinoma of the pancreas………………….35 
Table 2: Recommended dose modifications for neutropenia and thrombocytopenia at start or within 
a cycle………………………………………………………………………………………………..36 
Table 3: Recommended dose modifications for other adverse drug reactions………………………36 
Table 4:  Summary of clinical procedures and timepoints…………………………………………..51 
Table 5: Structure of the QLQ-C30 version 3.0……………………………………………………..55 
Table 6: Response of target lesions………………………………………………………………….59 
Table 7: Response of non-target lesions…………………………………………………………….59 
Table 8: Overall response per timepoint assessment ………………………………………………..60 
 
1.11 
List of appendices 
Appendix 1: EORTC QLQ-C30 quality of life questionnaire – Master document in English 
Appendix 2: NCI-CTCAE v.4.0 
Appendix 3: Nab-paclitaxel labels/packaging concept - example 
Appendix 4: BSA nomogram 
Appendix 5: WHO ECOG PS scale 
1.12 
List of abbreviations 
5-FU – 5 fluorouracil 
ADR – adverse drug reactions 
AE – adverse event 
ALAT – alanine aminotransferase 
ASAT – aspartate aminotransferase 
BSA – body surface area 
CA19-9 – carbohydrate antigen 19-9 


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CEA – carcinoembryonic antigen 
CHMP – EMA’s Committee for Medicinal Products for Human Use 
CI – confidence interval 
CoRs – certificate of release 
CR – complete response 
CRF – case report form 
CRO – clinical research organisation 
CRP – C-reactive protein 
CT – computerized axial tomography 
 
CTCAE – Common Terminology Criteria for Adverse Events 
dCK – deoxyctine kinase 
DNA – deoxyribonucleic acid 
EC – ethics committee 
ECG – electrocardiogram 
ECOG – Eastern Cooperative Oncology Group 
e-CRF – electronic case report form 
EGFR – epidermal growth factor receptor 
EMA – European Medicines Agency 
EMT – epithelial - mesenchymal transition 
EORTC – European Organization for Research and Treatment of Cancer 
EOT – End of treatment 
EUS – endoscopic ultrasound 
FDA – U.S. Food and Drug Administration 
FFPE – formalin fixed paraffin embedded 
FOLFIRINOX– 5-FU+LV+Irinotecan+Oxaliplatin 
G, GEM – gemcitabine 
GCP – Good Clinical Practice 
G-CSF – Granulocyte-Colony Stimulating Factor 
GHS – Global Health Score 
GMP – good manufacturing practice 
hENT1 – Human equilibrative nucleoside transporter 1 
HUS – Hemolytic uremic syndrome 
HR – hazard ratio 
IB – investigator brochure 
IV– intravenous 
ICH – International Conference on Harmonization 
ISF – investigator site file 
IST – investigator sponsored trials 
ITT – intent to treat 
LD – longest diameter 
LDH – lactate dehydrogenase 
LV – Leucovorin 
MAH – Marketing Authorisation Holder 
MOP – Manual of Procedures 


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MRI – magnetic resonance imaging 
MTD – maximum tolerated doses 
NC – no change 
NCI – National Cancer Institute 
NE – non evaluable 
nP – nab-Paclitaxel 
OR – odds ratio 
OS – overall survival 
PCR – polymerase chain reaction 
PD – progressive disease 
PFS – progression free survival 
PI – principal investigator 
PR- partial response 
PS – performance status 
Pt(s) – patient(s) 
RECIST – Response Evaluation Criteria in Solid Tumours 
RNA – ribonucleic acid 
RR – response rate 
RT – radiotherapy 
SAE – serious adverse event 
SAP – statistical analysis plan 
SD – stable disease 
SmPC – Summary of Product Characteristics 
SPARC – secreted protein acidic and rich in cysteine 
SUSAR – suspected unexpected serious adverse reactions 
QOL – quality of life 
TNM – tumour-nodes-metastasis 
TR – translational research 
TUDD – Time Until Definitive Deterioration 
UAR – unexpected adverse reaction 
ULN – upper limit of normal 
WHO – World Health Organisation 


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1.13 
Protocol synopsis 
Study Acronym 
QOLINPAC 
EUDRACT No. 
2013-004101-75 
Local study No. 
S56122 
Study Design 
Phase II, two arm, comparative, randomized, crossover, open label, multicenter. 
Patient 
Population 
Patients with metastatic or unresectable locally advanced pancreatic adenocarcinoma 
cancer histologically or cytologically confirmed, eligible for treatment with gemcitabine 
and nab-paclitaxel in a first line setting.  
Study Sponsor  
This is an investigator initiated academic study 
Sponsor: 
U.Z. Leuven (University Hospital Leuven) 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven 
Belgium 
Central principal 
investigator 
Prof. Dr. Eric Van Cutsem 
Countries, 
Investigators & 
Centers 
Belgian centers with experience in clinical research are selected. 
Study treatment 
 
Nab-paclitaxel (Abraxane®) 
Provided by: Celgene 
Formulation: 100 mg vials (5 mg/ml) 
Route: iv  
Dose & treatment mode: 125 mg/m2 infusion over 30 min 
 
Gemcitabine (Gemzar®) 
On prescription (standard indication and dose) 
Formulation: 1000 or 2000 mg vials  
Route: iv 
Dose & treatment mode: 1000 mg/m2 infusion over 30 min, after nab-paclitaxel 
 
Patients will be randomized to one of the following treatment regimens: 
 
Arm A: 
Nab-paclitaxel 125 mg/m² administered in combination with gemcitabine 
1000 mg/m² weekly for 3 weeks followed by one week of rest (4 week cycles) 
OR 
 
Arm B: 
Gemcitabine, 1000 mg/m² administered weekly for 7 weeks followed by a 
week of rest (Cycle 1 is 8 weeks), followed by weekly administrations for 3 
weeks followed by a week of rest (from Cycle 2 onward, 4 week cycles) 
 
Patients progressing in the gemcitabine alone arm are allowed to cross-over to the 
combination arm with nab-paclitaxel if eligibility is respected. 
 
Premedication is not necessary for nab-paclitaxel, however premedication with 
standard anti-emetics is recommended for gemcitabine and is to be administered 
prior to the infusion of nab-paclitaxel (in Arm A) and prior to the infusion of 
gemcitabine (in Arm B). 
 


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Treatment 
duration 
Until disease progression or death, toxicity or withdrawal of consent (median duration 
expected on treatment of 4 cycles/months).  
Translational 
research – 
samples, 
timepoints and 
analyses 
 
Blood 
Type of samples: whole blood, plasma, serum 
Timepoints: 
 
Baseline 
 
W9 
 
Progression or end of treatment for patients discontinued for other reason 
that progression or death. 
 
2nd progression in cross-overs 
Tissue  
Type of samples: Previously archived formalin fixed paraffin embedded (FFPE) 
samples from biopsy in block or minimum 15 slides. Cytology (smear) is not 
acceptable. If not available, tissues can be collected by core needle biopsy (US 
guided, preferably endoscopic or percutaneous) in consenting patients. Paraffin block 
embedded at site.  
Timepoints: Baseline only. 
Analyses: 
 
Potential SNPs that can be related with benefit to nab-paclitaxel 
 
Circulating DNA 
 
Circulating micro-RNA 
 
Selected cytokines (ELISA) 
 
hENT1, SPARC, dCK and S100A2 expression and correlation with outcome 
(immunohistochemistry/qPCR) 
 
Hypoxia studies 
Inclusion and 
exclusion criteria 
Inclusion criteria 
1. Written informed consent (+ optional for TR) must be given according to 
ICH/GCP and national/local regulations. 
2. Patient is at least 18 years of age1. 
3. Unresectable locally advanced or metastatic pancreatic cancer. 
4. Histologically or cytologically confirmed adenocarcinoma of the pancreas. 
Islet cell neoplasms and neuroendocrine tumours are excluded. 
5. Evaluable or measurable disease, not in a previously irradiated area. 
6. Life expectancy of at least 12 weeks. 
7. WHO ECOG performance status (PS) ≤ 2 
8. Adequate organ function. 
9. Adequate bone marrow, hepatic and renal function: 
a. Hemoglobin > 8.0 g/dL, absolute neutrophil count > 1.5 x 109/L, 
platelet count > 100 x 109/L 
b. ALAT, ASAT < 2.5 x ULN, up to < 5 x ULN in case of liver 
involvement 
c. Total bilirubin < 2 x ULN. No jaundice. 
d. Serum creatinine < 1.5 x ULN and /or calculated creatinine clearance 
> 60 mL/min (calculated according to Cockcroft and Gault). 
10. Acceptable coagulation determined on routine tests (e.g. prothrombin time, 
partial thromboplastin time, INR, etc, within +/- 15% of normal limits or as per 
                                                 
1 Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed for their ability to tolerate 
nab-paclitaxel in combination with gemcitabine with special consideration to performance status, co-morbidities and increased 
risk of infections. 


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clinical practice). 
11. No clinically significant abnormalities in urinalysis. 
12. Effective contraception for both male and female patients if applicable. 
Women of childbearing potential must have negative blood pregnancy test at 
screening visit. 
 
Exclusion criteria 
1. Prior chemotherapy, surgery or other investigational therapy for the treatment 
for metastatic disease. Adjuvant treatment with gemcitabine or 5-FU is 
allowed provided at least 6 months have elapsed since completion of the last 
dose.  
2. Major surgery within 4 weeks of the start of the study. 
3. Irradiation within 3 weeks prior to study entry.  
4. Brain metastasis (known or suspected). 
5. Serious medical risk factors involving any of the major organ systems, 
including high cardiovascular risk including coronary stenting or myocardial 
infarction in the last year and psychiatric disorders. 
6. Known infection with HIV or active infection with hepatitis B or C. 
7. History of connective tissue disorders (eg. lupus, scleroderma, arteritis 
nodosa, etc). 
8. History of interstitial lung disease. 
9. History of peripheral artery disease 
10. Previous (within 5 years) or concurrent malignancies at other sites with the 
exception of surgically cured or adequately treated carcinoma in-situ of the 
cervix and basal cell carcinoma of the skin.  
11. Known allergy or any other adverse reaction to any of the drugs or to any 
related compound. 
12. Use of oral anticoagulants that interfere with the metabolic path of nab-
Paclitaxel (cytochrome P450 isoenzymes CYP2C8 and CYP3A4) such as 
warfarin (Coumadin), rivaroxaban (Xarelto), etc, and the impossibility to 
switch anticoagulation treatment to low molecular weight heparin. 
13. Organ allografts requiring immunosuppressive therapy. 
14. Pregnancy or breast-feeding. 
15. Medical, social or psychological condition which, in the opinion of the 
investigator, would not permit the patient to complete the study or sign 
meaningful informed consent. 
NB: See protocol for the timing of screening evaluations. 
Arm allocation 
and cross-over 
Randomization will be performed in a 1:1 ratio performed by the electronic platform at 
patient registration (automated block randomization by center, performance status 0-
1 vs. 2, tumour localization head vs. other, locally advanced vs. metastatic).  
Patients progressing on gemcitabine alone are allowed to cross-over to the 
combination arm provided they still fulfill the eligibility criteria and no impeding toxicity 
or deterioration have occurred. 
Study Objectives 
& Endpoints 
 
 
Primary Objective 
To compare quality of life scores and 
times to definitive deterioration in 
patients 
receiving 
nab-paclitaxel 
+ 
gemcitabine versus gemcitabine alone 
using 
the 
EORTC 
QLQ-C30 
questionnaire. 
Primary Endpoint 
Time Until Definitive Deterioration (TUDD) 
is defined as the time from randomization 
to the first observation of a definitive 
deterioration of a quality of life score.  
The primary endpoint is the deterioration 
free rate at 3 months (% of patients free 
from definitive deterioration as defined 


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above) – minimal clinically important 
difference (MCID) between global health 
scores from baseline is 10 points. 
The QOL questionnaire EORTC QLQ-C30 
(Aaronson, et al., 1993)  will be applied at 
baseline, then every four weeks (on day 1 
of each cycle) for up to 12 months in all 
surviving 
patients, 
even 
in 
case 
of 
treatment discontinuation. 
The QOL scores will be calculated 
following the EORTC recommendations for 
scoring and statistical interpretation as in 
the EORTC QLQ-C30 Scoring Manual 
(Fayers, et al., 2001). All scales and 
scores of the questionnaire (global health, 
functional, symptoms) will be considered. 
The differences between treatment arms 
will be assessed using a time to event 
analysis methodology (Kaplan-Meier) and 
log rank tests. 
Secondary Objectives 
To evaluate in both treatment Arms:  
 Safety and tolerability profile (NCI-
CTCAE v. 4.0)  
 Overall response and duration of 
response as assessed by imaging 
(RECIST 1.1) and tumour markers 
 Disease control rates 
 Progression free survival (PFS) and 
overall survival (OS) 
 Changes in serum CA 19-9 and 
CEA and composite index CA19-
9xCEA 
 Exploratory biomarker and hypoxia 
studies on blood products and 
tumour 
tissues 
with 
possible 
correlations with efficacy outcomes.  
 
Secondary Endpoints 
 Descriptive 
safety; 
incidence 
of 
treatment-emergent toxicities in both 
Arms 
and 
incidence 
of 
dose 
modifications, 
interruptions 
and 
discontinuations. 
 Dose density and dose intensity. 
 Response and disease control rates - 
response evaluation will be performed 
every 8 weeks according to RECIST 
criteria (CT/MRI scan) 
 Duration of response 
 PFS 
 OS 
 Evolution of the levels of carbohydrate 
antigen 19-9 (CA19-9) on treatment (q 
8 weeks) and composite index. 
 Biomarkers that can be related with 
benefit to nab-paclitaxel: 
 Potential SNPs  
 Circulating DNA 
 Circulating micro-RNA 
 Selected cytokines (ELISA) 
 hENT1, SPARC, dCK and S100A2 
expression 
(immunohistochemistry/qPCR) 
 Hypoxia studies 
Statistical design 
parameters 
 
 
Rationale and methodology: 
Primary objective: to compare patient reported outcomes (QOL scores) in patients 
receiving nab-paclitaxel + gemcitabine vs gemcitabine alone using the QOL 
Questionnaire C30 (EORTC QLQ-C30). 
Time Until Definitive Deterioration (TUDD) is defined as the time from baseline to the 
first observation of a definitive deterioration of a QOL score.  
Primary endpoint: 3-month deterioration free rate (TUDD) (% patients free from 
definitive deterioration at 3 months).  


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The sample size calculation is based on the global health score (GHS) considering a 
10-point minimal clinically important difference. A definitive deterioration is considered 
when the score decreases by more than 10 points as compared to baseline.  
The hypotheses for sample size calculations are based on the results of the QOL 
analysis of the PRODIGE/ACCORD 11 trial (Gourgou-Burgade, et al., 2013). In this 
publication, the curves of TUDD of the global health score comparing folfirinox and 
gemcitabine show that the percentages of patients free from definitive deterioration at 
3 months are 83% in Folfirinox Arm and 69% in gemcitabine Arm. Assuming similar 
results for the nab-paclitaxel with gemcitabine versus gemcitabine alone, these 
percentages are used as hypotheses for sample size calculations for the present 
study. A 3-month deterioration free rate of 83% for nab-paclitaxel + gemcitabine Arm 
and of 69% for gemcitabine Arm are assumed for calculating the sample size using a 
log-rank test. 
 
Statistical assumptions for sample size calculation: 
Hypotheses : 
a. 2-sided alpha=0.05 
b. power=80% 
c. accrual 8-9 pts per month 
d. 3-months deterioration free rate of 83% for nab-paclitaxel + gemcitabine  
e.   3-months deterioration free rate of 69% for gemcitabine monotherapy 
Results: 
a. Accrual duration: 12-14 months 
b. Total study duration 21 months 
c. Total sample size N=100 
d. Number of events E=68 (number of patients with definitive deteriorations) 
 
The drop-out rate is defined as the proportion of patients that failed to provide at least 
one QOL questionnaire at the end of treatment. We assume a 30% drop-out rate at 
the end of study which is in line with current EORTC recommendations on QOL 
studies. 
To reach the number of events estimated at point d. of the sample size calculation 
above and considering a 70% patient compliance in providing post-treatment QOL 
data (30% drop-out rate) an increase of the initial sample size to 143 patients 
(100/0.7=142.86 =~143) is required for reaching the main endpoint of the study.   
 
Randomization will be performed in a 1:1 ratio. Cross-over to nab-paclitaxel + 
gemcitabine is allowed after progression in the gemcitabine monotherapy Arm.  
Assessment of the EORTC QLQ-C30 questionnaire version 3 will be performed at 
baseline and subsequently every 4 weeks for up to 12 months in surviving patients.  
TUDD, with the use of a 10-point minimal clinically important difference, will be 
analyzed with the use of the Kaplan-Meier method and the log-rank test.  
Changes in mean scores per domain will be presented. 
Imaging by CT or MRI will be performed every 8 weeks.  
Overall survival and progression-free survival will be estimated with the use of the 
Kaplan-Meier method. 
No formal statistical comparisons will be performed between the two Arms on 
secondary endpoints. Results will be presented using descriptive statistics. 
Safety interim analyses are foreseen every six months.  
Several subgroup analyses are planned, by Arm and thx cross-over, demographic 
factors, disease characteristics, etc.  
Translational research studies will be performed by U.Z. Leuven. 


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Study Timelines  
 
Protocol finalized: Q4 2013 
 
Submissions: Q1 2014 
 
First patient in: Q2 2014 
 
 
 
Last patient in: Q3 2015 
 
Interim analysis for safety at 1 year 
 
Last patient off treatment: Q1 2016 
 
Database lock: Q3 2016 
 
Start of analysis: Q3 2016 
 
Study report: Q1 2017 
 
 
 


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1.14 
Study overview 
Figure 1: Study overview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The QOL questionnaire (EORTC QLQ-C30) is applied at baseline and then every 4 weeks for up to 12 months. 
TR: Blood samples for translational research are required at baseline, after 8 weeks on treatment (2 cycles Arm A and 1 
cycle Arm B), at cross-over (if applicable) and at progression. Previously archived tissue samples available or samples 
collected by core needle biopsy from consenting patients are required at baseline. 
Tumour evaluations by CT or MRI scan are performed every 8 weeks until progression then routine practice. 
Tumour markers CA19-9 and CEA are measured every 8 weeks at the time of tumour evaluations. 
Screening 
Blood for TR 
Randomization 1:1 
Arm A 
Arm B 
Eligible consenting patients 
Blood / tissue for TR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle … 
Cycle 1 
G 1000 mg/m2 
G 1000 mg/m2 
Cycle 2 
G 1000 mg/m2 
G 1000 mg/m2 
G 1000 mg/m2 
G 1000 mg/m2 
REST 
G 1000 mg/m2 
Cycle … 
G 1000 mg/m2 
G 1000 mg/m2 
REST 
G 1000 mg/m2 
nP 125 mg/m2 + G 1000 mg/m2 
QOL 
D1 
nP 125 mg/m2 + G 1000 mg/m2 
D8 
nP 125 mg/m2 + G 1000 mg/m2 
D15 
REST 
D22 
nP 125 mg/m2 + G 1000 mg/m2 
D29 
nP 125 mg/m2 + G 1000 mg/m2 
D36 
nP 125 mg/m2 + G 1000 mg/m2 
D43 
REST 
D50 
nP 125 mg/m2 + G 1000 mg/m2 
nP 125 mg/m2 + G 1000 mg/m2 
nP 125 mg/m2 + G 1000 mg/m2 
REST 
… 
QOL 
QOL 
QOL 
… 
… 
Cross-over to nP + G 
Blood for TR 
Progression  
Stop study thx 
If toxicity or 
other reason 
Progression  
Stop study thx 
Blood for TR 
nP 125 mg/m2 + G 1000 mg/m2 
G 1000 mg/m2 
D1 
D8 
D15 
D1 
D8 
D15 
D22 
D1 
D22 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D1 
Blood / tissue for TR 


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2 Background and rationale 
2.1 
Pancreatic cancer 
In 2012 there were 78,700 new cases of pancreatic cancer in Europe with an estimated 
number of 77,900 deaths from the disease (Ferlay, et al., 2013). At diagnosis, most patients 
are inoperable and present with advanced disease, as a result of the lack of specific 
symptoms while the disease develops. Patients with advanced disease are usually treated 
with chemotherapy, with the intent of prolonging survival and palliate symptoms (pain, 
weight loss and decrease in performance status).  
Median survival time ranges from 4 to 6 months in patients with metastatic disease. Overall, 
the 5-year survival rate is about 4% for all stages combined and decreases to 1.6% for 
patients with metastatic pancreatic cancer.  
Since 1997, gemcitabine has become the standard chemotherapy for treatment of advanced 
pancreatic cancer, after demonstration in a comparative study between gemcitabine and 5-
fluorouracil (5-FU), that gemcitabine produced significant improvement in disease-related 
symptoms and prolonged survival (1-year survival: 18% versus 2%, respectively) (Burris, et 
al., 1997). In that study, median survival was 5.65 months for gemcitabine-treated patients 
and 4.41 months for 5-FU treated patients, while overall tumour response, as assessed by 
RECIST was 5.4% and 0%, respectively.  
Moore and collaborators (Moore, et al., 2007) reported that the addition of erlotinib (an oral 
epidermal growth factor inhibitor) to gemcitabine, improved median overall survival (OS) 
(6.24 months for the doublet vs. 5.91 months for gemcitabine alone), 1-year survival (23% 
vs. 17%, respectively) and progression free survival (PFS) [Hazard ratio (HR) 0.77 in favor 
of the doublet], all without a significant difference in objective response rates between the 
study Arms.  
Since then, some trials of newer cytotoxic or biologic agents combined with gemcitabine 
have not shown significant survival improvement compared with gemcitabine alone 
(Silvestris, et al., 2013). The addition of bevacizumab to gemcitabine-erlotinib did not lead 
to a statistically significant improvement in OS in patients with metastatic pancreatic cancer. 
PFS was longer in the bevacizumab group (Van Cutsem, et al., 2009). 
The use of FOLFIRINOX regimen (5-FU+LV+Irinotecan+Oxaliplatin) has demonstrated 
efficacious results (Conroy, et al., 2011), (Conroy, Gavoille, Samalin, Ychou, & Ducreux, 
2013). The median OS was 11.1 months in the FOLFIRINOX group as compared with 6.8 
months in the gemcitabine group (HR for death, 0.57; P<0.001). Median PFS was 6.4 
months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HR for 
disease progression, 0.47; P<0.001). The objective response rate was 31.6% in the 
FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events 
were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile 
neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive 
degradation of the quality of life versus 66% in the gemcitabine group (HR 0.47; P<0.001). 
Significant toxicity of the FOLFIRINOX regimen in this setting limits its administration 
exclusively to subjects with good performance status.  
The improvements in patient outcomes have been rather modest with existing or 
experimental treatments so far and new solutions are therefore needed in advanced 
pancreatic cancer. 


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2.2 
Response assessments in pancreatic cancer 
Unlike other solid tumours, where imaging provides an accurate and reliable means to 
assess tumour size, pancreatic cancer might pose difficulties in lesion measurements and 
response assessments due to the desmoplastic component of the lesions. If the lesion is 
mostly desmoplastic, successful therapy can result in minimal change in measurement 
(Tempero, 1997). For this reason, there is increasing interest in identifying alternative 
endpoints with which to evaluate effective therapy.  
A biological marker widely used in clinical practice in the assessment and follow-up of 
patients with pancreatic cancer is the carbohydrate antigen 19-9 (CA19-9). Serial 
measurements of CA19-9 are frequently performed for prognostic purposes, for following 
disease relapse and activity, and for monitoring patients undergoing therapy. The use of 
CA19-9 biomarker as surrogate endpoint in clinical trial design has not been universally 
established. However, a strong correlation between marker decline during chemotherapy 
and patient outcomes has been observed (Ko, Hwang, Venook, Abbruzzese, Bergsland, & 
Tempero, 2005), (Wong, Ko, Hwang, Venook, Bergsland, & Tempero, 2008), (Boeck, 
Stieber, Holdenrieder, Wilkowski, & Heinemann, 2006), (Poruk, et al., 2013), (Haas, et al., 
2013) and a recommendation has been made to use this biomarker as a surrogate endpoint in 
clinical trials in pancreatic cancer (Ko, Hwang, Venook, Abbruzzese, Bergsland, & 
Tempero, 2005) (Wong, Ko, Hwang, Venook, Bergsland, & Tempero, 2008). The 
remarkable CA19-9 decreases seen in the Celgene sponsored CA040 study in pancreas (Von 
Hoff, et al., 2011) justify the evaluation of changes in this biomarker in our proposed study 
as a surrogate indicator for efficacy. Expression and correlation with efficacy outcomes will 
be explored in this trial as secondary endpoint.  
Furthermore, newer studies have shown that a composite index of CA19-9 and CEA 
(carcinoembryonic antigen) is a stronger prognostic biomarker than each marker alone 
(Kanda, et al., 2013), (Distler, Pilarsky, Kersting, & Grützmann, 2013). The variation of the 
composite index CA19-9xCEA on treatment will also be explored in our study. 
The secreted protein acidic and rich in cysteine (SPARC) expression impacts proliferation 
and apoptosis in different solid tumours: ovarian, lung, cervix, hepatocellular carcinoma, 
gastric and others. Furthermore, nab-Paclitaxel has shown antitumour activity in some other 
advanced cancer types that overexpress SPARC including breast (Watkins, Douglas-Jones, 
Bryce, Mansel, & Jiang, 2005), (Gradishar, et al., 2005), (Lobo, Lopes, Silva, & al, 2007), 
(Yardley, Daniel, Inhorn, & al, 2010), lung (Koukourakis, Giatromanolaki, Brekken, & al, 
2003), (Socinski, Manikhas, Stroyakovsky, & al, 2010), (Socinski, Bondarenko, Karaeva, & 
al, 2011) and melanoma (Massi, Franchi, Borgognoni, & al, 1999), (Hersh, O'Day, Ribas, & 
al, 2010). In an analysis of specimens from patients with pancreatic cancer, SPARC was 
noted to be overexpressed in 13/16 (81%) of cases analysed (Von Hoff, Penny, Shack, & al, 
2006). A significant increase in OS was observed for patients in the high-SPARC group 
compared with patients in the low-SPARC group (median OS, 17.8 v 8.1 months, 
respectively; P = .0431). Furthermore, SPARC level remained a significant predictor for the 
OS in a multivariate analysis correcting for confounding factors in the same study. 
Specifically, stromal SPARC was significantly correlated with OS (P = .013), but not 
SPARC in tumour cells (P = .15). (Von Hoff, et al., 2011). These observations warrant 
further investigations of the hypothesis that stromal SPARC expression may be an important 
marker of early activity of gemcitabine plus nab-paclitaxel combination regimens in 
advanced pancreatic cancer. 
As in other disease settings, identification of predictive biomarkers for future development 
of new targeted agents active in pancreatic cancer must become a priority for clinical trials. 
Several signalling pathways targets are under investigation (VEGF/EGFR, IGF-1R, MMPs, 


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Hedgehog proteins, m-TOR, MEK, COX-2, etc.) (Silvestris, et al., 2013) and provide the 
rationale for own molecular exploratory analyses.  
2.3 
Quality of Life measures in pancreatic cancer 
Quality of life (QOL) measures have been performed in cancer populations (advanced lung, 
brain, pancreas, breast) in an attempt to characterize surrogate endpoints for progression 
free survival and overall survival or determine the prognostic value of patient self-reported 
outcomes on different health or general QOL domains. A literature review of studies 
published between 1982 and 2008 (Montazeri, 2009) provides the evidence for a positive 
relationship between quality of life data or some quality of life measures and the survival 
duration of cancer patients.  
Most of the recent studies have used the European Organization for Research and Treatment 
of Cancer (EORTC) QLQ-C30 quality of life questionnaire, a validated cancer specific 
instrument with precise scoring and interpretation methodology (Aaronson, et al., 1993), 
(Fayers, et al., 2001) which ensured reproducibility in different settings and the ability to 
consolidate the existing data from specific patient populations. 
A meta-analysis of randomized trials by EORTC including 7417 patients with cancer who 
filled the baseline QLQ-C30 questionnaire (Quinten, et al., 2009) revealed that scores on the 
physical, pain and anorexia domains were significant prognostic variables for survival in 
addition to age, gender and distant metastases. A more recent publication of the same 
quality of life research group at EORTC concludes that in pancreatic cancer the baseline 
global health status was predictive for survival (Quinten, et al., 2013). 
Several other published QOL studies performed in pancreatic cancer indicated that QOL 
scores at baseline and their evolution on treatment might improve the estimation of survival 
probability when added to clinical and demographic variables (Gourgou-Burgade, et al., 
2013), (Braun, Gupta, & Staren, 2013). A study estimating prognosis in advanced pancreatic 
cancer based on the tumour maker CA19-9 and QOL indicators (Bernhard, et al., 2010) 
showed that pain and fatigue are independent prognostic factors for survival. 
Our study will use the EORTC QLQ-C30 questionnaire to undertake a thorough analysis of 
each QOL domain in our target population. We aim to demonstrate the importance of 
patient self-reported health related QOL variables in the prognostic of advanced and 
metastatic pancreatic cancer and bring complementary QOL information on the effects of 
the combination nab-paclitaxel/gemcitabine on patients’ quality of life. 
2.4 
Gemcitabine 
Gemcitabine (Gemzar® Eli Lilly2) is a pyrimidine antimetabolite and is metabolised 
intracellularly by nucleoside kinase to the active diphosphate and triphosphate nucleosides. 
The cytotoxic effect of gemcitabine is due to inhibition of the DNA synthesis (masked chain 
termination). After incorporation into DNA, gemcitabine appears to induce the programmed 
cell death. 
Gemcitabine is approved in Europe in different indications in solid tumours: bladder cancer, 
advanced non-small cell lung cancer, locally advanced or metastatic pancreatic cancer, 
breast cancer and ovarian cancer. 
In locally advanced pancreatic cancer gemcitabine is standard of care at 1000 mg/m2, given 
by 30-minute intravenous (iv) infusion, repeated once weekly for up to 7 weeks followed by 
                                                 
2 Generics produced by several pharmaceutical companies are now available. 


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a week of rest. Subsequent cycles should consist of injections once weekly for 3 consecutive 
weeks out of every 4 weeks.  
2.5 
Paclitaxel 
Paclitaxel is an anti-microtubule agent that has a broad spectrum of activity against human 
cancers by stabilizing intracellular microtubules by blocking molecular depolymerisation 
(Abraxis BioScience, Celgene Corporation, 2013, p. 19). This stability results in the 
inhibition of the normal dynamic reorganization of the microtubule network that is essential 
for vital interphase and mitotic cellular functions. In addition, paclitaxel induces unusually 
unstable tubulin complexes and abnormal arrays or “bundles” of microtubules throughout 
the cell cycle which interfere with mitosis resulting in cell death.  
Paclitaxel was first authorized as Taxol® (Bristol-Myers Squibb) and is now available as 
generic equivalents. Taxol consists of paclitaxel dissolved in a proprietary solvent 
(Cremophor® EL (BASF) and ethanol.  
Taxol, together with other taxanes, is routinely used for treatment of breast and lung 
cancers, melanomas and other solid tumours.  
2.6 
Paclitaxel albumin-bound particles (nab-paclitaxel, Abraxane®, 
ABI-007) 
Nab-paclitaxel is a unique protein formulation of a non-crystalline, amorphous form of 
paclitaxel in an insoluble particle state. Nab-paclitaxel has been developed to improve the 
therapeutic index of paclitaxel (Taxol), also reducing the toxicities associated with Taxol, 
the Cremophor EL and the ethanol vehicle. 
Conditions which are responsive to paclitaxel such as non-hematological solid tumour 
malignancies are good clinical candidates for treatment with Nab-paclitaxel. Nab-paclitaxel 
alone and in combination has been evaluated in a number of cancers including metastatic 
melanoma, non-small cell lung cancer, pancreatic cancer, and other solid tumours. 
Nab-paclitaxel is approved globally (42 countries) for the treatment in different settings and 
lines of metastatic breast cancer based on the results of the phase III study CA012-0, 
(Abraxis BioScience, Celgene Corporation, 2013, p. 16), which demonstrated greater 
efficacy of nab-paclitaxel compared to Taxol. Additionally, nab-paclitaxel is approved in 
the United States for the first-line treatment of locally advanced or metastatic non-small cell 
lung cancer (NSCLC) in combination with carboplatin based on the results of the phase III 
study CA031, (Abraxis BioScience, Celgene Corporation, 2013, p. 16). 
Nab-paclitaxel was approved by the U.S. Food and Drug Administration (FDA) for the 
treatment of locally advanced and metastatic pancreatic cancer in September 2013 based on 
the results of the CA046 phase III study (Von Hoff, et al., 2013). On 21 November 2013, 
EMA’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive 
opinion recommending the change of the marketing authorization of Abraxane® in Europe 
to include “Abraxane in combination with gemcitabine is indicated for the first-line 
treatment of adult patients with metastatic adenocarcinoma of the pancreas”.  
2.6.1 
Preclinical studies with nab-paclitaxel 
A range of preclinical studies in the appropriate species have been completed with Nab-
paclitaxel including single and repeat-dose toxicity studies, carcinogenicity evaluations, 
reproductive toxicity assessments, and mutagenicity and toxicity studies. A thorough 
discussion of these is included in the Investigator’s Brochure (IB) (Abraxis BioScience, 
Celgene Corporation, 2013). 


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Preclinical studies comparing nab-paclitaxel to Taxol demonstrated lower toxicities, with a 
maximum tolerated dose (MTD) approximately 50% higher for nab-paclitaxel compared to 
Taxol. At equitoxic doses of paclitaxel, nab-paclitaxel was found to be markedly more 
efficacious in these animal models than Taxol. 
2.6.2 
Clinical studies with nab-paclitaxel - efficacy and safety data 
Early-phase clinical studies with nab-paclitaxel confirmed the efficacy and lower toxicity of 
nab-paclitaxel versus solvent-based paclitaxel. The advantages of using nab-paclitaxel 
included the ability to dose at higher levels (MTD at 300 mg/m2), elimination of 
premedication requirements, shorter infusion durations (30 min), and elimination of the 
need for specialized IV infusion supplies to accommodate the corrosive effect of the solvent 
vehicle). 
Nab-paclitaxel’s antitumour activity has been observed in patients with metastatic breast or 
lung cancers, melanomas and other solid tumours. 
Following numerous phase II studies of nab-paclitaxel (monotherapy or combinations) in 
breast cancer, a pivotal, controlled, multicenter, randomized, phase III study of nab-
paclitaxel  260 mg/m2 every 3 weeks without premedication in 460 patients with metastatic 
breast cancer (Celgene sponsored protocol CA 0120-0) demonstrated a superior target lesion 
response rate of nab-paclitaxel compared to that of solvent-based paclitaxel (175 mg/m2 IV 
q3w) with similar toxicity  and formed the basis for current approved indications in breast 
cancer and ongoing studies in other solid tumours indications (Abraxis BioScience, Celgene 
Corporation, 2013, p. 20), (Gradishar, et al., 2005).  
In non-small cell lung cancer, the randomized phase III study (Celgene sponsored protocol 
CA 031) comparing  the efficacy and safety of albumin-bound paclitaxel plus carboplatin 
with solvent-based paclitaxel plus carboplatin demonstrated that the administration of nab-
paclitaxel as first-line therapy in patients with advanced NSCLC was efficacious and 
resulted in a significantly improved overall response rate versus solvent based paclitaxel. 
Significantly less grade ≥ 3 neuropathy, neutropenia, arthralgia and myalgia occurred in the 
nab-paclitaxel Arm, and less thrombocytopenia and anemia occurred in the solvent-based 
paclitaxel Arm (Socinski, et al., 2012). 
Two clinical trials with nab-paclitaxel in combination with gemcitabine have been 
performed in pancreatic cancer:  
In the phase I/II Abraxis protocol CA040 (Von Hoff, et al., 2011), (Abraxis BioScience, 
Celgene Corporation, 2013, pp. 41,73), nab-paclitaxel in combination with gemcitabine was 
administered weekly. A total of 67 patients with advanced metastatic pancreatic cancer were 
treated with nab-paclitaxel at doses ranging from 100 to 150 mg/m2.  
The MTD was 1,000 mg/m2 of gemcitabine plus 125 mg/m2 of nab-paclitaxel once a week 
for 3 weeks, every 28 days. At the MTD, the response rate was 48%, with 12.2 median 
months of OS and 48% 1-year survival.  
Dose-limiting toxicities were sepsis and neutropenia. Sixty three patients (94%) experienced 
at least one treatment-related adverse event (AE) and 35 (52%) patients experienced at least 
one treatment-emergent SAE. Nab-paclitaxel related SAEs occurred overall in 14 (21%) of 
the patients. The largest percentage of nab-paclitaxel related SAEs were hematologic 
(overall 9%). 
With the exception of dehydration, fever, gastrointestinal obstruction, febrile neutropenia 
and lung infection, no treatment-emergent SAE categories had more than 2 events. Reported 
dose delays were mainly due to blood/bone marrow treatment related AEs (mostly 
neutropenia). There were 2 dose interruptions of nab-paclitaxel due to treatment related AEs 


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anemia and dehydration, and 4 instances of dose interruptions for gemcitabine. A total of 4 
treatment-related AEs involving blood/bone marrow (neutropenia) resulted in dose 
reductions, and 6 treatment-related AEs resulted in dose discontinuation. There were 3 
treatment-emergent AEs resulting in death (lung infection, systemic infection, and adult 
respiratory distress syndrome), but only systemic infection was considered treatment-
related. Patients treated with nab-paclitaxel in combination with gemcitabine had levels of 
myelosuppression consistent with those expected following treatment with taxanes. 
The conclusion of the phase I/II study was that the regimen of nab-paclitaxel plus 
gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting the 
subsequent phase III evaluation in the international multicenter CA046 protocol (Von Hoff, 
et al., 2013). This phase III study tested the efficacy of the combination of nab-paclitaxel 
and gemcitabine versus gemcitabine alone in improving the overall survival in patients with 
adenocarcinoma of the pancreas.  
A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 
patients) or gemcitabine (430). The median OS was 8.5 months in the combination Arm as 
compared with 6.7 months in the monotherapy Arm (HR for death, 0.72; P<0.001). The 
survival rate was 35% in the nab-paclitaxel–gemcitabine group versus 22% in the 
gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median PFS was 5.5 months 
in the nab-paclitaxel–gemcitabine group, as compared with 3.7 months in the gemcitabine 
group (HR for disease progression or death 0.69; P<0.001); the response rate according to 
independent review was 23% versus 7% in the two groups (P<0.001).  
The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-
paclitaxel–gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and 
neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in 
the two groups. In the combination Arm, neuropathy of grade 3 or higher improved to grade 
1 or lower in a median of 29 days. 
The proportion of patients with serious adverse events was similar in the two treatment 
groups (50% with nab-paclitaxel plus gemcitabine and 43% with gemcitabine). Fatal events 
were reported for 4% of the patients in each treatment group. Sepsis (all grades) was 
reported more often in the nab-paclitaxel–gemcitabine group than in the gemcitabine group 
(5% vs. 2%), as was pneumonitis (4% vs. 1%). 
The study concluded that in patients with metastatic pancreatic adenocarcinoma, nab-
paclitaxel plus gemcitabine significantly improved overall survival, progression-free 
survival, and response rate, with increases of peripheral neuropathy and myelosuppression 
rates. The results warranted the FDA approval of the combination nab-paclitaxel plus 
gemcitabine in first line of advanced or metastatic pancreatic cancer in September 2013. 
For known safety risks of nab-paclitaxel and gemcitabine also see Sections 5.1.4. and 5.2.3 
General safety information respectively. 
2.7 
Risk assessment 
The present study will involve standard of care and an investigational combination in some 
patients. The addition of nab-paclitaxel to gemcitabine has been shown to be safe with 
tolerable toxicity and with potentially further clinical benefit (Von Hoff, et al., 2013), (Von 
Hoff, et al., 2011).  
As detailed above, the most significant adverse events related to the administration of the 
combination regimen were myelosuppression and neuropathy. 
Three of 67 patients died during the phase I/II study, due to lung infection, systemic 
infection and adult respiratory distress syndrome. The event of sepsis was considered 


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treatment related. In the phase III study, there were 18 deaths (4%) due to adverse events in 
each Arm (from 18/421 patients in the combination Arm and 18/402 patients in gemcitabine 
Arm).  
Any drug related toxicity will be considered as per known safety risks defined in Sections 
5.1.4. and 5.2.3 General safety information of nab-paclitaxel and gemcitabine respectively, 
and the decision to continue treatment in case of toxicity will be performed after a careful 
risk assessment for each patient. Patients will be continuously monitored for expected and 
unexpected events. The risk of fatal outcomes of potentially life-threating events such as 
febrile neutropenia, sepsis or pneumonitis should be reduced by early diagnosis and 
treatment. 
The clinical risk-benefit relationship for administering the study regimens is regarded as 
favourable in both Arms. The combination treatment will also be made available to patients 
on monotherapy after progression.  
Tumour biopsies in consenting patients that cannot provide previously archived tumour 
tissue samples will be performed using core needles preferably during endoscopic 
ultrasound (EUS) where possible or percutaneous under ultrasound (or CT) control. The 
reported complication rate following pancreatic core biopsies using different guided 
techniques is between 0 and 3.3% (Paulsen, Nghiem, Negussie, Higgins, Caoilli, & Francis, 
2006), (Brandt, Charboneau, Stephens, Welch, & Goeliner, 1993), (Zech, Helmberger, 
Wichmann, Holzknecht, Diebold, & Reiser, 2002). The risk of secondary bleeding after 
biopsy although present is rare. The risk of infection is small, since tissue sampling is 
carried out under sterile conditions. More likely, complications could occur when structures 
near biopsy target are entered with needle (i.e. pancreatitis or other organ perforations with 
secondary fistulas). Secondary tumour seeding on the needle pass is also mentioned in 
literature. Immediate adverse events due to biopsies are easily detectable and are always 
searched for at the end of the procedure. Patients will be observed at the hospital for several 
hours after the procedure is completed. The patient has no direct known benefit from the 
tumour biopsy procedures at short term. However, biopsies are considered important for 
further translational research investigations that might bring new knowledge on the 
molecular profile of the disease. 
Risks of collecting blood samples are small and routine for laboratory testing and patient 
care. Additional samples required for the study will be taken at the same time as standard 
sampling to avoid supplementary visits and vein punctures. 
All other procedures (e.g. imaging, physical exams, etc.) are standard of care in this patient 
population. 
2.8 
Study rationale  
Pancreatic cancer remains one of the most lethal tumours. Gemcitabine is the only current 
treatment worldwide approved, however the overall benefit in terms of PFS and OS is small.  
The combination regimen of nab-paclitaxel and gemcitabine administered in patients with 
locally advanced or metastatic pancreatic cancer in a first line setting showed improved 
efficacy with acceptable toxicity. The study design allows patients in standard treatment to 
receive the combination treatment at tumour progression. 
The proposed study will explore the impact of treatment on the quality of life and compare 
the times to definitive deterioration of the quality of life scores using the validated EORTC 
QLQ-C30. Efficacy and safety secondary endpoints are to be reported in a descriptive 
manner. 


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Molecular studies will be performed on blood and tissue samples. Of special interest are 
questions as to:  
- patient specific factors contribute to response and clinical outcome 
- tumour markers as indicators of response 
- molecular profile of the disease 
On the basis of the preclinical and clinical data available to date, the selection of the study 
population and the conduct of the study are regarded as justifiable, with a positive risk-
benefit balance for patients in both treatment Arms. 
3 
Objectives of the trial 
3.1 
Primary objective 
To compare quality of life scores and times to definitive deterioration of the QOL scores in 
patients receiving nab-paclitaxel + gemcitabine versus gemcitabine alone using the EORTC 
QLQ-C30 questionnaire. 
3.2 
Secondary objectives 
To evaluate in both treatment Arms:  
 Safety and tolerability profile (NCI-CTCAE v. 4.0)  
 Overall response and duration of response as assessed by imaging (RECIST 1.1) and 
tumour markers 
 Disease control rates 
 Progression free survival and overall survival  
 Changes in serum CA 19-9 and CEA and composite index CA19-9xCEA 
 Exploratory biomarker analyses by immunohistochemistry, proteomics, microarray 
and polymerase chain reaction (PCR) studies on tissue, blood and blood products 
and correlations with outcome. 
 Exploratory hypoxia studies. See Section 10. Exploratory translational research. 
 
For exact descriptions of the corresponding endpoints, refer to Section 11. Statistics. 
4 
Investigational plan 
4.1 
Overall study design and plan 
This multicenter study is designed to compare quality of life scores in patients receiving 
nab-paclitaxel + gemcitabine versus gemcitabine alone using the EORTC QLQ-C30 
questionnaire. 
For this, two treatment Arms [a combination regimen nab-paclitaxel + gemcitabine 
(investigational Arm A) and a standard regimen gemcitabine in monotherapy (Arm B)] are 
foreseen as described in Section 5. Treatments below. 
Eligible patients must present with previously untreated, unresectable, histologically or 
cytologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas.  
Patients who fulfill all inclusion criteria (See Section 4.3.1. Inclusion criteria) and none of 
the exclusion criteria (see Section 4.3.2. Exclusion criteria) and sign informed consent may 
start treatment under this study protocol. 


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Eligible patients will be randomized between Arms by an automated 1:1 block 
randomization. The patients will be stratified by center, performance status (0 and 1 vs. 2), 
location of the tumour (head of the pancreas vs. other) and stage (locally advanced vs. 
metastatic). 
The study design, treatment and procedures are summarized in Figure 1: Study overview 
Clinical procedures and timepoints are described in Section 6. Methodology and study 
procedures and summarized in  
Table 4:  Summary of clinical procedures and timepoints (Arm A and Arm B respectively). 
4.2 
Selection of participating centers 
Belgian centers with experience in clinical research are selected.  
Complete lists of participating centers will be available at the time of submissions. 
4.3 
Selection of study population 
Patients are considered eligible for this trial if they fulfill all of the inclusion criteria and 
none of the exclusion criteria below. Refer to  
Table 4:  Summary of clinical procedures and timepoints for timing of screening evaluations 
in Arm A and Arm B respectively. 
4.3.1 
Inclusion criteria 
1. Written informed consent (+ optional for TR) must be given according to ICH/GCP 
and national/local regulations. 
2. Patient is at least 18 years of age3. 
3. Unresectable locally advanced or metastatic pancreatic cancer. 
4. Histologically or cytologically confirmed adenocarcinoma of the pancreas. Islet cell 
neoplasms or neuroendocrine tumors are excluded. 
5. Evaluable or measurable disease, not in a previously irradiated area. 
6. Life expectancy of at least 12 weeks. 
7. WHO ECOG performance status ≤ 2 
8. Adequate organ function. 
9. Adequate bone marrow, hepatic and renal function: 
 Hemoglobin > 8.0 g/dL, absolute neutrophil count > 1.5 x 109/L, platelet 
count > 100 x 109/L 
 ALAT, ASAT < 2.5 x ULN, up to < 5 x ULN in case of liver involvement 
 Total bilirubin < 2 x ULN. No jaundice. 
 Serum creatinine < 1.5 x ULN and /or calculated creatinine clearance > 60 
mL/min (calculated according to Cockcroft and Gault). 
                                                 
3 Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed for their 
ability to tolerate nab-paclitaxel in combination with gemcitabine with special consideration to performance 
status, co-morbidities and increased risk of infections. 


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10. Acceptable coagulation determined on routine tests (e.g. prothrombin time,, partial 
thromboplastin time, INR, etc within +/- 15% of normal limits or as per clinical 
practice). 
11. No clinically significant abnormalities in urinalysis. 
12. Effective contraception for both male and female patients if applicable. Women of 
childbearing potential must have negative blood pregnancy test at screening visit. 
4.3.2 
Exclusion criteria 
1. Prior chemotherapy, surgery or other investigational therapy for the treatment for 
metastatic disease. Adjuvant treatment with gemcitabine or 5-FU is allowed provided at 
least 6 months have elapsed since completion of the last dose.  
2. Major surgery within 4 weeks of the start of the study. 
3. Irradiation within 3 weeks prior to study entry.  
4. Brain metastasis (known or suspected). 
5. Serious medical risk factors involving any of the major organ systems, including high 
cardiovascular risk including coronary stenting or myocardial infarction in the last year 
and psychiatric disorders. 
6. Known infection with HIV or active infection with hepatitis B or C.  
7. History of connective tissue disorders (eg. lupus, scleroderma, arteritis nodosa, etc). 
8. History of interstitial lung disease. 
9. History of peripheral artery disease. 
10. Previous (within 5 years) or concurrent malignancies at other sites with the exception of 
surgically cured or adequately treated carcinoma in-situ of the cervix and basal cell 
carcinoma of the skin.  
11. Known allergy or any other adverse reaction to any of the drugs or to any related 
compound. 
12. Use of oral anticoagulants that interfere with the metabolic path of nab-Paclitaxel 
(cytochrome P450 isoenzymes CYP2C8 and CYP3A4) such as warfarin (Coumadin), 
rivaroxaban (Xarelto), etc, and the impossibility to switch anticoagulation treatment to 
low molecular weight heparin. 
13. Organ allografts requiring immunosuppressive therapy. 
14. Pregnancy or breast-feeding. 
15. Medical, social or psychological condition which, in the opinion of the investigator, 
would not permit the patient to complete the study or sign meaningful informed consent. 
4.3.3 
Additional eligibility criteria for cross-over 
Arm B:  
1. Progression of tumour in patients receiving gemcitabine alone 
and 
2. No significant gemcitabine related toxicity grade > 2 or events requiring 
treatment discontinuation. 
 
Patients assessed for cross-over must still comply with all the general 
inclusion/exclusion criteria above to be eligible for treatment with nab-Paclitaxel. 


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Clinical judgement on a case to case basis is to be employed. 
4.4 
Removal of subjects from the study or study treatment 
Subjects are free to discontinue the study at any time without giving their reason(s). 
Patients are discontinued from study treatment by the treating physician for the reasons 
detailed in Section 5.3.3. Study treatment discontinuation criteria.  
4.5 
Study termination 
Study termination is at the discretion of the sponsor in any of the following events: 
 Medical or ethical reasons affecting the continued performance of the study. 
 Difficulties in the recruitment of patients. 
 Occurrence of AEs unknown to date in respect of their nature, severity and duration, 
or, unexpected incidence/severity of known AEs. 
 
Safety data from the study will be reviewed by the sponsor, Celgene and investigators on an 
ongoing basis in order to ensure that the continuation of the study is appropriate. 
 
5 Treatments 
Patients will be randomized to receive nab-paclitaxel + gemcitabine or gemcitabine alone. 
5.1 
Nab-paclitaxel 
Nab-paclitaxel (Abraxane®) is provided by Celgene as study labelled medication. 
The medication will be produced under Good Manufacturing Practice (GMP) conditions.  
The instructions below are applicable for study labelled medication Abraxane®.  
5.1.1 
Handling, packaging and labelling 
Celgene will perform the labelling and the final packaging of the study medication under 
GMP conditions. Labels and handling instructions will be available in local languages.  
Study labels can be found in the current Appendix 3: Nab-paclitaxel labels/packaging 
concept – example. Details of drug request and shipping procedures can be found in the 
MOP and its appendices. 
The study medication will be delivered by Celgene to the participating sites in conformity 
with current regulations.  
Batch numbers will be given in the Certificates of Release (CoRs). From the documentation 
on the study drug, it shall be possible to retrace the composition and pharmaceutical quality 
according to the current GMP guidelines. Participating sites / pharmacists are to complete 
and return to Celgene the signed acknowledgements of receipts (AoRs) after each study 
medication delivery. 
5.1.2 
Storage, reconstitution and destruction 
Storage: 
The study drug must be carefully stored at the study site, safely and separately from other 
drugs. Unopened vials of nab-paclitaxel are stable until the date indicated on the vial when 
stored in the original cartons at a controlled room temperature (20 to 25°C, excursions 
permitted between 15 and 30°C). 


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It must be ensured at each study site that the study labelled medication is not used: 
 After the expiry date, or 
 After the retest date unless the study drug is reanalyzed and its release date extended. 
The local pharmacist is responsible for storage and accountability of the study labelled 
medication.  
Reconstitution: 
 Aseptically reconstitute each vial by injecting 20 ml of 0.9% sodium chloride 
injection over a minimum 1 minute using the sterile syringe to direct the solution 
flow onto the inside wall of the vial. 
 Do not inject the 0.9% sodium chloride solution directly into the lyophilized cake as 
this will result in foaming. 
 Allow the vial to sit for a min of 5 minutes to ensure proper wetting of the 
lyophilized powder 
 Gently invert the vial for at least 2 minutes until complete dissolution occurs. Avoid 
foaming. 
 If foaming or clumping occurs, stand solution for at least 15 minutes until foam 
subsides 
The reconstituted sample should be milky and homogenous, without visible particulates. 
Reconstituted nab-paclitaxel is compatible with standard infusion systems (tubing and 
bags). It was determined that in rare instances proteinaceous strands could appear in the 
infusion bag. Abraxane should always be administered using an infusion set that includes a 15 
μm filter. A 15 μm filter removes strands without changing the physical or chemical properties 
of the reconstituted product. More details regarding the acceptable filters and infusion sets are 
available in the MOP. 
From the microbiological point of view, reconstituted samples should be used immediately. 
If not used immediately, samples must be protected from light. Vials can be kept 
refrigerated at 2° to 8°C for a maximum of 8 hours if necessary. The suspension for infusion 
when prepared as recommended in an infusion bag should be used immediately but may be 
stored at ambient temperature (approx. 25°C) and protected from light for up to 4 hours. 
Discard any unused portion of the vial or bags. 
Destruction: 
All unused prepared product or left over at the end of the study will be disposed locally 
using own pharmacy forms and logs. The product should not be discarded into the 
environment. All used materials should be recovered and incinerated under controlled 
conditions in compliance with local and national regulations.  
Drug accountability will be closely monitored by the responsible monitor as per routine 
practice.  
For more instructions on storage, handling and preparation see the current Investigator’s 
Brochure. For more instructions on drug requests and return/destruction see the MOP. 
5.1.3 
Administration 
The study drug may not be used for any purpose other than the study and for registered, 
consenting patients. The administration of study medication to patients who have not been 
enrolled into the study is not covered by the study insurance. 
Nab-paclitaxel must be administered under the supervision of a physician experienced in the 
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and for at least one hour after the end of the infusion. Availability of resuscitation 
equipment must be ensured.  
Exact documentation of actual dose, date, start time and end time of nab-paclitaxel infusion 
in the e-CRF is mandatory. 
The administration procedures and dosage for nab-paclitaxel are as follows: 
 Sequence: Nab-paclitaxel will always be administered before gemcitabine. 
 Dose: Per protocol dose is 125 mg/m2. Each vial of the reconstituted formulation 
contains 5ml paclitaxel per ml. The actual dose in mg and volume of the drug to be 
infused are dependent upon the patient’s body surface area (BSA): Total dose (mg) = 
Per protocol dose (mg/m2)*BSA (m2). The exact dosing volume in ml required for 
the patient is calculated using the formula: Dosing volume (ml) = Total dose (mg) / 
5mg/ml. For dose adjustments in case of neutropenia, thrombocytopenia or adverse 
events see Appendix 4: BSA nomogram and Section 5.3. Dose modifications and 
treatment alterations. 
 Administration of nab-paclitaxel: The appropriate amount of reconstituted nab-
paclitaxel is injected into an empty sterile PVC or non-PVC type IV bag. 
The volume is administered over a period of 30 minutes. Sterile sodium chloride 
solution (0.9%) is used to flush the line at the end of infusion. A physician must be 
available during the infusion and observation period post-infusion and vital signs are 
to be checked for patient safety as required during chemotherapy treatment.  
 
 Schedule: The infusions will be repeated for three weeks followed by a week of rest 
(4 week cycles). Nab-paclitaxel infusions should be planned every 7 days on the 
same day of the week if possible; deviations more than 2 days are not allowed.  
 
 Premedication is not necessary for nab-paclitaxel, however premedication with 
standard anti-emetics is recommended for gemcitabine and is to be administered 
prior to the infusion of nab-paclitaxel.  
Patients randomized to Arm A may receive nab-paclitaxel until progression of disease 
occurs.  
Patients starting treatment on gemcitabine alone (Arm B) and progressed are allowed to 
cross-over to the combination Arm if still able to receive treatment. These patients will start 
receiving nab-paclitaxel at the same dose, administration and schedule as patients initially 
randomized to Arm A. 
5.1.4 
General safety information 
Through October 2012, approximately 3690 patients have been exposed to nab-paclitaxel 
during completed or ongoing Celgene-sponsored trials (Abraxis BioScience, Celgene 
Corporation, 2013) p.126. 
The most important safety risks are presented below as emerged from the nonclinical and 
clinical development program, systematic review of the literature and post-marketing safety 
surveillance for the product. The incidence and severity of some adverse events (e.g. 
neuropathy) might vary depending on the schedule of administration.  
Myelosuppression. The most important myelosuppressive of nab-paclitaxel is neutropenia. 
In 1310 patients treated with nab-paclitaxel monotherapy anemia was reported for 76% of 
patients, neutropenia for 74%, lymphopenia for 50% and thrombocytopenia for 19% of 
patients. Grade 3 neutropenia was reported for 22% and grade 4 neutropenia for 7% of 
patients. Of the 765 patients that received nab-paclitaxel in combination studies, 


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neutropenia was reported in 54% of patients, anemia for 41%, thrombocytopenia for 42% 
and leukopenia for 21%. Grade 3 or higher treatment related neutropenia was reported for 
43% of patients. 
Sensory neuropathy. Of 1310 patients treated with nab-paclitaxel monotherapy, 58% 
experienced sensory neuropathy. Of the 765 patients that received nab-paclitaxel in 
combination studies, peripheral sensory neuropathy was reported for 29%, which of 6% 
were grade 3 or higher. 
Hypersensitivity reaction. In monotherapy trials, a total of 8 (<1%) of 1310 patients 
treated with nab-paclitaxel have experienced treatment related hypersensitivity. In 
combination studies 5 of 765 (<1%) patients experienced drug hypersensitivity. None of the 
reactions were grade 3 or higher. In post marketing surveillance, rare events of severe 
hypersensitivity reactions, including very rare events of anaphylactic reactions with fatal 
outcome have been reported.  
Interstitial pneumonitis. Interstitial pneumonitis has been observed in less than 1% of 
treated patients both in monotherapy and combination trials. However, the risk appears to be 
somewhat higher for the combination of nab-paclitaxel with gemcitabine (4% in the 
combination Arm of the study CA046 (Von Hoff, et al., 2013) with two fatalities). Previous 
familial, environmental or occupational exposure, any episodes or transient dyspnea, cough, 
fever or respiratory infections during treatment should be carefully evaluated.  
Infection/sepsis. Of 1310 patients treated with nab-paclitaxel monotherapy, a total of 32% 
were reported to have experienced some type of infection. Most commonly reported were 
urinary tract infections (6%), upper respiratory tract infections (5%), nasopharyngitis (3%), 
sinusitis (3%), pneumonia (2%) and cellulitis (2%). In addition, febrile neutropenia has been 
reported in 2%, sepsis in 0.3% and neutropenic sepsis in 0.2% of these patients. The risk 
appears to be higher in patients with pancreatic cancer receiving nab-paclitaxel in 
combination with gemcitabine. In the study CA046 (Von Hoff, et al., 2013), 22/421 (5%) of 
patients in the combination Arm and 10/402 (2%) of patients in the gemcitabine 
monotherapy Arm were reported to have developed sepsis with 5 and 2 fatalities 
respectively. The presence of biliary stent at baseline and complications due to the disease 
(compression on the bile duct) have been identified as contributing factors. Sepsis occurred 
on both neutropenic and non-neutropenic patients.  
Cystoid macular edema is caused by intra- and extracellular edema leading to the 
formation of cystic spaces in the outer plexiform layer. Major symptoms are related to 
visual acuity. Frequency is less than 1 in 1000 patients. 
Cardiotoxicity. Non-serious cardiac events have been reported in monotherapy clinical 
trials, mainly tachycardia in 10/1310 (<1.0%) and palpitations in 3/1310 (<1%). In the 
combination studies the most frequent cardiac events were also tachycardia and arrhythmia 
in 1% of patients. None of the reported events were grade 3 or higher. Rare events of 
congestive heart failure and ventricular dysfunction have been observed among individuals 
receiving nab-paclitaxel. While cardiotoxicity unequivocally related to nab-paclitaxel has 
not been demonstrated, cardiac events are not uncommon in the indicated population 
especially those with underlying cardiac or pulmonary disease. Cardiac function should be 
monitored. 
Hepatotoxicity. In monotherapy studies, hepatotoxicity has been reported in 14% in 1310 
with the most frequent being ALAT and ASAT increased (4%), ALP increased (3%) and 
bilirubin increased (1%). In combination therapy studies ALAT increased in 9%, ASAT in 
8%, APL in 3% and bilirubin in 3% of patients. For pancreatic carcinoma nab-paclitaxel is 
not recommended for patients with moderate or severe hepatic impairment. 


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Gastrointestinal events. In some studies appeared that nausea, vomiting and diarrhea 
appeared to be more common with nab-paclitaxel than with solvent based paclitaxel, 
probably due to the prophylactic effect of the antiemetic medication normally administered 
in patients receiving the solvent-based paclitaxel. Of the 765 patients who received nab-
paclitaxel in the combination studies, nausea have been reported in 32% of patients, 
vomiting in 17 and diarrhea in 12%. Only about 1% were grade 3 and higher. Nausea, 
vomiting and diarrhea can be treated with commonly used anti-emetic or anti-diarrheic 
agents. 
Myalgia and arthralgia. Myalgia has been reported in 14% and arthralgia in 17% of 
patients both in monotherapy and combination studies with a 2% grade 3 or higher. 
Symptoms typically occurred 3 days after the nab-paclitaxel administration and resolved 
within one week. Myalgia and arthralgia are typically low grade, self-limiting and 
manageable with non-steroidal anti-inflammatory agents and acetaminophen.  
Cranial nerve palsies. Cases of cranial nerve paralysis, including facial palsy have been 
reported. If neuropathy involving a cranial nerve occur, dose modifications might be 
justified determined by the nature, location and extent of the affected cranial nerve and 
based on a careful risk-benefit assessment. 
Infusion site reactions/extravasations. Injection site reactions during IV administration 
may lead to localized edema, pain, erythema and indurations; on occasion, extravasation can 
result in cellulitis. 
Elderly population. For patients of 75 years and older, no benefit for the combination 
treatment of nab-paclitaxel and gemcitabine in comparison to gemcitabine monotherapy has 
been demonstrated. In the very elderly (≥75 years) who received nab-paclitaxel and 
gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions 
that led to treatment discontinuation including hematologic toxicities, peripheral 
neuropathy, decreased appetite and dehydration. Patients with pancreatic adenocarcinoma 
aged 75 years and older should be carefully assessed for their ability to tolerate nab-
paclitaxel in combination with gemcitabine with special consideration to performance 
status, co-morbidities and increased risk of infections. 
5.2 
Gemcitabine 
Gemcitabine is given in standard indication and regimen both to patients in Arm A (in 
combination) and to patients in Arm B (alone).  
5.2.1 
Handling 
Investigators should treat patients with commercially available forms of gemcitabine and 
use the approved harmonized European Summary of Product Characteristics (SmPC) 
(www.ema.europa.eu, 2008) for complete prescription information, storage, preparation and 
handling, administration, safety issues (warnings, precautions), adverse reactions, dose 
modifications and omissions. 
5.2.2 
Administration 
Investigators should follow the current SmPC and institutional procedures for the 
administration.  
Exact documentation of actual dose and date of infusions in the CRF is mandatory. 
 
 Sequence: Gemcitabine must be administered after the nab-paclitaxel infusion in 
Arm A. 
 


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 Dose: Per protocol dose: 1000 mg/m2. The actual dose in mg and volume of the drug 
to be infused are dependent upon the patient’s body surface area (BSA). See 
Appendix 4: BSA nomogram. 
 Preparation: instructions for handling and preparation of gemcitabine for infusion 
are as per SmPC and institutional practices.   
 Administration of gemcitabine: The infusion is administered over 30 minutes. 
Prolongation of the infusion time has been shown to increase toxicity. Sterile sodium 
chloride solution (0.9%) is used to flush the line before and after infusion. A 
physician must be available during the infusion and observation period post-infusion 
and vital signs are to be checked for patient safety as required during chemotherapy 
treatment.  
 Schedule: For patients in Arm A, gemcitabine will be given in the same day and 
following nab-paclitaxel, i.e. once weekly for the 3 weeks followed by a week of 
rest then repeat (4 week cycles). For patients in Arm B, gemcitabine will be given in 
an initial sequence of seven weeks followed by a week of rest (first cycle is 8 weeks) 
then every week for three weeks followed by a week of rest (cycle 2 and subsequent 
cycles are of 4 weeks). Gemcitabine infusions should be planned every 7 days on the 
same day of the week if possible; deviations more than 2 days are not allowed.  
 
 Premedication with standard anti-emetics is recommended prior to gemcitabine and 
is to be administered prior to the infusion of nab-paclitaxel for patients in Arm A 
and prior to the infusion of gemcitabine for patient in Arm B. 
 
For dose modifications and/or delays for gemcitabine-associated toxicity see the SmPC and 
Section 5.3. Dose modifications and treatment alterations below). 
Patients in Arm A will receive gemcitabine (+nab-paclitaxel) until disease progression or 
discontinuation for other reason. 
Patients starting treatment on gemcitabine alone (Arm B) and progressed are allowed to 
cross-over to the combination Arm if still able to receive treatment. These patients will start 
receiving nab-paclitaxel at the same dose, administration and schedule as patients initially 
randomized to Arm A while continuing to receive gemcitabine at the previous doses. 
5.2.3 
General safety information 
The frequency and severity of the adverse reactions are affected by the dose, infusion rate 
and intervals between doses. Dose-limiting adverse reactions are reductions in thrombocyte, 
leucocyte and granulocyte counts. 
The most commonly reported adverse drug reactions associated with gemcitabine treatment 
include nausea with or without vomiting, raised liver transaminases (AST/ALT) and 
alkaline phosphatase, reported in approximately 60% of patients; proteinuria and haematuria 
reported in approximately 50% patients; dyspnea reported in 10-40% of patients (highest 
incidence in lung cancer patients); allergic skin rashes occur in approximately 25% of 
patients and are associated with itching in 10% of patients. Fatigue, if not associated with 
anaemia, usually resolves after the first cycle. 
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with 
gemcitabine as a single agent and the risks are increased when combined with other drugs. 
In clinical trials, grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 
8%, and 5%, respectively of patients receiving single-agent. The frequencies of grade 3-4 
neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 
55%, respectively, in patients receiving gemcitabine in combination with another drug.  


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Pulmonary toxicity and respiratory failure. Pulmonary toxicity, including interstitial 
pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome 
(ARDS), has been reported. In some cases, these pulmonary events can lead to fatal 
respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms 
may occur up to 2 weeks after the last dose of gemcitabine.  
Hemolytic uremic syndrome. Hemolytic uremic syndrome (HUS) to include fatalities from 
renal failure or the requirement for dialysis can occur in patients treated with gemcitabine. 
In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal 
failure were due to HUS. Renal function should be carefully assessed prior to initiation of 
gemcitabine and periodically during treatment. Consider the diagnosis of HUS in patients 
who develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin 
or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation 
of serum creatinine or BUN). Permanently discontinue gemcitabine in patients with HUS or 
severe renal impairment. Renal failure may not be reversible even with discontinuation of 
therapy. Renal failure may not be reversible even with discontinuation of therapy. 
Hepatic toxicity. Drug-induced liver injury, including liver failure and death, has been 
reported in patients receiving gemcitabine alone or in combination with other potentially 
hepatotoxic drugs. Administration of Gemzar in patients with concurrent liver metastases or 
a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to 
exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to 
initiation of gemcitabine and periodically during treatment. Discontinue gemcitabine in 
patients that develop severe liver injury. 
Exacerbation of radiation therapy toxicity. As per the summary of product 
characteristics, gemcitabine is not indicated for use in combination with radiation therapy. 
Life-threatening mucositis, especially esophagitis and pneumonitis occurred in trials in 
which gemcitabine was administered at a dose of 1000 mg/m2 to patients with non-small 
cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation given 
together or less than 7 days apart. Excessive toxicity has not been observed when 
gemcitabine is administered more than 7 days before or after radiation. Radiation recall has 
been reported in patients who receive gemcitabine after prior radiation. Temporary 
discontinue or delay gemcitabine in patients that need radiotherapy for symptom control not 
on target lesions, such as gemcitabine is administered at least 7 days apart from 
radiotherapy. No concurrent radiotherapy and gemcitabine is permitted. 
Capillary leak syndrome Capillary leak syndrome (CLS) with severe consequences has 
been reported in patients receiving gemcitabine as a single agent or in combination with 
other chemotherapeutic agents. Discontinue gemcitabine if CLS develops during therapy. 
Cardiovascular. Due to the risk of cardiac and/or vascular disorders with gemcitabine, 
particular caution must be exercised with patients presenting a history of cardiovascular 
events. 
Elderly population (> 65 years). Gemcitabine has been well tolerated in patients over the 
age of 65. There is no evidence to suggest that dose adjustments, other than those already 
recommended for all patients, are necessary in the elderly. 
Sodium. Gemcitabine 1000 mg contains 17.5 mg (< 1 mmol) sodium per vial. This should 
be taken into consideration by patients on a controlled sodium diet. 
5.3 
Dose modifications and treatment alterations 
5.3.1 
General criteria for dose modifications 
Every effort will be made to administer the full doses of nab-paclitaxel and gemcitabine. 


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Decisions on dose modifications in accordance with the toxic effects observed will be made 
on the day of treatment. The doses are to be adjusted according to the highest degree of 
toxicity during the previous cycle/after the previous infusion. If a patient develops several 
different toxic effects and there are conflicting recommendations, the dose reduction 
required for the most severe toxic effect must be chosen. 
Toxicity will be graded using the NCI-CTCAE. See Appendix 2: NCI-CTCAE v.4.0. 
Dose modifications are permanent. Once a dose reduction has been made, this will be 
continued for all subsequent infusions (the dose cannot be re-escalated).  
Only two dose modifications are permitted. If a toxic effect of the same degree occurs again 
after one dose modification, a second dose modification is allowed. If further toxicity occurs 
or the criteria for resuming treatment are not met, the patient must be withdrawn from 
treatment. 
Arm A: If nab-paclitaxel is to be discontinued for other reason than progression, patients in 
Arm A could continue treatment with gemcitabine off study protocol, if appropriate. If 
gemcitabine is to be discontinued for other reason than progression, patients in Arm A could 
continue treatment with nab-paclitaxel alone, on study protocol, if appropriate. If 
progressive disease or both drugs have to be discontinued for other reason, patients will be 
taken off study. 
Arm B: If gemcitabine is to be discontinued for other reason than progression, patients in 
Arm B will be taken off study. In case of progressive disease, patients in Arm B are allowed 
to cross-over to the combination Arm A.  
The following guidelines apply to the combination Arm A only. They outline dose 
adjustments in response to different toxic effects and the criteria for restarting treatment. 
Modifications to the dosages are based on drug induced hematological and non-
hematological toxicity during the previous cycle.  
For patients on standard gemcitabine (Arm B), dose modifications are to be done in 
accordance to the reference document (SmPC) and routine practice. 
Dose level reductions for the combination of nab-paclitaxel with gemcitabine administered 
in patients with adenocarcinoma of the pancreas, as referenced in Table 2 and Table 3 are 
provided in Table 1. 
 
Table 1: Dose level reductions for patients with adenocarcinoma of the pancreas 
Dose level 
Nab-paclitaxel 
mg/m2 
(% of initial dose) 
Gemcitabine 
mg/m2 
(% of initial dose) 
Initial full dose 
125 
1000 
1st dose reduction 
100 
(80%) 
800 
(80%) 
2nd dose reduction 
75 
(60%) 
600 
(60%) 
3rd dose reduction 
Not allowed → 
Discontinue 
500 
(50%) 


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or discontinue 
If additional dose reduction required 
Discontinue 
 
Table 2: Recommended dose modifications for neutropenia and thrombocytopenia at 
start or within a cycle 
Cycle 
/ Day 
ANC 
(cells/mm3) 
 
Platelet 
(cells/m3) 
Nab-paclitaxel / Gemcitabine 
Day 1 
<1500 
OR 
<100000 
Delay doses until recovery 
Day 8 
500 to <1000 
OR 
50000 to < 75000 
Reduce 1 dose level from Day 1 
<500 
OR 
<50000 
Withhold doses 
Day 15: If Day 8 doses were given without modifications: 
 
500 to <1000 
OR 
50000 to < 75000 
Treat with Day 8 dose level and 
follow with WBC Growth Factors 
OR 
Reduce 1 dose level from Day 8 
doses 
 
<500 
OR 
<50000 
Withhold doses 
Day 15: If Day 8 doses were reduced: 
 
≥ 1000 
AND 
≥ 75000 
Treat with Day 8 dose level 
 
500 to <1000 
OR 
50000 to < 75000 
Treat with Day 8 dose levels and 
follow with WBC Growth Factors 
OR 
Reduce 1 dose level from Day 8 
doses 
 
<500 
OR 
<50000 
Withhold doses 
Day 15: If Day 8 doses were withheld: 
 
>1000 
OR 
>75000 
Treat with Day 1 dose levels and 
follow with WBC Growth Factors 
OR 
Reduce 1 dose level from Day 1 
doses 
 
500 to <1000 
OR 
50000 to < 75000 
Reduce one dose level from Day1 
doses and follow with WBC 
Growth Factors. 
 
<500 
OR 
<50000 
Withhold doses 
Abbreviations: ANC=Absolute Neutrophil Count; WBC=white blood cell 
 
Table 3: Recommended dose modifications for other adverse drug reactions 


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Adverse drug reaction 
Nab-paclitaxel (mg/m2) 
Gemcitabine 
(mg/m2) 
Febrile neutropenia gr. 3 or 4 
Withhold until fever resolves and ANC ≥ 1500; 
resume at next lower dose level 
Peripheral neuropathy gr. 3 or 4 
Withhold until improves to ≤ gr. 1; 
resume at next lower dose level. 
No dose reduction 
Cutaneous toxicity gr. 2 or 3 
Reduce to next lower dose level;  
discontinue treatment if toxicity persists. 
 
Gastrointestinal toxicity: 
gr. 3 mucositis or diarrhea 
 
Withhold until improves to ≤ Grade 1; 
resume at next lower dose level. 
 
In line with standard clinical practice, a patient that develops severe hypersensitivity 
reaction to nab-paclitaxel should be immediately discontinued from treatment and not be re-
challenged. 
Upon a diagnosis of interstitial pneumonitis, nab-paclitaxel and gemcitabine should 
permanently be discontinued. After ruling out an infectious etiology, intravenous high-dose 
corticosteroid therapy should be instituted without delay with appropriate premedication, 
secondary pathogen coverage, immunomodulation and supportive ventilation.  
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular 
weight heparin without interruption of therapy. Moderate to severe pulmonary embolism 
will require permanent discontinuation of treatment. 
Permanently discontinue gemcitabine for any of the following: unexplained dyspnea or 
other evidence of severe pulmonary toxicity, severe hepatic toxicity, hemolytic-uremic 
syndrome, capillary leak syndrome. 
Careful monitoring for infection / sepsis signs and symptoms is recommended with early 
intervention as appropriate: use broad spectrum antibiotics such as ciprofloxacin or 
augmentin at the first occurrence of fever >38.5°C regardless of neutrophil counts. On their 
first visit, patients should be provided with enough ciprofloxacin (or the alternative 
antibiotic) for use at home, and they should be instructed to begin taking it when they first 
record a temperature of ≥38.5 °C (or if they feel they are developing a fever and a 
thermometer is not available). A full sepsis diagnostic work-up should be performed while 
continuing broad spectrum antibiotics. If cultures are positive, the antibiotic may or may not 
be changed, depending on the sensitivity profile of the isolated organism. Patients with 
persisting fever after 3 weeks, despite uninterrupted antibiotic treatment, will discontinue 
study treatment. 
Colony stimulating factors may be given according to institutional guidelines for the 
treatment of neutropenic fever or infections associated with neutropenia and for the 
prevention of febrile neutropenia in patients with an ANC <500 cells/μL. Patients not 
experiencing resolution of neutropenia within 21 days, despite uninterrupted G-CSF  
(Granulocyte-Colony Stimulating Factor) treatment, will discontinue study treatment. 
If grade 3 mucositis or diarrhea occurs, study drug should be withheld until resolution to ≤ 
grade 1, then reinstituted at the next lower dose level of both drugs. Patients who develop 
grade 4 mucositis or diarrhea should have treatment discontinued. 
Study drug should only be administered if hepatic function is within the parameters 
established in the eligibility criteria. Hepatic toxicity from taxanes may occur but it is 
uncommon. Therefore, hepatic dysfunction that occurs while the patient is on study should 


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prompt an evaluation to determine the cause, including the possibility of progressive 
metastatic disease and hepatotoxicity from concurrent medications. 
Preventive steps for cystoid macular edema are unknown. Secondary prevention is focused 
on early detection of visual symptoms discontinuation of treatment in affected patients. 
Cystoid macular edema is expected to resolve within a couple of weeks from treatment 
discontinuation. 
If a patient develops an intercurrent illness (e.g., infection) that, in the opinion of the 
investigator, mandates the interruption of therapy, that intercurrent illness must resolve 
within a time frame such that no more than two consecutive infusions of nab-paclitaxel are 
withheld. After the interruption, treatment will resume at the last weekly dose before the 
interruption.  
Temporary discontinue or delay gemcitabine in patients that need radiotherapy for symptom 
control not on target lesions, such as gemcitabine is administered at least 7 days apart from 
radiotherapy. No concurrent radiotherapy and gemcitabine is permitted. Radiotherapy aimed 
at main disease (target lesions) is not allowed. 
If there are conflicting recommendations, the decision whether to restart treatment must be 
based on the most severe toxic effect observed. 
If therapy must be withheld for a longer period of time than 2 consecutive infusions and a 
week of rest, the patient will be discontinued from the study treatment.  
5.3.2 
Rules for Dose Omissions and Modified Schedules 
Arm A patients: 
Day 1 dose missed: 
If the dose held or missed was to be given on Day 1 of the next cycle, that next cycle will 
not be considered to start until the day the first dose is actually administered to the patient 
(i.e. 1-2-3-Rest, X-1-2-3-Rest, etc.). 
Day 8 dose missed: 
Cycle continues per protocol, with one dose not given (i.e., 1-2-3-Rest, 1-X-3-Rest, 1-2-3- 
Rest, etc.). Day 15 is administered as per cycle calendar if counts and chemistries permit. 
Day 15 dose missed: 
That week becomes the week of rest. Next dose (if counts and chemistries permit) becomes 
Day 1 of a new cycle, and the patient is considered to have had a x2q3 (21-day) cycle (i.e. 
1-2-3-Rest, 1-2-X, 1-2-3-Rest, etc.). 
The maximum delay between a missed scheduled dose and the next one (whichever dose 
was missed) should not be longer than 21 days that is 2 infusions and a week of rest, except 
for peripheral neuropathy grade 3 or 4 where an additional delay of 2 extra infusions and a 
week of rest might be acceptable after discussion with the central investigator.  
Arm B patients: 
As per reference document (SmPC) and routine practice. 
For more information on coding the infusion and cycle numbers in case of treatment delays 
see the MOP and its appendices. 
5.3.3 
Study treatment discontinuation criteria  
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 Disease progression4 of patients in Arm A or cross-overs. 
 Disease progression4 of patients in Arm B that are not suitable for continuing 
treatment with nab-paclitaxel + gemcitabine. 
 Unacceptable toxicity attributed to study therapy after appropriate dose adjustments 
see Section 5.3.1.General criteria for dose modifications. 
 Occurrence of an exclusion criterion which is clinically relevant and affects the 
patient’s safety, if discontinuation is considered necessary by the investigator. 
 Withdrawal of consent, patient request or decision of the investigator. 
 Intercurrent illness or treatment delays longer than the equivalent interval of two 
treatment administrations and a week of rest. 
 Patient best interest e.g. initiation of other anticancer therapy, radiotherapy, surgery, 
or other intervention5.  
 Intake of non-permitted medication or procedure. 
 Insufficient patient compliance (defined as missing more than two doses of nab-
paclitaxel).  
 Occurrence of pregnancy. 
 Study closure 
 
Arm A: If nab-paclitaxel is to be discontinued for other reason than progression, patients in 
Arm A could continue treatment with gemcitabine alone off study protocol, if appropriate. If 
gemcitabine is to be discontinued for other reason than progression, patients in Arm A could 
continue treatment with nab-paclitaxel alone on study protocol, if appropriate. If progressive 
disease or both drugs have to be discontinued for other reason, patients will be taken off 
study. 
Arm B: If gemcitabine is to be discontinued for other reason than progression, patients in 
Arm B will be taken off study. In case of progressive disease, patients in Arm B are allowed 
to cross-over to the combination Arm A, if appropriate.  
If there is a safety reason for the withdrawal, the patient will remain under the supervision 
of the investigator until the AEs have resolved. 
If a patient has failed to attend scheduled assessments in the study, the investigator must 
determine the reasons and the circumstances as completely and accurately as possible. 
In case of premature discontinuation of treatment by a subject, the investigations scheduled 
for the “End of Treatment” visit should be performed (specifically a CT- or MRI scan). 
In any case, the e-CRF section entitled "End of Treatment" must be completed. 
The quality of life questionnaire will be collected every four weeks from all living patients 
for a maximum of 12 months from treatment start regardless of the reason of 
discontinuation.  
                                                 
4 Appropriate imaging techniques should be used to document progression. If clinical progression occurs, a 
CT/MRI scan should be performed as soon as possible after cessation of treatment.  
5 If applicable, treatment could resume after recovery at previous treatment doses (if treatment interrupted for 
less than 21 days). 
 


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Survival status will be collected for all patients, at routine follow up visits if applicable or 
by telephone. Survival data will be documented in the CRF until the database lock and on 
simplified electronic forms for up to three years afterwards. 
5.4 
Prior and concomitant therapy 
All chemotherapy treatment administered before inclusion in the study must be recorded, 
including start date and stop date of the treatment, doses, regimen, and dose reductions 
(including reasons), relapse information. Only treatment administered in adjuvant settings is 
allowed. 
Concomitant medication or medication administered during the study (beginning at 3 weeks 
before treatment start) must be recorded. All pain and symptomatic medication that would 
influence quality of life must be listed in the CRF, frequency and doses specified. 
Over the course of this trial, additional medications may be required to manage aspects of 
the disease, including side effects from trial treatments or disease progression. Supportive 
care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the Investigator. Human albumin is the only excipient in the nab-paclitaxel; the 
formulation does not contain ethanol and does not require premedication with anti-
histamines. However, standard premedication for gemcitabine is recommended. 
Irradiation of target lesions is not allowed during the study. Radiotherapy for symptom 
control not on target lesions may be permitted at the condition that is administered at least 7 
days apart from the administration of gemcitabine. No concurrent radiation and gemcitabine 
is permitted. 
Administration of other chemotherapy, immunotherapy, or anti-tumor hormonal therapy 
during the study is not allowed.  
The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes 
CYP2C8 and CYP3A4. Therefore, caution should be exercised when administering nab-
paclitaxel concomitantly with medicines known to inhibit CYP2C8 or CYP3A4 (e.g. 
ketoconazole, erythromycin, fluoxetine, imidazole antifungals, gemfibrozil, cimetidine, 
some anti-virals).  
Similarly, the use of oral anticoagulants that interfere with the metabolic path of nab-
Paclitaxel (cytochrome P450 isoenzymes CYP2C8 and CYP3A4) such as warfarin 
(Coumadin), rivaroxaban (Xarelto), etc, is not allowed during this study; low-molecular 
weight heparins (LMWH) should be used instead.  
Erythropoietin or G-CSF may be administered at the discretion of the Investigator, 
consistent with institutional guidelines. Growth factors are not allowed in primary 
prophylaxis but may be used for management and secondary prophylaxis of hematological 
complications. 
Ciprofloxacin (or the alternative antibiotic) should be distributed to patients with 
instructions to begin treatment if they experience a febrile episode. Administration of long-
term prophylactic ciprofloxacin (or the alternative antibiotic) to prevent recurrences in 
patients already having experienced a first febrile episode (and managed as described in 
Section 5.3.1) will be at the discretion of the treating physician. 
Administration of prophylactic antibiotics to otherwise uncomplicated patients with biliary 
stents will be at the discretion of the treating physicians. Biliary stents should be monitored 
closely to determine need for replacement. 


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For information regarding other drugs that may interact with either nab-paclitaxel or 
gemcitabine and affect their metabolism, pharmacokinetics, or excretion see the reference 
documents. 
Yellow fever vaccine and other live attenuated vaccines are not recommended in patients 
treated with gemcitabine. 
Additionally, any diagnostic, therapeutic, or surgical procedures performed during this study 
period should be recorded in the e-CRF, including the date, indication, description of the 
procedures, and any clinical findings. 
5.5 
Treatment compliance 
Since study medication is administered in a hospital or in an outpatient setting, compliance 
can easily be supervised. The importance of adherence to the recommended treatments 
should be emphasized to the patient. 
The medication will be administered either by the investigator or under his direct 
supervision. 
Date and time of the start and end of infusion, the exact amounts of all drugs given at each 
infusion will be documented in the e-CRF. 
As a routine precaution, patients enrolled in this study will be observed during the 
administration of treatments and for at least one hour after the end of the gemcitabine 
infusion or longer if clinically necessary in an area with resuscitation equipment and 
emergency agents (epinephrine, prednisolone equivalents, etc.) available. In the event that 
the treatment has to be interrupted during infusion, the clinical staff should make an 
estimate of the percentage of dose received by the patient and document it in the e-CRF. 
Any reason for non-compliance should also be documented. Insufficient compliance is 
defined as a patient missing more than two infusions of either nab-paclitaxel or gemcitabine 
without medical reason. 
In the event of insufficient compliance, discontinuation of study treatment will be 
considered in mutual agreement between the investigator and the central PI on a case-by-
case basis. 
6 
Methodology and study procedures 
For a summary of procedures and timepoints for each Arm see  
Table 4:  Summary of clinical procedures and timepoints. 
6.1 
Screening 
All patients seen in clinic and considered potentially eligible for the study will be recorded 
on the provided screening log (See MOP). In cases when, after completing the screening 
process, a patient is subsequently not enrolled in the study, the reason of non-enrolment 
should be mentioned in the screening log. This document will be kept by each site and 
presented at monitoring visits or upon request.  
Screening procedures are: 
 Verification of all inclusion and exclusion criteria. 
 Tumour diagnosis / staging.  If the patient is registered, existing imaging studies can 
be used as baseline evaluations if performed within 28 days from the first day of 
treatment.  


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 Medical history – relevant conditions and treatments. Current symptoms if 
applicable. Assessment of concomitant medication.  
 History of adjuvant chemotherapy treatment(s), including duration and relapse 
information. 
 Clinical examination/physical exam. 
 Laboratory information: 
 Hematology: Erythrocytes, hemoglobin, hematocrit, white blood cell 
count, differential, and platelet count. 
 Chemistry: Glucose, total bilirubin, ALAT, ASAT, alkaline 
phosphatase, serum creatinine, total protein, sodium, potassium, 
magnesium (q8weeks), chloride, serum calcium, blood urea, and 
lactate dehydrogenase, CRP, routine coagulation tests. 
 Urine dipstick. 
If the patient is registered, existing laboratory data can be used as baseline evaluation if 
performed within 2 weeks from the first day of treatment. 
No clinical data will be recorded on screening failures in the e-CRF but the reason of non-
eligibility must be documented in the screening log. 
6.2 
Informed consent 
The informed consent form (s) (participation in the clinical trial, tissue retrieval or optional 
biopsy) must be signed by all eligible patients before undertaking any study related 
treatment, procedures or performing any data collection.  
No biological materials for translational research can be collected before signature of the 
informed consent form. 
See Section 13.3. Subject consent and the Patient information and consent form for details.  
6.3 
Randomization and allocation of patient number 
All eligible patients that signed informed consent will be registered in the e-CRF. Separate 
consent signature for optional biopsies if applicable will also be recorded in the e-CRF. 
Patients will be centrally and automatically randomized by the electronic CRF (for patient 
registration online see MOP).  
A minimization technique [minimizing imbalance in the distributions of treatment numbers 
within the levels of each individual prognostic factor (Pocock & Simon, 1975)] will be used 
for random treatment allocation stratifying by the following factors: 
 Center 
 WHO ECOG performance status (0 and 1 versus 2) 
 Location of tumour (head of the pancreas versus other location) 
 Stage (locally advanced versus metastatic disease)  
At registration, the electronic system will automatically assign a unique patient number in 
the format CC-PPP (C=center, P=patient). 
Patients entering the study will retain this number throughout the study. The assigned 
unique patient number will not be reused. 


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6.4 
Baseline 
 Perform complete physical examination with WHO ECOG performance status and 
vital signs if not done during screening (within 2 weeks from start of treatment). 
Repeat WHO ECOG PS and vital signs prior to start of therapy. See Appendix 5: 
WHO ECOG PS scale. 
 Repeat imaging studies if screening/eligibility scans were performed more than 28 
days prior to the expected start of therapy.  
Disease evaluation: CT- or MRI-scan for baseline tumour assessment (chest, 
abdomen, pelvis). Date of diagnosis, histology, localization of tumour and TNM 
staging are required at registration. A chest X-Ray is not considered appropriate for 
the purpose of disease evaluation at baseline. However, if no lesion was observed in 
the thorax by CT or MRI during screening, at the subsequent visits a chest X-Ray 
could be used to evaluate the disease status. In these cases, any new suspected 
lesion on X-Ray will be confirmed by CT or MRI. NB. The same evaluation 
method of the target lesions should be consistently used throughout the study. For 
subsequent tumour evaluation timepoints in each Arm see  
Table 4:  Summary of clinical procedures and timepoints. 
 Cardiac examination: Electrocardiogram (ECG) performed at baseline for all 
patients (within 28 days prior to start of therapy). If a patient shows any sign of a 
cardiac event during the course of the study, a complete cardiac assessment should 
be performed. 
 Laboratory examination. Repeat if not done within 2 weeks prior to treatment start. 
Blood counts at maximum 48 hours prior to the first infusion. NB. All clinical 
laboratory evaluations (hematology, chemistry, CA 19-9, CEA and pregnancy test) 
will be performed by the local laboratory of the investigational site complying with 
the principles of Good Clinical Practice (GCP) and local requirements. For 
subsequent safety and tumour evaluation timepoints in each Arm see  
 Table 4:  Summary of clinical procedures and timepoints. 
 CA 19-9 and CEA within 2 weeks prior to treatment start.  
 Perform pregnancy test on blood within 7 days prior to treatment start in women 
with childbearing potential, if applicable. 
 Record demographic and medical baseline data (including baseline symptoms and 
concomitant medication). Record baseline laboratory values with local normal 
ranges. 
6.5 
Baseline blood and tissue samples for translational research 
For the duration of the study, every effort should be made that blood collection for 
translational research is performed at the same time with sampling for clinical laboratory 
where applicable, so the numbers of vein punctures and visits are reduced (for example, 
routine hematology and biochemistry and TR samples may be collected the same day, 1 
hour before infusion).  
Prior to the first infusion on study the following materials are required for translational 
research: 
 Blood samples for translational research (10 ml whole blood, 10 ml for plasma and 
10 ml for serum).  


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 Previously archived tissue from the pancreatic tumour if available. Paraffin 
embedded blocks (preferred) or a minimum of 15 slides. 
OR 
 Tissue from pancreatic lesion collected by core needle biopsy (during EUS or 
percutaneous with ultrasound or CT guidance in consenting patients if archived 
tissue is not available. Biopsy is to be performed after signature of consent and 
before the first infusion. 
See Section 10. Exploratory translational research and the MOP for details on collection, 
handling, storage and shipping. 
6.6 
Cycle 1 
6.6.1 
Infusion visit Day 1 
 Have the patient complete the Quality of Life questionnaire. It is recommended the 
patient completes the forms in clinic, before any appointment or procedure. Enough 
time should be allowed prior to his/her appointment. 
 Physical safety check (presence of any new symptoms) every week. 
 BSA every week. See Appendix 4: BSA nomogram. 
 WHO ECOG performance status every week. 
 Blood sampling for routine hematology and chemistry testing (local labs): the results 
of these tests must be available before the administration of medication. Hematology 
testing (blood counts) must be performed within 48 hours prior to infusion for safety 
reasons. Chemistry is allowed within two weeks. If the lab results are not acceptable 
for treatment, infusions may be delayed for a maximum of two consecutive weeks.  
 TR blood samples if not previously taken. 
 Check of vital signs as needed for patient safety. 
Medication: 
 Flush line. Premedication: standard anti-emetics 
 Arm A: Administration of nab-paclitaxel. Flush line with sodium chloride. 
Administration of gemcitabine. Flush line with sodium chloride.   
 Arm B: Administration of gemcitabine. Flush line. 
It is a prerequisite that a physician is present during this first administration of study 
medication. Means of resuscitation must be available. 
 Recording of clinical and QOL data and adverse events: infusion related symptoms, 
concomitant 
medication 
(pain 
and 
symptomatic), 
premature 
infusion 
discontinuation, etc. 
6.6.2 
Infusion visits Day 8 and Day 15 
 Physical safety check every week. 
 BSA every week.  
 WHO ECOG performance status every week 
 Blood sampling for routine hematology and chemistry testing (local labs): the results 
of these tests must be available before the administration of medication. Hematology 
testing (blood counts) must be performed within 48 hours prior to infusion for safety 


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reasons. Chemistry is allowed within two weeks. If the lab results are not acceptable 
for treatment, infusions may be delayed for a maximum of two consecutive weeks. 
(See Section 5.3. Dose modifications and treatment alterations.) 
 Check of vital signs as needed for patient safety. 
Medication: 
 Flush line. Premedication: standard anti-emetics 
 Arm A: Administration of nab-paclitaxel. Flush line with sodium chloride. 
Administration of gemcitabine. Flush line with sodium chloride.   
 Arm B: Administration of gemcitabine. Flush line. 
 Recording of clinical data and adverse events: infusion related symptoms, 
concomitant 
medication 
(pain 
and 
symptomatic), 
premature 
infusion 
discontinuation, etc. 
6.6.3 
Infusion visit Day 22 – Arm B only 
 Physical safety check every week. 
 BSA every week. 
 WHO ECOG performance status every week. 
 Blood sampling for routine hematology and chemistry testing (local labs): the results 
of these tests must be available before the administration of medication. . 
Hematology testing (blood counts) must be performed within 48 hours prior to 
infusion for safety reasons. Chemistry is allowed within two weeks.  If lab results 
are not acceptable for treatment, infusions may be delayed for a maximum of two 
consecutive weeks. (See Section 5.3. Dose modifications and treatment alterations.) 
 Check of vital signs as needed for patient safety. 
Medication: 
 Flush line. Premedication: standard anti-emetics 
 Arm B: Administration of gemcitabine. Flush line. 
 Recording of clinical data and adverse events: infusion related symptoms, 
concomitant 
medication 
(pain 
and 
symptomatic), 
premature 
infusion 
discontinuation, etc.  
Patients in Arm A have a week of rest. 
6.6.4 
Infusion visit Day 29 – Arm B only 
 Have the patient complete the Quality of Life questionnaire. It is recommended the 
patient completes the form in clinic, before any appointment or procedure. Enough 
time should be allowed prior to his/her appointment. 
 Physical exam every 4 weeks. 
 BSA every week. 
 WHO ECOG performance status every week. 
 Blood sampling for routine hematology and chemistry testing (local labs): the results 
of these tests must be available before the administration of medication. Hematology 
testing (blood counts) must be performed within 48 hours prior to infusion for safety 
reasons. Chemistry is allowed within two weeks. If lab results are not acceptable for 


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treatment, infusions may be delayed for a maximum of two consecutive weeks. (See 
Section 5.3. Dose modifications and treatment alterations.) 
 Check of vital signs as needed for patient safety. 
Medication: 
 Flush line. Premedication: standard anti-emetics 
 Arm B: Administration of gemcitabine. Flush line. 
 Recording of clinical and QOL data and adverse events: infusion related symptoms, 
concomitant 
medication 
(pain 
and 
symptomatic), 
premature 
infusion 
discontinuation, etc. 
Patients in Arm A start Cycle 2. Repeat procedures as in Cycle 1. See Section 6.7. Cycle 
>= 2. 
6.6.5 
Infusion visits Day 36 and Day 43 – Arm B only 
 Physical safety check every week. 
 BSA every week. 
 WHO ECOG performance status every week 
 Blood sampling for routine hematology and chemistry testing (local labs): the results 
of these tests must be available before the administration of medication. . 
Hematology testing (blood counts) must be performed within 48 hours prior to 
infusion for safety reasons. Chemistry is allowed within two weeks. If the lab results 
are not acceptable for treatment, infusions may be delayed for a maximum of two 
consecutive weeks. (See Section 5.3. Dose modifications and treatment alterations.) 
 Check of the vital signs as needed for patient safety. 
Medication: 
 Flush line. Premedication: standard anti-emetics 
 Arm B: Administration of gemcitabine. Flush line. 
 Recording of clinical data and adverse events: infusion related symptoms, 
concomitant medication, premature infusion discontinuation, etc. 
Week 8 beginning at Day 50 is a week of rest. 
6.7 
Cycle >= 2 
6.7.1 
Infusion visit Day 1 
 Have the patient complete the Quality of Life questionnaire. It is recommended the 
patient completes the form in clinic, before any appointment or procedure. Enough 
time should be allowed prior to his/her appointment. The QOL questionnaire will 
be completed every four weeks (first visit of the cycle). If delays of treatment 
occur and the patient is present in clinic, the QOL questionnaire can be 
completed even if the treatment is not administered. If the patient is not present 
in clinic, the QOL questionnaire will be completed at the next visit without 
delay. 
 Physical exam every 4 weeks. 
 BSA every week. 


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 WHO ECOG performance status every week. 
 Blood sampling for routine hematology and chemistry testing (local labs): the results 
of these tests must be available before the administration of medication. Hematology 
testing (blood counts) must be performed within 48 hours prior to infusion for safety 
reasons. Chemistry is allowed within two weeks. If lab results are not acceptable for 
treatment, infusions may be delayed for a maximum of two consecutive weeks. (See 
Section 5.3. Dose modifications and treatment alterations.) 
 Check of the vital signs as needed for patient safety. 
Medication: 
 Flush line. Premedication: standard anti-emetics 
 Arm A: Administration of nab-paclitaxel. Flush line with sodium chloride. 
Administration of gemcitabine. Flush line with sodium chloride.   
 Arm B: Administration of gemcitabine. Flush line. From this week on, 
patients in arm B will receive gemcitabine every week for three (3) weeks, 
followed by a week of rest. 
 Recording of clinical and QOL data and adverse events: infusion related symptoms, 
concomitant medication, premature infusion discontinuation, etc. 
6.7.2 
Infusion visit Day 8 and 15 
 Physical safety check every week. 
 BSA every week. 
 WHO ECOG performance status every week. 
 Blood sampling for routine hematology and chemistry testing (local labs): the results 
of these tests must be available before the administration of medication. Hematology 
testing (blood counts) must be performed within 48 hours prior to infusion for safety 
reasons. Chemistry is allowed within two weeks. If lab results are not acceptable for 
treatment, infusions may be delayed for a maximum of two consecutive weeks. (See 
Section 5.3. Dose modifications and treatment alterations.) 
 Check of the vital signs as needed for patient safety. 
Medication: 
 Flush line. Premedication: standard anti-emetics 
 Arm A: Administration of nab-paclitaxel. Flush line with sodium chloride. 
Administration of gemcitabine. Flush line with sodium chloride.   
 Arm B: Administration of gemcitabine. Flush line. From this week on, 
patients in arm B will receive gemcitabine every week for three (3) weeks, 
followed by a week of rest. 
 Recording of clinical and QOL data and adverse events: infusion related symptoms, 
concomitant medication, premature infusion discontinuation, etc. 
6.7.3 
Infusion visit Day 22 
After three administrations, a week of rest should be observed for patients in both Arms. 
Treatment should continue following the schema stated in Figure 1: Study overview until 
one of the reasons for discontinuation occurs. See Section 5.3.3. Study treatment 
discontinuation criteria. 


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For timing of procedures in each Arm during study see  
Table 4:  Summary of clinical procedures and timepoints. 
6.8 
Blood samples for translational research during treatment 
Prior to the infusion at week 9 (after 2 cycles in Arm A and 1 cycle in Arm B) the following 
materials are required for translational research: 
 Blood samples for translational research (10 ml for plasma and 10 ml for serum).  
Details on procedures, handling, shipping and analyses are described in Section 10. 
Exploratory translational research and MOP.  
6.9 
Evaluations at each 8 weekly visit – tumour (response) evaluation 
visits 
Additionally to the regular physical and laboratory evaluations, the following procedures 
will be performed every 8 weeks: 
 Imaging: CT or MRI scan of abdomen and pelvis + chest CT or MRI (or chest X-ray 
if no lung lesion was detected at baseline. If a lesion is detected on chest X-ray it 
will be confirmed by CT or MRI scan). The same evaluation method should be 
consistently used throughout the study. 
 CA 19-9 and CEA 
 Magnesium 
The tumour load/tumour response will be evaluated every 8 weeks for the duration on study, 
afterwards as per routine practice. 
6.10 
Cross-over – Arm B only 
Patients in Arm B progressing on gemcitabine alone and still able to receive treatment (See 
Section 4.3.3. Additional eligibility criteria for cross-over are allowed to cross-over to 
the combination Arm and receive nab-paclitaxel at 125mg/m2 and gemcitabine at the last 
received dose level while on Arm B. 
First progression should be carefully documented. 
An interruption of maximum one cycle (28 days) is allowed for the cross-over. Cycles will 
be of 4 weeks, as described for Arm A. 
6.11 
Blood samples for translational research at cross-over 
At cross-over, the following materials are required for translational research: 
 Blood samples for translational research (10 ml for plasma and 10 ml for serum). 
Details on procedures, handling, shipping and analyses are described in Section 10. 
Exploratory translational research and MOP.  
6.12 
End of Treatment visit  
Whatever the reason for treatment discontinuation is, a complete assessment of the disease 
status and safety has to be performed within 30 days from treatment cessation. (“End of 
Treatment” visit).  
The End of Treatment (EOT) visit will be performed within one month from treatment stop 
and will always consist of the following examinations: 


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 Physical examination. 
 Assessment of WHO ECOG PS. 
 Check of vital signs. 
 Blood sampling for hematology and chemistry.  
 CA 19-9 and CEA. 
 If applicable: CT- or MRI-scan if patient is withdrawn for other reason than 
progressive disease documented by imaging and/or if previous CT/MRI scan is older 
than 4 weeks. (Chest CT could be replaced by chest X-ray if absence of lung lesion 
at baseline). 
 Tumour evaluation. Best response overall. 
 Recording of adverse events / concomitant medication. 
 Cardiac evaluation: ECG (to be done at the latest before any new cancer treatment). 
Completion of the QOL questionnaire will continue every four weeks for a total of 12 
months in surviving patients, regardless of treatment discontinuation. 
 
6.13 
Blood samples for translational research at the “End of 
Treatment” visit 
Blood samples for translational research are required at End of treatment from all patients. 
 Blood samples for translational research (10 ml for plasma and 10 ml for serum). 
Details on procedures, handling, shipping and analyses are described in Section 10. 
Exploratory translational research and MOP.  
Patients that crossed-over and already provided a blood sample at their first progression are 
required to provide another blood sample at the time of the second progression.  
If the patient is taken off study for other reason than progression or death, blood samples are 
required at the time of the visit or within 30 days from treatment discontinuation, but before 
starting of any new treatment. 
Details on procedures, handling, shipping and analyses are described in Section 10. 
Exploratory translational research and MOP.  
6.14 
Follow up 
6.14.1 
First Follow-Up visit 
Completion of the QOL questionnaire will continue every 4 weeks for a maximum of 12 
months in all surviving patients and may be posted to the patient with return envelopes to 
avoid supplementary visits if applicable. 
The “First Follow Up” visit will be done at 6-8 weeks after the “End of treatment” visit. 
The “First Follow Up” visit will consist of the following examinations: 
 QOL questionnaire if applicable. 
 Physical examination. 
 Assessment of WHO ECOG PS. 
 Check of vital signs. 


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 Blood sampling for hematology and chemistry 
 If applicable (not done within the last 12 weeks, not-progressed patients, etc.): 
disease evaluation by imaging if a CT- or MRI-scan and CA19-9 and CEA.  
 Recording of adverse events / concomitant medication. 
 Survival status update if applicable.  
6.14.2 
Subsequent follow up visits 
Follow up of the tumours of progressed patients is at the discretion of the investigator. If a 
patient was taken off study for other reasons than progression of disease, the disease status 
and date of progression should be regularly documented by imaging. The date of 
progression should be carefully documented in the e-CRF. Survival and progression data 
will be collected for a maximum of three years after the database lock. Survival status will 
be documented in the CRF until the database lock and on simplified electronic forms 
afterwards. 
For 
patients 
undertaking 
subsequent 
anti-cancer 
treatments 
(e.g. 
radiotherapy, 
chemotherapy, surgery) the clinical data (date of start, duration, outcome, if applicable) 
should be collected and recorded in the e-CRF. See exceptions in censoring and definition 
of PFS in Section 11.2. Secondary variables. 
Treatment related toxicity still present at the “First Follow Up” visit will be followed up 
until resolution or outcome is stable. 
Survival status should be documented by the investigator after the “End of Treatment” Visit 
at each routine follow up visit. In case the patient is not scheduled for assessment visits 
survival status of all known living patients will be checked by telephone for a maximum of 
three years after the database lock. The date and reason of death should be clearly 
documented in the respective section of the e-CRF or in the simplified FU forms provided 
after the database lock. 
The central electronic database will be hosted and thus accessible for 9 months after the 
“First Follow Up” visit of the last patient on study. In this time interval, clean up/queries of 
data must be finalized. After the database lock, the follow up and survival data will be 
completed and locally stored at each site (in provided electronic password protected forms). 
Summary reports to the sponsor will be required every six months for a maximum of three 
years after the database lock. Data identified by patient number will be sent to U.Z. Leuven 
or its assigned representative.  


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Table 4:  Summary of clinical procedures and timepoints 
ARM A 
  
D-28 to D1 
RANDOMIZATION11 
D-14 to D1 
Treatment period 
End of thx 
FIRST FOLLOW UP VISIT15 
FU 
C1D1 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
C2D15 
C2D22 
Continuing    
thx 
Screening1 
X 
  
 
 
 
 
 
 
 
 
 
 
  
Informed consent  
(main+optional for biopsy2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
  
 
 
 
 
 
 
 
 
 
 
  
Medical history/sy and thx 
X 
  
 
 
 
 
 
 
 
 
 
 
  
Physical exam 
X 
 X3 
 
 
 
 
X 
 
 
 
X (Q4wks) 
X 
X (routine) 
QOL questionnaire4 
   
 
X 
 
 
 
X 
 
 
 
X (Q4wks) 
X 
X (q4wks) 
Tumour assessment5 
  
  
 
 
 
 
 
 
 
 
 
 
  
CT/MRI of abdomen and pelvis 
X 
  
 
 
 
 
 
 
 
X 
X (Q8wks) 
X (Q8wks) 
X (routine) 
Chest X-Ray or CT/MRI 
X 
  
 
 
 
 
 
 
 
X 
X (Q8wks) 
X (Q8wks) 
X (routine) 
CA19-9 and CEA 
X 
X6 
 
 
 
 
 
 
 
X 
X (Q8wks) 
X (Q8wks) 
X (routine) 
WHO PS 
X 
X 
X 
X 
X 
- 
X 
X 
X 
- 
X (3xq4wks) 
X 
X (routine) 
Cardiac assessment (ECG)7 
X 
 
 
 
 
 
 
 
 
 
 
X 
  
Clinical lab8  
X 
X 
X9 
X 
X 
- 
X 
X 
X 
- 
X (3xq4wks) 
X 
X (routine) 
Magnesium8 
X 
X 
 
 
 
 
 
 
 
X 
X (Q8wks) 
X 
X (routine) 
Pregnancy test10 
  
F 
 
 
 
 
 
 
 
 
 
 
  
Premedication antiemetics12 
 
 
X 
X 
X 
- 
X 
X 
X 
- 
X (3xq4wks) 
 
 
Nab-paclitaxel 
  
  
X 
X 
X 
- 
X 
X 
X 
- 
X (3xq4wks) 
 
  
Gemcitabine 
 
 
X 
X 
X 
- 
X 
X 
X 
- 
X (3xq4wks) 
 
 
Blood samples for TR13 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Archived tissue / biopsy for TR14 
  
X 
 
 
 
 
 
 
 
 
 
 
 
Toxicity and AE/ safety check 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (cont) 
X 
  X16 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (cont) 
X 
X 
Subsequent anti-cancer thx 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival status 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X (cont) 
X 
X (cont)17 


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Notes: 
1 All screened patients to be recorded in the screening log. Reason for no registration to be documented, if applicable. Screening failures are not recorded in the CRF. 
2 Biopsies remain optional in patients for whom previously archived tumour samples are not available. An additional signature is required from patients consenting to biopsies. 
3 Physical exam to be repeated before infusion if done more than 2 weeks before start of treatment. 
4 The QOL questionnaire (EORTC QLQ-C30) is applied at baseline and then every 4 weeks for up to 12 months in surviving patients. 
5 The assessment of tumour, response and disease status by imaging, CA19-9 and CEA will be done every 8 weeks.  
6 Repeat CA19-9 and CEA if done more than 2 weeks before start of treatment. 
7 Cardiac assessment by ECG at baseline and end of study. In the event of cardiac emergent symptoms, it will be performed at any time. 
8 Clinical laboratory for safety within 2 weeks prior to first infusion.  
Hematology (5 ml): Erythrocytes count, hemoglobin, hematocrit, white blood cell count, differential and platelet count. Blood cell counts should be monitored weekly during therapy, always within 
48 hours prior to the infusion. 
Clinical Chemistry (10 ml): Glucose, total bilirubin, ALAT, ASAT, alkaline phosphatase, serum creatinine, total protein, sodium, potassium, magnesium (q8weeks), chloride, serum calcium, blood 
urea and lactate dehydrogenase (LDH), CRP. Follow current practice, at least every two weeks. 
Urine dipstick: at baseline and when clinically indicated. 
9 Repeat blood cell counts if not done within 48 hrs from infusion. 
10 Pregnancy test on blood sample for female patients (F) able to become pregnant at max 7 days prior to treatment start. 
11 Randomization will be done 1:1 by the automated system. Registration online at https://www.qolinpac.net. Unique study identifier will be automatically assigned at the time of randomization. 
12 Premedication with standard anti-emetics as per current practice is recommended prior to each infusion of gemcitabine. For patients in Arm A premedication is administered prior to the infusion of 
nab-paclitaxel. 
13 Blood samples for TR: Whole blood, plasma serum at baseline. Plasma, serum at week 9 and progression. If reason for discontinuation is other than progression, the last sample is required at the 
time of the End of treatment visit or within 30 days from discontinuation, but before starting of any new treatment.  
14 Retrieval of previously archived tissue (block or min 15 slides) or biopsy during EUS or percutaneous with ultrasound or CT control in consenting patients that cannot provide archived tumour 
samples. 
15 The “First Follow Up” visit will be performed at 6-8 weeks after the end of treatment visit. Afterwards, the FU visits are routine practice. For un-progressed patients discontinued for other reasons, 
date of progression should be documented. 
16 Until resolution of residual toxicity or documented outcome. 
17 Updated reports every 6 months for a maximum of 3 years after the database lock. 
 
 
 
 


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Table 4:  Summary of clinical procedures and timepoints 
ARM B 
 
D-28 to D1 
RANDOMIZATION11 
D-14 to D1 
Treatment period 
End of thx 
FIRST FOLLOW UP VISIT16 
FU 
C1D1 
C1D8 
C1D15 
C1D22 
C1D29 
C1D36 
C1D43 
C1D50 
C2D1 
C2D8 
C2D15 
C2D22 
Continuing    
thx 
Cross-over 
Screening1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
(main+optional for biopsy2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/sy and thx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X3 
 
 
 
 
X 
 
 
 
X 
 
 
 
X (Q4wks) 
 
X 
X (routine) 
QOL questionnaire4 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X (Q4wks) 
 
X 
X (q4wks) 
Tumour assessment5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI of abdomen and pelvis 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X (Q8wks) 
 
X (Q8wks) 
X (routine) 
Chest X-Ray or CT/MRI 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X (Q8wks) 
 
X (Q8wks) 
X (routine) 
CA19-9 and CEA 
X 
X6 
 
 
 
 
 
 
 
X 
 
 
 
 
X (Q8wks) 
 
X (Q8wks) 
X (routine) 
WHO PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
- 
X(3xq4wks) 
 
X 
X (routine) 
Cardiac assessment (ECG)7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical lab8  
X 
X 
X9 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
- 
X (3xq4wks) 
 
X 
X (routine) 
Magnesium8 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X (Q8wks) 
 
X 
X (routine) 
Pregnancy test10 
 
F 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premedication anti-emetics12 
 
 
X 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
- 
X (3xq4wks) 
X (3xq4wks) 
 
 
Nab-paclitaxel 
 
 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X13 (3xq4wks) 
 
 
Gemcitabine 
 
 
X 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
- 
X (3xq4wks) 
X (3xq4wks) 
 
 
Blood samples for TR14 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Archived tissue / biopsy for TR15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity and AE/ safety check 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (cont) 
X 
X 
X17 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (cont) 
X 
X 
X 
Subsequent anti-cancer thx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival status 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (cont) 
X 
X 
X (cont)18 


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Notes: 
1 All screened patients to be recorded in the screening log. Reason for no registration to be documented, if applicable. Screening failures are not recorded in the CRF. 
2 Biopsies remain optional in patients for whom previously archived tumour samples are not available. An additional signature is required from patients consenting to biopsies. 
3 Physical exam to be repeated before infusion if done more than 2 weeks before start of treatment. 
4 The QOL questionnaire (EORTC QLQ-C30) is applied at baseline and then every 4 weeks for up to 12 months in surviving patients. 
5 The assessment of tumour, response and disease status by imaging, CA19-9 and CEA will be done every 8 weeks.  
6 Repeat CA19-9 and CEA if done more than 2 weeks before start of treatment. 
7 Cardiac assessment by ECG at baseline and end of study. In the event of cardiac emergent symptoms, it will be performed at any time. 
8. Clinical laboratory for safety within 2 weeks prior to first infusion.  
Hematology (5 ml): Erythrocytes count, hemoglobin, hematocrit, white blood cell count, differential and platelet count. Blood cell counts should be monitored weekly during therapy always within 
48 hours prior to the infusion. 
Clinical Chemistry (10 ml): Glucose,total bilirubin, ALAT, ASAT, alkaline phosphatase, serum creatinine, total protein, sodium, potassium, magnesium (q8weeks), chloride, serum calcium, blood 
urea and lactate dehydrogenase (LDH), CRP, routine coagulation tests. Follow current practice, at least every two weeks. 
Urine dipstick: at baseline and when clinically indicated. 
9 Repeat if not done within 48 hrs from infusion. 
10 Pregnancy test on blood sample for female patients (F) able to become pregnant at max 7 days prior to treatment start. 
11 Randomization will be done 1:1 by the automated system. Registration online at https://www.qolinpac.net. Unique study identifier will be automatically assigned at the time of randomization. 
12 Premedication with standard anti-emetics as per current practice is recommended prior to each infusion of gemcitabine. For patients in Arm A premedication is administered prior to the infusion of 
nab-paclitaxel. 
13 For patients eligible for cross-over 
14 Blood samples for TR: Whole blood, plasma serum at baseline. Plasma, serum at week 9, cross-over and 2nd progression. If reason for discontinuation is other than progression, last sample is 
required at the time of the End of treatment visit or within 30 days from discontinuation, but before starting of any new treatment. 
15 Retrieval of previously archived tissue (block or min 15 slides) or biopsy during EUS or percutaneous with ultrasound or CT control in consenting patients that cannot provide archived tumour 
samples. 
16 The “First Follow Up” visit will be performed at 6-8 weeks after the end of treatment visit. Afterwards, the FU visits are routine practice. For un-progressed patients discontinued for other reasons, 
date of progression should be documented. 
17 Until resolution of residual toxicity or documented outcome. 
18 Updated reports every 6 months for a maximum of 3 years after the database lock. 


6.15 
Subsequent anti-cancer treatments 
For patients taken off study for progressive disease, toxicity or other reasons, further 
management will remain at the discretion of the investigator. The start date and type of the 
any new treatment should always be documented in the e-CRF in the FU forms.  
Patients discontinuing study treatment for other reasons than progression and undertaking a 
different anti-cancer treatment will be censored for progression at the date of starting the 
new anti-cancer treatment.  
Data regarding any procedure determining interruption of treatment will be recorded in the 
e-CRF. Also, the date of subsequent progression should be updated in the e-CRF or 
reported as instructed in the FU procedures, see Section 6.14. Follow up. 
7 
Assessment of quality of life 
The EORTC quality of life questionnaire QLQ-C30 (Aaronson, et al., 1993) is an 
integrated system for assessing the health related quality of life (QOL) of cancer patients. 
To date, more than 2200 studies using the QLQ-C30 have been registered. 
This questionnaire was designed to be cancer specific, multidimensional in structure, 
appropriate for self-administration (i.e. brief and easy to complete) and applicable across a 
range of cultural settings.  
The core questionnaire is the product of more than a decade of collaborative research. 
Several versions have been improved and further developed over time.  
A supplementary module specifically for patients with pancreatic cancer is now being 
developed but it will not be used for the purpose of this study. 
7.1 
Structure of the questionnaire  
The current version 3.0 incorporates a total of 30 items/questions within five functional 
scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, 
pain, and nausea and vomiting), a global health status / QOL scale, 6 single items assessing 
additional common symptoms (dyspnea, loss of appetite, insomnia, constipation and 
diarrhea) and perceived financial impact of the disease as presented in Table 5.  
Table 5: Structure of the QLQ-C30 version 3.0 
 
Scale 
Number of items 
Item numbers 
Global health status / QOL scale 
 
 
 
Global health status / QOL 
QL2 
2 
29, 30 
Functional scales 
 
 
 
Physical scale 
PF2 
5 
1 to 5 
Role functioning 
RF2 
2 
6,7 
Emotional functioning 
EF 
4 
21 to 24 
Cognitive functioning 
CF 
2 
20,25 
Social functioning 
SF 
2 
26,27 
Symptom scales/single items 
 
 
 
Fatigue 
FA 
3 
10,12,18 


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Nausea and vomiting 
NV 
2 
14,15 
Pain 
PA 
2 
9,19 
Dyspnea 
DY 
1 
8 
Insomnia 
SL 
1 
11 
Appetite loss 
AP 
1 
13 
Constipation 
CO 
1 
16 
Diarrhea 
DI 
1 
17 
Financial difficulties 
FI 
1 
28 
 
7.2 
Completion of the questionnaire 
The EORTC QLQ-C30 will be used in patient’s first language, see Appendix 1: EORTC 
QLQ-C30 quality of life questionnaire – Master document in English. Dutch and French 
validated translations are available and provided by EORTC, submitted with the patient 
information sheet and consent form. 
QOL questionnaires are to be completed by all patients at baseline and every four weeks 
afterwards. During the treatment period the questionnaires are filled in the clinic, prior to 
the infusion, before interaction with study staff or physician. If delays of treatment occur 
and the patient is present in clinic, the QOL questionnaire can be completed even if the 
treatment is not administered. If the patient is not present in clinic, the QOL questionnaire 
will be completed at the next visit without delay. 
During the follow up period the questionnaires should also be completed every four weeks 
up to a maximum of 12 months in surviving patients and may be posted to the patient with 
return envelopes to avoid supplementary visits if applicable. 
Before handing the questionnaire to the patient, the study nurse, coordinator or physician 
must complete the patient study number on the form. 
Patients should be instructed to fill in their initials, birth date and date of completion and 
respond to all questions, by circling the appropriate number corresponding to the answer of 
choice. There are two types of questions, type 1 to rate items from “Not at all” to “Very 
much” on a scale from 1 to 4 and type 2 to rate health and quality of life on a scale from 1 
to 7. 
7.2.1 
Missing forms 
QOL assessments are likely to be missed because of the negative events experienced by 
patients, such as treatment toxicities, discontinuation due to disease progression, rapid 
deterioration, death. The information is to be provided by patient self-report at a particular 
point in time and cannot be retrieved at a later date from medical charts. 
The QOL main endpoint of this trial depends on the quality and completeness of data 
provided by the QOL questionnaires. 
Adequate infrastructure, trained personnel, sufficient printed materials and time for 
completion must be allocated to carry out the QOL assessments at the indicated timepoints. 
Patients should be instructed every time to answer all questions. 
It is useful to document and report the extent of and reasons for missing data e.g. 
administrative failure, patient refusal, patient too ill, visit not done, etc. The reasons why 


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questionnaires have not been completed may provide useful information to take into 
account at the time of analysis.  
Always complete the reason for missing questionnaires in the provided comment 
boxes in the CRF. 
7.3 
QOL data handling 
Data recording 
The study nurse or physician must ensure that the questionnaire has been properly 
completed and handed by the patient at each required timepoint. At receipt, the nurse must 
quickly check the completeness of the questionnaire. 
The study nurse must transcribe the exact answers provided by the patient on the paper 
form in the electronic CRF. If a questionnaire has not been completed at a certain 
timepoint, the reason for non-completion is to be specified in the CRF. If answers are 
missing to one or more questions, the reasons, if known, should also be mentioned in the 
corresponding form in the CRF.  
Data monitoring and quality assurance 
As the QOL patient self-reported scores are the main basis for the primary endpoint of the 
study, 100% of the data recorded in the CRF will be source data verified by monitors. 
Paper forms should be properly filed in order in patient files. 
8 
Assessment of efficacy 
8.1 
Disease (tumour) assessments 
Only patients with measurable or evaluable pancreatic disease at baseline as defined by the 
RECIST criteria (v. 1.1) (Eisenhauer, et al., 2009) may be enrolled in this study. 
Evaluation of lesions should be based on images obtained by either CT or MRI scan (if CT 
is contraindicated). The same method of assessment and the same technique should be used 
to characterize the disease at baseline and during the study. 
Baseline evaluations should be performed as close as possible to the treatment start 
(maximum 28 days before start of study treatment). The number of organs in which 
metastatic disease has been confirmed should be defined. 
If CT/MRI of chest is negative at baseline then the patient may be followed with chest X-
rays. Once a lesion is detected by chest X-ray it will be confirmed by CT or MRI scan. 
Evaluation of lesions should be performed every 8 weeks during treatment, at the “End of 
Treatment” visit if not already done within 4 weeks and at the “First Follow Up” visit. In 
case the discontinuation of treatment is not related to progression documented by imaging, 
a CT-scan or MRI will be performed at the End of Treatment visit and then as per routine 
practice. Date of progression should be documented in the CRF.  
If treatment discontinuation was based on clinical judgement (i.e. clinical progression) 
tumour evaluation should be done as soon as possible after the treatment stop.  
CA19-9 and CEA changes will be assessed by ELISA.  
Patient clinical condition will be evaluated with periodic physical examinations and 
scoring of performance status. The correlation between objective tumour response change 
in CA19-9, CEA and overall survival will be assessed at the end of the study. Increases in 
CA19-9 or CEA levels should not be used as evidence for progressive disease or for 
removing patients from study. 


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8.2 
Criteria for target and non-target lesions (RECIST) 
To assess whether there is progression of disease, the tumour burden at baseline will be 
calculated and used for comparison with subsequent measurements. At baseline tumour 
lesions will be categorized as follows: 
 
 Measurable: The lesion has clear borders and can be accurately measured in at least 
one dimension with longest diameter (LD) >10 mm with spiral CT scan (CT slice 
thickness is 5 mm or less) and 20 mm by chest X-Ray. Malignant lymph nodes > 
15 mm in short axis with spiral CT scan (CT slice thickness is 5 mm or less). 
 
 Non-measurable: all other lesions including small lesions (LD < 10 mm with spiral 
CT scan or pathological lymph nodes > 10 mm to <15 mm short axis) and truly 
non-measurable lesions. Lesions considered truly non-measurable include the 
following: 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by clinical exam that are not 
measurable by reproducible  imaging techniques, bone lesions and cystic lesions 
Additionally, a tumour that is located in a previously irradiated area should not be 
considered measurable. Superficial and palpable lesions will be considered as non-
measurable lesions for the purpose of this study. 
8.2.1 
Target lesions 
 When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total and a maximum 2 lesions per organ, representative 
of all involved organs, should be identified as target lesions and will be measured at 
baseline. 
 Target lesions should be selected on the basis of their size (lesions with the longest 
diameters), their suitability for accurate repetitive measurements by imaging 
techniques, and how representative they are for the patient’s tumour burden. 
 The same lesions should be evaluated at each measurement timepoint. The exact 
reference/location on CT slices should be recorded as additional identification of 
target lesion. 
 Target lesions will be measured in one dimension (longest diameter). In addition to 
each measurement, the sum of all LDs of all target lesions will be calculated at each 
time point. 
 The baseline sum of LDs will be used as the reference by which to characterize the 
objective tumour response while progression will be diagnosed taking the smallest 
sum of longest diameters achieved (either at baseline or during study treatment) as 
reference. 
8.2.2 
Non-target lesions 
 All other lesions (or sites of disease) should be identified as non- target lesions and 
also be documented. Measurements of these lesions are not required but 
nevertheless the presence, absence or unequivocal progression or regression of 
these lesions should be noted throughout the study. 
8.3 
Response criteria per timepoint 
Overall response will be defined based on the assessments for target and non-target lesions 
as well as considering the occurrence of new lesions. RECIST definitions are as described 
in Table 6 and Table 7: 


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Table 6: Response of target lesions 
Complete response (CR) 
Disappearance of all target lesions. No pathological lymph 
nodes (<10 mm in short axis). No new lesions. 
Partial response (PR) 
A 30% or more decrease in the sum of LD of target lesions, 
taking as reference the baseline sum of LDs, with no evidence 
of PD in non-target lesions or occurrence of new lesions. 
Stable disease (SD) 
Neither sufficient decrease to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest 
sum of LDs achieved throughout the study. No new lesions. 
Progressive disease (PD) 
A 20% or more increase in the sum of LDs of target lesions, 
compared to the smallest sum of LDs recorded for the study 
period (nadir sum of LDs). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. The appearance of any new lesion is 
automatically considered PD. 
 
Table 7: Response of non-target lesions 
Complete response (CR) 
Disappearance of all non-target lesions and normalization of 
tumour marker level. No pathological lymph nodes (<10 mm 
in short axis). No new lesions.  
No change (NC) 
No significant change in non-target lesions to qualify for 
either CR or PD and/or maintenance of the tumour marker 
level above the normal limits. No new lesions. 
Progressive disease (PD) 
Appearance of one or more new lesions, and/or unequivocal 
progression of existing non-target lesions (worsening or new 
effusions or ascites in case of stable or responding target 
lesions will not be considered radiologic progression)* 
*Although a clear isolated progression of “non-target” lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail. 
 
In certain circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (i.e. biopsy) before confirming the 
complete response status.  
 
To assign a status of partial response, changes in tumour measurements must be confirmed 
to show 30% decrease in the sum of LDs compared to baseline, no less than 8 weeks after 
first dose of treatment. 
 
In case of stable disease, measurements must have met the SD criteria at least once, no less 
than 8 weeks after first dose of treatment, otherwise the response will be not evaluable 
(NE). If the duration of SD is less than 8 weeks, the best response will be disease 
progression 
 
If progressive disease was assigned to a timepoint due to unavailable scans, and is 
followed chronologically by a timepoint with no evidence of progression, then the 
timepoint with unavailable scans will be overruled in determination of the best overall 
response. Otherwise the response remains as PD. 
When no imaging/measurement is done at all (or some lesions were not measured) at a 
particular timepoint, the patient is not evaluable (NE) at that timepoint. 


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Overall response per time point will be derived from the tumour response assessments 
obtained for target lesions and non-target lesions considering whether new lesions 
appeared at the respective time point or not. Overall responses for all possible 
combinations of tumour responses are provided in Table 8. Assessments of overall 
response should be provided and recorded in the CRF for each individual visit when 
tumour (response) evaluation is scheduled.  
No confirmation of response is planned for this trial (Eisenhauer, et al., 2009). 
 
Table 8: Overall response per timepoint assessment 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
If no technically adequate baseline imaging data are available for one or more regions (e.g. 
abdomen, thorax, pelvis), then: 
 If no lesions are detected on follow-up scans of unavailable regions at baseline, 
then response assessment will be based on the available scans of the other regions. 
 If one or more lesions are detected on follow-up scans of unavailable regions at 
baseline, then these lesions are regarded to be new lesions, resulting in an overall 
response of PD for this timepoint. 
 If at a follow-up timepoint no technically adequate scans are available for one or 
more regions that were involved at baseline, and there is no evidence of progression 
on the available scans of other region, then: 
 If unavailable regions at a follow-up timepoint contain no target lesion, 
then response assessment will be based on the available scans of the other 
regions. 
 If one or more target lesions are located in unavailable regions at a follow-
up timepoint, then an overall response of PD will be assigned at this 
timepoint. This assignment is subject to review and change before 
determination of the best overall response across all time points. 
8.4 
Best overall response 
The best overall response is the best response recorded from the study start until the end of 
treatment across all time points. The best overall response will be derived from the 
assessments of overall response at the individual time points captured every 8 weeks in the 
CRF. 
Once a CR is observed, any unequivocal reappearance of disease results in progression. 


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Once a PR is observed, the status remains PR until criteria for progression are met. 
In patients with CR or PR, the date of response is the date when the criteria for CR or PR 
are first met. 
If the response is not evaluable (e.g. target lesion difficult to visualize or evaluation not 
done) and there is no other evidence of PD at the time of evaluation, then the best overall 
response at that evaluation will be Not Evaluable (NE). 
Early progression is defined as documented progressive disease that occurred in the first 8 
weeks of treatment. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy. The objective 
response status of such patients is to be determined by evaluation of target and non-target 
disease as shown in Table 6 and Table 7 above. 
9 
Assessment of safety 
9.1 
Adverse events 
9.1.1 
Reference documents 
The product reference documents are:  
Nab-paclitaxel: Current version of the Investigator’s Brochure, yearly updated.  
Gemcitabine (marketed product administered on prescription in standard indication):  
Summary of Product Characteristics (SmPC) which can be found on:  
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Gemzar_30
/WC500008487.pdf 
Main risks and risk management for administering nab-paclitaxel and gemcitabine are 
detailed in Section 5. Treatments. 
Printed or electronic versions of the reference documents will be provided to all 
investigators. Acknowledgements of receipt are required as per GCP. 
Toxicity will be graded using the NCI CTCAE v. 4.0 available on: 
http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
9.1.2 
Definitions  
Adverse Event (or Adverse Experience) (AE): 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable change and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
Any worsening (i.e., any clinically significant adverse change in the frequency or intensity 
of a pre-existing condition) should be considered an AE.  A diagnosis or syndrome should 
be recorded on the AE page of the CRF rather than the individual signs or symptoms of the 
diagnosis or syndrome. 


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Disease progression is not to be reported as an adverse event. 
Due to regulatory requirements, events occurring during pre- and post-treatment periods 
should also be designated as AEs. Therefore, safety surveillance (reporting of AEs) 
commences at the time when the patient is enrolled into the study (date of signature of the 
informed consent) until 30 days after the last dose of medication has been administered. 
Therefore, events occurring in the period between the signature of the informed consent 
and beginning of treatment or within 30 days after stopping treatment are to be designated 
as AEs. This procedure complies with requirements by some authorities and insurance 
policies. Relationship with study treatments must always be carefully documented.  
Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions (ADRs). 
All adverse events judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is evidence 
or argument to suggest a causal relationship. 
Unexpected Adverse Reaction (UAR) is any adverse reaction, the nature, or severity of 
which is not consistent with the applicable product information (e.g. investigator's 
brochure for the study drug given in non-standard regimen or summary of product 
characteristics (SmPC) for products on prescription). 
When the outcome of the adverse reaction is not consistent with the applicable product 
information this adverse reaction should be considered as unexpected. 
Severity: The term “severe” is often used to describe the intensity (severity) of a specific 
event. This is not the same as “serious,” which is based on patient/event outcome or action 
criteria. 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
An SAE or SAR is any untoward medical occurrence that at any dose: 
 results in death, 
 is life-threatening, 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
 requires in-patient hospitalization or prolongation of existing hospitalization, 
 results in persistent or significant disability/incapacity, 
 is a congenital anomaly/birth defect, or 
 is an important medical event. 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate in cases of important medical events that may not be immediately 
life-threatening or did not result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition 
above. 
Examples of such events are intensive treatment in an emergency room, or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; development of drug dependency or drug abuse; or malignant tumours 
when they are histologically different from the primary tumour. 
Other events to be treated as SAEs:  


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 Exposure to drug during pregnancy/lactation. 
In principle, pregnancy and the lactation period are exclusion criteria. In the event of a 
pregnancy occurring during the course of a study, the patient must be withdrawn from 
treatment immediately. The sponsor must be notified without delay and the patient 
followed during the entire course of the pregnancy and postpartum period. Parental and 
neonatal outcomes must be recorded even if they are completely normal and without AEs. 
The standard SAE report form should be used to report a pregnancy.  
 Overdose and intoxication. 
In the event of a drug overdose occurring in the course of the present study, this must be 
reported as a SAE. 
 Misuse, abuse and occupational exposure 
 
Events not treated as SAEs: 
Progression of disease is not to be regarded as a SAE unless the disease progression is due 
to the study drug. 
Due to the seriousness of the disease in this study, certain conditions defined as SAEs will 
be excluded from reporting on a SAE report form, i.e.: 
 A standard procedure for protocol therapy administration.  However, 
hospitalization or prolonged hospitalization for a complication of therapy 
administration will be reported as an SAE.  
 A procedure for protocol or disease-related procedures (e.g., surgery, stenting, 
scans, endoscopy, sampling for laboratory tests, bone marrow sampling).  
However, hospitalization or prolonged hospitalization for a complication of such 
procedures remains a reportable SAE. 
 Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
 Elective or planned hospitalization for treatment of a pre-existing condition. 
 Death due to progression of disease not related to the study drug. 
 
If an AE is considered serious, both the AE page/screen of the CRF and the SAE report 
form must be completed. 
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome. 
 
SUSAR: Suspected Unexpected Serious Adverse Reactions 
All suspected SAEs that are assessed as “Unexpected” not currently foreseen in the SmPC 
(for the medication on prescription) or in the IB (for study labelled medication) must be 
filed as SUSARs. The definitions and conditions of the SAE above apply. 
Mortality within the first 60 days on trial will be reported. 
9.1.3 
Methods of recording and assessing adverse events 
All AEs must be documented in the e-CRF under symptoms/toxicity/lab values. Severity 
and relationship to study treatment will be documented and taken into account in the 
analysis. 
If in any one patient the same AE occurs on several occasions, then the AE in question 
must be documented and assessed and graded anew each time.  


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Among the AEs, all events that meet the “seriousness” criteria, SAEs and SAE follow up 
data (See Section 9.1.1. Reference documents) must be additionally documented in the 
SAE report form. A paper copy of the SAE report form must be kept in the Investigator’s 
file. Any pertinent information recorded in the e-CRF in the AE section must be attached 
to the SAE report form, if applicable.  
9.1.4 
Procedure for reporting Serious Adverse Events 
In the event of the occurrence of any clinical AE or abnormal laboratory test value that is 
serious or medically important or in the event of a pregnancy during the course of the study 
or the post-treatment period, irrespective of the treatment received by the patient, the 
investigator should immediately complete the pertinent data on the provided SAE report 
form and e-mail or fax it to the sponsor’s assigned representative as instructed on the form 
and MOP.  
Each study manager or study nurse will forward the completed SAE report form within 24 
hours of receipt to the pharmacovigilance contact. This is to ensure that the initial reporting 
of SAEs to regulatory authorities is made within the requested timeframe. 
As a principle, the SAE must be documented and medically assessed by the investigator in 
terms of severity (graded based on the NCI CTCAE v. 4.0) and relationship to treatment. 
The action taken, duration of event and outcome should be described and updated if 
applicable on the SAE report form and in the AE section of the e-CRF.  
Where necessary, the SAE report form should be accompanied by other relevant pages 
from the CRF, e.g., for medical history, AEs, and concomitant drugs. If relevant, 
anonymized medical reports, lab reports or other documents allowing precise evaluation of 
the case may be joined or requested, including summary and/or complete translations in 
English when applicable. 
The medical review of data will be performed by the sponsor or its delegates. Additional 
information or clarifications might be requested, if necessary, by the sponsor or its 
representatives or by the regulatory authorities, ethics committees or MAH. The 
investigator must provide the responses within the indicated timeframes. 
The sponsor or appointed representative will set up, host and complete the 
pharmacovigilance database with all data submitted by the centers and will perform the 
regulatory requirements regarding SAE reporting as required by law. 
The appointed CRO or representative will be in charge of expedited reporting to the 
competent authorities whenever applicable, in accordance with international and local laws 
and regulations. All SUSARs will be forwarded to all participating investigators, Celgene, 
ethics committees and the Eudravigilance CTM. 
The appointed CRO or representative will provide an annual summary of all SAE reports 
for local submission purposes; the annual development safety report will be distributed to 
participating investigators and parties.  
For further details, refer to the MOP. 
9.2 
Laboratory safety assessments 
All clinical laboratory evaluations will be performed at the local laboratory of the 
investigational site complying with GCP and local requirements. 
Hematology/chemistry laboratory parameters must be performed within 48 hours prior to 
each treatment administration. Treatment should not be administered if laboratory data are 
unavailable. If the patient’s hematology data is not acceptable, treatment may be delayed 
for a maximum of two weeks.  


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A safety laboratory examination consisting of hematology and clinical chemistry must be 
performed at baseline and before each administration of nab-paclitaxel and/or gemcitabine.  
Clinical laboratory tests are required at the “End of Treatment” visit and at the ““First 
Follow Up” visit”. If treatment related toxicity persist after the “End of Treatment” visit, it 
must be followed until resolution. If severe related toxicity persists after the “End of 
Treatment” visit, laboratory assessments should be performed at least every 2 weeks until 
resolution. 
CA19-9 and CEA must be performed at baseline, at each 8-weekly tumour (response) 
evaluation visit, at the “End of Treatment” visit.  
Pregnancy test must be performed at baseline in women of childbearing potential then in 
accordance with local regulations. Women of childbearing potential must have a negative 
serum pregnancy test (minimum sensitivity according to local regulation) within 7 days 
prior the start of the medication. 
 
Safety laboratory parameters: 
Hematology (5 ml) (weekly except for the weeks of rest) 
 Erythrocytes count, hemoglobin, hematocrit, white blood cell count, differential 
and platelet count. 
Clinical Chemistry (10 ml) (weekly except for the weeks of rest) 
 Glucose, total bilirubin, ALAT, ASAT, alkaline phosphatase, serum creatinine, 
total protein, sodium, potassium, chloride, serum calcium, blood urea and lactate 
dehydrogenase (LDH), CRP, routine coagulation.  
 urine (standard dipstick and/or urinalysis) at baseline and when clinically indicated. 
 magnesium (q8weeks) 
Tumour markers (q8weeks) 
 CA 19-9 level. 
 CEA level. 
Pregnancy test (if applicable) (within 7 days from start of treatment).  
Male or female patients and their partners must be practicing a medically accepted 
contraception if applicable. 
9.3 
Vital signs, physical examinations, and other safety assessments 
The following variables will be measured at baseline and periodically during the course of 
the study as applicable: 
 
 physical examination (always comprises the following body systems: general 
appearance, skin, extremities, cardiovascular, pulmonary, abdominal, lymphatic or 
any other relevant clinical sign). 
 WHO ECOG PS. See Appendix 5: WHO ECOG PS scale. 
 vital signs 
 heart rate (after 5 minutes rest) 
 blood pressure (systolic/diastolic, supine, after 5 minutes rest) 
 body temperature 
 weight/height 
 cardiac examination: ECG (at baseline, EOT and when indicated) 
 toxicity 
 


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10 Exploratory translational research 
10.1 
Background 
SPARC (secreted protein, acidic and rich in cysteine) was found to be epigenetically 
silenced in pancreatic cancer cells but frequently expressed in the adjacent stromal 
fibroblasts. Nab-paclitaxel was thought to play an important role in enhancing paclitaxel 
delivery to the pancreatic tumor, by binding to SPARC in the stroma, thus facilitating gp-
60‒mediated endothelial transcytosis. A retrospective study found that patients with 
pancreatic cancer with high stromal SPARC expression had poorer survival than those with 
low expression (Infante, et al., 2007). In a phase II study with gemcitabine and nab-
paclitaxel, a significant increase in OS was observed for patients in the high-SPARC group 
compared with patients in the low-SPARC group (Von Hoff, et al., 2011).  
Human equilibrative nucleoside transporter 1 (hENT1) and deoxyctine kinase (dCK) are 
two metabolizing gemcitabine proteins and may play an important role in predicting 
clinical outcome of treatment with gemcitabine (Maréchal, et al., 2012), (Wei, Gorgan, 
Elashoff, Hines, Farrell, & Donahue, 2013), (Kahramanoğullari, Fantaccini, Lecca, 
Morpurgo, & Priami, 2012), (Skrypek, Duchêne, Hebbar, Leteurtre, van Seuningen, & 
Jonckheere, 2013), (Fujita, et al., 2010), (Tanaka, Javle, Dong, Eng, Abbruzzese, & Li, 
2010), (Okazaki, M, Tanaka, Abbruzzese, & Li, 2010), (Ashida, et al., 2009), (Nakano, et 
al., 2007), (Giovannetti, et al., 2006). 
S100A2 has been recently suggested as a negative prognostic biomarker in PAC. Among 
patients who received an adjuvant therapy, moderate/high levels of S100A2 were 
significantly associated with longer OS and DFS in multivariate, whereas low S100A2 
levels were not (Bachet, et al., 2013). 
Immunohistochemistry and q-PCR analyses for SPARC, hENT1, dCK and S100A2 
expression are planned. 
It has now clearly been demonstrated that hypoxia can induce epithelial to mesenchymal 
transition (EMT) and metastatic behaviour of cancer cells.  Some hypoxia-induced 
modifications of gene expression in tissue might be prognostic of survival in hepatocellular 
carcinoma (van Malenstein, et al., 2010) or colon cancer (Dekervel & al, 2014). Hypoxia 
also influences epigenetic factors like promoter methylation in different cancers 
(Rawluszko, Bujnicka, Horbacka, Krokowicz, & Jagodzi Ski, 2013), (Hatzimichael, et al., 
2010).  
For the identification and validation of hypoxia-induced predictive biomarkers in 
pancreatic cancer we will investigate gene expression in tumour tissue and correlate results 
with promoter methylation in blood (Cen, Ni, Yang, Graham, & Li, 2012), using a PCR-
based methylation-sensitive high resolution melting technique for accurate quantification 
of the methylation status (Hernández, Tse, Pang, Arboleda, & Forero, 2013).  
10.2 
Translational research objectives 
The main translational research objectives of this trial are: 
1. To study biomarkers that might inform on a predictive signature of response 
2. To match mutation and expression data (to assess whether mutation status can in 
the future be used as a substitute for expression analysis). 
3. To study molecular subgroups, gene pathways, signalling networks and potentially 
new molecular targets in pancreatic cancer. 
4. To explore protein profiles in the development of resistance. 
 


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The analyses will focus on biomarkers that can be related with benefit to nab-paclitaxel: 
 Potential SNPs  
 Circulating DNA 
 Circulating micro-RNA 
 Selected cytokines (ELISA) 
 hENT1, SPARC, dCK and S100A2 expression (immunohistochemistry/qPCR) 
 Hypoxia induced biomarkers 
10.3 
Samples, timepoints, preparation and analyses 
Sampling of blood is mandatory for all participating patients. If archived tissue is not 
available from a previous diagnostic biopsy or surgical specimen, the sampling of tumour 
tissue for translational research remains optional in consenting patients.  
10.3.1 
Blood and blood products 
Samples: 
Whole blood in EDTA tube 10 ml (baseline only) 
Whole blood for plasma in EDTA tube 10 ml 
Whole blood for serum in SST tube 10 ml 
 
Timepoints: 
Venous blood will be collected from all patients at 3-4 timepoints depending on the Arm, 
see  
 
Figure 2: Translational research timepoints – overview:  
 
Baseline: 3x10ml (whole blood, plasma and serum) 
Week 9: 2x10ml (plasma and serum) 
Cross-over: 2x10ml (plasma and serum). Only from patients in Arm B eligible to cross-
over. 
Progression: 2x10ml (plasma and serum). If patients discontinued for reasons other than 
progression or death, these blood samples will be collected immediately or within a 
maximum of 30 days after treatment discontinuation but before any other treatment. 
 
Preparation: 
Whole blood tube (baseline only):  
 
No centrifugation.  
 
Store as is at –80°C. 
 
EDTA tube for plasma:  
 
Centrifuge 10 minutes at 2000g (4°C). 
 
Transfer 3 x 1.5 ml plasma to 2 ml vials. 
 
Discard pellets in EDTA tube. 
 
Store aliquots at -80°C. 
 
SST tube for serum: 
 
Wait until the blood is clotted: 20-60 minutes at room temperature. 
 
Centrifuge 10 minutes at 2000g (4°C). 
 
Transfer 3 x 1 ml serum to 1.5 ml vials.  
 
Store aliquots at -80°C. 
 
 


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Analyses: 
Whole blood at baseline only for: 
 
Analysis of potential SNPs that might correlate with benefit to nab-
paclitaxel 
Plasma for: 
 
Circulating micro-RNA 
 
Circulating DNA 
 
Selected cytokines (ELISA) 
 
Serum for: 
 
Hypoxia-induced biomarkers 
 
Circulating micro-RNA 
 
The actual date and time of sampling and number of samples obtained will be documented 
in the e-CRF. Detailed description of sampling, labelling, processing, storage and shipment 
of specimens could be found in the MOP. 
10.3.2 
Tissue 
Archived tissue (paraffin embedded) from a previous diagnostic biopsy or surgery is 
required when available, in form of blocks (that can be returned to the hospital of origin) or 
minimum 15 slides. If archived tissue is not available, consenting patients may provide 
tissue samples taken by core needle biopsy collected either endoscopically during EUS or 
percutaneous under ultrasound or CT control before the start of treatment. Tissue collected 
by biopsy will be formalin fixed and embedded in paraffin at the site, then the block 
(preferred) or minimum 15 slides will be shipped to U.Z. Leuven. 
Patients will be informed in a verbal and written form about the procedures of biopsy 
taking. An addendum to the main informed consent will be presented to patients for the 
purpose of biopsies. 
Previously archived tissues or biopsy samples shall be used for: 
 Immunohistochemistry analysis / qPCR for hENT1, SPARC and dCK expression. 
 Hypoxia studies 
 
In the context of this protocol a biopsy sample is defined as the entire quantity of tumour 
material obtained after one pass of the biopsy needle (core, not fine needle). 
Fine needle biopsy aspirate (cytology) is not acceptable.  
The actual date and time of biopsy taking and number of samples obtained will be 
documented in the e-CRF. Detailed description of the biopsy sampling, labelling, 
processing, storage and shipment of specimens could be found in the MOP. 
All analyses will be performed by U.Z. Leuven. 
 
 
 


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Figure 2: Translational research timepoints – overview   
  
 
 
 
 
 
 
         
 
  
 
 
       Baseline 
         
 D1     D8                 W9            
 
                      Cross-over (1)     ………  Progression or EoT (2)       
  
 
 
 
   
   
 
 
 
 
            
 
 
 
 
 
                                                
   
 
 
 
 
 
 
 
                     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
     
 
 
              
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
            
 
          
 
 
 
 
 
 
 
 
 
            
 
 
                        
 
 
Legend: 
 
 
 
 
Previously archived tumour tissue or FFPE biopsy samples (from consenting patients) – blocks (preferred) or min 15 slides 
 
10 ml whole blood in EDTA tube (pre-infusion, baseline only) –stored at -80°C 
 
10 ml blood for plasma in EDTA tube (pre-infusion) – 3x1.5 ml cryovials stored at -80°C 
       10 ml blood for serum in SST tube (pre-infusion) – 3x1 ml cryovials stored at -80°C 
  
(1) Patients in Arm B who crossed-over to combination Arm only: TR blood samples to be collected before first nab-paclitaxel infusion. 
(2) Patients that were taken off study for other reasons than progression or death: TR blood samples to be collected immediately or within 30 days from discontinuation, but 
before starting of any new treatment. 
 


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11 Statistics 
11.1 
Primary variables 
The deterioration free survival rate at 3 months is defined as the Kaplan-Meier estimate of 
the probability of being alive and free of deterioration of the QOL scores at 3 months.  The 
deterioration of the QOL score is a decrease of at least 10 points (minimal clinical 
important difference) between the score at baseline and any timepoint. The time interval 
will be calculated from the time of completion of the baseline QOL questionnaire. 
The deterioration free rate at 3 months, comparatively in both treatment Arms is the study 
primary variable. 
QOL scoring 
For ease of statistical interpretations and psychometric validation, all scale and item scores 
entered by patients will linearly be transformed to a scale from 0 to 100. 
A high score for a functional scale represents a high / healthy level of functioning. 
A high score for the global health status / QOL represents a high QOL. 
A high score for a symptom scale / item represents a high level of symptomatology / 
problems. 
Scoring procedures and use with main statistical packages are provided by EORTC 
(Fayers, et al., 2001), (Scott, et al., 2008). 
Definitions 
Each patient will have a set of reference baseline scores: per scale as described above 
(general health, functional, symptom etc.). These will be used to calculate mean changes 
from baseline to each timepoint when the questionnaire is completed (i.e. every four 
weeks). 
Osoba et al. (Osoba, Rodrigues, Myles, Zee, & Pater, 1998) showed that a mean change 
(from baseline to the timepoint considered) of 5 to 10 points in a QLQ-C30 score 
corresponds to a “little” change in QOL, a change of 10 to 20 points corresponds to a 
“moderate” change and change of more than 20 points corresponds to a “large” change.  
We will use the 10 point difference as cut off for “minimal clinically important difference” 
for changes observed. Clinically significant definitive deterioration is indicated when a 
certain score decreases by 10 points as compared to baseline, without later improvement of 
at least 10 points when compared to baseline or without any further available score. 
TUDD for QOL scores is defined as the time from baseline questionnaire to the first 
observation of a definitive deterioration of a QLQ-C30 score. 
TUDDs will be calculated and analysed for each scale: TUDD of the general health, 
functional and symptom TUDDs. 
11.2 
Secondary variables 
11.2.1 
Efficacy variables 
 
Progression free survival (PFS) 
Progression free survival is defined as the time from Day 1 of therapy (day of first infusion 
of medication on study), until the first observation of disease progression (documented by 
appropriate imaging techniques) or the date of death due to any cause, if death occurred 
within 60 days after the last valid tumour assessment. 


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For patients who deceased more than 60 days after either the last valid tumour assessment 
or after the date of Day 1 of therapy without having had imaging performed, the PFS time 
will be censored on the date of last tumour assessment or date of Day 2 of therapy 
respectively. 
Non-progressed patients discontinuing study treatment and not undertaking a different anti-
cancer treatment will be censored for progression at the date of the last valid tumour 
assessment. 
Non-progressed patients discontinuing study treatment and undertaking a different anti-
cancer treatment will be censored for progression at the date of starting the new anti-cancer 
treatment. Exceptions of this rule may be applied for patients undertaking procedures that 
are not aimed at the main disease i.e. stenting, radiotherapy for symptom control not on 
target lesions, and possibly other treatments on a case by case basis. 
Overall survival time 
The survival time of a patient is defined as the time from Day 1 of therapy to death.  For 
patients who are still alive at the time of study analysis or who are lost to follow up, 
survival will be censored at the last recorded date that the patient is known to be alive or at 
the date of data cut-off, whatever occurs earlier. 
Overall response 
Tumour (response) evaluation will be performed at baseline (within 28 days from 
treatment start) and every 8 weeks afterwards, according to RECIST criteria v. 1.1 (CT 
scan or MRI). The overall response rate is the percent of patients achieving a best response 
of either CR or PR (CR+PR).  
Disease control 
The disease control rate is the percent of patients achieving a best response of either CR, 
PR, or SD (CR+PR+SD). 
Duration of response 
The duration of response in responding patients is defined as the time interval from the 
time measurement criteria are first met for CR/PR to either the first time disease 
progression is documented or death (for not progressed patients who deceased within 60 
days from last tumour assessment). The duration of response will be censored on the date 
of last known tumour assessment for not progressed patients lost to follow up or deceased 
prior to the next planned tumour assessment (within 60 days). Not evaluable patients at one 
time point assessment will be censored at the date of last known assessment. 
11.2.2 
Safety variables 
Safety and tolerability will be assessed throughout the study by evaluating the following 
safety variables: 
 Adverse events throughout the study for which the following data are to be 
recorded: 
 Description 
 Start and stop date and time 
 NCI-CTCAE v. 4.0 grade. See Appendix 2: NCI-CTCAE v.4.0. 
 Causal relationship with medication 
 Action taken 
 Outcome 
 Seriousness 
 Expectedness. 


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 Laboratory safety assessments performed as specified in Section 6. Methodology 
and study procedures.  They are mandatory prior to the administration of study 
medication.  They are required at the End of Treatment visit and the First Follow 
Up visit.  Pregnancy test is performed within 7 days from start of treatment if 
applicable.  The tumour markers CA 19-9 and CEA are measured at baseline, at 
each 8-weekly tumour (response) evaluation visit, and at the End of Treatment 
visit.  The following clinical safety tests are foreseen: 
 Hematology: Erythrocytes, hemoglobin, hematocrit, white blood cell 
count, differential, and platelet count. 
 Chemistry: Glucose, total bilirubin, ALAT, ASAT, alkaline 
phosphatase, serum creatinine, total protein, sodium, potassium, 
magnesium (q8weeks), chloride, serum calcium, blood urea, and 
lactate dehydrogenase, CRP, routine coagulation tests. 
 Urine dipstick at baseline and when clinically indicated. 
 Vital signs, physical examination, ECG, and WHO ECOG performance status (PS) 
are recorded. 
11.3 
Analysis sets 
The following analysis sets are considered: 
 
Intent to treat total set (ITT): 
All patients who consented to participate in the study. 
 
Safety Set (SS): 
All patients for whom there is evidence any dose of 
nab-paclitaxel and/or gemcitabine on study had been 
administered. 
 
Per Protocol Set (PPS): 
All patients receiving treatment without any major 
protocol deviation. 
 
The primary set for the quality of life analysis is the ITT.  A sensitivity analysis of the 
primary variables and of PFS will be performed on the basis of the PPS. 
Subgroup analyses: 
A minimization technique [minimizing imbalance in the distributions of treatment numbers 
within the levels of each individual prognostic factor (Pocock & Simon, 1975)] will be 
used for random treatment allocation stratifying by the following factors: 
 Center 
 WHO ECOG performance status (0 and 1 versus 2) 
 Location of tumour (head of the pancreas versus other location) 
 Stage (locally advanced versus metastatic disease)  
 
The following subgroups are considered for key analyses: 
 Gender: female, male. 
 Age: <70 and >70. 
 Location of the tumour: head of the pancreas versus other locations. 
 Stage: locally advanced versus metastatic disease 
 WHO EGOC PS at baseline: 0 and 1 versus 2 
 Arm A, Arm B and cross-overs. 


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11.4 
Statistical design 
11.4.1 
Sample size 
The sample size calculation is based on the deterioration of the global health score (See 
Section 7.1. Structure of the questionnaire) considering a 10-point minimal clinically 
important difference. A definitive deterioration is considered when the score decreases by 
more than 10 points as compared to baseline.  
The hypotheses for sample size calculations are based on the results of the QOL analysis of 
the PRODIGE/ACCORD 11 trial (Gourgou-Burgade, et al., 2013). In this publication, the 
curves of TUDD comparing folfirinox and gemcitabine show that the percentages of 
patients free from definitive deterioration of the global health score at 3 months were 83% 
in Folfirinox Arm and 69% in the gemcitabine Arm. 
Assuming similar results for the nab-paclitaxel + gemcitabine Arm versus gemcitabine 
alone, these percentages are used as hypotheses for sample size calculations for the present 
study. A 3-month deterioration free rate of the global health score of 83% for nab-
paclitaxel + gemcitabine Arm and of 69% for gemcitabine Arm are assumed for 
calculating the sample size using a log-rank test. 
 
Statistical assumptions for sample size calculation: 
Hypotheses : 
a. 2-sided alpha=0.05 
b. power=80% 
c. accrual 8-9 pts per month 
d. 3-months deterioration free rate of 83% for nab-paclitaxel + gemcitabine 
e. 3-months deterioration free rate of 69% for gemcitabine monotherapy 
Results: 
a. Accrual duration: 12-14 months 
b. Total study duration 21 months 
c. Total sample size N=100 
d. Number of events E=68 (number of patients with definitive deteriorations) 
 
The drop-out rate is defined as the proportion of patients that failed to provide at least one 
QOL questionnaire at the end of treatment. We assume a 30% drop-out rate at the end of 
study which is in line with current EORTC recommendations on QOL studies. 
To reach the number of events estimated at point d. of the sample size calculation above 
and considering a 70% patient compliance in providing post-treatment QOL data (30% 
drop-out rate) an increase of the initial sample size to 143 patients (100/0.7=142.86 =~143) 
is required for reaching the main endpoint of the study. 
 
 
11.4.2 
Statistical analysis - general considerations 
The statistical analysis will be performed using the SPSS statistical package, version 11.0 
or later.  All analyses will be performed separately for the Arm A and Arm B data. Cross-
over patients will be also described separately in a subgroup analysis. There will be no 
statistical tests or models to compare efficacy or safety between the two Arms. For the 


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QOL data, an analysis of data missingness will be performed. There will be no imputation 
of missing efficacy or safety data in the secondary analyses. 
 
The statistical analysis will consist of: 
 Descriptive statistics for quantitative variables consisting of the mean, standard 
deviation, 95% CI of the mean, minimum, Q1, median, Q3, maximum, and number 
of observations. For categorical variables frequencies and percentages will be given 
for all values or categories.  Exact 95% Clopper-Pearson confidence intervals will 
be provided for key categorical variables. 
 Kaplan-Meier analysis of time to event variables. 
 Multivariable analysis of time to event variables by means of Cox proportional 
hazards. The independent variables to be used will be specified in the final 
Statistical Analysis Plan.   
 
All analyses are regarded as exploratory therefore no significance level is fixed. 
11.4.3 
QOL analyses 
The QOL data obtained from the patient population will be analysed following the EORTC 
guidelines (Fayers, et al., 2001), (Scott, et al., 2008).  
Several types of statistical analyses will be performed: 
Longitudinal analysis of data. Changes of mean QOL scores during treatment and follow 
up will be assessed descriptively in both Arms. Comparison between baseline and the end 
of treatment will be performed using the sign rank test. The internal consistency of the 
questionnaire will be estimated by using the Cronbach’s alpha for each dimension and 
visit. 
Time Until Definitive Deterioration analysis. TUDDs will be determined according to a 
minimal clinically important difference (MCID) of at least 10 points in QLQ-C30 scores 
for the different domains in both Arms using a time to event analysis (Kaplan-Meier). The 
log-rank test will be used to compare treatment Arms. TUDDs will be alternately analysed 
using a MCID of 20 points and integrating death as an event. 
Analysis of variance. Multivariate analyses will be used to determine baseline prognostic 
factors for overall survival, following the method published by EORTC (ref meta-analysis) 
 Analysis of compliance and missingness of data. Missing questionnaires will be 
accounted for in a descriptive manner. Reasons will be summarized per Arm and type. 
11.4.4 
Efficacy analyses 
The statistical analysis of efficacy will consist of: 
 Kaplan-Meier analysis of PFS, OS and duration of response.   
 Multivariable analysis of PFS and OS by means of Cox proportional hazards. 
 Estimate with exact 95% confidence interval of best overall response rate and 
disease control rate. 
 Descriptive analysis of the relationship between time to progression and TR data. 
11.4.5 
Safety analyses 
Safety analyses will be performed on the basis of the Safety Set.  No formal statistical 
comparisons between Arms are planned on the secondary variables. 


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The extent of exposure to nab-paclitaxel and gemcitabine will be characterized per 
treatment group by duration (weeks), number of infusions, cumulative dose (mg/m²), dose 
intensity (mg/m²/week), relative dose intensity (actual dose given/planned dose), number 
of dose reductions, and number of dose delays. 
AEs will be graded according to NCI-CTCAE toxicity criteria v. 4.0. and coded according 
to the Medical Dictionary for Regulatory Affairs (MedDRA) current version. The analysis 
of AEs will only consider treatment-emergent AEs, defined as AEs with an onset date on 
or after Day 1 of study therapy and up to the End of Treatment visit within one month from 
treatment discontinuation.  Frequencies will be given of patients with AEs, SAEs, related 
AEs, related SAEs, AEs leading to withdrawal, dose modification or discontinuation of 
treatment, broken down by treatment group. The frequency of patients with AEs will be 
provided: 
 Broken down by system organ class, preferred term, and maximal NCI-CTCAE v 
4.0 grade. 
 Broken down by system organ class, preferred term, grade and relationship to 
treatment.  AEs reported with a causal relationship of “definitely related”, “possibly 
related” and “unknown relationship/not assessable” to medication will be 
considered related to treatment. In case of missing relationship assessment AEs will 
be considered as related to the treatment. 
Frequency distributions will be provided for all deaths, deaths within 60 days after first 
dose, and death within 30 days after last dose of study treatment. 
Laboratory results will be classified according to the NCI-CTCAE v. 4.0.  The worst on-
study grade after the first treatment dose on study will be summarized. Incidence of NCI-
CTCAE v. 4.0 grade 3 or 4 laboratory abnormalities under treatment.  
Clinically significant abnormal findings from the physical examination and vital sign 
measurements are to be reported as AEs.  Therefore, no separate summaries will be 
provided of the physical examination data. 
11.4.6 
Interim analyses 
Six monthly safety analyses have been planned. 
11.4.7 
Reporting deviations from the analysis plan 
Deviations from the analysis plan, along with the reasons for the deviations, will be 
described in annual reports, eventual protocol amendments, the complete statistical plan, 
the clinical study report, or any combination of these, as appropriate. 
12 Study management 
12.1 
Electronic case report form 
The appointed developer will be responsible for creating and hosting a functional 
electronic platform for data collection in conformity with standard regulations. Staff and 
assigned representatives from each site will gain access to the electronic forms upon site 
registration and after the required investigator authorizations and site agreements have 
been signed. 
An electronic CRF entry for every subject participating in the clinical study is mandatory 
and will be individually created by the investigator or assigned study nurse by using the 
provided electronic platform.  


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The main objective is to obtain the required data in a complete, accurate, legible, verifiable 
and timely fashion. The data in the e-CRF should be consistent with the relevant source 
documents. Printable formats will be available for use and filing, if needed. However, all 
data recorded in the course of this study must be timely documented in the electronic CRF 
to allow for prompt processing and evaluations. Automated verification checks will be 
built within the electronic platform for continuous monitoring purposes.  
All data will be stored anonymously in accordance with the data-protection regulations. 
Each investigator must ensure that the data is regularly updated and that the timescales 
specified for SAE reporting are respected. 
Any amendments and corrections necessary must be undertaken by the investigator or 
designated staff. All modifications will be electronically tracked in an audit trail. The 
investigator or staff must state his/her reasons for the correction of important data in 
comments or as response to the data clarification requests. 
In the case of missing data/remarks, the entry spaces provided for in the e-case report form 
will be highlighted. Follow-up inquiries will be programmed and performed automatically. 
In case missing data cannot be completed, the investigator or nurse must state a reason to 
avoid further monitoring queries. 
The completed e-CRF will be printable, totally or partially if needed. Relevant pages 
should accompany the SAE report. Printing (on paper or as .pdf files saved on CD-roms) 
of all CRF data entered electronically will be needed for archiving requirements at the end 
of the study.  The electronic CRF platform will be maintained active and opened for data 
entry 9 months after the last patient’s “First Follow-Up” visit. Afterwards, disease and 
survival follow up data will be updated on simplified local and central files. Instructions 
will be provided in the MOP and its appendices. 
12.2 
Source data and subject files 
The available demographic and medical information of a subject transcribed in the CRF 
has to be retrievable in source documentation (subject medical file), in particular the 
following: year of birth, sex, height, weight, subject history, concomitant diseases and 
concomitant drugs (including changes during the study), statement of entry into the study, 
study identification, subject number, the date of informed consents, all study visit dates, 
predefined performed examinations and clinical findings, observed AEs (if applicable), 
reason for withdrawal from the study if applicable, etc. It should be possible to verify the 
inclusion and exclusion criteria for the study from the available data in patient’s medical 
file. 
Additionally, any other data transcribed in the CRF (i.e. lab results or other automated 
testing reports) or data recorded on printed forms used to collect patient information at the 
time of visits will be filed in or retrievable from source documentation.  
12.3 
Investigator Site File, Pharmacy file and archiving 
The investigator will be provided with an investigator site file (ISF) and a Pharmacy file at 
the start of the study. These files contain all relevant documents necessary for the conduct 
of the study and drug accountability, respectively. These files must be safely archived after 
the termination of the study. 
It is the responsibility of the investigator to ensure that the patient-identification sheets are 
stored for at least 20 years beyond the end of the clinical study. All original patient files 
must be stored for the longest possible time permitted by the regulations at the hospital, 


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research institute, or practice in question. If archiving can no longer be maintained at the 
site, the investigators will notify the sponsor. 
12.4 
Monitoring, Quality Assurance and inspection by authorities 
This study is to be conducted in accordance with the International conference of 
Harmonization (ICH) Note for Guidance on Good Clinical Practice (ICH, Topic E6, 1995) 
dated July 17, 1996 and the Ethical Principles for Medical Research Involving Human 
Subjects in the WHO Declaration of Helsinki.  
Further to automated verification checks and monitoring queries built in the electronic 
platform, appointed clinical monitors will perform regular visits to the participating 
center(s) on a regular basis. Detail description can be found in the monitoring guidelines 
and MOP. 
In line with ICH GCP guidelines monitoring will include verification of data entered in the 
e-CRFs against original patient records. This verification will be performed by direct 
access to the original patient records and the sponsor/appointed CRO guarantees that 
patient confidentiality will be respected at all times. Participation in this study will be 
taken as agreement to permit direct source data verification. Data generated at the pre-
screening visit are verified against source data only in case the patient enters the study. 
In addition, the representatives of the sponsor, Clinical Quality Assurance department at 
Celgene, their appointed monitoring organizations, and international regulatory authorities 
are permitted to inspect the study documents (study protocol, case report forms, 
medication, original medical records/files). All patient data shall be treated confidentially. 
The study protocol, each step of the data-recording procedure, and the handling of the data 
as well as the study report could be subject to the independent Clinical Quality Assurance 
by Celgene. Audits can be conducted to assure the validity of the study data. 
12.5 
Changes to the study protocol 
Changes to, or formal clarifications of, the study protocol must be documented in writing. 
Changes to the protocol will be described in a "Protocol Amendment". All amendments 
will be submitted to the relevant ECs and to authorities where required.  
Approval/favourable opinion from the relevant ECs will be required prior to 
implementation of the amendment. 
Amendments will be signed by all signatories of the protocol. 
All investigators will acknowledge receipt and confirm by their signature on the 
Amendment Signature Sheet that they will adhere to the change. This sheet will be issued 
in duplicate and after signing one will be filed in the Investigator Site File and one in the 
Study Master File.  
Any Amendment affecting the patients requires the subjects' informed consent prior to 
implementation. 
12.6 
Study report and publication policy 
After the database lock and analysis, the sponsor will produce the integrated study report. 
The first publication will be a full publication of all data of all sites. Any publications of 
the results, either in part or in total (abstracts in journals or newspapers, oral presentations, 
etc.) by investigators or their representatives will require pre-submission review by the 
Sponsor. 


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The Sponsor is entitled to delay publication if justified. First author of the first original 
article in an appropriate journal is the principal investigator Prof. Dr. E Van Cutsem. Co-
authors will be the members of the writing committee and investigators who have recruited 
patients to the study. The order of co-authorship will be defined according to the 
recruitment rate of the investigational centers and intellectual/scientific input. The number 
of co-authors will be determined by the type of publication and the criteria set by the 
respective journal or conference board. 
A publication plan for multiple publications will be set up together with the investigators. 
13 Ethical and regulatory aspects 
13.1 
Responsibilities of the Investigator 
The investigators shall be responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki (World Medical Association Declaration of Helsinki) as well as with the 
International Conference on Harmonization of Technical Requirements of Pharmaceuticals 
for Humans Use (ICH) Note for Guidance on Good Clinical Practice (ICH, Topic E6, 
1995) approved July 17, 1996 and applicable regulatory requirements.  
13.2 
Subject information 
An unconditional prerequisite for a subject participating in the study is his/her written 
informed consent. Adequate information must therefore be given to the subject by the 
investigator before informed consent is obtained. A person designated by the investigator 
may give the information, if permitted by local regulations. A subject information sheet in 
the local language and prepared in accordance with the ICH Note for Guidance on Good 
Clinical Practice (ICH, Topic E6, 1995) will be provided by investigator for the purpose of 
obtaining informed consent. In addition to this written information, the investigator or his 
designate will inform the subject verbally. In doing so, the wording used will be chosen so 
that the information can be fully and readily understood by laypersons. 
 
The subject information sheet will be revised whenever important new information 
becomes available that may be relevant to the consent of subjects. The amendments to 
consent forms should be presented to all participating patients. 
13.3 
Subject consent 
13.3.1 
Informed consent procedures 
If the patient is eligible (See Inclusion/Exclusion criteria and definition of eligibility), the 
study information and consent forms will be presented, see Patient information and 
consent form. Local approved versions of these documents are available in each national 
language (French and Dutch) – submitted separately.  
If patient agrees to the participation into the trial, the signature of the participant and of the 
investigator conducting the study will be collected prior to any study-related procedures. 
The signature of the patients means he/she agrees to participate in the study, provide blood 
samples for translational research and allow previously archived tissue (if available) to be 
sent and analysed by U.Z. Leuven.    
Additional information and consent pages for tissue biopsies are to be presented to patients 
from whom no previously archived tumour tissue is available. Although the biopsy at 


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baseline remains optional, it is recommended that investigators make every effort to 
provide tumour tissue for translational research studies.  
Provision of consent and type of consent (i.e. participation in the clinical trial and 
agreement for biopsy if applicable) will be confirmed in the e-CRF by the investigator. The 
signed and dated original declaration of informed consent will remain at the investigators' 
site and must be safely archived by the investigator so that the forms can be retrieved at 
any time for monitoring, auditing and inspection purposes. A copy of the signed and dated 
information and consent should be provided to the subject prior to study start. 
13.3.2 
Witnessed informed consent 
Illiterate subjects 
If the subject is unable to read, a reliable and independent witness should be present during 
the entire informed consent discussion. The choice of the witness must not breach the 
subject’s right to confidentiality. A reliable independent witness is defined as one not 
affiliated with the institution or engaged in the investigation. A family member or 
acquaintance can be appropriate independent witnesses. 
 
After the subject orally consents and has signed, if capable, the witness should sign and 
personally date the consent form attesting that the information is accurate and that the 
subject or has fully understood the content of the informed consent agreement and is giving 
true informed consent. 
13.4 
Compensation to subjects 
Insurance coverage will be provided by the sponsor for all subjects enrolled in the study 
from the time of subjects' inclusion into the study (i.e. date of signing consent or screening 
visit). Insurance confirmations, policies and certificates are made available to participating 
centers and filed in the investigator site file.  
No financial benefit or incentive to participate will be offered to patients neither by the 
sponsor nor by Celgene. 
13.5 
Ethics Committee or Institutional Review Board 
Prior to commencement of the study, the study protocol will be submitted together with its 
associated documents (patient information, consent form, investigator's brochure) to the 
relevant ethics committees (ECs) or institutional ethics review boards for their favourable 
opinion. The favourable opinion/approval of the ECs will be filed in the investigator site 
file and a copy in the trial master file handled by the sponsor. 
The study will only commence following provision of a written favourable opinion from 
central EC after consultation with all local ECs as per national practices.  
Any document arising from an Ethics Committee meeting, such as date of the meeting, 
name of people attending the meeting, voting members, comments, remarks will be 
collected and filed in the proper section of the trial master file handled by the sponsor. 
Written evidence that clearly identifies the protocol version, and consent documents 
reviewed by ECs will also be filed.  
Any amendments to the protocol will be submitted to the EC and they will be informed 
about SAEs in accordance with national and/or local requirements (development safety 
update reports). 


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All submission procedures and necessary documentation including translations in national 
languages of the information sheet and patient informed consent will be performed by the 
sponsor and delegates. 
13.6 
Notification to authorities 
The study protocol and applicable documentation (subject information, consent form, 
quality of life questionnaire, etc.) will be notified to authorities in accordance with the 
European regulations and/or the laws of Belgium. 
 
 


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14 Trial sponsorship and financing 
U.Z. Leuven is the legal sponsor for all participants and is represented by the central PIs 
for the purpose of this study  
Contract and subcontracting information for participants/investigator fees and 
invoicing: 
Prof. Dr. Eric Van Cutsem 
U.Z. Leuven 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven, Belgium 
phone: 
     
+ 32 16 344225 
fax:      
 
+ 32 16 344419 
e-mail: 
     
eric.vancutsem@uz.kuleuven.be 
 
Dr. Gabriela Chiritescu 
U.Z. Leuven 
Digestive Oncology Unit 
Herestraat 49 
B-3000 Leuven, Belgium 
phone: 
     
+ 32 16 340495 
fax:      
 
+ 32 16 344419 
e-mail: 
     
gabriela.chiritescu@uz.kuleuven.be 
 
 
Celgene International sarl provides a research grant and supplies study labelled Abraxane® 
(nab-paclitaxel) for the conduct of this trial in all participating centers. 
 
 


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Investigator signature page 
 
 
Protocol title:  
 
Randomized crossover trial to assess the effects and quality of life in 
patients with locally advanced or metastatic pancreatic cancer treated 
with gemcitabine in combination with nab-paclitaxel: QOLINPAC 
 
EudraCT # 2013-004101-75;  
U.Z. Leuven reference # S56122 
 
 
Date/Version number of the protocol:08/06/2015 – Version 3.0 
Name, academic degree of the site PI: 
Site number: 
Hospital/Institution 
Address: 
Telephone: 
Fax: 
e-mail address: 
 
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that: 
I understand and will conduct the trial according to the clinical trial protocol, any approved 
protocol amendment, ICH Good Clinical Practice (ICH Topic E6 GCP) and all applicable 
Health Authority requirements and national laws. 
I will not deviate from the clinical trial protocol without prior written permission from the 
Sponsor and prior review and written approval from the Institutional Review Board or 
Ethics Committees, except where necessary to prevent immediate danger to the subject. 
 
 
 
Date: ........................ 
Signature: .................................... 


QOLINPAC. EudraCT # 2013-004101-75, U.Z. Leuven reference # S56122 
QOLINPAC Version 3.0 – 08/06/2015 
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Appendices