Nab-Paclitaxel Plus Gemcitabine Versus Gemcitabine For The First Line Treatment of Metastatic or Locally Advanced Unresectable Adenocarcinoma of The Pancreas: A Phase II Randomized Study
Phase: PHASE2
Conditions: Pancreatic Neoplasm
Sponsor: Hacettepe University

 
Nab-Paclitaxel plus gemcitabine 
 
1st line in advanced Pancreatic Cancer 
 
 
 
NAB-PACLITAXEL PLUS GEMCITABINE VERSUS GEMCITABINE FOR THE 
FIRST LINE TREATMENT OF METASTATIC OR LOCALLY ADVANCED 
UNRESECTABLE ADENOCARCINOMA OF THE PANCREAS: A PHASE II 
RANDOMIZED STUDY 
 
PROTOCOL VERSION DATED: 07 January 2014 
EudraCT: 2013-004180-32 
Protocol No: AX-PANC-SY001 
SPONSOR: Prof.Dr.Suayib Yalcin 
Hacettepe University, Institute of Cancer 
Department of Medical Oncology 
SPONSOR CONTACT: 
Prof. Suayib Yalcin 
Hacettepe University Institute of Oncology 
Department of Medical Oncology 
Sihhiye, Ankara, Turkey 
Phone:+90 312  305 2929 
Fax:+90 312 305 2905 
E-Mail: syalcin@hacettepe.edu.tr 
PRINCIPAL INVESTIGATOR: 
Prof. Suayib Yalcin 
Hacettepe University Institute of Oncology 
Department of Medical Oncology 
Sihhiye, Ankara, Turkey 
Phone: +90 312  305 2929 
Fax: +90 312 305 2905 
E-Mail: syalcin@hacettepe.edu.tr 
This clinical study will be conducted in accordance with International Conference on 
Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
CONFIDENTIAL 
The information contained in this document is the property of Suayib Yalcin and is 
provided for the use of the Investigator and other designated site personnel. It may also 
be distributed to appropriate Ethics Committees/Institutional Review Boards/Regulatory 
Authorities. These groups are also required to keep the enclosed information 
confidential. This document contains strictly confidential information and no part of this 
document may be published or disclosed, except as necessary to obtain consent from 
persons who are considering participation in the study. 
 
 
 
 
 

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1st line in advanced Pancreatic Cancer 
 
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Investigator-Initiated Trial Protocol 
 
 
Study title: 
Nab-paclitaxel plus gemcitabine versus gemcitabine for the first line treatment of metastatic or locally 
advanced unresectable adenocarcinoma of the pancreas: A Phase II randomized study 
Phase 
II 
Kind of study 
(interventional, 
non-
interventional or 
pre-clinical): 
Interventional 
Indication 
Metastatic or unresectable locally advanced pancreatic cancer 
Rationale 
Pancreatic cancer is responsible for 38,000 deaths per year, and is the fourth most 
common cause of death from cancer in both sexes combined, a position relatively high 
when compared to incidence (tenth position) because of the very poor prognosis (the M/I 
ratio is 98%) (Siegel et al, 2013). The incidence of pancreatic carcinoma has increased 
almost 300% since 1950 and now exceeds the incidence of stomach cancer. Carcinoma of 
the exocrine pancreas is nearly always a fatal disease. The overall 5-year survival rate for 
the disease is approximately 4%. 
Locally advanced or metastatic pancreatic cancer is relatively unresponsive to 
chemotherapy. Gemcitabine therapy provides some benefit and modestly improves survival 
compared with fluorouracil, but median survival in patients with advanced disease remains 
less than 6 months (Burris, 1997). Until recently, cytotoxic drug combinations were not able 
to show survival advantage compared to Gemcitabine alone in numerous randomized 
phase III studies. 
Randomized phase III Prodige trial evaluated FOLFIRINOX regimen in metastatic 
pancreatic cancer patients (Conroy et al, 2011). Both median progression-free survival 
(PFS) (6.4 vs 3.3 months, p<0.001) and median overall survival (OS) (11.1 vs 6.8 months, 
p<0.001) were dramatically improved. In patients with good performance status 
FOLFIRINOX remains a viable first-line option. However, toxicity of FOLFIRINOX regimen 
still remains a concern. 
The effect of FOLFIRINOX on quality of life (QoL) in metastatic pancreatic cancer was 
analyzed from the PRODIGE 4/ACCORD 11 trial. FOLFIRINOX combination was found to 

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significantly reduce QoL impairment compared with single-agent gemcitabine. Baseline 
QoL scores improved estimation of survival probability when added to baseline clinical and 
demographic variables.  
Nab-paclitaxel is an albumin-bound nanoparticle form of paclitaxel. In a recent phase III 
study of Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) including 861 
patients, patients were randomly assigned to 1 of 2 regimens: nab-paclitaxel 125 mg/m² 
followed by gemcitabine 1000 mg/m² for 3 weeks, then a week of rest; or gemcitabine 
1000 mg/m² administered weekly for 7 weeks, then a week of rest, followed by cycles of 
weekly gemcitabine administration for 3 weeks and a week of rest (von Hoff et al, 2013). 
OS was improved significantly with nab-paclitaxel + gemcitabine combination compared to 
gemcitabine alone (median, 8.5 vs. 6.7 months; hazard ratio [HR], 0.72; P = .000015). 
These improvements suggest a 31% reduction in the risk of progression or death. At 12 
months, the survival rate was 35% with the combination versus 22% with gemcitabine 
alone, translating into a 59% increase in survival (p = 0.00020). In addition to OS, the nab-
paclitaxel combination surpassed gemcitabine alone for median PFS (5.5 vs. 3.7 months; 
HR: 0.69; p = 0.000024) and the overall response rate (23% vs. 7%).The toxicity of the 
combination was modest and easily manageable. This combination may represent a new 
standard in the management of these patients. 
QoL changes in patients receiving nab-paclitaxel in combination with gemcitabine for the 
first-line treatment of metastatic or locally advanced unresectable pancreatic carcinoma 
have not been explored. This randomized, phase II study analyzes the effect of nab-
paclitaxel plus gemcitabine on QoL of these patients. Efficacy and safety of the combination 
will also be analyzed. 
Study 
objectives 
 
 
Primary objectives: 
3-months deterioration-free rate (percentage of patients free from definitive 
deterioration) 
EORTC QLQ-C30 (validated version for Turkish using a reduction of at least 10 points as a 
meaningful clinical difference) will be used to calculate “time until definitive deterioration” 
(TUDD) and compare patients receiving first-line Nab-Paclitaxel plus Gemcitabine versus 
first-line gemcitabine for metastatic or locally advanced unresectable adenocarcinoma of 

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the pancreas. 
EORTC QLQ-C30 scores will be calculated every four weeks following the EORTC QLQ-
C30 recommendations for calculations and scoring (EORTC QLQ-C30 published manual). 
 
Secondary objectives: 
Overall survival (OS) 
Progression-free survival (PFS) 
Response rate 
Safety and toxicity 
Predictive and prognostic factors: Serum and archived tumor tissue biomarkers (available 
patients) for prognosis and prediction to response to treatment and toxicity. 
Study design 
This is a randomized, multicenter, phase II study of with nab-paclitaxel plus gemcitabine or 
gemcitabine alone for the treatment of chemotherapy-naïve patients with locally advanced 
or metastatic pancreatic cancer. 
Arm 1: Nab-paclitaxel plus gemcitabine  
Arm 2: Gemcitabine alone 
Study 
Duration: 
The first patient is planned to be enrolled in March 2014. The recruitment period is 
estimated to be around 14 months. Patients will receive study treatment until death, 
disease progression (PD), occurrence of intolerable side effects, or withdrawal of consent, 
whichever comes first.   
All patients will be followed for survival.  
A patient is considered “Discontinued from Study Follow-up” only if study treatment has 
been discontinued AND one of the following occurs: 
a. Patient withdraws consent. 
b. Patient is lost to follow-up. 
c. Patient dies.  
d. Patient completes 1-year follow-up. 
e. Study is completed or terminated by the Sponsor. 
Patient 
Chemotherapy-naïve patients presenting with unresectable locally advanced or metastatic 

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population 
pancreatic adenocarcinoma and a measurable disease by RECIST. 
Inclusion 
criteria: 
 
1. Patients presenting with metastatic or unresectable pancreatic adenocarcinoma and with 
no prior chemotherapy 
2. Patients with a measurable/evaluable disease by RECIST 
3. Age ≥ 18 years 
4. ECOG performance status 0 or 1 
5. Patients with signed informed consent form 
6. Patients with adequate bone marrow function: granulocyte count ≥1500 and platelet 
count ≥100,000 per cubic milimeter. 
7. Patients with adequate liver function defined as: 
 
a. Total bilirubin <2 mg/dl 
 
b. ALP/GGT <5x upper normal limit (ULN) 
 
c. ALT/AST <2.5x upper normal limit (ULN) 
Exclusion 
criteria: 
 
1. Any prior systemic or investigational therapy for metastatic pancreatic cancer. Systemic 
therapy administered alone or in combination with radiation in the adjuvant setting is 
permitted if it is completed > 6 months prior to the time of study enrollment.  
2. Inability to comply with study and/or follow-up procedures. 
3. Presence of significant comorbidity including clinically significant cardiac disease (e.g. 
congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not 
well controlled with medication) or myocardial infarction within the last 12 months and any 
other major organ failure. 
4. Presence of any condition that, in the opinion of the investigator, renders the subject at 
high risk from treatment complications or might affect the interpretation of the results of the 
study.  
5. Presence of central nervous system or brain metastases. 
6. Life expectancy < 12 weeks.  
7. Pregnancy (positive pregnancy test) or lactation.  
8. Prior malignancy except for adequately treated basal cell skin cancer, in situ cervical 

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cancer, adequately treated Stage I or II cancer from which the patient is currently in 
complete remission, or any other form of cancer from which the patient has been disease-
free for 5 years.  
9. Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.  
10. Known, existing uncontrolled coagulopathy.  
11. Pre-existing sensory neuropathy > grade 1.  
12. Major surgery within 4 weeks of the start of study treatment, without complete recovery.  
13. Concurrent/pre-existing use of coumadin. 
14. Patients older than 76 years of age. 
15. Patients with active infection. 
16. Patients with chronic diarrhea. 
 
Treatment 
regimen 
Arm 1: 
Nab-paclitaxel 125 mg/m2 as 30- to 40-minute infusion (maximum infusion time not to 
exceed 40 minutes) once weekly for 3 weeks followed by a week of rest. 
plus  
Gemcitabine 1000 mg/m2 as a 30- to 40-minute infusion (maximum 40 minutes) once 
weekly for 3 weeks followed by a week of rest.  
OR 
Arm 2: 
Gemcitabine 1000 mg/m2 as a 30- to 40-minute infusion (maximum 40 minutes) 
administered weekly for 7 weeks followed by a week of rest (8-week cycle; cycle 1 only), 
followed by cycles of weekly administration for 3 weeks (on days 1, 8, and 15) followed by 
one week of rest (4-week cycle). 
All patients will be considered for available second-line therapies or best supportive care on 
the discretion of the investigators. 
Dose 
modification 
plan: 
 
Rules for Dose Omissions and Modified Schedules  
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 

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not be considered to start until the day the first dose is actually administered to the patient 
(ie, 1-2-3-Rest, X-1-2-3-Rest, etc). 
Day 8 dose is missed;  
Cycle continues per protocol, with one dose not given (ie, 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 (ie, 1-2-3-Rest, 1-2-X, 1-2-3-Rest, etc).  
 
The maximum delay: The maximum delay between a missed scheduled dose and the next 
one (whichever dose was missed) should not be longer than 21 days (except for peripheral 
neuropathy) 
Two dose modifications are permitted. If a toxicity requiring dose modification occurs 
following the second dose reduction of either drug, further treatment should be 
discontinued.  
 
Dose Modifications; 
Dose Level  
Nab-Paclitaxel Dose (mg/m2) a  
Gemcitabine (mg/m2) a  
Study dose  
125  
1000  
-1  
100  
800  
-2 b  
75  
600  
a) Dose reductions may or may not be concomitant. Please refer to Tables 2-4 for specific 
recommendations regarding dose reductions.  
b) A maximum of 2 dose-level reductions are allowed. 
 
Patients experiencing study drug-related toxicities that require a delay in scheduled nab-
paclitaxel or gemcitabine dosing for ≥21 days will be discontinued from further treatment in 

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1st line in advanced Pancreatic Cancer 
 
Protocol Version dated 30 Sep 2013 
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this study (except for peripheral neuropathy). When a dose reduction is required, no dose 
re-escalation will be permitted for the duration of study treatment.  
 
DOSE MODIFICATIONS AT DAY 1; 
In the event dose modifications are required at the beginning of a cycle due to AEs or 
hematologic toxicities, doses of nab-paclitaxel and gemcitabine may be adjusted  
 
Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity);  
Treatment day counts and toxicity  
ANC  
Platelets  
Timing  
≥1.5 x 109/L  And  ≥100 x 109/L  
Treat on time  
<1.5 x 109/L  Or  
<100 x 109/L  
Delay by 1 week intervals until recovery  
 
Dose Modifications for Day 1 of Each Cycle (Non-Hematologic Toxicity)  
Non Hematologic Toxicity and/or Dose Hold with Previous Cycle 
Toxicity/dose held 
Gemcitabine/Gemcitabine+Nab-paclitaxel dose this cycle 
Grade 0, 1 or 2 toxicity 
Same as Day 1 previous cycle (except for cutaneous 
toxicity) 
Grade 3 toxicity 
Decrease gemcitabine and nab-paclitaxel to next lower dose 
level 
Grade 4 toxicity 
Off protocol treatment 
Dose held in 2 previous 
consecutive cycles 
Decrease gemcitabine to next lower dose level and continue 
throughout the rest of treatment 
a) If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced 
b) Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, 
will be exempt from this requirement.  
Gemcitabine and nab-paclitaxel or gemcitabine monotherapy will be provided within the 

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study protocol until patients progress or are unable to tolerate the treatment. 
Patients on single-agent gemcitabine arm will be allowed cross-over to the combination arm 
in case of a definitive deterioration in the GHS score of at least 10 points. 
Endpoints: 
Primary endpoint: 
3-months deterioration-free rate (percentage of patients free from definitive 
deterioration). 
Quality of life (QoL): EORTC QLQ-C30 (validated version for Turkish using a reduction of at 
least 10 points as a meaningful clinical difference) will be used to calculate “time until 
definitive deterioration” (TUDD) and compare patients receiving first-line Nab-Paclitaxel 
plus Gemcitabine versus first-line gemcitabine for metastatic or locally advanced 
unresectable adenocarcinoma of the pancreas. 
Secondary 
Overall survival (OS) 
Progression-free survival (PFS) 
Overall Response Rate (ORR) 
Safety and toxicity 
Predictive and prognostic factors: Serum and archived tumor tissue biomarkers (available 
patients) for prognosis and prediction to response to treatment and toxicity.  
Statistical 
plan 
 
Rationale and Methodology: 
The objective of the trial is to compare QoL in patients receiving Nab-paclitaxel plus 
gemcitabine versus gemcitabine.  
QoL will be assessed using the EORTC QLQ-C30 for at least 12 months (in those who are 
still alive) for all patients (even if they deteriorate 10 points and meet the study end point). 
Sample size calculations will be based on the GHS score 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. Thus, “time until definitive 
deterioration” (TUDD) is defined as the time from randomization to the first observation of a 
definitive deterioration of the score.  
The hypotheses for sample size calculations are based on the results of the article “Impact 

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of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic 
pancreatic cancer: results from the PRODIGE/ACCORD 11 randomized trial”, published in 
Journal of Clinical Oncology. 
The curves of TUDD comparing FOLFIRINOX and gemcitabine show that the percentages 
of patients free from definitive deterioration at 3-months are 83% in the FOLFIRINOX arm 
and 69% in the gemcitabine arm. Assuming the same for Nab-Paclitaxel plus Gemcitabine 
arm, these percentages are used as hypotheses for sample size calculations. So, a 3-
month deterioration-free rate of 83% for Nab-Paclitaxel plus Gemcitabine arm and 69% for 
gemcitabine arm will be assumed for calculating the sample size using a log-rank test. 
Primary end-point will be 3-months deterioration-free rate (percentage of patients free from 
definitive deterioration as defined above). 
Sample size calculations: 
• 
Hypotheses  
a. 2-sided alpha=0.05 
b. power=80% 
c. accrual 7 pts per month 
d. 3-month deterioration-free rate of 83% for Nab-Paclitaxel plus 
Gemcitabine 
e. 3-month deterioration-free rate of 69% for gemcitabine arm  
• 
Results 
a. Accrual duration 14 months 
b. Total study duration 21 months 
c. Total sample size n=100 
d. Number of events E=68 (number of patients with deteriorations). 
 
Accounting for a 20% missing or incomplete forms, the total sample size will be n=125.  
 

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THERAPY SYNOPSIS 
NAME, SURNAME 
Birthday  - -  - -  - - - -       STID - - -  
 
 
DAY 
WEEK 
NABPACLITAX
GEMCITABINE 
CT/ MRI (SCREENING) 
QoL 
APPLICATION WEEKLY: 
Nab-paclitaxel 125 mg/m2 
Plus  
Gem 1000 mg/m2  
(3 weeks on, 1 week off)    
          OR 
Gem 1000 mg/m2 iv 30’   
 
1 
1 
 
 
8 
2 
 
 
15 
3  
 
 
22 
4 
REST 
29 
5 
 
 
36 
6 
 
QoL 
43 
7 
 
 
CT / MRI (FOLLOW UP # 1) 
50-56 
8 
PD: OFF STUDY 
SD/PR/CR: FURTHER 
THERAPY 
APPLICATION WEEKLY: 
Nab-paclitaxel 125 mg/m2 
Plus  
Gem 1000 mg/m2  
(3 weeks on, 1 week off)    
          OR 
Gem 1000 mg/m2 iv 30’   
 
57 
9 
 
 
64 
10 
 
 
71 
11 
 
 
78 
12 
REST 
85 
13 
 
 
92 
14 
 
QoL 
99 
15 
 
 
CT / MRI (FOLLOW UP # 2) 
106-112 
16 
PD: OFF STUDY 
SD/PR/CR: FURTHER 
THERAPY 
APPLICATION WEEKLY: 
(see above, 
 CT/ MRI follow up every 7-8 
weeks) 
113 
17 
 
 
120 
18 
 
 
127 
19 
 
 
134 
20 
REST 

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TABLE OF CONTENTS 
List of in-text table ..........................................................................   .     ..15 
List of appendices ....................................................................................................  .16 
Abbreviations and definitions of terms ......................................................................  .17 
Signature Page................................................................................................................19 
1.0 Introduction and Study Rationale ........................................................................ 20 
1.1. Background......................................................................................................... 20 
  1.2. Nab-paclitaxel ..................................................................................................... 22 
  1.3. Nab-paclitaxel preclinical studies ........................................................................ 23 
  1.4. Nab-paclitaxel Pharmacokinetics  ...................................................................... 23 
  1.5. Nab-paclitaxel in metastatic breast cancer .......................................................... 23 
  1.6 Nab-paclitaxel in metastatic breast cancer  ......................................................... 24 
  1.7. Toxicity ................................................................................................................ 25 
  1.8 Rationale for the Study ........................................................................................ 26 
2.0 Study Objectives ................................................................................................... 27 
  2.1. Primary Study Objectives......................................................................................27 
  2.2. Secondary Study Objectives.................................................................................28 
3.0 Investigational Plan ............................................................................................... 28 
3.1. Study Design ...................................................................................................... 28 
  3.2. Study Duration .................................................................................................... 29 
3.3. Study Population ................................................................................................. 29 
  3.4 Inclusion Criteria .................................................................................................. 29 
  3.5 Exclusion Criteria ................................................................................................. 30 
4.0 Study Medication ................................................................................................... 31 
4.1. Provision of the study medication ........................................................................ 31 
4.2. Stability / Application ........................................................................................... 31 
4.3. Storage ............................................................................................................... 32 
4.4. Accountability ...................................................................................................... 32 
4.5. Study Medication Administration and Dose Modification Procedures .................. 33 
  4.5.1. Concomitant Treatments .................................................................................. 33 
  4.5.2. Study Treatment .............................................................................................. 33 
  4.5.3. Dose Delays and Modifications ........................................................................ 34 
5.0. Study Schedule and Procedures ......................................................................... 37 
  5.1. Study Schedule ................................................................................................... 37 
  5.2. Study Procedures ............................................................................................... 38 

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  5.2.1. Informed Consent ............................................................................................ 38 
  5.2.2. Medical History and Cancer Related Signs and Symptoms .............................. 38 
  5.2.3. Physical Examination ....................................................................................... 38 
  5.2.4. Vital Signs, Weight, and Height ........................................................................ 38 
  5.2.5. Performance Status and Quality-of-Life assessment ........................................ 39 
  5.2.6. Electrocardiogram (ECG) ................................................................................. 39 
  5.2.7. Chest X-ray (CXR)/Chest Computed Tomography (CT) ................................... 39 
  5.2.8. Clinical Laboratory Evaluations......................................................................... 39 
  5.2.8.1. Hematology.....................................................................................................39 
  5.2.8.2. Serum Chemistry............................................................................................ 40 
  5.2.8.3. Urinalysis ...................................................................................................... 41 
  5.2.9. Pregnancy Test ................................................................................................ 41 
  5.2.10. Carbohydrate Antigen (CA) 19-9 Levels ......................................................... 42 
  5.2.11. Concomitant Medications and Therapies ........................................................ 42 
  5.2.12. Adverse Event and Toxicity Assessment ........................................................ 42 
  5.2.13. Tumor Assessments/Scans............................................................................. 42 
  5.2.13.1. Tumor Measurements................................................................................... 43 
  5.2.13.2. Methods of Measurement ........................................................................... 43 
  5.2.13.3. Measurability of Lesions............................................................................... 44 
  5.2.14. End of Treatment Procedures ........................................................................ 47 
  5.2.15. Follow-up Study Procedures .......................................................................... 47 
6.0 Reporting safety information ................................................................................ 47 
  6.1. Monitoring, Recording and Reporting of Adverse Events .................................... 47 
  6.2. Evaluation of Adverse Events ............................................................................. 48 
  6.2.1. Seriousness....................................................................................................... 48 
  6.2.2. Severity / Intensity............................................................................................ 50 
  6.2.3. Causality .......................................................................................................... 51 
  6.2.4. Duration ........................................................................................................... 51 
  6.2.5. Action Taken .................................................................................................... 51 
  6.2.6. Outcome .......................................................................................................... 51 
  6.3. Abnormal Laboratory Values ............................................................................... 51 
  6.4. Expedited Reporting of Adverse Events .............................................................. 52 
  6.4.1. Reporting to Regulatory Authorities and the Ethics Committee ........................ 52 
  6.4.2. Immediate Reporting by Investigator to Sponsor and Sponsor to Celgene ....... 52 
 

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7.0 Statistical Analysis ................................................................................................ 53 
  7.1. Primary Aim and Primary Endpoints..................................................................... 53 
  7.2. Secondary Aims and Secondary Endpoints......................................................... 53 
  7.3. Safety................................................................................................................... 54 
  7.4. Statistical Analysis................................................................................................ 54 
8.0 Ethics ..................................................................................................................... 55 
  8.1. Ethical Considerations ........................................................................................ 55 
  8.2. Informed Consent and Patient Information .......................................................... 55 
  8.3. Institutional Review Board/Independent Ethics Committee Approval .................. 56 
9.0 Administrative Considerations ............................................................................. 57 
9.1. Regulatory Requirements-Sponsor/Investigator Obligations ............................... 57 
9.2. Protocol Amendments ......................................................................................... 57 
9.3. Curriculum Vitae ................................................................................................. 57 
  9.4. Monitoring Procedures..........................................................................................57 
  9.4.1. Study Monitoring................................................................................................ 57 
  9.4.2. Case Report Form............................................................................................. 58 
9.5. Archiving of Records ........................................................................................... 58 
9.6. Final Report ........................................................................................................ 60 
9.7. Use and Publication of Study Results ................................................................. 60 
9.8. Termination of the Study ..................................................................................... 61 
9.9. Information Material ............................................................................................ 61 
10.0 Confidentiality ..................................................................................................... 61 
11.0 Signatures of Sponsor and Investigator ............................................................ 62 
11.1. Declaration of Sponsor...................................................................................... 62 
11.2. Declaration of Investigator ................................................................................ 62 
12.0 References ........................................................................................................... 63 

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LIST OF IN-TEXT TABLES 
Table 1: Frequency of important adverse events: Nab-paclitaxel vs CrEL-paclitaxel.  
Table 2: Dose modifications. 
Table 3: Dose modifications for Day 1 of each cycle (hematologic toxicity). 
Table 4: Dose Modifications for Day 1 of each cycle (non-hematologic toxicity). 
Table 5: Hematology parameters measured before each application. 
Table 6: Hematology parameters measured before start of new cycle. 
Table 7: Serum chemistry measurements. 
Table 8: Tumor assessments.  
Table 9: Tumor response assessment of target lesions.  
Table 10: Tumor response assessment of non-target lesions.  
Table 11: Overall assessment of response. 
 

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LIST OF APPENDICES 
A. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 
QUICK REFERENCE 
B. DECLARATION OF HELSINKI 
C. FLOW CHART (PATIENT/INVESTIGATOR) 
D. TOXICITY CRITERIA (NCI-CTCAE 4.0) 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase (SGPT) 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase (SGOT) 
β-HCG 
Beta Human Chorionic Gonadotrophin 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CA 
Cyanuric Acid, Carbohydrate Antigen 
CBC 
Complete blood chemistry 
CFR 
Code of Federal Regulations 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Toxicity Criteria For Adverse Events 
CXR 
Chest X-ray 
CYP2A6 
Cytochrome P-450 Drug Metabolizing Enzyme 2A6 
DAR 
Drug Accountability Record 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DR 
Duration of Response 
ECG 
Electrocardiogram 
EORTC 
European Organization for Research and Treatment of Cancer 
EU 
Europe 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
G-CSF 
Granulocyte Colony-stimulating Factor 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 

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IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IU 
International Units 
KPS 
Karnofsky Performance Status 
LDH 
Lactic Dehydrogenase 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
Ng 
Nanogram(s) 
NYHA 
New York Heart Association 
ORR 
Overall Tumor Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease, Disease Progression 
PR 
Partial Response 
PT 
Prothrombin Time 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease; Standard Deviation 
SOP 
Standard Operating Procedure 
TTP 
Time to Tumor Progression 
TUDD 
Time until definitive deterioration  
ULN 
Upper Limit of Normal 
US 
Ultrasound 
USA 
United States of America 
WBC 
White Blood Cell 
WHO 
World Health Organization 

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Signature page 
 
Principal investigator 
 
 
 
 
 
Prof. Suayib Yalcin 
 
 
 
___________________________ 
Location, date 
 
____________________________ 
Signature 
 
 
 
Sponsor 
 
 
 
Hacettepe University Institute 
of Oncology Department of 
Medical Oncology Sihhiye, 
Ankara, Turkey / Prof.Dr. 
Suayib Yalçın 
 
 
 
____________________________ 
Location, date 
 
____________________________ 
Signature 
 

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1st line in advanced pancreatic cancer 
 
 
 
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1. 
INTRODUCTION AND STUDY RATIONALE 
1.1.  Background 
Pancreatic cancer is responsible for 38,000 deaths per year, and is the fourth most 
common cause of death from cancer in both sexes combined, a position relatively high 
when compared to incidence (tenth position) because of the very poor prognosis (the M/I 
ratio is 98%) (Siegel R et al, 2013). This number represents 27% of all deaths from 
gastrointestinal malignancy in the United States. The annual incidence of pancreatic 
cancer in the Surveillance, Epidemiology, and End Results (SEER) database for the 
USA is 8.9 cases per 100,000. The incidence of pancreatic carcinoma has increased 
almost 300% since 1950 and now exceeds the incidence of stomach cancer and cancer 
of the rectum (Benarde MA et al, 1977; Mack TM et al, 1981). Carcinoma of the exocrine 
pancreas is nearly always a fatal disease. The overall 5-year survival rate for the 
disease is approximately 4% (SEER Cancer Statistics Review 1973-1996). 
Complete tumor resection is the only treatment with a chance of cure but only feasible in 
5-15% of patients. Despite curative resection, median survival does not exceed 12-18 
months. After 2 years, 20-35% of the patients remain alive, after 5 years 5-10% of 
patients. About 30-40% of patients have locally advanced disease. Median survival of 
these patients is 3-8 months without further treatment. However, about 70% of all 
patients present with disseminated disease at the first diagnosis or with relapse after 
curative resection. Median survival for these patients is 3-5 months.  
At the University of Chicago, the 3-year survival rate of 912 patients with pancreatic 
cancer was only 2.5% (Connolly MM et al, 1987). At the Memorial Sloan-Kettering 
Cancer Center, only 18% of patients were eligible for a potantially curative resection, 
with a 30-day operative mortality rate of 3.4%. The actuarial 5-year survival rate in 
patients who did not undergo resection was 0%, compared with 24% in patients who 
underwent resection (Geer RJ et al, 1993). 
The patterns of failure after potentially curative resection include local relapse and 
metastatic involvement of the liver or peritoneal cavity. In one study of 36 patients, 19% 
experienced local failure only, whereas 73% had distant and local failure (Griffin JF et al, 
1990). The most common sites of failure were in the liver (62%) and peritoneal cavity 
(42%).  

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In chemotherapy and radiation therapy trials, the most important factor that has 
consistently been of greatest prognostic importance is the performance status of the 
patient: The better the level of performance, the better the response rate or survival rate, 
or both. 
Using traditional criteria of antitumor response, advanced adenocarcinoma of the 
pancreas rarely responds to single-agent chemotherapy. In clinical studies, single-agent 
chemotherapy generally does not reach response rates (complete or partial response) of 
20% using WHO criteria. Response rates are usually below 15% (Burris HA, 2005; 
Heinemann V et al, 2006).  
This is also true for treatment with the nucleoside analogue gemcitabine which showed 
response rates of about 11% in locally advanced or metastatic pancreatic cancer 
patients (Casper ES et al, 1994). There is considerable interest, however, in its use as a 
single agent or as a component of combination chemotherapy because of a randomized 
trial conducted by Burris and coworkers (Burris HA et al, 1997). These investigators 
randomized patients to receive either Gemcitabine or 5-FU. End points were survival 
and a nontraditional benefit criterion called “clinical benefit response”, defined as a 
composite of pain control, Karnofsky performance status, and weight. Gemcitabine 
achieved a clinical benefit response in 24% of patients, whereas 5-FU achieved benefit 
in only 5% of the patients (p=0.0022). Survival was also improved for Gemcitabine 
(median survival, 5.6 months) compared to 5-FU (median survival 4.4 months) 
(p=0.0025). Largely as a result of this study, Gemcitabine has been marketed for 
palliative treatment of advanced pancreatic cancer. Despite the apparent, although 
modest, activity of gemcitabine in the treatment of advanced pancreatic cancer, the use 
of gemcitabine in combination with other agents has been disappointing until recently, 
achieving modest responses (Hidalgo M et al, 1999; Berlin JD et al, 2002; Rocha-Lima 
CM et al, 2006; Ueno H et al, 2007; Kulke MH et al, 2009).  
Randomized phase III Prodige trial evaluated FOLFIRINOX regimen in metastatic 
pancreatic cancer patients (Conroy et al, 2011). Both median progression-free survival 
(PFS) (6.4 vs 3.3 months, p<0.001) and median overall survival (OS) (11.1 vs 6.8 
months, p<0.001) were dramatically improved. In patients with good performance status 
FOLFIRINOX remains a viable first-line option. However, toxicity of FOLFIRINOX 
regimen still remains a concern. 

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The effect of FOLFIRINOX on QoL in metastatic pancreatic cancer was analyzed from 
the PRODIGE 4/ACCORD 11 trial (Gourgou-Bourgade S et al, 2013). Time until 
definitive deterioration ≥20 points was significantly longer for FOLFIRINOX combination 
compared to gemcitabine alone for global health status, physical, role, cognitive, and 
social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, 
anorexia and constipation). Physical functioning, constipation and dyspnea were 
independent significant prognostic factors for survival with treat ment arm, age older 
than 65 years, and low serum albumin. FOLFIRINOX combination was found to 
significantly reduce QoL impairment compared with single-agent gemcitabine. Baseline 
QoL scores improved estimation of survival probability when added to baseline clinical 
and demographic variables (Gourgou-Bourgade S et al, 2013).  
1.2. 
Nab-paclitaxel 
Nab-paclitaxel is an albumin-bound nanoparticle form of paclitaxel. Nab-paclitaxel is a 
novel formulation of paclitaxel that does not require solvents such as polyoxyethylated 
castor oil (Cremophor EL®: CrEL) and ethanol. Use of these solvents has been 
associated with toxic response, including hypersensitivity reactions and prolonged 
sensory neuropathy, as well as a negative impact in relation to the therapeutic index of 
paclitaxel. Use of nab-paclitaxel can potentially avoid these limitations. Consequently, 
nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base 
paclitaxel. 
Nab-paclitaxel is prepared by high-pressure homogenization of paclitaxel in the 
presence of serum albumin, resulting in a colloidal suspension comprising nanoparticles 
of 130 nm on average, which prevent the risk of capillary blockage after intravenous 
infusion (Desai et al, 2006). Nab-paclitaxel consists of a lyophilized powder, which is 
reconstituted with 20 mL 0.9% sodium chloride solution before intravenous infusion. 
Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human 
albumin. The final colloid solution contains 5 mg/mL of paclitaxel and approximately 45 
mg/mL of albumin. Based upon in vivo study, it seems that the nab particles disperse 
into the individual albumin molecules with bound paclitaxel immediately after introduction 
into aqueous solution, as would occur after injection into the bloodstream (Gradishar, 
2006). 

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1.3. 
Nab-paclitaxel preclinical studies 
In athymic mice bearing human cancer xenografts, the antitumor activity and toxicity 
profile of nab-paclitaxel was better than that of CrEL- paclitaxel (Desai et al, 2006). The 
lethal dose (LD)50 and maximum tolerated dose (MTD) for nab-paclitaxel and CrEL-
paclitaxel were 47 and 30 mg/kg/day and 30 and 13.4 mg/kg/day, respectively. At 
equitoxic doses, nab-paclitaxel had significantly better antitumor effects including tumor-
free survival, time to tumor recurrence (P = 0.004), tumor doubling time (P = 0.0015), 
and tumor volume (P = 0.009) compared with CrEL-paclitaxel. At an equal dose of 
paclitaxel, the level of intratumoral paclitaxel accumulation was higher in nab-paclitaxel-
treated mice than those in receipt of CrEL-paclitaxel. The extent of endothelial binding 
and transcytosis of paclitaxel was significantly greater for nab-paclitaxel than CrEL-
paclitaxel. These findings indicated that nab-paclitaxel mediates greater intratumoral 
accumulation of paclitaxel and associated increased efficacy compared with CrEL-
paclitaxel. 
1.4. 
Nab-paclitaxel pharmacokinetics 
In a phase I study of nab-paclitaxel administration over 30 minutes every 3 weeks in 19 
patients with metastatic melanoma or breast cancer, the MTD was determined to be 300 
mg/m2 (Ibrahim et al, 2002). Plasma levels of paclitaxel declined in a biphasic manner 
after intravenous administration of nab-paclitaxel with a rapid first phase representing 
distribution to the peripheral tissue and the second slower phase representative of drug 
elimination. 
In another pharmacokinetic study, nab-paclitaxel (260 mg/m2 given as a 30-minute 
infusion) was compared with CrEL-paclitaxel (175 mg/m2 given as a 180-minute infusion) 
(Gardner et al, 2008). The mean fraction unbound of paclitaxel was significantly higher 
for nab-paclitaxel than CrEL-paclitaxel (0.063 ± 0.021 vs 0.024 ± 0.009; P < 0.001), 
although the total drug exposure was comparable between the two drug formulations. 
These findings are in agreement with the greater antitumor efficacy of nab-paclitaxel 
compared with that of CrEL-paclitaxel. 
1.5. 
Nab-paclitaxel in metastatic breast cancer 
Nab-paclitaxel is widely approved for the treatment of metastatic breast cancer on the 
basis of results from pivotal trials showing that it has superior antitumor effects and 
improved tolerability than solvent-based paclitaxel (Gradishar et al, 2005). Forty-six 

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patients were randomized to nabpaclitaxel (260 mg/m2 over a 30-minute infusion) 
without premedication or CrEL-paclitaxel (175 mg/m2 over a 3-hour infusion) with 
standard premedication. Inclusion criteria included no receipt of taxane for metastatic 
disease and no relapse with metastatic disease within 1 year of adjuvant taxane therapy. 
The objective response rate (ORR) and median time to progression (TTP) were 
significantly higher in nab-paclitaxel-treated patients than those receiving CrEL-paclitaxel 
(ORR: nab-paclitaxel 33% vs CrEL-paclitaxel 19%; P = 0.001, TTP: nab-paclitaxel 23.0 
weeks vs CrEL-paclitaxel 16.9 weeks; hazard ratio [HR] = 0.75, P = 0.001). Maximum 
responses occurred by cycle 3 in 91% of responders in the nab-paclitaxel group and in 
81% of responders in the CrEL-paclitaxel group. The OS in the nab-paclitaxel group was 
greater than that in CrEL-paclitaxel group (65.0 weeks vs 55.7 weeks, respectively), but 
this did not reach statistical significance (P = 0.374). This trial showed that nab-paclitaxel 
has superior clinical benefit including greater efficacy and a favorable safety profile 
without premedication compared with CrEL-paclitaxel.  
1.6. 
Nab-paclitaxel in metastatic pancreatic cancer 
Initial phase I/II study showed substantial antitumor activity of gemcitabine/nab-paclitaxel 
combination in metastatic pancreatic cancer (Von Hoff et al, 2011). The schedule was as 
follows: gemcitabine 1000 mg/m2 and nab-paclitaxel at 125 mg/m2 doses weekly for 
three doses in a 4 week schedule. A 48% response rate was achieved at MTD , with 
12.2 median months of overall survival and 48% 1-year survival. Interestingly, preclinical 
part of the same study showed increased intratumoral concentration of gemcitabine by 
2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving 
gemcitabine alone.  
This study was followed by a phase III study of Metastatic Pancreatic Adenocarcinoma 
Clinical Trial (MPACT) (Von Hoff et al, 2013). A total of 861 patients were randomly 
assigned to 1 of 2 regimens: nab-paclitaxel 125 mg/m² followed by gemcitabine 
1000 mg/m² for 3 weeks, then a week of rest; or gemcitabine 1000 mg/m² administered 
weekly for 7 weeks, then a week of rest, followed by cycles of weekly gemcitabine 
administration for 3 weeks and a week of rest (von Hoff et al, 2013). OS was improved 
significantly with nab-paclitaxel + gemcitabine combination compared to gemcitabine 
alone (median, 8.5 vs. 6.7 months; hazard ratio [HR], 0.72; P = .000015). These 
improvements suggest a 31% reduction in the risk of progression or death. At 12 
months, the survival rate was 35% with the combination versus 22% with gemcitabine 

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alone, translating into a 59% increase in survival (p = 0.00020). In addition to OS, the 
nab-paclitaxel combination surpassed gemcitabine alone for median PFS (5.5 vs. 3.7 
months; HR: 0.69; p = 0.000024) and the overall response rate (23% vs. 7%).The 
toxicity of the combination was modest and easily manageable.  
1.7. 
Toxicity 
In the pivotal, randomized phase III metastatic breast cancer trial, the toxicity of single 
agent nab-paclitaxel (260 mg/m2 every 3 weeks) was compared with that mediated by 
CrEL-paclitaxel (175 mg/m2 every 3 weeks) (Gradishar et al, 2005) (Table 1). Treatment 
compliance of both groups was equally high with 96% (nab-paclitaxel) or 94% (CrEL-
paclitaxel) of patients receiving 90% of the protocol-specified dose despite a higher 
dose-intensity of paclitaxel in the nab-paclitaxel group (85.1 mg/m2/week) than the CrEL-
paclitaxel group (57.02 mg/m2/week). Treatment discontinuation, dose reduction and 
dose delay due to adverse events were also infrequent in both treatment groups. In 
addition, the safety profile of nab-paclitaxel was comparable to that of CrEL-paclitaxel 
although there were some differences between the two groups. Consistent with the 
safety data, no differences in quality of life (QOL) were observed between the two 
groups. 
 
Table 1. 
 

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Grade 4 neutropenia was significantly lower in the nabpaclitaxel group than in the CrEL-
paclitaxel group (9% vs 22%, respectively; P < 0.0001). These findings suggest that the 
CrEL vehicle may be responsible for the noted toxicity in patients treated with CrEL-
paclitaxel. Hematologic toxicities were dose-dependent and reversible. 
Hypersensitivity reactions, such as dyspnea, flushing, chest pain, hypotension, and 
arrhythmia, can occur during infusion of drugs. Almost all patients treated with 
nabpaclitaxel received no premedication. On the other hand, almost all patients treated 
with CrEL-paclitaxel received premedication with corticosteroids and antihistamines to 
avoid hypersensitivity reaction. The incidence of this adverse event was low for both 
groups in the randomized trial. The incidence of severe hypersensitivity reaction was 2% 
in the CrEL-paclitaxel group despite their having received standard premedication. 
As expected, with a higher dose of paclitaxel, the incidence of a severe sensory 
neuropathy was greater in the nab-paclitaxel group than the CrEL- paclitaxel group (10% 
vs 2%, respectively; P < 0.001), as well as the overall incidence of this toxicity (71% vs 
56%, respectively; P < 0.05), in the pivotal randomized comparative study. 
Nabpaclitaxel- induced peripheral neuropathy could be managed with treatment 
interruption and dose reduction.  
1.8. 
Rationale for the Study 
Pancreatic cancer is responsible for 38,000 deaths per year, and is the fourth most 
common cause of death from cancer in both sexes combined, a position relatively high 
when compared to incidence (tenth position) because of the very poor prognosis (the M/I 
ratio is 98%) (Siegel R et al, 2013). The incidence of pancreatic carcinoma has 
increased almost 300% since 1950 and now exceeds the incidence of stomach cancer. 
Carcinoma of the exocrine pancreas is nearly always a fatal disease. The overall 5-year 
survival rate for the disease is approximately 4%. 
Locally advanced or metastatic pancreatic cancer is relatively unresponsive to 
chemotherapy. Gemcitabine therapy provides some benefit and modestly improves 
survival compared with fluorouracil, but median survival in patients with advanced 
disease remains less than 6 months (Burris HA et al, 1997). Cytotoxic drug combinations 
were not able to show survival advantage compared to Gemcitabine alone in numerous 
randomized phase III studies.  

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Nab-paclitaxel is an albumin-bound nanoparticle form of paclitaxel. Nab-paclitaxel 
demonstrated the capacity of increasing the gemcitabine bioavailability inside the tumors 
in a preclinical study (Von Hoff et al, 2011). This was followed by a phase I/II study 
demonstrating feasibility of nab-paclitaxel in combination with gemcitabine in metastatic 
pancreatic cancer.  
Following this initial study, phase III MPACT study (Metastatic Pancreatic 
Adenocarcinoma Clinical Trial) including 861 patients showed statistically significant and 
clinically meaningful improvements in all endpoints across all subgroups compared with 
gemcitabine alone including overall survival. This combination may represent a new 
standard in the management of these patients and could become a “backbone” in future 
trials in these patients.  
The effect of Nab-paclitaxel plus gemcitabine combination on QoL of patients with 
metastatic pancreatic cancer has not been analyzed. The objective of the trial is to 
compare QoL in patients receiving Nab-Paclitaxel plus Gemcitabine versus gemcitabine. 
QoL will be assessed using the EORTC QLQ-C30 for at least 12 months (in those who 
are still alive) for all patients (even if they deteriorate 10 points and meet the study end 
point). 
 
2. 
STUDY OBJECTIVES 
2.1. 
Primary study objectives 
• 
3-months deterioration-free rate (percentage of patients free from definitive 
deterioration). EORTC QLQ-C30 (validated version for Turkish using a 
reduction of at least 10 points as a meaningful clinical difference) will be used to 
calculate “time until definitive deterioration” (TUDD) and compare patients 
receiving first-line Nab-Paclitaxel plus Gemcitabine versus first-line gemcitabine 
for metastatic or locally advanced unresectable adenocarcinoma of the pancreas. 
EORTC QLQ-C30 scores will be calculated every four weeks following the 
EORTC QLQ-C30 recommendations for calculations and scoring (EORTC QLQ-
C30 published manual). 
2.2. 
Secondary study objectives 
• 
Overall survival (OS). 

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• 
Progression-free survival (PFS).  
• 
Response rate.  
• 
Safety and toxicity 
• 
Predictive and prognostic factors: Serum and archived tumor tissue biomarkers 
(available patients) for prognosis and prediction to response to treatment and 
toxicity. 
 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
Arm 1: 
Nab-paclitaxel 125 mg/m2 as 30- to 40-minute infusion (maximum infusion time not to 
exceed 40 minutes) once weekly for 3 weeks followed by a week of rest. 
plus  
Gemcitabine 1000 mg/m2 as a 30- to 40-minute infusion (maximum 40 minutes) once 
weekly for 3 weeks followed by a week of rest.  
OR 
Arm 2: 
Gemcitabine 1000 mg/m2 as a 30- to 40-minute infusion (maximum 40 minutes) 
administered weekly for 7 weeks followed by a week of rest (8-week cycle; cycle 1 only), 
followed by cycles of weekly administration for 3 weeks (on days 1, 8, and 15) followed 
by one week of rest (4-week cycle). 
All patients will be considered for available second-line therapies or best supportive care 
on the discretion of the investigators. 
3.2. 
Study Duration 
The first patient is planned to be enrolled in March 2014. The recruitment period is 
estimated to be around 14 months.  
Patients will receive study treatment until death, disease progression (PD), occurrence 
of intolerable side effects, or withdrawal of consent, whichever comes first.   

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All patients will be followed for QoL and survival.  
A patient is considered “Discontinued from Study Follow-up” only if study treatment has 
been discontinued AND one of the following occurs: 
a. Patient withdraws consent. 
b. Patient is lost to follow-up. 
c. Patient dies.  
d. Patient completes 1-year follow-up. 
e. Study is completed or terminated by the Sponsor. 
3.3. 
Study Population 
Chemotherapy-naïve patients presenting with metastatic or unresectable locally 
advanced pancreatic adenocarcinoma and a measurable disease by RECIST. 
3.4. 
Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible for enrollment in 
this study: 
1. Written informed consent. 
2. Histologically or cytologically confirmed treatment-naïve metastatic or locally 
advanced adenocarcinoma of the pancreas not amenable to curative radiotherapy or 
surgery. 
3. Measurable disease as defined by RECIST (ie, target lesions that can be accurately 
measured in at least one dimension with the longest diameter ≥ 20 mm using 
conventional techniques or ≥ 10 mm using spiral computed tomography [CT] scan).  
4. Age ≥ 18 years. 
5. ECOG Performance Status 0 or 1. 
6.  Adequate bone marrow function: granulocyte count ≥1500 and platelet count 
≥100,000 per cubic milimeter. 
7. Adequate liver function as defined by the following criteria: 
o Total serum bilirubin <2 mg/dl. 
o ALP/GGT <5 x ULN. 

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o Transaminases ALT/AST ≤ 2.5 x ULN. 
3.5. 
Exclusion Criteria 
1. 
Any prior systemic or investigational therapy for metastatic pancreatic cancer. 
Systemic therapy administered alone or in combination with radiation in the adjuvant 
setting is permitted if it is completed > 6 months prior to the time of study enrollment.  
2. 
Inability to comply with study and/or follow-up procedures. 
3. 
Presence of significant comorbidity including clinically significant cardiac disease 
(e.g. congestive heart failure, symptomatic coronary artery disease and cardiac 
arrhythmias not well controlled with medication) or myocardial infarction within the 
last 12 months and any other major organ failure. 
4. 
Presence of any condition that, in the opinion of the investigator, renders the subject 
at high risk from treatment complications or might affect the interpretation of the 
results of the study.  
5. 
Presence of central nervous system or brain metastases. 
6. 
Life expectancy <12 weeks.  
7. 
Pregnancy (positive pregnancy test) or lactation.  
8. 
Prior malignancy except for adequately treated basal cell skin cancer, in situ cervical 
cancer, adequately treated Stage I or II cancer from which the patient is currently in 
complete remission, or any other form of cancer from which the patient has been 
disease-free for 5 years.  
9. 
Lack of physical integrity of the upper gastrointestinal tract or malabsorption 
syndrome.  
10. Known, existing uncontrolled coagulopathy.  
11. Pre-existing sensory neuropathy > grade 1.  
12. Major surgery within 4 weeks of the start of study treatment, without complete 
recovery.  

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13. Concurrent/pre-existing use of coumadin. 
14. Patients older than 76 years of age. 
15. Patients with active infection. 
16. Patients with chronic diarrhea. 
 
4.0 
STUDY MEDICATION 
4.1. 
Provision of the study medication 
NAB-PACLITAXEL  
Nab-paclitaxel is available as lyophilized powder in vials containing 100 mg paclitaxel 
individually packaged in a cartonEach vial is reconstituted by injecting 20 mL of 0.9% 
Sodium Chloride Injection.  
Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. Inject the 
appropriate amount of reconstituted drug into an empty, sterile intravenous bag 
[plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type intravenous bag]. 
The use of specialized DEHP-free solution containers or administration sets is not 
necessary to prepare or administer nab-paclitaxel infusions. The use of an in-line filter is 
not recommended. 
GEMCITABINE 
Gemcitabine is available as lyophilized powder in vials of 200 mg and 1000 mg. The 
powder is constituted with 5 mL and 25 mL of sodium chloride 0.9% iv infusion solution, 
respectively. The solution may be further diluted with sodium chloride 0.9% infusion 
solution.  
4.2. 
Stability/Application 
Unopened vials of ABRAXANE are stable until the date indicated on the package when 
stored between 20ºC to 25ºC (68ºF to 77ºF) in the original package. Neither freezing nor 
refrigeration adversely affects the stability of the product.  
Stability of Reconstituted Suspension in the Vial  
Reconstituted ABRAXANE in the vial should be used immediately, but may be 
refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for a maximum of 8 hours if necessary. If not 

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used immediately, each vial of reconstituted suspension should be replaced in the 
original carton to protect it from bright light. Discard any unused portion.  
Stability of Reconstituted Suspension in the Infusion Bag  
The suspension for infusion when prepared as recommended in an infusion bag should 
be used immediately but may be stored at ambient temperature (approximately 25ºC) 
and lighting conditions for up to 4 hours. Discard any unused portion.  
4.3. 
Storage 
The vials should be stored in original cartons at 20ºC to 25ºC and in the original package 
to protect from bright light. All study medication must be kept in a locked area with 
restricted access to specific study personnel. 
4.4. 
Accountability 
In accordance with International Conference on Harmonisation (ICH) and United States 
Food and Drug Administration (FDA) requirements, the Investigator and/or pharmacist 
must at all times be able to account for all study agents furnished to the institution. The 
appropriate site personnel must acknowledge receipt of all study medication by signing, 
dating and immediately faxing the medication packing form included with each shipment. 
Record the use of the study medication on the appropriate Drug Accountability Record 
(DAR).  All study medication must be accounted for, whether used or unused, by the 
Investigator and/or pharmacist during the course of and at the conclusion of the study.  
The Study Monitor will check the supplies of study medication and will review the 
accountability records during monitoring visits. Study medication reconciliation will be 
completed at the end of the study. 
At the conclusion of the study or early termination of patients, all used and unused study 
medication of that patient shipped to the Investigator must be returned to the designated 
sponsor accompanied by a study medication reconciliation form (unless site policy 
requires on-site destruction). If on-site destruction is policy, such requirement must be 
documented in the institution’s Standard Operating Procedure (SOP) and provided to the 
designated sponsor for review. No study medication is to be used outside of this study. 

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4.5. Study concomitant treatments, medication administration and dose 
modification procedures    
4.5.1. Concomitant treatments 
Hematologic Support 
Hematologic support (including prophylactic use) as medically indicated is permitted (eg, 
blood transfusions, granulocyte-colony stimulating factor [G-CSF], etc) according to the 
institutional site standards.  (If there are no standard procedures for the use of growth 
factors, follow American Society of Clinical Oncology [ASCO] Guidelines for Use of 
Hematopoietic Colony-Stimulating Factors available at www.asco.org).   
Other Supportive Treatment 
Supportive treatments such as antiemetics, analgesics, etc, are permitted and should be 
administered according to the institutional standard of care. Analgesic consumption will 
be monitored and recorded throughout the study. 
A mouth rinse is permitted as a curative or prophylactic treatment for stomatitis. 
Palliative Radiotherapy 
Concurrent radiotherapy is not permitted. If palliative radiotherapy is required the patient 
will be off study. Thorough clinical examination for presence of PD is then 
recommended. 
All concomitant treatments will be recorded in the CRF. 
4.5.2. Treatment 
Arm 1: 
Nab-paclitaxel 125 mg/m2 as 30- to 40-minute infusion (maximum infusion time not to 
exceed 40 minutes) once weekly for 3 weeks followed by a week of rest. 
plus  
Gemcitabine 1000 mg/m2 as a 30- to 40-minute infusion (maximum 40 minutes) once 
weekly for 3 weeks followed by a week of rest.  
OR 
Arm 2: 

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Gemcitabine 1000 mg/m2 as a 30- to 40-minute infusion (maximum 40 minutes) 
administered weekly for 7 weeks followed by a week of rest (8-week cycle; cycle 1 
only), followed by cycles of weekly administration for 3 weeks (on days 1, 8, and 15) 
followed by one week of rest (4-week cycle). 
BSA will be calculated according to site standard practice. If no standard is available, the 
DuBois formula provided below should be used.  BSA should be calculated to two 
decimal places: 
BSA (m2) = ([Weight (kg)]0.425) x ([Height (cm)]0.725) x 0.007184 
If the patient’s weight increases or decreases by ≥ 10% from the previous calculation (e.g. 
start of previous treatment cycle), and is clearly not related to fluid retention, the patient’s 
BSA must be recalculated at the start of a new cycle. 
4.5.3. 
Dose delays and modifications 
Rules for Dose Omissions and Modified Schedules  
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 (ie, 1-2-3-Rest, X-1-2-3-Rest, etc). 
Day 8 dose is missed;  
Cycle continues per protocol, with one dose not given (ie, 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 (ie, 1-2-3-Rest, 1-2-X, 1-2-3-Rest, etc).  
 
The maximum delay: The maximum delay between a missed scheduled dose and the 
next one (whichever dose was missed) should not be longer than 21 days (except for 
peripheral neuropathy) 

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Two dose modifications are permitted. If a toxicity requiring dose modification occurs 
following the second dose reduction of either drug, further treatment should be 
discontinued.  
 
Table 2: Dose Modifications 
Dose Level  
NAB-PACLITAXEL Dose (mg/m2) a  
Gemcitabine (mg/m2) a  
Study dose  
125  
1000  
-1  
100  
800  
-2 b  
75  
600  
 
a) Dose reductions may or may not be concomitant. Please refer to Tables 2-4 for 
specific recommendations regarding dose reductions.  
b) A maximum of 2 dose-level reductions are allowed. 
 
Patients experiencing study drug-related toxicities that require a delay in scheduled 
NAB-PACLITAXEL or gemcitabine dosing for ≥21 days will be discontinued from further 
treatment in this study (except for peripheral neuropathy). When a dose reduction is 
required, no dose re-escalation will be permitted for the duration of study treatment.  
 
DOSE MODIFICATIONS AT DAY 1; 
In the event dose modifications are required at the beginning of a cycle due to AEs or 
hematologic toxicities, doses of NAB-PACLITAXEL and gemcitabine may be adjusted  
 
Table 3: Dose modifications for Day 1 of each cycle (hematologic toxicity);  
Treatment day counts and toxicity  
ANC  
Platelets  
Timing  
≥1.5 x 109/L  And  
≥100 x 109/L  
Treat on time  
<1.5 x 109/L  Or  
<100 x 109/L  
Delay by 1 week intervals until recovery  
 
 
 

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Table 4: Dose modifications for Day 1 of each cycle (non-hematologic toxicity)  
Non-Hematologic Toxicity and/or Dose Hold with Previous Cycle 
Toxicity/dose held  
Gemcitabine/Gemcitabine+nab-paclitaxel dose this cycle  
Grade 0, 1 or 2 toxicity  
Same as Day 1 previous cycle (except for cutaneous toxicity)  
Grade 3 toxicity  
Decrease gemcitabine and nab-paclitaxel to next lower dose 
level  
Grade 4 toxicity  
Off protocol treatment 
Dose held in 2 previous 
consecutive cycles  
Decrease gemcitabine to next lower dose level and continue 
throughout the rest of treatment  
a)  If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced 
b) Pulmonary embolism (Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, 
will be exempt from this requirement.  
Gemcitabine and nab-paclitaxel or gemcitabine monotherapy will be provided within the 
study protocol until patients progress or are unable to tolerate the treatment. 
Patients on single-agent gemcitabine arm will be allowed cross-over to the combination 
arm in case of a definitive deterioration in the GHS score of at least 10 points. 

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5.0. 
STUDY SCHEDULE AND PROCEDURES 
5.1. 
Study schedule 
THERAPY SYNOPSIS 
NAME, SURNAME 
Birthday  - -  - -  - - - -       STID - - -  
 
DAY 
WEEK 
NABPACLITAXL 
GEMCITABINE 
CT/ MRI (SCREENING) 
QoL 
APPLICATION WEEKLY: 
Nab-paclitaxel 125 mg/m2 
Plus  
Gem 1000 mg/m2  
(3 weeks on, 1 week off)    
          OR 
Gem 1000 mg/m2 iv 30’  
 
1 
1 
 
 
8 
2 
 
 
15 
3  
 
 
22 
4 
REST 
29 
5 
 
 
36 
6 
 
QoL 
43 
7 
 
 
CT / MRI (FOLLOW UP # 1) 
50-56 
8 
PD: OFF STUDY 
SD/PR/CR: FURTHER THERAPY 
APPLICATION WEEKLY: 
Nab-paclitaxel 125 mg/m2 
Plus  
Gem 1000 mg/m2  
(3 weeks on, 1 week off)    
          OR 
Gem 1000 mg/m2 iv 30’     
 
57 
9 
 
 
64 
10 
 
 
71 
11 
 
 
78 
12 
REST 
85 
13 
 
 
92 
14 
 
QoL 
99 
15 
 
 
CT / MRI (FOLLOW UP # 2) 
106-112 
16 
PD: OFF STUDY 
SD/PR/CR: FURTHER THERAPY 
APPLICATION WEEKLY: 
(see above, 
 CT/ MRI follow up every 7-8 
weeks) 
113 
17 
 
 
120 
18 
 
 
127 
19 
 
 
134 
20 
REST 

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5.2. 
Study procedures 
5.2.1. Informed consent 
Obtain signed and dated ICF from the patient prior to the implementation of any study 
procedures required by the protocol. Give a signed and dated copy of the completed ICF 
to the patient.   
5.2.2. Medical history and cancer related signs and symptoms 
Obtain a complete medical history at Baseline within 7 days prior to planned study 
medication administration on Day 1 of Week 1. Record the patient’s medical history in 
the Medical History section of the CRF. 
Signs and symptoms present within 7 days prior to study medication administration on 
Day 1of Week 1 should be recorded on the Existing Signs and Symptoms Related to 
Cancer section of the CRF. 
5.2.3. Physical examination 
Perform a complete physical examination at the time points listed below: 
• 
Baseline within 7 days prior to study medication administration on Day 1 
• 
At the beginning of every new cycle 
• 
At the end of study treatment 
5.2.4. Vital signs, weight, and height 
Obtain the patient’s height at baseline within 7 days prior to dosing on Day 1.   
Collect the patient’s vital signs (blood pressure, heart rate, body temperature, and 
respiratory rate) and weight (also recalculate BSA if weight changes by ≥ 10% from 
previous calculation; see Section 0) at the time points listed below. Obtain all the vital 
signs in a position that is consistent for all time points for each patient. 
• 
Baseline within 7 days prior to first study medication administration on Day 1 
• 
Within 24 hours prior to each subsequent study drug medication 
• 
At the end of study treatment 
 

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5.2.5. Performance Status and quality-of-life (QoL) assessment 
ECOG performance status score will be measured by a qualified person at the site at 
the following time points: 
• 
Baseline within 7 days prior to first study medication administration on Day 1 
• 
Within 24 hours prior to each subsequent study drug administration 
• 
At the end of study treatment 
 
The same person should obtain PS at baseline and at each assessment throughout the 
study for a given patient.  
 
Quality-of-Life will be assessed with the EORTC QLQ -C30 module at the following 
time points: 
• 
Baseline within 7 days prior to first study medication administration on Day 1 
• 
Every 4 weeks. 
• 
At the end of study treatment 
• 
The questionnaire will be completed by the patient. 
5.2.6. Electrocardiogram (ECG) 
Perform a 12-lead ECG at Baseline within 28 days prior to first study medication 
administration on Day 1. 
5.2.7. Chest X-ray (CXR)/Chest Computed Tomography (CT) 
Perform a CXR at Baseline within 14 days prior to first study medication administration 
as part of Baseline physical examination. If chest CT is obtained as part of the baseline 
tumor assessment, the chest X-ray can be omitted.   
5.2.8. Clinical Laboratory Evaluations 
5.2.8.1. Hematology 
Collect blood for hematology assessments at the following time points and when 
clinically indicated: 
• 
Baseline within 7 days prior to first administration of study medication on Day 1 
• 
Prior to each subsequent study drug medication 
• 
At the end of study treatment  
 

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Measure the following hematology parameters (before each application):  
Table 5: Hematology parameters measured before each application 
Red Blood Cell (RBC) count 
Hemoglobin 
Hematocrit 
Platelets 
White Blood Cell (WBC)  
 
Measure the following hematology parameters (before start of new cycle): 
Table 6: Hematology parameters measured before start of new cycle 
 
Red Blood Cell (RBC) count 
White Blood Cell (WBC) count with differential 
Hemoglobin 
Neutrophils 
Hematocrit 
Lymphocytes 
Platelets 
Basophils 
Quick 
Monocytes 
Thrombin time   
Eosinophils 
Partial thrombin time 
 
 
5.2.8.2. Serum Chemistry 
Collect blood for serum chemistry assessments at the following time points: 
• 
Baseline within 7 days prior to study medication administration on Day 1 
• 
Within 24 hours prior to study drug medication on Days 1 of every new cycle all 
parameters (see below) plus tumor marker. 
• 
At the end of study treatment 
 
 

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Table 7: Serum chemistry measurements 
Total protein 
Calcium 
Alkaline phosphatase 
Creatininea 
Alanine aminotransferase (ALT; SGPT) 
Lactic dehydrogenase (LDH) 
Aspartate aminotransferase(AST; SGOT)  
Blood Glucose  
Bilirubin 
Potassium 
Gamma-GT 
Magnesium 
Blood Urea Nitrogen (BUN) 
Sodium 
CA 19-9 
a Calculated creatinine clearance (CrCl) should be calculated before each 
subsequent cycle of treatment according to Cockcroft-Gault formula. 
 
5.2.8.3.Urinalysis 
Collect urine samples at the time points listed below: 
• 
Baseline within 7 days prior to study medication administration on Day 1 
• 
At the end of study treatment 
Measure protein, glucose, RBC and WBC semiquantitatively by dipstick. 
5.2.9. 
Pregnancy test 
If the patient is female and of child-bearing potential, exclude the possibility of pregnancy 
by testing serum or urine Beta Human Chorionic Gonadotrophin (β-HCG) within 7 days 
prior to the start of study medication administration on Day 1. For urine β-HCG 
pregnancy test, record the date, time and test results in the patient’s source documents. 
Female patients who are not of child-bearing potential must have a history of being post-
menopausal with a minimum of 1 year without menses, tubal ligation or hysterectomy. 
5.2.10. Carbohydrate antigen (CA) 19-9 levels 
Blood samples for analysis of serum CA19-9 levels will be obtained at the following 
timepoints: 
• 
Baseline within 7 days prior to study medication administration on Day 1 

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• 
At the beginning of every new cycle 
• 
At the end of study treatment 
5.2.11. Concomitant medications and therapies 
Record all medications, prescription and over-the-counter, in the Concomitant 
Medication section of the CRF. Additionally, record modifications to these medications 
and newly prescribed pharmacological treatments and therapeutic measures in this 
section.  Analgesic consumption will be monitored and recorded throughout the study 
as a component of the QoL-assessment (5.2.5).  
Collect concomitant medication information from time of signed ICF through the end of 
treatment.  Any concomitant medication used to treat AEs during the 30 days after 
administration of last dose of study medication should also be collected. Otherwise, 
collect only anti-cancer therapy during follow-up. Use of concomitant medication should 
be documented in the patient’s source documents.   
5.2.12.  Adverse event and toxicity assessment 
Monitor patients for any untoward medical events from the time of signed ICF through 
end of treatment, including any AEs and SAEs reported during the 30-day follow-up 
period.  
5.2.13. Tumor assessments/scans 
Tumor assessments/scans must be obtained at the time points listed below for all 
patients; however, if a patient develops PD, discontinue treatment with study medication. 
The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at Baseline, throughout the study.  
 
Table 8: Tumor assessments. 
Baseline 
During week 8, 16, 24, etc)a 
Within 2 weeks prior to Day 1 
Within 7 days prior to initiation of subsequent cycle 
a If a patient discontinues for reason other than PD, obtain imaging studies for tumor assessment prior to 
initiation to another treatment regimen. 
 

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On-site tumor assessments will be performed by the Investigator/local radiologist. 
Results of these assessments will be the basis for the continuation or discontinuation of 
treatment. Tumor scans must be collected and forwarded for independent review.   
For a patient who responds, response confirmation would be obtained earliest 4 
and preferably 6 weeks after the first documentation of response.   
The same schedule for clinical assessments should be followed. If the patient develops 
PD during clinic visits, study treatment should be discontinued.   
All radiological images must be available for source verification.  Images will be 
submitted for extramural review for final assessment of antitumor activity. 
5.2.13.1. Tumor measurements 
The determination of antitumor efficacy will be based on objective tumor assessments.  
Tumor assessments will be based on the RECIST criteria of unidimensional evaluation 
as determined by a Core Imaging Laboratory. 
5.2.13.2. Methods of measurement 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of treatment. All measurements 
should be recorded in metric notation using a ruler or calipers. 
Contrast enhanced CT is the preferred method for tumor assessments. If contrast CT is 
contraindicated in a patient, then magnetic resonance imaging (MRI) should be used. 
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm or less contiguous 
reconstruction algorithm. This applies to the chest, abdomen, and pelvis. Clinical lesions 
will only be considered measurable when they are superficial (eg, skin nodules, palpable 
lymph nodes).  In the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended.  
Ultrasound (US) should not be used to measure tumor lesions that are clinically not 
easily accessible for objective response evaluation (eg, visceral lesions). Ultrasound is a 
possible alternative to clinical measurements of superficial palpable nodes, 
subcutaneous lesions, and thyroid nodules. Ultrasound might also be useful to confirm 

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the complete disappearance of superficial lesions usually assessed by clinical 
examination. 
5.2.13.3. Measurability of lesions 
At baseline, lesions will be categorized by the Investigator as measurable or non-
measurable and as target and non-target lesions by the RECIST as described below. 
• 
Measurable: Lesions that can be accurately measured in at least one dimension 
with the longest diameter (to be recorded) ≥ 20 mm with conventional techniques 
or ≥  10 mm with spiral CT scan.    
• 
Non-Measurable: All other lesions, including small lesions (longest diameter  
< 20 mm with conventional techniques or < 10 mm with spiral CT scan), ie, bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and 
abdominal masses that are not confirmed and followed by imaging techniques. 
 
Recording Tumor Measurements 
All measurable and non-measurable lesions should be identified at baseline and at the 
stipulated intervals during treatment.  
One or two lesions will be defined as target lesions. The target lesions should be 
selected on the basis of its size (lesions with the longest and second-longest diameter) 
and its suitability for accurate measurements by imaging techniques. The diameters will 
be recorded for the target lesions. The sum of the longest diameters as determined at 
baseline will be used as a reference to further characterize the objective tumor response 
during treatment.  
All measurements should be performed using a caliper or ruler and should be recorded 
in metric notation in centimeters.  
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements are not required, and these lesions 
should be followed as “present” or “absent.” 
Tumor response assessment  
Only measurable lesions will be assessed for tumor response.  

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Table 9: Tumor response assessment of target lesions.  
Target Lesions Response: Definition: 
Complete Response (CR) 
The disappearance of all target lesions  
Partial Response (PR) 
At least a 30% decrease in the sum of the longest 
dimensions of target lesions, taking as a reference the 
baseline sum of longest dimensions  
Progressive Disease (PD) 
At least a 20% increase in the sum of the longest 
dimensions of the target lesions, taking as a reference the 
smallest sum of the longest dimensions recorded since the 
treatment started, or the appearance of one or more new 
lesions 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as a reference the 
smallest sum of the longest dimensions since the 
treatment started  
a Modified from RECIST criteria 
 
Table 10: Tumor response assessment of non-target lesions.  
Non-Target Lesions Response: 
Definition: 
Complete Response (CR) 
The disappearance of all non-target lesions and 
normalization of tumor marker level  
Incomplete Response (non-CR)/ 
Stable disease (SD) 
A persistence of ≥ 1 non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits  
Progressive Disease (PD) 
Appearance of one or more new lesions and/or  
unequivocal progression of existing non-target 
lesions 
a Modified from RECIST criteria 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
SD is mandatory to differentiate between response and SD or PD.  
The overall assessment of response will involve all parameters as depicted below. The 
best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for tumor progression the smallest 

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measurements recorded since the treatment started), until 30 days after end of individual 
treatment, death or lost to follow up. 
  
Table 11: Overall assessment of response. 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
Response/Stable Disease 
(SD) 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration". Every effort should be made to document the objective 
progression even after discontinuation of treatment. It should also be noted that a tumor 
marker increase does not constitute adequate objective evidence of tumor progression.  
However, such a tumor marker increase should prompt a repeat radiographic evaluation 
to document whether or not tumor objective tumor progression has occurred.  
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of a CR depends upon this determination, it is 
recommended that the residual lesion be investigated by fine needle aspirate or biopsy 
before confirming the CR status.  
 
Confirmation of Tumor Response 
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed 
earliest 4 and preferably 6 weeks after the criteria for response are first met. In the case 

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of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 6 weeks.  
5.2.14. End of treatment procedures 
The end of treatment is defined as the time of withdrawal of study medication (see 
Discontinuation Criteria). End of treatment assessments will be performed at the time of 
withdrawal of study medication if a patient discontinued due to toxicity or withdrawn 
consent. If a patient discontinues treatment due to PD, end of treatment assessments 
may be collected within 2 weeks of PD assessment.  
First-line standard therapy in advanced pancreatic cancer is gemcitabine therapy. There 
is no established second-line therapy for recurrence patients. Patients in good general 
condition can be offered therapy with other agents. Provided that appropriate studies are 
conducted, they can be included in Phase I / II studies with novel agents or new 
combinations. 
5.2.15. Follow-up study procedures 
If a patient discontinues treatment for any reason prior to 1 year from first day of 
treatment, survival status will be collected every 2 months. For the same time period, 
also record any other antitumor therapies received.   
Following premature discontinuation of study treatment for reasons other than 
withdrawal of consent, death, or PD, follow all patients for tumor response every 6 
weeks until PD or initiation of non-study anti-cancer therapy. The same collection and 
documentation procedures conducted during the treatment period apply to the follow-up 
period. 
 
6.0. REPORTING SAFETY INFORMATION 
6.1. Monitoring, Recording and Reporting of Adverse Events 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that 
may appear or worsen in a subject during the course of a study. It may be a new 
intercurrent illness, a worsening concomitant illness, an injury, or any concomitant 
impairment of the subject’s health, including laboratory test values (as specified by the 
criteria below), regardless of etiology. Any worsening (i.e., any clinically significant 
adverse change in the frequency or intensity of a pre-existing condition) should be 

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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.  
Disease progression is not to be reported as an adverse event. Pancreatic cancer is 
expected to progress under treatment; therefore progression can not be regarded as AE 
(See 2.Study Objectives and 7.2. Secondary aims and secondary endpoints). 
An overdose, accidental or intentional, whether or not it is associated with an AE, or 
abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported 
as an AE.  If an overdose is associated with an AE, the overdose and adverse event 
should be reported as separate terms. 
All subjects will be monitored for AEs during the study.  Assessments may include 
monitoring of any or all of the following parameters:  the subject’s clinical symptoms, 
laboratory, pathological, radiological or surgical findings, physical examination findings, 
or other appropriate tests and procedures. 
All AEs will be recorded by the Investigator from the time the subject signs informed 
consent to 30 days after the last dose of IP or until the last study visit, whichever period 
is longer.  AEs and serious adverse events (SAEs) will be recorded on the AE page of 
the CRF and in the subject’s source documents.  All SAEs must be reported to sponsor 
within 24 hours of the Investigator’s knowledge of the event by facsimile, or other 
appropriate method, using the SAE Report Form, or approved equivalent form. 
6.2. Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to:  
6.2.1. Seriousness  
A serious adverse event (SAE) is any AE occurring at any dose that: 
• 
Results in death; 
• 
Is life-threatening (i.e., in the opinion of the Investigator, the subject is at 
immediate risk of death from the AE); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of 
stay); 

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• 
Results in persistent or significant disability/incapacity (a substantial 
disruption of the subject’s ability to conduct normal life functions); 
• 
Is a congenital anomaly/birth defect; 
• 
Constitutes an important medical event. 
Important medical events are defined as those occurrences that may not be immediately 
life threatening or result in death, hospitalization, or disability, but may jeopardize the 
subject or require medical or surgical intervention to prevent one of the other outcomes 
listed above.  Medical and scientific judgment should be exercised in deciding whether 
such an AE should be considered serious. 
Events not considered to be SAEs are hospitalizations for:  
• 
A standard procedure for protocol therapy administration.  However, 
hospitalization or prolonged hospitalization for a complication of therapy 
administration will be reported as an SAE.  
• 
Routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
• 
A procedure for protocol/disease-related investigations (e.g., surgery, 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. 
• 
A procedure that is planned (i.e., planned prior to starting of treatment on 
study); must be documented in the source document and the CRF.  
Hospitalization or prolonged hospitalization for a complication remains a 
reportable SAE. 
• 
An elective treatment of a pre-existing condition unrelated to the studied 
indication.  
• 
Emergency outpatient treatment or observation that does not result in 
admission, unless fulfilling other seriousness criteria above. 

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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. 
6.2.2. Severity / Intensity 
For both AEs and SAEs, the Investigator must assess the severity / intensity of the 
event.  
The severity / intensity of AEs will be graded based upon the subject’s symptoms 
according to the current active minor version of National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE, Version 4.0); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
AEs that are not defined in the NCI CTCAE should be evaluated for severity / intensity 
according to the following scale: 
• 
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
• 
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance 
may be needed; no or minimal medical intervention/therapy required 
• 
Grade 3 = Severe – marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, hospitalization is possible 
• 
Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable 
• 
Grade 5 = Death - the event results in death] 
 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache).  This criterion is not the same 
as “serious” which is based on subject/event outcome or action criteria associated with 
events that pose a threat to a subject’s life or functioning.   
Seriousness, not severity, serves as a guide for defining regulatory obligations. 

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6.2.3. Causality  
The Investigator must determine the relationship between the administration of IP and 
the occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected: 
The temporal relationship of the adverse event to IP 
administration makes a causal relationship unlikely or 
remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the 
observed event. 
Suspected: 
The temporal relationship of the adverse event to IP 
administration makes a causal relationship possible, and 
other medications, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the 
observed event. 
6.2.4. Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates 
of the event. 
6.2.5. Action Taken 
The Investigator will report the action taken with IP as a result of an AE or SAE, as 
applicable (e.g., discontinuation or reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event.  
6.2.6. Outcome 
The investigator will report the outcome of the event for both AEs and SAEs. 
All SAEs that have not resolved upon discontinuation of the subject’s participation in the 
study must be followed until recovered, recovered with sequelae, not recovered (death 
due to another cause) or death (due to the SAE).  
6.3. Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• 
results in discontinuation from the study; 

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• 
requires treatment, modification/ interruption of IP dose, or any other 
therapeutic intervention; or 
• 
is judged to be of significant clinical importance. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness 
criterion need to be documented as a serious adverse event.   
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page/screen of the CRF.  If the 
abnormality was not a part of a diagnosis or syndrome, then the laboratory abnormality 
should be recorded as the AE. 
6.4. Expedited Reporting of Adverse Events 
6.4.1. Reporting to Regulatory Authorities and the Ethics Committee 
The Sponsor will inform relevant Regulatory Authorities and Ethics Committees; 
- 
Of all relevant information about serious unexpected adverse events suspected 
to be related to the IP that are fatal or life-threatening as soon as possible, and in 
any case no later than seven days after knowledge of such a case.  Relevant 
follow-up information for these cases will be subsequently be submitted within an 
additional eight days 
- 
Of all other serious unexpected events suspected to be related to the IP as soon 
as possible, but within a maximum of fifteen days of first knowledge by the 
investigator. 
6.4.2. Immediate reporting by Investigator to Sponsor and Sponsor to Celgene 
The investigator will inform the Sponsor of all SAEs within 24 hours in order that the 
sponsor can fulfill their regulatory reporting obligations within the required timeframes. 
 
The Sponsor will supply Celgene with a copy of all SAEs which involve exposure to a 
Celgene product within 24 hours of being made aware of the event regardless of 
whether or not the event is listed in the reference document (e.g. IB, SmPC). 
 
 

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The contact details of Celgene’s Drug Safety Department for the purposes above are: 
 
Celgene Drug Safety Department  
Phone: 
+90 216 600 1108 
Fax:  
+90 216 290 7894  
Email:  drugsafetyturkey@celgene.com  
 
When necessary, the Investigator/Sponsor may contact the following address for 
questions regarding the safety of any Celgene product relevant to the Study. 
 
The Sponsor will provide Celgene with a copy of the annual periodic safety report e.g. 
Development Update Safety Report (DSUR) at the time of submission to the Regulatory 
Authority and Ethics Committee. 
Contact details for Sponsor 
Prof. Suayib Yalcin 
Hacattepe University Institute of Oncology 
Department of Medical Oncology 
Sihhiye, Ankara, Turkey 
Phone:+90 312 305 2929 
Fax: +90 312 305 2905 
E-Mail: syalcin@hacettepe.edu.tr 
 
 
7.0 
STATISTICAL ANALYSIS  
The biostatistical methods applied for this study are subject to GCP guidelines 
(Guidelines of the International Conference on Harmonisation [ICH]) e.g.   
- ICH E3: Structure and Contents of Clinical Study Reports, 
- ICH E6: Good Clinical Practice (GCP). Consolidated Guideline, 
- ICH E9: Note for Guidance on Statistical Principles in Clinical Trials. 
7.1. 
Primary aim and primary endpoints  
3-months deterioration-free rate (percentage of patients free of definitive deterioration). 

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Quality of life (QoL): EORTC QLQ-C30 (validated version for Turkish using a reduction 
of at least 10 points as a meaningful clinical difference) will be used to calculate “time 
until definitive deterioration” (TUDD) and compare patients receiving first-line Nab-
paclitaxel plus gemcitabine versus first-line gemcitabine for metastatic or locally 
advanced unresectable adenocarcinoma of the pancreas.  
7.2. 
Secondary aims and secondary endpoints 
Secondary aims of the trial are the effectiveness of the therapy and characterization of 
tolerability and safety. The secondary endpoints are analysed in a descriptive way and 
are not relevant for sample size.  
The secondary aims are: 
Overall Survival (OS) 
Survival is defined as the time from the date of randomization to date of death. In 
the absence of death confirmation, survival time will be censored at the date of the 
last study follow up.  
Progression-free survival (PFS) 
PFS is defined as the time elapsed between treatment initiation and tumor 
progression or death from any cause, with censoring of patients who are lost to 
follow-up 
Rate of Overall Response (ORR)  
ORR is calculated as ratio of the number of patients with confirmed response 
between 8 and 24 weeks (6 months) over the number of pts evaluable for tumor 
response within the 8 and 24 weeks after randomization. Responder (CR or PR) 
are patients in status CR or PR according to RECIST criteria. Confirmation is 
required earliest after 4 weeks preferably after 6 weeks. Pts without confirmed PR, 
CR are at best SD. 
Safety and toxicity 

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Predictive and prognostic factors: Serum and archived tumor tissue biomarkers 
(available patients) for prognosis and prediction to response to treatment and toxicity. 
7.3. 
Safety 
Safety will be assessed by the type, incidence, severity (graded by the NCI CTCAE 
Version 4.0), and relatedness of AEs to treatment and by laboratory assessments. 
7.4. 
Statistical analysis 
Sample size calculations will be based on the GHS score 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. Thus, “time until definitive 
deterioration” (TUDD) is defined as the time from randomization to the first observation 
of a definitive deterioration of the score.  
The hypotheses for sample size calculations are based on the results of the article 
“Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with 
metastatic pancreatic cancer: results from the PRODIGE/ACCORD 11 randomized trial”, 
published in Journal of Clinical Oncology. 
The curves of TUDD comparing FOLFIRINOX and gemcitabine show that the 
percentages of patients free from definitive deterioration at 3-months are 83% in the 
FOLFIRINOX arm and 69% in the gemcitabine arm. Assuming the same for Nab-
Paclitaxel plus Gemcitabine arm, these percentages are used as hypotheses for sample 
size calculations. So, a 3-month deterioration-free rate of 83% for Nab-Paclitaxel plus 
Gemcitabine arm and 69% for gemcitabine arm will be assumed for calculating the 
sample size using a log-rank test. 
Primary end-point will be 3-months deterioration-free rate (percentage of patients free 
from definitive deterioration as defined above). 
 
Sample size calculations: 
• 
Hypotheses  
e. 2-sided alpha=0.05 
f. power=80% 
g. accrual 7 pts per month 

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h. 3-month deterioration-free rate of 83% for Nab-Paclitaxel plus 
Gemcitabine 
i. 
3-month deterioration-free rate of 69% for gemcitabine arm  
• 
Results 
a. Accrual duration 14 months 
b. Total study duration 21 months 
c. Total sample size n=100 
d. Number of events E=68 (number of patients with deteriorations). 
Accounting for a 20% missing or incomplete forms, the total sample size will be n=125.  
 
8.0 
ETHICS 
8.1. 
Ethical considerations 
It is mandatory that all considerations regarding the protection of human subjects be 
carried out in accordance with the protocol, Good Clinical Practices (GCP), ICH, ethical 
principles that have their origin in the Declaration of Helsinki, and all applicable 
regulatory requirements. 
8.2. 
Informed consent and patient information 
All patients must sign and personally date an approved ICF after receiving detailed 
written and verbal information about the reason, the nature, and the possible risks 
associated with the administration of the study medication.  This must be done 
according to the guidelines provided in the Declaration of Helsinki, ICH E6 Guideline for 
Good Clinical Practice, requirements of Title 21 CFR 50.20 through 50.27. 
The patient must be made aware and agree that personal information may be 
scrutinized during monitoring and audit by competent authorities and properly authorized 
persons. However, personal information will be treated as strictly confidential and will not 
be publicly available. 
Prior to Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
submission, the Investigator must send a copy of the ICF to be used at their institution to 
the Sponsor/Study Monitor for review to assure compliance with the ICH, local, national, 
and Code of Federal Regulations (CFR) requirements. 

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8.3. Institutional review board/independent ethics committee approval 
Prior to initiation of the study, the Investigator will submit the study protocol, sample ICF, 
and any other documents that pertain to patient information, recruitment methods such 
as patient diaries, and advertisements, to the IRB/IEC. The IRB/IEC must be 
appropriately constituted, as required in Title 21 CFR 56.107 through 56.115, in Chapter 
3 of the ICH E6 Guidelines. The Investigator must also submit any other information that 
may be requested to the IRB/IEC for review and approval. The Investigator will request 
that the IRB/IEC provide written approval of the study and will keep on file records of 
approval of all documents pertaining to this study. A letter confirming the approval must 
be forwarded to the Study Monitor prior to initiation of this study. This letter will be 
forwarded to Sponsor prior to the initiation of the study. 
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the ICF. The Investigator 
should notify the IRB/IEC of deviations from the protocol or SAEs occurring at the site, 
as well as other AE reports received from Sponsor, in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IRB/IEC approval or renewal 
throughout the duration of the study. Copies of the Investigator’s reports and the 
IRB/IEC continuance of approval must be sent to the Sponsor. 
 
9.0 
ADMINISTRATIVE CONSIDERATIONS  
9.1. 
Regulatory requirements-sponsor/investigator obligations 
This study will be conducted in accordance with ICH E6 Guideline, Declaration of 
Helsinki, local and national requirements, Title 21 CFR 312.50 through 312.70. To 
ensure compliance the Investigator agrees, by written consent to this protocol, to fully 
cooperate with compliance checks by allowing access to all documentation by 
authorized individuals. 
9.2. 
Protocol amendments 
No change to the protocol may be made without the joint agreement of both the 
Investigator and Sponsor. Any amendment to the original protocol will be signed by both 
parties and submitted to the IRB/IEC and appropriate regulatory authorities for approval 
or notification. 

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9.3. 
Curriculum vitae 
The Investigator and any Subinvestigator(s) must provide the Sponsor with current 
signed and dated (within 1 year) copies of their own curriculum vitae. 
9.4. 
Monitoring procedures 
9.4.1. Study monitoring 
An initiation visit will be conducted by the Study Monitor to discuss the protocol and the 
obligations of both the Sponsor and the Investigator. The Investigator must allow the 
Study Monitor to perform periodic, interim monitoring visits. The purposes of these visits 
are to: 
a. Verify that signed and dated ICF was obtained prior to each patient’s 
participation in the trial.   
b. Assess the progress of the study.  
c. Review compliance with the study protocol. 
d. Determine whether all adverse events were appropriately reported. 
e. Determine whether the Investigator is maintaining the essential documents. 
f. Discuss any emergent problem.  
g. Check the CRF for legibility, accuracy, and completeness.  
h. Validate the contents of the CRF against source documents.  
i. 
Assess the status of medication storage, dispensing, and retrieval. 
All data required by the protocol must be reported accurately on the CRF and must be 
consistent with the source documents. Source documents are original documents, data 
and records (eg, hospital records, clinical and office charts, laboratory notes, 
memoranda, patients' diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, X-rays or other diagnostic images, patient files, pharmacy 
records, and laboratory records).  The Investigator will make available the source 
documents for inspection. This information will be considered as confidential. 

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The Study Monitor will perform a close-out visit at the conclusion of the Investigator’s 
involvement in the study. 
9.4.2. Case report form 
CRFs must be completed for all patients who sign ICFs even if the patient fails to 
complete the study.  No section of the CRF is to be left blank without an appropriate 
explanation by the Investigator, since the lack of such explanation may necessitate 
discarding an otherwise unusable observation. 
CRFs must be typed or clearly printed with a black ball point pen; erasable ink, pencil, or 
free handwriting is not acceptable. Any corrections or deletions are to be made by 
crossing out with a single line (so it is still legible), then initialing and dating by the 
Investigator or other authorized person. The use of correction fluids to "white-out" 
mistakes in data entry is not permitted. 
If requested, copies of the CRFs are to be made available to the appropriate regulatory 
agencies. 
9.5. 
Archiving of records 
All unused study materials are to be returned to Sponsor after the study has been 
completed. The following records must be retained by the Investigator for the maximum 
period of time as required by the study center. This time period must be at least 2 years 
after the last approval of the marketing application of the study medication in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study medication: 
a. Protocol.  
b. Signed and dated ICF documents for all patients.  
c. Patient identification code list, screening log (if applicable), and enrollment log.  
d. Record of all communications between the Investigator and the IRB/IEC.  
e. Composition of the IRB/IEC or other applicable statement.  
f. Record of all communications between the Investigator and Sponsor. 

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g. List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles 
in the study and their signatures.  
h. Copies of CRFs and of documentation of corrections for all patients.  
i. 
Drug Accountability Records.  
j. 
Record of any body fluids or tissue samples retained.  
k. All other source documents (patient records, hospital records, laboratory records, 
etc).  
l. 
All other documents as listed in Section 8 of the ICH Consolidated Guideline on 
GCPs (Essential Documents for the Conduct of a Clinical Trial). 
However, because of international regulatory requirements, the Sponsor may request 
retention for a longer period of time. The Investigator must therefore obtain approval in 
writing from the Sponsor prior to destruction of any records. 
No study document should be destroyed without prior written agreement between 
Sponsor and the Investigator. 
Normally, these records will be held in the Investigator's archives. If the Investigator is 
unable to meet this obligation, he or she must ask the Sponsor for permission to make 
alternative arrangements. Details of these arrangements should be documented. 
Originals of all documentation and copies of outgoing correspondence concerning the 
study will be retained in the Trial Master File and stored in a safety area for at least two 
years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications in an ICH region, or for at least 2 years following 
the formal discontinuation of clinical development of the investigational product, or for a 
longer period if required by the applicable regulatory requirements.  In particular, the 
final report must be retained by Sponsor or the subsequent owner, for 5 years beyond 
the lifetime of the study medication. 
9.6. 
Final report 
The final report of the trial will be written by the investigator. 

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9.7. 
Use and publication of study results 
All unpublished documentation (including the protocol, CRF, and IB) given to the 
Investigator is strictly confidential. All recipients must agree not to disclose the 
information herein contained to any person without the prior written authorization of 
Sponsor. The submission of these documents to the IRB/IEC is expressly permitted.  
The Investigator agrees that Sponsor maintains the right to use the results of this study 
in their original form and/or in a global report for submission to governmental and 
regulatory authorities of any country. 
The results of the study may be presented during scientific symposia or published in a 
scientific journal only after review by Sponsor in accordance with the guidelines set forth 
in the applicable publication or financial agreement.  
The Principal Investigator (PI) retains the privilege to be the first presenter of the primary 
results at a major medical meeting; however, the privilege of presenting data at USA and 
EU scientific and medical meetings might be offered to the Investigator who accrues the 
highest number of evaluable patients in the study. All other authors will be in descending 
order of patient accrual. If the Investigator with the highest accrual chooses not to 
present the data, the next highest accruing Investigator may take his/her place. In that 
case, the PI can choose to be the senior author on the abstract(s). The PI will have the 
privilege to be the first or last author on the primary manuscript originating from this 
study. The first authorship on secondary publications may be rotated based on accrual. 
The PI will be senior author on secondary publications (manuscripts/abstracts).  The 
order of all other authors will be based on the number of evaluable patients accrued.  It 
may become necessary for the Sponsor to choose a Writing Committee, if the number of 
Investigators/potential authors exceeds 12. The Sponsor will be responsible for providing 
the data to the appropriate Investigators for publication within 12 months of each major 
analysis, such as the planned interim analyses and final analysis (irrespective of the 
nature of the results from the study). 
9.8. 
Termination of the study 
In the event that the Investigator is unable to continue the study, another suitable person 
will be designated Investigator, and documentation testifying to this will be submitted to 
the Study Monitor and Medical Monitor within 10 days. The new Investigator must be 
approved by Sponsor and the IRB/IEC before the study can be continued. 

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If Sponsor and/or the Investigator should discover conditions arising during the study 
that indicate it should be terminated, an appropriate schedule for termination will be 
instituted. If the Investigator terminates the study, an explanatory letter will be provided 
to Sponsor. 
Sponsor also reserves the right to discontinue this study for administrative reasons at 
any time. The Investigator will be reimbursed for reasonable expenses incurred, if it is 
necessary to terminate the study or an individual patient's participation. Sponsor will not 
reimburse the Investigator for the evaluation of patients if the evaluations are not 
conducted in compliance with the present protocol. 
9.9. 
Information material 
Before the beginning of the study the Investigator will be given the last updated IB. If the 
IB is revised during the study, the Investigator will receive a copy of the revised version. 
The IB and the protocol are confidential communications of Sponsor.  Acceptance 
constitutes the agreement by the recipient that no unpublished information herein 
contained will be published or disclosed without Sponsor’s prior written approval except 
that this document may be disclosed to an appropriate IRB/IEC as long as they are 
required to keep it confidential. 
 
10.0 
CONFIDENTIALITY 
All information provided to the Investigator dealing with the study medication will be 
regarded as confidential.  The members of the research team agree not to discuss such 
information in any way without prior written permission from Sponsor. 

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11.0 
SIGNATURES OF SPONSOR AND INVESTIGATOR 
A randomized, multicenter, phase II study of nab-paclitaxel plus gemcitabine versus 
gemcitabine for the first-line treatment of metastatic or locally advanced unresectable 
adenocarcinoma of the pancreas. 
11.1. Declaration of Sponsor 
This study protocol was subject to critical review and has been approved by the 
appropriate protocol review committee of the Sponsor. The information it contains is 
consistent with: 
• 
The current risk-benefit evaluation of the investigational product 
• 
The moral, ethical, and scientific principles governing clinical research as set out in 
the Declaration of Helsinki and the principles of ICH GCP. 
The Investigator will be supplied with details of any significant or new findings, including 
AEs, relating to treatment with the investigational product. 
Date:_________________________ Signature:  
 _________________  
 
 
 
11.2. Declaration of Investigator 
I confirm that I have read the above protocol, appendices, and referenced documents.  I 
understand the contents and intend to fully comply with all requirements. No changes 
will be made without formal authorization by Sponsor in the form of a protocol 
amendment. I will work according to the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and the principles of 
ICH GCP. 
I confirm that I am not banned from conducting clinical research and I will immediately 
contact Sponsor if I cannot fulfill my obligations to complete this protocol. 
Investigator 
Date:_________________________ Signature 
______________________ 
 
 
 
 
Name (block letters): ____________________________

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12.0 
 
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APPENDIX A 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST)  
Quick Reference 
Eligibility 
Only patients with measurable disease at baseline should be included in 
protocols where objective tumor response is the primary endpoint. 
Measurable disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should 
be confirmed by cytology/histology. 
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter >20 mm using conventional techniques or >10 
mm with spiral CT scan. 
Non-measurable lesions - all other lesions, including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm with spiral CT scan), 
ie, bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and 
also abdominal masses that are not confirmed and followed by imaging 
techniques; and 
• 
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
• 
Clinical lesions will only be considered measurable when they are superficial (eg, 
skin nodules and palpable lymph nodes). For the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
Methods of Measurement 
• 
CT and MRI are the best currently available and reproducible methods to measure 
target lesions selected for response assessment. Conventional CT and MRI should 
be performed with cuts of 10-mm or less in slice thickness contiguously. Spiral CT 
should be performed using a 5-mm contiguous reconstruction algorithm. This applies 
to tumors of the chest, abdomen and pelvis. Head and neck tumors and those of 
extremities usually require specific protocols. 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound 
(US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions and thyroid nodules. Ultrasound might also be useful to 
confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination. 
• 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not 

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yet been fully and widely validated. Their uses in this specific context require 
sophisticated equipment and a high level of expertise that may only be available in 
some centers.  Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers.  
However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained. 
• 
Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response when all lesions have disappeared. 
• 
Cytology and histology can be used to differentiate between PR and CR in rare 
cases (eg, after treatment to differentiate between residual benign lesions and 
residual malignant lesions in tumor types such as germ cell tumors). 
 
Baseline Documentation of “Target” and “Non-Target” Lesions 
• 
All measurable and non-measurable lesions should be identified at baseline and at 
the stipulated intervals during treatment.  
• 
One or two lesions will be defined as target lesion. The target lesions should be 
selected on the basis of its size (lesions with the longest and second-longest 
diameter) and its suitability for accurate measurements by imaging techniques. The 
diameters will be recorded for the target lesions. The sum of the longest diameters 
as determined at baseline will be used as a reference to further characterize the 
objective tumor response during treatment.  
• 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-up. 
 
 

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Response Criteria 
Evaluation of Target Lesion 
Complete Response (CR) 
Disappearance of all target lesions for at least 4 weeks 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD for at 
least 4 weeks 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or 
more new lesions 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started for at least 6 weeks 
 
 
Evaluation of Non-target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization 
of tumor marker level for at least 4 weeks 
Incomplete Response/ 
Stable Disease (SD) 
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits 
for at least 6 weeks 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.** 
**Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the 
progression status should be confirmed later on by the review panel (or Study 
Chair). 

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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). In general, the patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
Response/Stable Disease 
(SD) 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
• 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
• 
In some 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 (fine needle aspirate/biopsy) 
to confirm the complete response status. 
Confirmation 
• 
The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed. In cases where confirmation of response is not feasible, it 
should be made clear when reporting the outcome of such studies that the 
responses are not confirmed. 
• 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks 
after the criteria for response are first met. Longer intervals as determined by the 
study protocol may also be appropriate. 
• 
In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval (in general, not less than 6-8 weeks) 
that is defined in the study protocol. 
Duration of Overall Response 
• 
The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever status is recorded first) until the first date that 
recurrence or PD is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started. 

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Duration of Stable Disease 
• 
SD is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements recorded since 
the treatment started. 
• 
The clinical relevance of the duration of SD varies for different tumor types and 
grades. Therefore, it is highly recommended that the protocol specify the minimal 
time interval required between two measurements for determination of SD. This time 
interval should take into account the expected clinical benefit that such a status may 
bring to the population under study. 
 
Response Review 
• 
For trials where the response rate is the primary endpoint it is strongly recommended 
that all responses be reviewed by an expert(s) independent of the study at the 
study’s completion. Simultaneous review of the patients’ files and radiological images 
is the best approach. 
 
Reporting of Results 
• 
All patients included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible.  Each patient 
will be assigned one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). 
• 
All of the patients who met the eligibility criteria should be included in the main 
analysis of the response rate. Patients in response categories 4-9 should be 
considered as failing to respond to treatment (disease progression). Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate. Precise definitions for categories 4-9 will be 
protocol specific. 
• 
All conclusions should be based on all eligible patients. 
• 
Subanalyses may then be performed on the basis of a subset of patients, excluding 
those for whom major protocol deviations have been identified (eg, early death due 
to other reasons, early discontinuation of treatment, major protocol violations, etc).  
However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. 
• 
The 95% confidence intervals should be provided. 

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APPENDIX B 
Declaration of Helsinki 
Initiated: 1964 17.C 
 Original: 
English 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Recommendations guiding physicians 
in biomedical research involving human subjects 
Adopted by the 18th World Medical Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th World Medical Assembly, Tokyo, Japan, October 1975 
35th World Medical Assembly, Venice, Italy, October 1983 
41st World Medical Assembly, Hong Kong, September 1989 
and the 
48th General Assembly,Somerset West, Republic of South Africa, October 1996 
 
INTRODUCTION 
It is the mission of the physician to safeguard the health of the people. His or her 
knowledge and conscience are dedicated to the fulfillment of this mission. The 
Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The Health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient." The purpose of biomedical research involving human 
subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the 
understanding of the aetiology and pathogenesis of disease. In current medical practice 
most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies 
especially to biomedical research. Medical progress is based on research which 
ultimately must rest in part on experimentation involving human subjects. In the field of 
biomedical research a fundamental distinction must be recognized between medical 
research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying 
direct diagnostic or therapeutic value to the person subjected to the research. Special 
caution must be exercised in the conduct of research which may affect the environment, 
and the welfare of animals used for research must be respected. Because it is essential 
that the results of laboratory experiments be applied to human beings to further scientific 
knowledge and to help suffering humanity, the World Medical Association has prepared 
the following recommendations as a guide to every physician in biomedical research 
involving human subjects. They should be kept under review in the future. It must be 
stressed that the standards as drafted are only a guide to physicians all over the world. 
Physicians are not relieved from criminal, civil and ethical responsibilities under the laws 
of their own countries. 
 
I. BASIC PRINCIPLES 
1. 
Biomedical research involving human subjects must conform to generally accept 
scientific principles and should be based on adequately performed laboratory and 
animal experimentation and on a thorough knowledge of the scientific literature. 
2. 
The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol which should be 
transmitted for consideration, comment and guidance to a specially appointed 

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1st line in advanced pancreatic cancer 
 
 
 
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committee independent of the investigator and the sponsor provided that this 
independent committee is in conformity with the laws and regulations of the country 
in which the research experiment is performed. 
3. 
Biomedical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically competent 
medical person. The responsibility for the human subject must always rest with a 
medically qualified person and never rest on the subject of the research, even 
though the subject has given his or her consent. 
4.  
Biomedical research involving human subjects cannot legitimately be carried out 
unless the importance of the objective is in proportion to the inherent risk to the 
subject. 
5.  
Every biomedical research project involving human subjects should be preceded 
by careful assessment of predictable risks in comparison with foreseable benefits 
to the subject or to others. Concern for the interests of the subject must always 
prevail over the interests of science and society. 
6.  
The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject 
and to minimize the impact of the study on the subject's physical and mental 
integrity and on the personality of the subject. 
7. 
Physicians should abstain from engaging in research projects involving human 
subjects unless they are satisfied that the hazards involved are believed to be 
predictable. Physicians should cease any investigation if the hazards are found to 
outweigh the potential benefits. 
8  
In publication of the results of his or her research, the physician is obliged to 
preserve the accuracy of the results. Reports of experimentation not in accordance 
with the principles laid down in this Declaration should not be accepted for 
publication. 
9.  
In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, anticipated benefits and potential hazards of the 
study and the discomfort it may entail. He or she should be informed that he or she 
is at liberty to abstain from participation in the study and that he or she is free to 
withdraw his or her consent to participation at any time. The physician should then 
obtain the subject's freely-given informed consent, preferably in writing. 
10.  When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or 
may consent under duress. In that case the informed consent should be obtained 
by a physician who is not engaged in the investigation and who is completely 
independent of this official relationship. 
11.  In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation. Where physical or mental 
incapacity makes it impossible to obtain informed consent, or when the subject is a 
minor, permission from the responsible relative replaces that of the subject in 
accordance with national legislation. Whenever the minor child is in fact able to 
give a consent, the minor's consent must be obtained in addition to the consent of 
the minor's legal guardian. 
12.  The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that the principles enunciated in the 
present Declaration are complied with. 
 
 
 

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II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
(Clinical Research) 
1.  In the treatment of the sick person, the physician must be free to use a new 
diagnostic and therapeutic measure, if in his or her judgement it offers hope of 
saving life, reestablishing health or alleviating suffering. 
2.  The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
3.  In any medical study, every patient - including those of a control group, if any - 
should be assured of the best proven diagnostic and therapeutic method. This 
does not exclude the use of inert placebo in studies where no proven diagnostic or 
therapeutic method exists. 
4.  The refusal of the patient to participate in a study must never interfere with the 
physician-patient relationship. 
5.  If the physician considers it essential not to obtain informed consent, the specific 
reasons for this proposal should be stated in the experimental protocol for 
transmission to the independent committee (I, 2). 
6.  The physician can combine medical research with professional care, the objective 
being the acquisition of new medical knowledge, only to the extent that medical 
research is justified by its potential diagnostic or therapeutic value for the patient. 
 
III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
SUBJECTS (Non-Clinical Biomedical Research) 
1.  In the purely scientific application of medical research carried out on a human 
being, it is the duty of the physician to remain the protector of the life and health of 
that person on whom biomedical research is being carried out. 
2.  The subject should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient's illness.  
3.  The investigator or the investigating team should discontinue the research if in 
his/her or their judgement it may, if continued, be harmful to the individual. 
4.  In research on man, the interest of science and society should never take 
precedence over considerations related to the wellbeing of the subject 
 
 
 

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APPENDIX C 
Flow Chart 
 
 
Visits 
Enrollment 
examination 
Before each 
medication 
administration 
Week 8 
(days 50-56)  
Week 16 
(days 106-112) 
 
Final 
examination 
 
Baseline 
 
With therapy 
At 
Progression  
Inclusion and 
exclusion criteria 
X 
 
 
 
Patient consent 
X 
 
 
 
Demographic data 
X 
 
 
 
Anamnesis 
X 
 
 
 
Chest X-ray 
X 
 
 
 
Physical 
examination 
X 
Beginning of 
every new 
cycle 
 
X 
Blood samples 
X 
X 
 
X 
Urine status 
X 
 
 
X 
Vital signs, weight, 
height 
X 
X 
 
X 
Tumor staging 
X 
 
X 
X 
ECG 
X 
 
 
 
Toxicity 
determination 
X 
X 
 
X 
(S)AE / ADR 
documentation 
 
X 
 
X 
Drugs dispensed 
X 
X 
 
X 
CA 19-9 
X 
Beginning of 
every new 
cycle 
 
X 
Quality-of-life 
X 
 
Week 4 and 
every 4 weeks 
thereafter 
X 
 
Exit questionnaire 
 
 
 
X 
 
 
 

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APPENDIX D 
Toxicity criteria: NCI-CTCAE version 4.0 
CTC 
1 
2 
3 
4 
5 
Karnofsky ≥16 J. 
Lansky      <16 
J. 
80-70% 
80-70% 
60-50% 
60-50% 
40-30% 
40-30% 
20-10% 
20-10% 
Death 
Haemoglobin    
[g/l]  
<LLN – 100 
<100-80 
<80-65 
<65 
Death 
Leukocytes     
[Gpt/l]  
<LLN - 3.0 
<3.0-2.0 
<2.0-1.0 
<1.0 
Death 
Neutrophiles   
[Gpt/l]  
<LLN - 1.5 
<1.5-1.0 
<1.0-0.5 
<0.5 
Death 
Plateletes        
[Gpt/l] 
<LLN – 75 
<75-50 
<50-25 
<25 
Death 
Haemorrhage/Ble
eding: 
 Abdomen 
NOS 
 Stomach 
 Esophagus
Mild bleeding, 
no transfusion 
Groos 
bleeding, 
1-2 transfusion 
per 
episode 
Severe, 
3-4 transfusions 
per 
epsiode 
Life-
threatening, 
>4 
transfusions 
per 
epsiode
Death 
Skin/Exanthema 
Rash/Erythem
a 
Dry 
desquamation,  
mild Pruritis 
Moist 
desquamations, 
ulcerations 
Generalizied 
exfoliative/ulce
rative or 
bullous 
dermatitis, 
necrosis 
____ 
Infection  
--------- 
Local, 
local 
intervention 
indicated 
i.v.-Antibiotics, 
antimycotics 
or antiviral 
therapy 
indicated 
Life-
threatening 
(e.g. septic 
shock, 
hypotension, 
acidosis) 
Death 
Febrile 
neutropenia 
[Fever of 
unknown origin 
(FUO) ≥38.5°C,  
Neutrophiles <1.0 
Gpt/l] 
--------- 
---------- 
Existent 
Life-
threatening 
(e.g. septic 
shock, 
hypotension, 
acidosis) 
Death 
Fever [°C]  
38 – 39 
>39 – 40 
>40 for <24 hrs. 
>40 for >24 
hrs.  
Death 
Nausea 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
altered without 
significant 
weight loss or 
malnutrition, 
oral nutritional 
supplements 
No oral intake 
with significant 
weight loss, 
infusion, 
enterale 
nutrition or TPN 
>24 hrs. 
Life-
threatening 
TPN >24 hrs. 
indicated 
 
Death 

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1st line in advanced pancreatic cancer 
 
 
 
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indicated, 
dehydration or 
infusion <24 
hrs. 
indicated 
Vomiting/24 hrs. 
1x/24 hrs. 
2-5x/24 hrs., 
infusion <24 
hrs. 
>6x/24 hrs., 
infusion or 
TPN ≥24 hrs. 
Life-
threatening 
 
Death 
Stomatitis 
(oral 
cavity)/ Mucositis  
(lower 
gastrointestinal 
tract) 
Erythema,  
mild pain,  
no 
interventions 
indicated 
Patchy 
ulcerations or 
pseudomembr
anes, 
moderate pain, 
analgesics,  
no interfering 
with function 
Confluent 
ulcerations or 
pseudomembra
nes, 
bleeding with 
minor trauma, 
severe pain, 
analgesics, 
infusion, 
interfering with 
function 
Tissue 
necrosis, 
significant 
spontaneous 
bleeding, 
severe pain, 
infusion, TPE 
life-threatening 
Death 
CTC 
1 
2 
3 
4 
5 
Diarrhea/ 
Stool frequency 
<4x/24 hrs. 
without 
alteration in 
daily habits 
4-6x/24 hrs.  
infusion <24 
hrs., mild pain 
without 
alteration in 
daily habits 
≥7x/24 hrs. or 
incontinence or 
infusion >24 
hrs., 
hospitalization, 
severe pain with 
alteration in 
daily habits 
Life-
threatening 
 (e.g. 
haemodynami
c collapse) 
Death 
 
Constipation 
Occasional or 
intermittent 
symptoms, 
dietary, 
occasional use 
of stool 
softeners, 
laxatives or 
enema 
Persistent 
symptoms with 
regular use of 
laxatives or 
enema 
indicated 
Constipation 
with manual 
evacuation 
indicated, 
alteration in 
daily habits 
Life-
threatening 
 (e.g.. 
obstruction, 
toxic 
megacolon) 
Death 
Creatinine 
i.S. 
 
[mg/dl] 
>ULN – 
1,5xULN 
<1.5-3.0xULN 
>3.0-6.0xULN 
>6.0xULN 
Death 
Proteinuria  
[Stick]  
1 + 
2+ - 3+  
4+ 
Nephrotic 
syndrome 
Death 
Haematuria  
Microscopic 
Macroscopic 
without 
coagulae 
Macroscopic 
with coagulae 
Transfusions 
indicated 
Death 
Creatinine 
Clearance 
(ml/min/1,73 m²) 
60-89 
40-59 
20-39 
≤19 
 
Bilirubin i.S. 
>ULN – 
1.5xULN 
>1.5-3.0xULN 
<3.0-10.0xULN 
>10.0xULN 
 
SGOT/SGPT  
>ULN  - 
2.5xULN 
>2.5-5.0xULN 
>5.0-20.0xULN 
>20.0xULN 
 

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Alkaline 
phosphatase 
>ULN – 
2.5xULN 
>2.5-5.0xULN 
>5.0-20.0xULN 
>20.0xULN 
 
Pulmonary 
Toxicitiy 
Dyspnoe 
Mild dyspnoe 
on exertion, but 
can walk 1 
flight of stairs 
without 
stopping 
Moderate 
dyspnoe on 
exertion, but 
unable to walk 
1 flight of 
stairs without 
stopping 
Severe dyspnoe 
with alteration in 
daily habits 
Life-
threatening 
Dyspnoe at 
rest; 
intubation/venti
lator indicated 
Death 
Restrictive  
Cardiomyopathy 
Asymptomatic,  
therapy not 
indicated 
Asymptomatic
, 
therapy 
indicated 
Symptomatic 
cardiac failure, 
responsive to 
interventions 
Life-
threatening, 
refractory 
cardiac failure 
Death 
Echocardiograph
y:  
Left ventricular 
systolic 
dysfunction 
EF <60-50% 
SF <30-24% 
EF <50-40% 
SF <24-15% 
EF <40-20% 
SF <15% 
EF <20% 
Death 
Ototoxicity 
Asymptomatic 
threshold shift 
of 15-25 dB 
relative to 
baseline 
Symptomatic, 
threshold shift 
of 25-90 dB 
relative to 
baseline, 
tinnitus, mild 
hypacusis 
Symptomatic, 
adults: threshold 
shift of 25-90 dB 
relative to 
baseline, 
children: 
bilateral >20 dB 
hearing loss, 
tinnitus, severe 
hypacusis, need 
of hearing aids 
Profound 
bilateral 
hearing loss 
(>90 dB in 
adults, 
indication for 
cochlear 
implant in 
children) 
____ 
Neurology –  
Central 
Neurotoxicity 
Mild 
somnolence or 
agitation 
Somnolence 
or sedation 
interfering 
with function, 
disorientation, 
brief 
generalized 
seizure 
(controlled) 
Obtundation or 
stupor, 
disorientation, 
hallucinations, 
seizures with 
altered 
consciousness 
(poorly 
controlled) 
Life-
threatening 
coma,  
seizure difficult 
to control,  
status 
epilepticus 
Death 
Neurology - 
Peripheral 
Neurotoxicity 
Asymptomatic 
weakness, mild 
paraesthesia, 
loss of deep 
tendon 
reflexes, not 
interfering with 
function  
Moderate 
motor or 
sensory 
alteration, 
paraesthesia, 
including 
tingling, 
interfering with 
function but 
not with daily 
habits 
Severe motor 
dysfunction or 
sensory loss or 
paraesthesia 
interfering with 
function and 
daily habits 
Disabling, 
paralysis 
life-threatening 
Death 
 
http-Address of NCI - Common-Terminology-Criteria Version 3.0/4.0: 

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http://www.nci.nih.gov/ 
http://ctep.cancer.gov/reporting/ctc.html 
 
Abbreviations: 
LLN  Lower Limit of Normal (according to the normal values in the investigator centre) 
ULN  Upper Limit of Normal (according to the normal values in the investigator centre) 
nd  
 not done  
EF  
 ejection fraction 
SF  
 left ventricular shortening fraction 
TPN  total parenteral nutrition 
 
Toxicity scales:  
Grade 1 to 5 according to Common Terminology-Criteria for Adverse Events v4.0 
(CTCAE) – related to complication during anti-cancer therapy (see also Chapter 8, 
Assessment of safety): 
Grade 1 
 
mild adverse event 
Grade 2 
 
moderate adverse event 
Grade 3 
 
severe adverse event 
Grade 4 
 
life-threatening or disabling adverse event (e.g. paresis) 
Grade 5 
 
death related to adverse event (death of therapy related 
complications) 
 
Remarks: 
The documentation of the toxicity (AE/ADR) will be performed on the AE-Log or in case 
of SAE/SADR on both the AE-Log and the SAE-Log (see also Chapter 8, Assessment of 
safety). The SAE-Log has to be faxed within 24 hours of a working day to the study 
headquarters/the principal investigator. In case of death or termination of the study it is 
necessary to fill out the CRFs for the exit visit, e.g. the last follow-up examinations, and 
to send a copy of them to the study headquarters.