Clinical trial NCT03126435
Conditions: Metastatic Pancreas Cancer Locally Advanced Pancreatic Cancer Pancreatic Adenocarcinoma
Keywords: FOLFIRINOX 5-Fluorouracil folinic acid irinotecan oxaliplatin Gemcitabine
Sponsor: SynCore Biotechnology Co., Ltd.
Start date: 2018-10-16; Completion date: 2021-10-08
Enrollment: 218 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this adaptive Phase 3 trial is to show a statistically significant superiority of EndoTAG-1 in combination with gemcitabine compared to gemcitabine monotherapy in patients with locally advanced/metastatic pancreatic cancer after FOLFIRINOX failure.

Detailed description:
The objective of the study was to assess the safety and efficacy of a combination therapy of EndoTAG-1 plus gemcitabine vs. gemcitabine monotherapy in patients with locally advanced and/or metastatic adenocarcinoma of the pancreas eligible for second-line therapy after failing first line therapy with FOLFIRINOX

Arms: arm 1: EndoTAG-1 22 mg/m² twice weekly plus Gemcitabine 1000mg/m² once weekly for 1 cycle (8 weeks) consisting of 3 weeks of treatment and 1 week rest followed by 3 weeks of treatment and 1 week rest until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. arm 2: Gemcitabine 1000mg/m² once weekly, for 1 cycle (8 weeks) consisting of 3 weeks of treatment and 1 week rest followed by 3 weeks of treatment and 1 week rest until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent.
Interventions: intervention 1: EndoTAG-1 intervention 2: Gemcitabine
Intervention descriptions: intervention 1: twice weekly intervention 2: once weekly

Protocol documents:
Prot_000.pdf: 
 
 
Protocol No: CT 4006 
 
 
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Page 1 of 125 
 
 
 
 
 
A Randomized Controlled, Open label, Adaptive Phase-3 Trial to Evaluate 
Safety and Efficacy of EndoTAG-1 Plus Gemcitabine versus Gemcitabine 
alone in Patients with Measurable Locally Advanced and/or Metastatic 
Adenocarcinoma of the Pancreas Failed on FOLFIRINOX Treatment 
 
 
 
 
Protocol Number:   
CT 4006 
 
Investigational Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
 
Development Phase: 
 
Phase 3 
 
Version/Date: 
 
Version 4.2 /28-Jan-2021 
 
 
            Sponsor: 
 
SynCore Biotechnology Co., Ltd. 
 
 
 
 
 
4F, No.69, DongXing Rd., XinYi Dist.,  
Taipei City 110, Taiwan 
Tel:+886-2-2760-3688  
Fax: +886-2-2763-9287 
 
 
 
Global Coordinating 
 
Investigator:  
 
Li-Tzong Chen, M.D., Ph.D. 
 
 
 
 
 
National Institute of Cancer Research,  
 
 
 
 
 
National Health Research Institutes  
 
 
 
 
 
Department of Internal Medicine,  
 
 
 
 
 
National Cheng Kung University Hospital 
 
 
 
 
 
Tainan, Taiwan, R.O.C 
 
Confidentiality Statement 
 
This document is a confidential communication of SynCore Biotechnology Co., Ltd. It 
is provided for the conduct of a clinical research study. The information contained in 
this document is confidential and, except to the extent necessary to obtain informed 
consent or IEC/IRB approval, cannot be disclosed unless required by governmental 
regulation. Persons to whom any portion of the contents of this document is disclosed 
must be informed that the information is confidential and may not be further disclosed 
by them. 


 
 
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PROTOCOL APPROVAL PAGE 
 
 
Protocol Number:  
CT 4006 
 
Version: 
 
4.2 
 
Date: 
 
28-Jan-2021 
 
Protocol Title:  A Randomized Controlled, Open label, Adaptive Phase-3 Trial to 
Evaluate Safety and Efficacy of EndoTAG-1 Plus Gemcitabine versus Gemcitabine 
alone in Patients with Measurable Locally Advanced and/or Metastatic 
Adenocarcinoma of the Pancreas Failed on FOLFIRINOX Treatment 
 
PROTOCOL APPROVAL FOR USE 
 
 
 
 
 
Muh-Hwan Su, PhD 
 
 
 
 
General Manager 
 
 
 
 
SynCore Biotechnology Co., 
Ltd. 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
Lin Jia, MS; 
 
 
 
 
Statistician 
 
 
 
 
Amarex Clinical Research, LLC 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
Victoria Martin, MS; 
 
 
 
 
Medical Writer 
 
 
 
 
Amarex Clinical Research, LLC 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
Albert Lin 
Head of Clinical Quality 
Department 
 
 
 
 
SynCore Biotechnology Co., Ltd.  
 
 
 
 
 
Signature 
 
Date 


 
 
Protocol No: CT 4006 
 
 
Version 4.2; 28-Jan-2021 
 
 
Confidential 
Page 3 of 125 
INVESTIGATOR SIGNATURE PAGE 
 
 
Protocol Number:  
CT 4006 
 
Version: 
 
4.2 
 
Date: 
 
28-Jan-2021 
 
Protocol Title:  A Randomized Controlled, Open label, Adaptive Phase-3 Trial to 
Evaluate Safety and Efficacy of EndoTAG-1 Plus Gemcitabine versus Gemcitabine 
alone in Patients with Measurable Locally Advanced and/or Metastatic 
Adenocarcinoma of the Pancreas Failed on FOLFIRINOX Treatment 
 
 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices and the current Investigator’s 
Brochure (IB), and I agree that it contains all necessary details for me and my staff to 
conduct this study as described. I will conduct this study as outlined herein and will 
make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and 
access to all information provided by SynCore Biotechnology. I will discuss this 
material with them to ensure that they are fully informed about the drugs and the study. 
I will conduct the trial in accordance with the guidelines of Good Clinical Practice (GCP) 
including the archiving of essential documents, the Declaration of Helsinki, any 
applicable local health authority, and Institutional Review Board (IRB) requirements. 
 
 
 
 
Investigator Name (Printed) 
 
Institution 
 
 
 
 
Signature 
 
Date 
 
 
Please retain the original for your study files. 


 
 
 
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List of Changes from Previous Version 
Page no. 
Protocol v.4.1 08 Sep 2020 
Protocol v.4.2 28-Jan-2021 
Note 
Protocol Synopsis 
17, 46 
Objectives:  
The objective of the study is to assess the safety, efficacy 
and quality of life of a combination therapy of EndoTAG-
1 plus gemcitabine vs. gemcitabine monotherapy in 
patients with locally advanced and/or metastatic 
adenocarcinoma of the pancreas eligible for second-line 
therapy after failing first-line therapy with FOLFIRINOX. 
Objectives:  
The objective of the study is to assess the safety and efficacy 
and quality of life of a combination therapy of EndoTAG-1 
plus gemcitabine vs. gemcitabine monotherapy in patients 
with locally advanced and/or metastatic adenocarcinoma of 
the pancreas eligible for second-line therapy after failing 
first-line therapy with FOLFIRINOX. 
Remove quality of life from 
study objective 
17, 46 
Efficacy Objectives 
• 
Assessment of survival (progression-free survival 
[PFS], overall survival [OS]) 
• 
Tumor response evaluation via Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST v.1.1) 
• 
Clinical benefit assessment via quality of life (QoL) 
scale (EORTC-QLQ-C30 [European Organization 
for Research and Treatment of Cancer Quality of Life 
Questionnaire], and PAN-26 module) 
Efficacy Objectives 
• 
Assessment of survival (overall survival [OS], 
progression-free survival [PFS]) 
• 
Tumor response evaluation via Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST v.1.1) 
• 
Clinical benefit assessment via quality of life (QoL) 
scale (EORTC-QLQ-C30 [European Organization for 
Research and Treatment of Cancer Quality of Life 
Questionnaire], and PAN-26 module) 
Remove questionnaire from 
study objective 
18, 47/48 
• 
Change From Baseline in European Organization for 
Research and Treatment of Cancer, Quality of Life 
Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC QLQ-C30: included functional scales 
(physical, role, cognitive, emotional, and social), 
global health status (GHS), symptom scales (fatigue, 
pain, nausea/vomiting), and single items (dyspnoea, 
• 
Change From Baseline in European Organization for 
Research and Treatment of Cancer, Quality of Life 
Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC 
QLQ-C30: 
included 
functional 
scales 
(physical, role, cognitive, emotional, and social), 
global health status (GHS), symptom scales (fatigue, 
pain, nausea/vomiting), and single items (dyspnoea, 
Move EORTC QLQ- C30 
and EORTC QLQ- PAN26 
to Exploratory Endpoint 


 
 
 
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appetite loss, insomnia, constipation/diarrhea, and 
financial difficulties). Most questions used 4- point 
scale (1 'Not at All' to 4 'Very Much'); 2 questions 
used 7-point scale (1 'Very Poor' to 7 'Excellent'). 
Scores averaged, transformed to 0- 100 scale; higher 
score=better level of functioning or greater degree of 
symptoms. Change from baseline=Cycle/Day score 
minus baseline score. 
• 
Change from baseline in European Organization for 
Research and Treatment of Cancer Quality of Life 
Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) 
Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to 
disease symptoms, treatment (Tx) side effects and 
emotional issues specific to pancreatic cancer (PC). 
Questions include on altered bowel habits, pain, 
dietary changes, disease and Tx-related symptoms 
and issues related to the emotional and social well-
being of participants with PC. All 26 Qs are answered 
on 4-point Likert scale ranging from '1=not at all' to 
4='very much' and subsequently transformed into 
scales that range from 0-100; higher scores= greater 
degree of symptoms or treatment side effects and 
emotional issues. 
appetite loss, insomnia, constipation/diarrhea, and 
financial difficulties). Most questions used 4- point 
scale (1 'Not at All' to 4 'Very Much'); 2 questions used 
7-point scale (1 'Very Poor' to 7 'Excellent'). Scores 
averaged, transformed to 0- 100 scale; higher 
score=better level of functioning or greater degree of 
symptoms. Change from baseline=Cycle/Day score 
minus baseline score. 
• 
Change from baseline in European Organization for 
Research and Treatment of Cancer Quality of Life 
Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) 
Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to 
disease symptoms, treatment (Tx) side effects and 
emotional issues specific to pancreatic cancer (PC). 
Questions include on altered bowel habits, pain, 
dietary changes, disease and Tx-related symptoms 
and issues related to the emotional and social well-
being of participants with PC. All 26 Qs are answered 
on 4-point Likert scale ranging from '1=not at all' to 
4='very much' and subsequently transformed into 
scales that range from 0-100; higher scores= greater 
degree of symptoms or treatment side effects and 
emotional issues. 
18, 47/48 
The tumor measurement according to RECIST v.1.1 
criteria will be reviewed by a qualified independent 
review board. The review is independent of the on-site 
tumor evaluation performed during study conduct. 
The tumor measurement according to RECIST v.1.1 criteria 
will be reviewed by a qualified independent review board. 
The review is independent of the on-site tumor evaluation 
performed during study conduct. 
Move EORTC QLQ- C30 
and EORTC QLQ- PAN26 
to Exploratory Endpoint 


 
 
 
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Exploratory Endpoints: 
• 
Change From Baseline in European Organization for 
Research and Treatment of Cancer, Quality of Life 
Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC 
QLQ-C30: 
included 
functional 
scales 
(physical, role, cognitive, emotional, and social), 
global health status (GHS), symptom scales (fatigue, 
pain, nausea/vomiting), and single items (dyspnoea, 
appetite loss, insomnia, constipation/diarrhea, and 
financial difficulties). Most questions used 4- point 
scale (1 'Not at All' to 4 'Very Much'); 2 questions used 
7-point scale (1 'Very Poor' to 7 'Excellent'). Scores 
averaged, transformed to 0- 100 scale; higher 
score=better level of functioning or greater degree of 
symptoms. Change from baseline=Cycle/Day score 
minus baseline score. 
• 
Change from baseline in European Organization for 
Research and Treatment of Cancer Quality of Life 
Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) 
Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to 
disease symptoms, treatment (Tx) side effects and 
emotional issues specific to pancreatic cancer (PC). 
Questions include on altered bowel habits, pain, 
dietary changes, disease and Tx-related symptoms and 
issues related to the emotional and social well-being of 
participants with PC. All 26 Qs are answered on 4-
point Likert scale ranging from '1=not at all' to 4='very 


 
 
 
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much' and subsequently transformed into scales that 
range from 0-100; higher scores= greater degree of 
symptoms or treatment side effects and emotional 
issues. 
57, 58, 59 
Note: Assessments of laboratory performed 1 day prior to 
treatment is acceptable. 
Note: Assessments of laboratory parameters performed 1 
day prior to treatment is acceptable. 
Addition of “parameters” 
for clarity. 
 
7.14.3 Baseline documentation of ‘target’ and ‘non-
target’ lesions 
… 
Target Lesions: 
• 
Select largest reproducibly measurable lesions. If the 
largest lesion cannot be measured reproducibly, select the 
next largest lesion which can be  
7.14.3 Baseline documentation of ‘target’ and ‘non-
target’ lesions 
… 
Target Lesions: 
• 
Select largest reproducibly measurable lesions. If the 
largest lesion cannot be measured reproducibly, select the 
next largest lesion which can be measured 
Addition of “measured” for 
clarity 
22, 51 
Exclusion Criteria 
8. Laboratory tests (hematology, chemistry) outside 
specified limits: 
a) WBC ≤ 3 x 10³/mm³ 
b) ANC ≤ 1.5 x 10³/mm³ 
c) Platelets ≤ 100.000/mm³ 
Exclusion Criteria 
8. Laboratory tests (hematology, chemistry) outside 
specified limits: 
a) WBC ≤ 3 x 10³/mm³ 
b) ANC ≤ 1.5 x 10³/mm³ 
c) Platelets ≤ 100,000/mm³ 
Corrected 
typo 
in 
the 
number 100,000 
Statistical Considerations: 
25 
Sample Size Determination and Rationale:  
… 
The sample size is event-driven to collect a pre-specified 
number of primary efficacy outcomes. Based on the 
sample size calculation, the primary endpoint analysis 
will require 167 events (deaths) for 196 subjects. This 
sample size is sufficient to detect a 40% reduction in the 
risk of death in Arm A, as compared with Arm B (hazard 
ratio, 0.60) using a 2-sided log-rank test with 90% power 
Sample Size Determination and Rationale:  
… 
The sample size is event-driven to collect a pre-specified 
number of primary efficacy outcomes. Based on the 
sample size calculation, the primary endpoint analysis for 
overall survival will require 167 events (deaths) for 196 
subjects. The primary endpoint analysis for progression-
free survival will require 169 events (disease progression) 
from 182 subjects. This sample size is sufficient to detect a 
Calculate Sample Size for 
PFS as one of the Primary 
Endpoints 


 
 
 
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and an overall significance level of 0.05 two sided 
test.  Sample size estimation is depicted in Figure 9-1, 
total sample size requirement vs. the median survival time 
(month) in the treatment arm. 
40% reduction in the risk of death in Arm A, as compared 
with Arm B (hazard ratio, 0.60) using a 2-sided log-rank 
test with 90% power and an overall significance level of 
0.05 two sided test. This sample size is also sufficient to 
detect a 35% reduction of progressive free survival in the 
risk of disease progression in Arm A, as compared with 
Arm B (hazard ratio, 0.647) using a 2-sided log-rank test 
with more than 80% power and an overall significance 
level of 0.05 two sided test. Sample size estimation is 
depicted in Figure 9-1and Figure 9-2, total sample size 
requirement vs. the median survival time (month) in the 
treatment arm.  
 
25/26 
The overall survival assumption for the sample size are 
based on published literature data comparing therapeutic 
effect of gemcitabine monotherapy and gemcitabine 
combination regimen on patients with advanced 
pancreatic cancer after previous FOLFIRINOX treatment. 
The hazard ratio for death of 0.60 with median overall 
survival of 4.4 months for gemcitabine monotherapy 
(Conroy et al. 2011) and 7.3 months for gemcitabine + 
paclitaxel combination (Portal et al. 2015) was used for 
the sample size calculation. 
The overall survival assumption for the sample size are 
based on published literature data comparing therapeutic 
effect of gemcitabine monotherapy and gemcitabine 
combination regimen on patients with advanced pancreatic 
cancer after previous FOLFIRINOX treatment. The hazard 
ratio for death of 0.60 with median overall survival of 4.4 
months for gemcitabine monotherapy (Conroy et al. 2011) 
and 7.3 months for gemcitabine + paclitaxel combination 
(Portal et al. 2015) was used for the sample size calculation. 
The progression-free survival assumption for the sample 
size are based on hazard ratio of 0.647 with median 
progression-free survival of 3.3 months for gemcitabine 
monotherapy (Conroy et al. 2011) and 5.1 months for 
gemcitabine + paclitaxel combination (Portal et al. 2015) 
was used for the sample size calculation. 
Calculate Sample Size for 
PFS as one of the Primary 
Endpoints 
9 
Statistical Considerations 


 
 
 
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98 
Description of Study Endpoints 
Secondary Efficacy Endpoints 
 
4. Change From Baseline in European Organization for 
Research and Treatment of Cancer, Quality of Life 
Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC QLQ-C30: included functional scales (physical, 
role, cognitive, emotional, and social), global health 
status 
(GHS), 
symptom 
scales 
(fatigue, 
pain, 
nausea/vomiting), and single items (dyspnoea, appetite 
loss, insomnia, constipation/diarrhea, and financial 
difficulties). Most questions used 4- point scale (1 'Not at 
All' to 4 'Very Much'); 2 questions used 7-point scale (1 
'Very Poor' to 7 'Excellent'). Scores averaged, 
transformed to 0- 100 scale; higher score=better level of 
functioning or greater degree of symptoms. Change from 
baseline=Cycle/Day score minus baseline score. 
5. Change from baseline in European Organization for 
Research and Treatment of Cancer Quality of Life 
Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) 
Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to 
disease symptoms, treatment (Tx) side effects and 
emotional issues specific to pancreatic cancer (PC). 
Questions include on altered bowel habits, pain, dietary 
changes, disease and Tx-related symptoms and issues 
related to the emotional and social well-being of 
participants with PC. All 26 Qs are answered on 4-point 
Description of Study Endpoints 
Secondary Efficacy Endpoints 
1. Change From Baseline in European Organization for 
Research and Treatment of Cancer, Quality of Life 
Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC 
QLQ-C30: 
included 
functional 
scales 
(physical, role, cognitive, emotional, and social), 
global health status (GHS), symptom scales (fatigue, 
pain, nausea/vomiting), and single items (dyspnoea, 
appetite loss, insomnia, constipation/diarrhea, and 
financial difficulties). Most questions used 4- point 
scale (1 'Not at All' to 4 'Very Much'); 2 questions used 
7-point scale (1 'Very Poor' to 7 'Excellent'). Scores 
averaged, transformed to 0- 100 scale; higher 
score=better level of functioning or greater degree of 
symptoms. Change from baseline=Cycle/Day score 
minus baseline score. 
2. Change from baseline in European Organization for 
Research and Treatment of Cancer Quality of Life 
Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) 
Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to 
disease symptoms, treatment (Tx) side effects and 
emotional issues specific to pancreatic cancer (PC). 
Questions include on altered bowel habits, pain, 
dietary changes, disease and Tx-related symptoms and 
issues related to the emotional and social well-being of 
participants with PC. All 26 Qs are answered on 4-
Move EORTC QLQ- C30 
and EORTC QLQ- PAN26 
to Exploratory Endpoint 


 
 
 
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Likert scale ranging from '1=not at all' to 4='very much' 
and subsequently transformed into scales that range from 
0-100; higher scores= greater degree of symptoms or 
treatment side effects and emotional issues. 
 
point Likert scale ranging from '1=not at all' to 4='very 
much' and subsequently transformed into scales that 
range from 0-100; higher scores= greater degree of 
symptoms or treatment side effects and emotional 
issues. 
 
Exploratory Endpoints 
• 
Change From Baseline in European Organization for 
Research and Treatment of Cancer, Quality of Life 
Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC 
QLQ-C30: 
included 
functional 
scales 
(physical, role, cognitive, emotional, and social), 
global health status (GHS), symptom scales (fatigue, 
pain, nausea/vomiting), and single items (dyspnoea, 
appetite loss, insomnia, constipation/diarrhea, and 
financial difficulties). Most questions used 4- point 
scale (1 'Not at All' to 4 'Very Much'); 2 questions used 
7-point scale (1 'Very Poor' to 7 'Excellent'). Scores 
averaged, transformed to 0- 100 scale; higher 
score=better level of functioning or greater degree of 
symptoms. Change from baseline=Cycle/Day score 
minus baseline score. 
• 
Change from baseline in European Organization for 
Research and Treatment of Cancer Quality of Life 


 
 
 
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Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) 
Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to 
disease symptoms, treatment (Tx) side effects and 
emotional issues specific to pancreatic cancer (PC). 
Questions include on altered bowel habits, pain, 
dietary changes, disease and Tx-related symptoms and 
issues related to the emotional and social well-being of 
participants with PC. All 26 Qs are answered on 4-
point Likert scale ranging from '1=not at all' to 4='very 
much' and subsequently transformed into scales that 
range from 0-100; higher scores= greater degree of 
symptoms or treatment side effects and emotional 
issues. 
 
98 
9.3 
Sample Size Determination and Rationale 
… 
The sample size is event-driven to collect a pre-specified 
number of primary efficacy outcomes. Based on the 
sample size calculation, the primary endpoint analysis 
will require 167 events (deaths) from the 196 subjects. 
This sample size is sufficient to detect a 40% reduction in 
the risk of death in Arm A, as compared with Arm B 
(hazard ratio, 0.60) using a 2-sided log-rank test with 90% 
power and an overall significance level of 0.05 two sided 
test.  Sample size estimation is depicted in Figure 9-1, 
total sample size requirement vs. the median survival time 
(month) in the treatment arm. Sample size is estimated 
using PASS (15) sample size software. 
9.3 
Sample Size Determination and Rationale 
… 
The sample size is event-driven to collect a pre-specified 
number of primary efficacy outcomes. Based on the 
sample size calculation, the primary endpoint analysis for 
overall survival will require 167 events (deaths) from the 
196 subjects. The primary endpoint analysis for 
progression-free survival will require 169 events (disease 
progression) from 182 subjects. This sample size is 
sufficient to detect a 40% reduction of overall survival in 
the risk of death in Arm A, as compared with Arm B 
(hazard ratio, 0.60) using a 2-sided log-rank test with 90% 
power and an overall significance level of 0.05 two sided 
test. This sample size is also sufficient to detect a 35% 
reduction of progression free survival in the risk of disease 
Calculate Sample Size for 
PFS as one of the Primary 
Endpoints 


 
 
 
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progression in Arm A, as compared with Arm B (hazard 
ratio, 0.647) using a 2-sided log-rank test with more than 
80% power and an overall significance level of 0.05 two 
sided test. Sample size estimation for overall survival is 
depicted in Figure 9-1, total sample size requirement vs. 
the median survival time (month) in the treatment arm. 
Sample size is estimated using PASS (15) sample size 
software. 
Sample size estimation for progression-free survival is 
depicted in Figure 9-2, total sample size requirement vs. the 
median survival time (month) in the treatment arm. Sample 
size is estimated using PASS (15) sample size software. 
 
98 
The hazard ratio for death of 0.60 with median overall 
survival of 4.4 months for gemcitabine monotherapy 
(Conroy et al. 2011) and 7.3 months for gemcitabine + 
paclitaxel combination (Portal et al. 2015) was used for 
the sample size calculation. 
The hazard ratio for death of 0.60 with median overall 
survival of 4.4 months for gemcitabine monotherapy 
(Conroy et al. 2011) and 7.3 months for gemcitabine + 
paclitaxel combination (Portal et al. 2015) was used for the 
sample size calculation. The progression-free survival 
assumption for the sample size are based on hazard ratio of 
0.647 with median progression-free survival of 3.3 months 
for gemcitabine monotherapy (Conroy et al. 2011) and 5.1 
months for gemcitabine + paclitaxel combination (Portal et 
al. 2015) was used for the sample size calculation. 
 
Calculate Sample Size for 
PFS as one of the Primary 
Endpoints 
99 
Figure 9-1 Size Plot: Total sample size requirement vs. 
the median survival time (month) in the treatment arm A.  Figure 9 1: 
Overall Survival Sample Size Plot: Total 
sample size requirement vs. the median survival time 
(month) in the treatment arm A. 
Specify the sample size plot 
for Overall Survival 


 
 
 
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99 
none 
Figure 9 2: 
Progression-Free Survival Sample Size Plot: 
Total sample size requirement vs. the median survival time 
(month) in the treatment arm A.  
 
Create sample size plot for 
Progression Free Survival 
105 
9.8.3 
Efficacy Analyses 
… 
Primary Endpoints: 
1. 
Progression Free Survival (PFS) 
Progression Free Survival time is defined as the time from 
randomization to either first observation of progressive 
disease or occurrence of death.  
2. 
Overall survival (OS) 
9.8.3 
Efficacy Analyses 
… 
Primary Endpoints: 
1. 
Overall survival (OS) 
Overall survival time is defined as time from randomization 
to death from any cause or last day known to be alive.  
2. 
Progression Free Survival (PFS) 
Order Overall Survival to 
be 
the 
first 
primary 
endpoint; PFS to be the 
second primary endpoint in 
order 


 
 
 
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Overall survival time is defined as time from 
randomization to death from any cause or last day known 
to be alive. 
Progression Free Survival time is defined as the time from 
randomization to either first observation of progressive 
disease or occurrence of death. 
106 
Primary Endpoints 
… 
PFS and OS will be compared between the treatment 
groups using Cox proportional hazards model with the 
stratification factors included in the model. The hazard 
ratio for treatment effect and its 95% CI will be estimated. 
The validity of the proportional hazards assumption will 
first be checked by defining a time dependent covariate 
and employing it in the model. If the assumption of 
proportional hazards holds then the estimate for the time-
dependent covariate will not differ significantly from 
zero. 
If the proportional hazards assumption is violated, then 
the adjusted hazard ratio arising from inclusion of the 
time-dependent covariate will be reported.  
The Score likelihood test (i.e., which is equivalent to log-
rank test) from the Cox proportional hazards model will 
be used to assess the difference between treatment arms.   
In addition, the Kaplan-Meier method will also be used to 
depict the median time to death from any cause for the 
treatment groups. 
Primary Endpoints 
… 
OS and PFS will be compared between the treatment groups 
using stratified log-rank test with the stratification factors 
included in the model. The differences for treatment effect 
and its 95% CI will be estimated. 
The validity of the proportional hazards assumption will 
first be checked by defining a time dependent covariate and 
employing it in the model. If the assumption of proportional 
hazards holds then the estimate for the time-dependent 
covariate will not differ significantly from zero. 
If the proportional hazards assumption is violated, then the 
adjusted hazard ratio arising from inclusion of the time-
dependent covariate will be reported.  
The Score likelihood test (i.e., which is equivalent to log-
rank test) from the Cox proportional hazards model will be 
used to assess the difference between treatment arms.   
In addition, the Kaplan-Meier method will also be used to 
depict the median time to death from any cause for the 
treatment groups.  
 
Proportional hazards model 
removed – replaced with 
stratified log-rank test. 


 
 
 
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106 
Secondary Endpoints: 
… 
4. 
Change From Baseline in European Organization 
for Research and Treatment of Cancer, Quality of Life 
Questionnaire Core-30 (EORTC QLQ- C30) Score  
5. 
Change from baseline in European Organization 
for Research and Treatment of Cancer Quality of Life 
Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) 
Score 
… 
Secondary Endpoints: 
… 
4. 
Change 
From 
Baseline 
in 
European 
Organization for Research and Treatment of Cancer, 
Quality of Life Questionnaire Core-30 (EORTC QLQ- 
C30) Score  
5. 
Change 
from 
baseline 
in 
European 
Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire-Pancreatic 26 (EORTC QLQ- 
PAN26) Score 
… 
Exploratory Endpoints:  
• 
Change from Baseline in European Organization for 
Research and Treatment of Cancer, Quality of Life 
Questionnaire Core-30 (EORTC QLQ- C30) Score  
• 
Change from baseline in European Organization for 
Research and Treatment of Cancer Quality of Life 
Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) 
Score  
Similar analysis methods used for secondary endpoints will 
be applied to the analysis of the exploratory endpoints. 
Detailed analysis methods will be described in the SAP. 
Move EORTC QLQ- C30 
and EORTC QLQ- PAN26 
to Exploratory Endpoint 
12 
Data and Safety Monitoring Board (DSMB) 
112 
… 
… 
Futility is not planned for 
DSMB. 


 
 
 
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The DSMB will monitor the safety of the trial from the 
beginning and at approximately six month intervals based 
on enrolment thereafter; the DSMB will also assess the 
study for futility once approximately 60% (~167 events) 
have been randomized on the trial and followed up for at 
least 48 weeks or have deaths, whichever comes first. 
The DSMB will monitor the safety of the trial from the 
beginning and at approximately six month intervals based 
on enrolment thereafter; the DSMB will also assess the 
study for futility once approximately 60% (~167 events) 
have been randomized on the trial and followed up for at 
least 48 weeks or have deaths, whichever comes first. 
 
Other editorial changes to be in line with the order of primary endpoints: 1. OS, 2. PFS. 


 
 
 
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Protocol Synopsis 
Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
Title of Study:  
A Randomized Controlled, Open label, Adaptive Phase-3 Trial to Evaluate Safety and Efficacy of 
EndoTAG-1 Plus Gemcitabine versus Gemcitabine alone in Patients with Measurable Locally 
Advanced and/or Metastatic Adenocarcinoma of the Pancreas Failed on FOLFIRINOX Treatment 
Study Center(s): Up to 100 multinational centers 
Planned Number of Subjects:  
A total of 218 (109 per arm) subjects will be randomized. 
Study Development Phase:  
Phase 3 
Indication for Use: Lipid Complexed Paclitaxel (EndoTAG-1), in combination with gemcitabine, 
is indicated for the combination regimen in patients with locally advanced and/or metastatic 
adenocarcinoma of the pancreas who are eligible for second-line therapy after failing first-line 
therapy with FOLFIRINOX. 
Study Rationale: 
EndoTAG-1 is a novel formulation of cationic liposomes for the treatment of solid tumors, carrying 
paclitaxel embedded in the liposome membrane. Cationic liposomes are known to bind and 
internalize at tumor endothelial cells after intravenous administration, which is the basis for the 
new mode of action of EndoTAG-1. Using a cationic liposome formulation, the cytostatic and 
cytotoxic activities of paclitaxel are targeted to the activated tumor endothelial cells. Therefore, in 
contrast to conventional chemotherapy aiming at tumor-cell toxicity, EndoTAG-1 specifically 
displays antivascular and antiangiogenic activity. 
Based on the results of preclinical studies and clinical phase 1/2 studies and its new therapeutic 
concept, EndoTAG-1 represents a promising candidate for the treatment of solid malignancies, 
both for taxane-sensitive and taxane-insensitive tumors. 
Pancreatic cancer, which is the 4th leading cause of cancer death in the United States (Jemal et al. 
2008), is an indication with high need for improvement of systemic therapy. Less than 20% of 
pancreatic cancer patients are diagnosed with resectable and potentially curable disease while the 
vast majority of patients have advanced disease at the time of diagnosis with a median survival of 
approximately 6 months.  
FOLFIRINOX regimen is the standard first-line treatment for pancreatic cancer patients with good 
performance status. However, the optimal management strategy for patients who fail initial 
FOLFIRINOX remains undefined. There is still no standard of care in second-line therapy for 
patients with disease progression. 
Gemcitabine has been the standard systemic therapy for unresectable pancreatic cancer for the last 
decade, though 1-year survival rates ranging around 18% are still unsatisfactory (Burris et al. 1997; 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
Moore et al. 2007). Numerous trials have aimed to demonstrate superiority of combinations of 
gemcitabine with other chemotherapeutics or targeted agents with disappointing results.  
Results of a controlled, randomized Phase 2 clinical trial comprising 200 patients indicate a 
considerable survival benefit for patients with advanced pancreatic cancer treated with EndoTAG-
1 in combination with gemcitabine compared to gemcitabine monotherapy. 
The aim of this adaptive Phase 3 trial is to show a statistically significant superiority of EndoTAG-
1 in combination with gemcitabine compared to gemcitabine monotherapy in patients with locally 
advanced/metastatic pancreatic cancer after FOLFIRINOX failure. 
Objectives:  
The objective of the study is to assess the safety and efficacy of a combination therapy of 
EndoTAG-1 plus gemcitabine vs. gemcitabine monotherapy in patients with locally advanced 
and/or metastatic adenocarcinoma of the pancreas eligible for second-line therapy after failing first-
line therapy with FOLFIRINOX. 
Efficacy Objectives: 
To assess the efficacy of twice weekly infusions of EndoTAG-1 with weekly infusions of 
gemcitabine versus gemcitabine monotherapy according to: 
• 
Assessment of survival (overall survival [OS], progression-free survival [PFS]) 
• 
Tumor response evaluation via Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST v.1.1) 
Safety Objectives: 
To assess the safety of twice weekly infusions of EndoTAG-1 with weekly infusions of 
gemcitabine versus gemcitabine monotherapy according to: 
• 
Incidence and percentage of subjects with treatment-emergent adverse events (TEAEs) 
• 
Laboratory abnormalities (hematology, coagulation parameters, clinical chemistry) 
• 
Dose reductions, pausing, and/or discontinuation of EndoTAG-1 and/or gemcitabine 
Endpoints: 
Primary Efficacy Endpoints: 
• 
Overall survival (OS) 
Overall survival time is defined as time from randomization to death from any cause or last 
day known to be alive.  
• 
Progression Free Survival (PFS) 
Progression Free Survival time is defined as the time from randomization to either first 
observation of progressive disease or occurrence of death.  
Secondary Efficacy Endpoints: 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
• Percentage of subjects with Objective Response (OR) according to Response Evaluation Criteria 
in Solid Tumors Version 1.1 (RECIST v.1.1)* 
Percentage of subjects with objective response is based on assessment of complete response 
(CR) or partial response (PR) according to RECIST v.1.1. 
• Duration of Response (DR)* 
Duration of Response is defined as the time from the first documentation of objective tumor 
response (date of the first CR or PR) to objective tumor progression or death due to any cause.  
• 
Percentage of subjects with disease control according to RECIST v.1.1* 
Percentage of subjects with disease control is based on assessment of complete response (CR) 
or partial response (PR) or stable disease (SD) according to RECIST v.1.1 
• 
Serum Carcinoma Antigen 19-9 (CA 19-9) response rate 
Responders are defined as subjects with a reduction in CA 19-9 levels by least 50% from 
baseline to the end of cycle 1 (or end of full treatment course). 
*The tumor measurement according to RECIST v.1.1 criteria will be reviewed by a qualified 
independent review board. The review is independent of the on-site tumor evaluation performed 
during study conduct. 
Exploratory Endpoints: 
• 
Change From Baseline in European Organization for Research and Treatment of Cancer, 
Quality of Life Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and 
social), global health status (GHS), symptom scales (fatigue, pain, nausea/vomiting), and 
single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, and financial 
difficulties). Most questions used 4- point scale (1 'Not at All' to 4 'Very Much'); 2 questions 
used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores averaged, transformed to 0- 100 
scale; higher score=better level of functioning or greater degree of symptoms. Change from 
baseline=Cycle/Day score minus baseline score. 
• 
Change from baseline in European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to disease symptoms, treatment (Tx) side 
effects and emotional issues specific to pancreatic cancer (PC). Questions include on altered 
bowel habits, pain, dietary changes, disease and Tx-related symptoms and issues related to 
the emotional and social well-being of participants with PC. All 26 Qs are answered on 4-
point Likert scale ranging from '1=not at all' to 4='very much' and subsequently transformed 
into scales that range from 0-100; higher scores= greater degree of symptoms or treatment 
side effects and emotional issues. 
 
Safety Assessments: 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
Safety will be assessed based on the following assessments: 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs), including serious 
adverse events and adverse events resulting in permanent discontinuation of protocol-defined 
therapy.  
• 
Changes in selected laboratory test results (i.e.,  
o 
Serum chemistry including urea, serum creatinine, sodium, potassium, chloride, 
bicarbonate, glucose, bilirubin, albumin, ALT, AST, ALP, total protein; and  
o 
Full blood count (FBC) including hemoglobin, hematocrit, RBC count, Platelets 
count, total leukocyte count, differential leukocyte count and absolute neutrophil 
count)  
• 
Changes in vital signs including systolic and diastolic blood pressure and pulse  
• 
Changes in electrocardiogram (ECG) results  
• 
Changes in physical examination results  
Trial Design:  
This is a randomized controlled, open label, adaptive phase-3 study to evaluate the safety and 
efficacy of a combination regimen of twice weekly infusions of EndoTAG-1 (Lipid Complexed 
Paclitaxel) with weekly administration of gemcitabine compared with gemcitabine monotherapy 
in subjects with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas 
who are eligible for second-line therapy after failing first-line therapy with FOLFIRINOX. 
Eligible subjects will be randomized to one of the two treatment arms : 
 
Arm A: Treatment with EndoTAG-1 22 mg/m2 twice weekly plus gemcitabine 1000mg/m² 
once weekly, for 1 cycle (8 weeks) consisting of 3 weeks of treatment and 1 week rest 
followed by 3 weeks of treatment and 1 week rest until any one of the following occurs: 
progressive disease or unacceptable toxicity or withdrawal of consent. 
Subjects will be eligible for continuing treatment beyond first cycle in absence of disease 
progression or unacceptable toxicity. Subsequent Treatment Cycles (8 weeks/ cycle) will be 
administered as 3 weeks of treatment and 1 week rest followed by 3 weeks of treatment and 1 
week rest. 
 
Arm B: Treatment with gemcitabine 1000mg/m² once weekly, for 1 cycle (8 weeks) consisting 
of 3 weeks of treatment and 1 week rest followed by 3 weeks of treatment and 1 week rest 
until any one of the following occurs: progressive disease or unacceptable toxicity or 
withdrawal 
of 
consent.  
Subjects will be eligible for continuing treatment beyond first cycle in absence of disease 
progression or unacceptable toxicity. Subsequent Treatment Cycles (8 weeks/ cycle) will be 
administered as 3 weeks of treatment and 1 week rest followed by 3 weeks of treatment and 1 
week rest. 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
The randomization will be stratified by  
• 
Subjects with locally advanced vs metastatic pancreatic cancer 
• 
Subjects with ECOG performance status 0 vs 1 
The first treatment cycle will last at least 8 weeks and include 3 weeks of treatment and 1 week 
rest followed by 3 weeks of treatment and 1 week rest. Subjects may continue to receive additional 
cycles of therapy until progressive disease or intolerable toxicity as per clinical judgment of the 
Investigator. 
Tumor response according to RECIST (version 1.1; Eisenhauer et al. 2009) will be evaluated on a 
scheduled basis every 8 weeks (±3 days) from randomization (regardless of the timing of treatment 
cycles) until disease progression is documented or until the cut-off date of the study, whichever 
comes earlier. Subjects will be monitored regularly for safety parameters, pain and quality of life.  
After completing treatment, subjects who are not diagnosed with progressive disease (PD) will 
attend up to 6 Follow-up Visits every 8 weeks for 48 weeks, following which subjects will be 
followed-up by telephone every 8 weeks for survival. Subjects who experienced PD during 
Treatment Phase will undergo only one safety follow-up visit (4-8 weeks after the EOT visit), and 
then enter phone follow-up directly. Follow-up visits will be performed for the evaluation of 
survival status, safety parameters, QoL (EORTC QLQ-C30 and EORTC PAN-26) and 
administration of other anti-tumor treatment until death or end of the study, whichever comes first. 
Anti-tumor therapy after termination of study treatment will be at the discretion of the Investigator.  
A single, pre-planned Interim Analysis (IA) will be conducted when approximately 101 subjects 
have died (60% of the expected 167 events). 
The cut-off date for the final analysis will be 12 months after the last subject was randomized or 
the last subject alive has been followed up for at least 48 weeks, whatever applies first. Subjects 
being still under treatment with study medication at this cut-off date will enter the extension phase 
of this trial. These subjects will be followed up until 28 days after the last administration of study 
medication.  
A Data and Safety Monitoring Board (DSMB), composed of independent representatives, will be 
in charge of reviewing the accrual, baseline, and safety data at periodic intervals. Representatives 
of the Sponsor will serve only as coordinating members of the committee, without having full 
member responsibilities or privileges. 
The schedule of assessments for the study is provided in Table 0-1 and Table 0-2. 
Duration of Treatment:  
• 
Screening Phase (Screening to Baseline): Up to 14 days 
• 
Treatment Phase:  
o 
First Treatment Cycle:  


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
 
Treatment Group A: 8 weeks or potentially longer in the event of postponements (a 
total of 6 weekly infusions of gemcitabine and 12 twice weekly infusions of 
EndoTAG-1). 
 
Treatment Group B: 8 weeks or potentially longer in the event of postponements (a 
total of 6 weekly infusions of gemcitabine).  
o 
Subsequent Treatment Cycles: Subjects will be eligible for continuing treatment with 3 
weeks of treatment and 1 week rest followed by 3 weeks of treatment and 1 week rest until 
any one of the following occurs: progressive disease or unacceptable toxicity or 
withdrawal of consent. 
• 
Follow-Up Phase: Follow-up visits will be performed every 8 weeks until death or end of the 
study, whichever comes first. 
Inclusion Criteria: Potential subjects are required to meet all of the following criteria for 
enrollment into the study and subsequent randomization: 
1. Age ≥ 18 years 
2. Written informed consent  
3. Histologically or cytologically confirmed adenocarcinoma of the pancreas 
4. Metastatic or locally advanced disease that is considered unresectable 
5. Measurable / assessable disease according to RECIST v.1.1 
6. Documented disease progression on first line FOLFIRINOX   
7. Negative pregnancy test 
8. Both male and female patients and their partners of childbearing potential must agree to use 
two medically accepted methods of contraception (e.g., barrier contraceptives [male condom, 
female condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, 
injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], or 
one of the following methods of birth control (intrauterine devices, tubal sterilization or 
vasectomy) or must practice complete abstinence from intercourse of reproductive potential 
during the whole treatment duration and for at least 6 months after last treatment for arm A 
and arm B (excluding women who are not of childbearing potential and men who have been 
sterilized). 
9. ECOG performance status 0 or 1 
Exclusion Criteria: Potential subjects meeting any of the following criteria will be excluded from 
enrollment and subsequent randomization: 
1. Cardiovascular disease, New York Heart Association (NYHA) III or IV 
2. History of severe supraventricular or ventricular arrhythmia 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
3. History of coagulation or bleeding disorder  
4. History of acute myocardial infarction within 6 months before randomization 
5. History of congestive heart failure 
6. Acute or chronic inflammation (autoimmune or infectious) 
7. Significant active/unstable non-malignant disease likely to interfere with study assessments 
8. Laboratory tests (hematology, chemistry) outside specified limits: 
d) WBC ≤ 3 x 10³/mm³ 
e) ANC ≤ 1.5 x 10³/mm³ 
f) Platelets ≤ 100,000/mm³ 
g) Hb ≤ 9.0 g/dl (≤ 5.6 mmol/l) 
h) aPTT > 1.5 x ULN 
i) 
Serum creatinine > 2.0 mg/dl (> 176.8 µmol/l) 
j) 
AST and/or ALT > 2.5 x ULN; for patients with significant liver metastasis AST and/or 
ALT > 5 x ULN 
k) Alkaline phosphatase > 2.5 x ULN 
l) 
Total bilirubin > 2 x ULN 
m) Albumin < 2.5 g/dL 
9. Clinically significant ascites 
10. Any anti-tumor treatment (except FOLFIRINOX as the first-line therapy) for pancreatic 
adenocarcinoma before enrollment. 
Note: Patients who have undergone surgical interventions for pancreatic adenocarcinoma 
will be eligible. 
11. Any radiotherapy for pancreatic adenocarcinoma before enrollment except for treatment of 
bone metastases if target lesions are not included in the irradiated field 
12. Major surgery < 4 weeks prior to enrollment 
13. Pregnant or nursing 
14. Investigational medicinal product < 4 weeks of enrollment 
15. Documented HIV history 
16. Active hepatitis B infection requiring acute therapy 
Note: Subjects infected by the hepatitis B virus will be eligible for the study if they have no 
signs of hepatic decompensation and meet the liver function tests eligibility criteria. 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
17. Known hypersensitivity to any component of the EndoTAG-1 and/or gemcitabine 
formulations 
18. History of malignancy other than pancreatic cancer < 3 years prior to enrollment, except non-
melanoma skin cancer or carcinoma in situ of the cervix treated locally 
19. Vulnerable populations (e.g. subjects unable to understand and give voluntary informed 
consent) 
Test Product, Dose and Mode of Administration: 
Test product: EndoTAG-1 
Mode of administration: Intravenous infusion 
Dose: 22 mg/m²  twice weekly 
Study Treatment 
Arm A:  
• 
Treatment cycle 1: EndoTAG-1 will be given at a dose of 22 mg/m2 as an intravenous 
infusion which should be started slowly and increased to a maximum of 1.5 ml/min (15 min 
at 0.5 ml/min, 15 min at 1.0 ml/min. and thereafter 1.5 ml/min.) on days 1, 4, 8, 11, 15, 18, 
29, 32, 36, 39, 43 and 46 plus gemcitabine 1000 mg/m², 30 min. i.v. infusion on days 4, 11, 
18, 32, 39, and 46 of cycle 1 until any one of the following occurs:  progressive disease or 
unacceptable toxicity or withdrawal of consent 
• 
Subsequent treatment cycles: EndoTAG-1 on days 1, 4, 8, 11, 15, 18, 29, 32, 36, 39, 43 and 
46 plus gemcitabine on days 4, 11, 18, 32, 39, and 46 of all subsequent cycles, until any one 
of the following occurs:  progressive disease or unacceptable toxicity or withdrawal of 
consent 
Arm B: 
• 
Treatment cycle 1: gemcitabine 1000 mg/m², 30 min. i.v. infusion on days 4, 11, 18, 32, 39, 
and 46 of cycle 1 until any one of the following occurs:  progressive disease or unacceptable 
toxicity or withdrawal of consent 
• 
Subsequent treatment cycles: gemcitabine on days 4, 11, 18,  32, 39, and 46 of all subsequent 
cycles, until any one of the following occurs: progressive disease or unacceptable toxicity or 
withdrawal of consent 
Dose adjustment in the event of toxicities: 
The doses and timing of treatment will be modified based on toxicities experienced by the subject. 
Dose modification and retreatment are outlined below: 
Dose Modifications for EndoTAG-1: 
Criteria for Dose Modifications 
• 
Grade 4 neutropenia lasting 7 or more days 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
• 
Febrile neutropenia 
• 
Grade 4 thrombocytopenia  
• 
Grade 3 thrombocytopenia with significant bleeding or requiring transfusion 
• 
Grade ≥ 3 stomatitis/vomiting/diarrhea 
• 
Other ≥ Grade 3 and 4 toxicities a, b 
a Except Grade 3 fatigue/asthenia or transient arthralgia/myalgia for which no dose modification 
is required. 
b To be adjusted as medically indicated after discussion between Investigator and Sponsor 
If any of the above mentioned toxicity criteria are present, no study medication is to be 
administered at this visit. If the toxicity criteria are no longer fulfilled at the next scheduled visit, 
EndoTAG-1 is to be administered at a reduced dose of 11 mg/m². If the subject tolerates treatment 
at the reduced dose (i.e. does not develop any of the above mentioned toxicities), the EndoTAG-1 
dose should be re-escalated to 22 mg/m². If re-escalation is not tolerated by the subject, the dose is 
to be permanently reduced to 11 mg/m². The attempt for re-escalation of the EndoTAG-1 dose is 
to be made only once throughout the study. Subjects not tolerating treatment even after dose 
reduction will be taken off study.  
Dose Modifications for Gemcitabine: 
Dose Modifications for Hematologic Adverse Reactions  
Absolute granulocyte 
count 
(x 106/L) 
 
Platelet count 
(x 106/L) 
% of full dose 
≥ 1000 
And 
≥100,000 
100% 
500-999 
Or 
50,000 – 99,999 
75% 
<500 
Or 
<50,000 
Hold 
Dose Modifications for Non-Hematologic Adverse Reactions  
Permanently discontinue gemcitabine for any of the following:  
• Unexplained dyspnea or other evidence of severe pulmonary toxicity  
• Severe hepatic toxicity  
• Hemolytic-uremic syndrome  
• Capillary leak syndrome  
• Posterior reversible encephalopathy syndrome  
Note: Withhold gemcitabine or reduce dose by 50% for other severe (Grade 3 or 4) non-
hematological toxicity until resolved. No dose modifications are recommended for alopecia, 
nausea, or vomiting. 
If a subject fails to meet criteria for retreatment on the day the next treatment is scheduled, 
treatment should be omitted and the subject will be re-evaluated at least weekly. Treatment may 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
be omitted for a maximum of 2 weeks. If treatment is omitted for >1 week, a new cycle should be 
started upon continuation of treatment. Any subject who fails to recover from a treatment related 
adverse event to baseline or Grade 2  within 2 weeks of scheduled retreatment will be withdrawn 
from the study with the exception of subjects who benefit from study treatment (non-progressive 
disease according to RECIST v.1.1), who may continue treatment on study after consultation and 
approval of the Sponsor. 
Subjects assigned to Arm A (EndoTAG-1 plus Gemcitabine) 
Subjects may start a new cycle of combination therapy if ANC is > 1,500/mm3, platelets are > 
100,000/mm3 and treatment-related non-hematologic adverse event including neuropathy has 
resolved to baseline or Grade 2. Subjects with Grade 2 neuropathy will not be retreated until 
resolved to Grade 1. 
Note: Subjects on treatment arm A who require discontinuation of gemcitabine will not continue 
on single-agent EndoTAG-1 alone. However, subjects in Treatment Arm A who require 
discontinuation of EndoTAG-1 due to toxicity may continue on gemcitabine monotherapy. 
Subjects on Arm B (gemcitabine alone) will not be offered treatment with EndoTAG-1 at the time 
of discontinuation (no cross-over allowed). 
Statistical Considerations: 
Sample Size Determination and Rationale:  
A total of 218 subjects will be enrolled and randomized in a 1:1 ratio to Arm A (EndoTAG-1 plus 
gemcitabine) and Arm B (gemcitabine monotherapy). The sample size is event-driven to collect a 
pre-specified number of primary efficacy outcomes. Based on the sample size calculation, the 
primary endpoint analysis for overall survival will require 167 events (deaths) for 196 subjects. 
The primary endpoint analysis for progression-free survival will require 169 events (disease 
progression) from 182 subjects.  This sample size is sufficient to detect a 40% reduction in the risk 
of death in Arm A, as compared with Arm B (hazard ratio, 0.60) using a 2-sided log-rank test with 
90% power and an overall significance level of 0.05 two sided test.  This sample size is also 
sufficient to detect a 35% reduction of progressive free survival in the risk of disease progression 
in Arm A, as compared with Arm B (hazard ratio, 0.647) using a 2-sided log-rank test with more 
than 80% power and an overall significance level of 0.05 two sided test. Sample size estimation is 
depicted in Figure 9-1 and Figure 9-2, total sample size requirement vs. the median survival time 
(month) in the treatment arm.  
A dropout rate of 10% is factored in the sample size calculations for a total sample size of 218 
subjects. Sample size is estimated using PASS (15) sample size software.  
The overall survival assumption for the sample size are based on published literature data 
comparing therapeutic effect of gemcitabine monotherapy and gemcitabine combination regimen 
on patients with advanced pancreatic cancer after previous FOLFIRINOX treatment. The hazard 
ratio for death of 0.60 with median overall survival of 4.4 months for gemcitabine monotherapy 
(Conroy et al. 2011) and 7.3 months for gemcitabine + paclitaxel combination (Portal et al. 2015) 
was used for the sample size calculation. The progression-free survival assumption for the sample 


 
 
 
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Name of Sponsor/Company:  
SynCore Biotechnology Co., Ltd. 
Name of Study Product:  
EndoTAG-1 (paclitaxel in cationic liposomes) 
Protocol Number:  
CT 4006 
Indication:  
Unresectable Locally Advanced/ Metastatic Adenocarcinoma of the 
Pancreas 
size are based on hazard ratio of 0.647 with median progression-free survival of 3.3 months for 
gemcitabine monotherapy (Conroy et al. 2011) and 5.1 months for gemcitabine + paclitaxel 
combination (Portal et al. 2015) was used for the sample size calculation. 
Randomization and Stratification:  
Prior to randomization, subjects will be stratified by extent of disease (subjects with locally 
advanced and metastatic pancreatic cancer) and the performance status (ECOG performance status 
0 and 1).  Then they will be randomized with a 1:1 ratio. 
Analysis Populations:  
The Intent-to-Treat (ITT) population is defined as all subjects randomized regardless of actual 
treatment received. The ITT population will be the primary population for the analysis of primary 
and secondary endpoints.  
The Per Protocol (PP) population is defined as the set of subjects who meet the ITT population 
requirements, and were not associated with a major protocol violation. This population will be 
identified before the database lock.  
The Safety population is defined as any subject receiving the treatment after randomization. This 
population will be used for the analysis of safety parameters. 
Analysis Considerations:  
A detailed Statistical Analysis Plan (SAP) accompanies the protocol and any amendments to the 
SAP will be finalized prior to final database lock. Any significant changes to the analyses described 
in this protocol will be highlighted in the SAP and the Clinical Study Report. 
Analysis of time-to-event parameters (OS, PFS): times to event will be estimated together with the 
respective 95% CIs for each treatment group using the Kaplan-Meier method. The log-rank test 
(stratification factors ECOG and TNM) will be calculated for comparison of OS and PFS for the 
combination therapy treatment versus the gemcitabine monotherapy group. 
Tumor response: For each subject, the overall response to treatment after the initial 7-week 
treatment cycle will be assessed according to RECIST v.1.1 criteria. The proportions of subjects 
with CR, PR, OR, SD, PD, disease control (CR, PR or SD), at the end of cycle 1, as well as the 
overall response to treatment, will be calculated for each treatment group and presented with exact 
95% confidence intervals (CIs). 
Change from baseline in CA 19-9: The proportion of subjects with a change from normal to 
abnormal, no change, or a change from abnormal to normal, and the proportion of subjects with a 
response will be calculated. Exact 95% CIs will be calculated for the proportion of subjects with a 
change from abnormal to normal and for the proportion of subjects with a response. 
Change from baseline in QLQ-C30 and PAN-26: Differences in proportions between treatment 
groups will be estimated and exact 95% CIs will be calculated for these estimates. These analyses 
will be performed for all individual QoL scores, QLQ-C30 Global Health score and for the PAN-
26 score at the end of treatment cycle 1 and also for the full treatment course. 
 


 
 
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TABLE OF CONTENTS 
List of Changes from Previous Version ...................................................................... 4 
Protocol Synopsis ........................................................................................................ 17 
List of Abbreviations .................................................................................................. 34 
1 
Introduction ......................................................................................................... 38 
1.1 
Background Information ............................................................................... 38 
1.2 
EndoTAG-1 ................................................................................................... 38 
1.2.1 
Non-clinical studies using EndoTAG-1 .................................................... 39 
1.2.2 
Clinical studies using EndoTAG-1 ........................................................... 41 
2 
Study Objectives and Endpoints ........................................................................ 47 
2.1 
Study Objectives ........................................................................................... 47 
2.1.1 
Efficacy Objectives ................................................................................... 47 
2.1.2 
Secondary Objective ................................................................................. 47 
2.2 
Study Endpoints ............................................................................................ 47 
2.2.1 
Primary Efficacy Endpoints ...................................................................... 47 
2.2.2 
Secondary Efficacy Endpoints .................................................................. 47 
2.2.3 
Safety Assessments: .................................................................................. 48 
2.2.4 
Exploratory Endpoints .............................................................................. 49 
3 
Investigational Plan............................................................................................. 50 
3.1 
Study Design ................................................................................................. 50 
3.2 
Study Center(s) ............................................................................................. 51 
3.3 
Study Population ........................................................................................... 51 
3.4 
Eligibility Criteria ......................................................................................... 51 
3.4.1 
Inclusion Criteria ...................................................................................... 51 
3.4.2 
Exclusion Criteria ..................................................................................... 52 
4 
Study Schedule .................................................................................................... 54 
4.1 
Screening Visit .............................................................................................. 54 
4.2 
Treatment Phase ............................................................................................ 56 
4.2.1 
Treatment Visit 1 (Baseline for Arm A) ................................................... 57 
4.2.2 
Treatment Visit 1G (Baseline for Arm B) ................................................ 57 
4.2.3 
Treatment Visits 2, 3, 5, 6 and 7 ............................................................... 58 
4.2.4 
Treatment Visits 2G, 3G, 5G, 6G and 7G ................................................. 59 
4.2.5 
Treatment Visit 8 / End of Treatment (EOT) Visit ................................... 60 
4.2.6 
Continuation of Treatment, Subsequent Cycles ........................................ 61 
4.3 
Follow-Up Phase ........................................................................................... 63 
4.3.1 
Follow-Up Visit 1 (8 weeks after last study treatment) ............................ 63 
4.3.2 
Subsequent Follow-Up Visits ................................................................... 64 
4.4 
Unscheduled Visits ....................................................................................... 65 
5 
Subject completion and withdrawal .................................................................. 66 
5.1 
Subject Completion ....................................................................................... 66 
5.2 
Withdrawal of Subject from Therapy or Assessment ................................... 66 


 
 
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5.2.1 
Discontinuation of Study Treatment ......................................................... 67 
5.2.2 
Data Collected for Withdrawn Subjects ................................................... 67 
5.3 
Screen Failures .............................................................................................. 68 
6 
Study Treatments ................................................................................................ 69 
6.1 
Investigational Product (IP): EndoTAG-1 .................................................... 69 
6.2 
Comparator Product (IP): Gemcitabine ........................................................ 70 
6.3 
Packaging and Labeling of Investigational Product ..................................... 70 
6.4 
EndoTAG-1: Dose Justification .................................................................... 70 
6.5 
Study Dosing Schedule ................................................................................. 71 
6.6 
Dispensing, Storage and Accountability ....................................................... 72 
6.6.1 
Preparation of EndoTAG-1 and i.v. administration .................................. 72 
6.6.2 
Preparation of gemcitabine and i.v. administration .................................. 73 
6.7 
Dose adjustments .......................................................................................... 73 
6.7.1 
Dose Modifications for EndoTAG-1 ........................................................ 74 
6.7.2 
Dose Modifications for Gemcitabine ........................................................ 74 
6.7.3 
Dose Modification for Subjects Assigned to Arm A (EndoTAG-1 plus 
Gemcitabine) ......................................................................................................... 75 
6.8 
Contraindications, Precautions, and Warnings for EndoTAG-1 .................. 75 
6.8.1 
Contraindications ...................................................................................... 75 
6.8.2 
Precautions and Warnings ......................................................................... 76 
6.8.3 
Emergency Medication for infusion related toxicity ................................ 76 
6.9 
Contraindications, Precautions, and Warnings for Gemcitabine .................. 76 
6.10 
Other study medication ................................................................................. 77 
6.11 
Prior and Concomitant Medication ............................................................... 77 
6.11.1 
Prior Treatment ..................................................................................... 77 
6.11.2 
Permitted Treatment .............................................................................. 77 
7 
Description of Study Assessments and Procedures .......................................... 79 
7.1 
Informed Consent .......................................................................................... 79 
7.2 
Assessment of Eligibility .............................................................................. 79 
7.3 
Disease History ............................................................................................. 79 
7.4 
Medical History ............................................................................................ 79 
7.5 
Demographic Information ............................................................................. 80 
7.6 
ECOG Performance Status ........................................................................... 80 
7.7 
Physical Examination .................................................................................... 81 
7.8 
BSA Calculation ........................................................................................... 81 
7.9 
Vital Signs ..................................................................................................... 81 
7.10 
Laboratory Assessments ............................................................................... 82 
7.11 
PK Blood Sample Collection ........................................................................ 82 
7.12 
Quality of Life Questionnaire ....................................................................... 83 
7.13 
Tumor Imaging ............................................................................................. 83 
7.14 
Tumor Response Evaluation ......................................................................... 83 
7.14.1 
Definition of lesions .............................................................................. 83 


 
 
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7.14.2 
Method of Assessment .......................................................................... 84 
7.14.3 
Baseline documentation of ‘target’ and ‘non-target’ lesions ................ 85 
7.14.4 
Evaluation of target lesions ................................................................... 85 
7.14.5 
Evaluation of non-target lesions ........................................................... 86 
7.14.6 
Evaluation of Best Overall Response ................................................... 86 
7.15 
Electrocardiogram ......................................................................................... 87 
7.16 
Concomitant Medication ............................................................................... 87 
7.17 
Randomization .............................................................................................. 88 
7.18 
Study Treatment Administration ................................................................... 88 
7.19 
Appropriateness of Measurements ................................................................ 88 
8 
Adverse Events Definitions and Reporting ....................................................... 89 
8.1 
Adverse Events (AE) .................................................................................... 89 
8.1.1 
Impact on Study Treatment ....................................................................... 90 
8.1.2 
Intensity Assessment ................................................................................. 90 
8.1.3 
Causality Assessment ................................................................................ 91 
8.1.4 
Treatment Given as a Result of the Event ................................................ 91 
8.1.5 
Outcome Assessment ................................................................................ 91 
8.2 
Adverse Event Reporting .............................................................................. 91 
8.3 
Serious Adverse Events (SAEs) .................................................................... 92 
8.4 
Serious Adverse Event Reporting ................................................................. 93 
8.5 
SAE Follow-Up ............................................................................................ 93 
8.6 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ...................... 94 
8.7 
Expedited Reporting of SUSAR ................................................................... 94 
8.8 
Pregnancies ................................................................................................... 94 
9 
Statistical Considerations ................................................................................... 97 
9.1 
Treatment Groups ......................................................................................... 97 
9.2 
Description of Study Endpoints .................................................................... 97 
9.2.1 
Efficacy Endpoints .................................................................................... 97 
9.2.2 
Safety Assessments ................................................................................... 98 
9.2.3 
Exploratory Endpoints .............................................................................. 98 
9.3 
Sample Size Determination and Rationale ................................................... 99 
9.4 
Randomization and Stratification ............................................................... 100 
9.5 
Blinding ....................................................................................................... 101 
9.6 
Interim Analysis .......................................................................................... 101 
9.6.1 
Metrics to be Calculated for the Interim Analysis .................................. 102 
9.6.2 
Rules and Methods for Decisions at the Time of the IA ......................... 103 
9.6.3 
Rule and Method for Protection of Type I Error Rate ............................ 104 
9.7 
General Statistical Considerations .............................................................. 104 
9.7.1 
Analysis Populations ............................................................................... 105 
9.7.2 
Covariates ............................................................................................... 105 
9.7.3 
Subgroups ............................................................................................... 105 
9.7.4 
Missing data ............................................................................................ 105 


 
 
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9.8 
Analysis Methods ........................................................................................ 105 
9.8.1 
Subject Disposition ................................................................................. 106 
9.8.2 
Demographic and Baseline Characteristics ............................................ 106 
9.8.3 
Efficacy Analyses ................................................................................... 106 
10 Direct Access to Source Data/Documentation ................................................ 109 
11 Quality Control and Quality Assurance ......................................................... 110 
11.1 
Monitoring Requirements ........................................................................... 110 
11.2 
Acceptability of electronic Case Report Forms (eCRFs) ........................... 110 
11.3 
Modification of Protocol ............................................................................. 110 
11.4 
Reporting Protocol Deviations .................................................................... 111 
11.4.1 
Major Protocol Deviation or Violation ............................................... 111 
11.4.2 
Minor Protocol Deviation or Violation ............................................... 111 
12 Data and Safety Monitoring Board (DSMB) .................................................. 113 
13 Ethics and Regulatory Requirements ............................................................. 114 
13.1 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ..... 114 
13.2 
Investigator’s Responsibilities .................................................................... 114 
13.3 
Subject Informed Consent Requirements ................................................... 114 
14 Data Handling and Record Keeping ............................................................... 116 
14.1 
Recording and Collection of Data ............................................................... 116 
14.2 
Clinical Data Management ......................................................................... 116 
14.3 
Archiving .................................................................................................... 116 
15 Publication Plan ................................................................................................ 118 
16 References .......................................................................................................... 120 
17 Appendices ......................................................................................................... 122 
17.1 
Appendix-I: EORTC QLQ-C30 (version 3) ............................................... 122 
17.2 
Appendix-II: EORTC  QLQ - PAN26 ........................................................ 124 
 


 
 
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TABLES 
 
Table 0-1: 
Schedule of Assessments – Screening and Treatment Phase ................ 36 
Table 0-2: 
Schedule of Assessments – Subsequent Treatment Cycles and Follow-up 
Phase ..................................................................................................... 37 
Table 6-1: 
Excipients of EndoTAG-1 .................................................................... 70 
Table 7-1: 
ECOG Performance Status Scale .......................................................... 80 
Table 7-2: 
Target Lesion Evaluation ...................................................................... 86 
Table 7-3: 
Non-Target Lesion Evaluation .............................................................. 86 
Table 7-4: 
Time point response: subjects with target (± non-target) disease ......... 87 
Table 8-1:  
CTCAE v4.03 General Guidelines ....................................................... 90 
 
 
 
 


 
 
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FIGURES 
 
Figure 6-1: 
Structural Formula - EndoTAG-1 (paclitaxel) ...................................... 69 
Figure 9-1: 
Overall Survival Sample Size Plot: Total sample size requirement vs. the 
median survival time (month) in the treatment arm A. ............................................... 100 
Figure 9-2:  
Progression-Free Survival Sample Size Plot: Total sample size 
requirement vs. the median survival time (month) in the treatment arm A ................ 100 
 


 
 
 
 
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List of Abbreviations 
Abbreviation 
Definition 
AE(s) 
Adverse Event(s) 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
API 
Active Pharmaceutical Ingredient 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
BW 
Body Weight 
CL 
Clearance 
Cmax 
Maximum Plasma Concentration 
CR 
Complete Response 
eCRF 
Electronic Case Report Form 
CRO 
Clinical Research Organization 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
DOPC 
dioleoyl-phosphatidylcholine 
DOTAP 
dioleoyl-trimethylammonium-propane  
DOTAP-Cl 
dioleoyl-trimethylammonium-propane chloride 
DR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
GCP 
Good Clinical Practice 
GEM 
gemcitabine 
GGT 
Gamma Glutamyl Transferase 
Hb 
Hemoglobin 
HDL 
High-density Lipoprotein 
Hct 
Hematocrit 
HIPAA 
Health Insurance Portability Accountability Act 
HIV 
Human Immunodeficiency Virus 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 


 
 
 
 
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Abbreviation 
Definition 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LAR 
Legally Acceptable Representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MRI 
Magnetic Resonance Imaging 
NCI-CTC 
National Cancer Institute - Common Terminology Criteria 
NOAEL 
no observed adverse effect level 
NSCLC 
Non-Small Cell Lung Cancer 
OR 
Objective Response 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PR 
Partial Response 
PT 
Prothrombin 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE(s) 
Serious Adverse Event(s) 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
TNBC 
Triple-Negative Breast Cancer 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WOCBP 
Women Of Child Bearing Potential 
 
 


 
  
 
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Table 0-1: 
Schedule of Assessments – Screening and Treatment Phase 
 
Screening 
Phase 
Treatment Phase 
First cycle 
VISIT NUMBER 
SV 
11 
1 G2 
2 
2 G 
3 
3 G 
rest 
5 
5 G 
6 
6 G 
7 
7 G 
83/ 
EOT 
DAY 
Within 14 
days from 
D1 
Wk 1  
(D1) 
Wk 1 
(D4) 
Wk 2 
(D8) 
Wk 2 
(D11) 
Wk3 
(D15) 
Wk 3  
(D18) 
Wk 4 
 
Wk 5 
(D29) 
Wk 5 
(D32) 
Wk 6  
(D36) 
Wk 6  
(D39) 
Wk 7  
(D43) 
Wk 7  
(D46) 
Wk 8 
(D53) 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical examination 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Laboratory assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology  
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry 
X 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
X 
Coagulation parameter 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
CA 19-9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PK blood sample collection 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
QoL questionnaires 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tumor imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Group A  
(EndoTAG-1 + gemcitabine) 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Treatment Group B 
(gemcitabine monotherapy) 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
1 Visit without suffix “G”: administration of EndoTAG-1 only; visit applies only to subjects of treatment group A 
2 Visits with suffix “G”: administration of gemcitabine (Treatment Groups A and B) +/- EndoTAG-1 (Treatment group A) 
3   End of Cycle visit 
 
4   Imaging every 8 weeks irrespective of timing of treatment cycle 


 
  
 
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Table 0-2: 
Schedule of Assessments – Subsequent Treatment Cycles and Follow-up Phase 
 
Treatment Phase 
Subsequent cycles 
Follow-up Phase 
VISIT NUMBER 
11 
1 G2 
2 
2 G 
3 
3 G 
rest 
5 
5 G 
6 
6 G 
7 
7 G 
83/EO
T
Follow-
up visit 1 
Subsequ
ent 
Follow-
up visits 
DAY 
Wk 1  
(D1) 
Wk 1 
(D4) 
Wk 2 
(D8) 
Wk 2 
(D11) 
Wk3 
(D15) 
Wk 3  
(D18) 
Wk4 
Wk 5 
(D29) 
Wk 5 
(D32) 
Wk 6  
(D36) 
Wk 6  
(D39) 
Wk 7  
(D43) 
Wk 7  
(D46) 
Wk 8  
(D53) 
8 weeks  
after last 
study 
treatment
5 
until end 
of study5 
ECOG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Physical examination 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Chemistry 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
Coagulation parameter 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
CA 19-9 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
QoL questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Tumor imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
X4 
 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
Group 
A 
(EndoTAG-1 + gemcitabine) 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Treatment 
Group 
B 
(gemcitabine monotherapy) 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Change in tumor therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
1 Visit without suffix “G”: administration of EndoTAG-1 only; visit applies only to subjects of treatment group A 
2 Visits with suffix “G”: administration of gemcitabine (Treatment Groups A and B) +/- EndoTAG-1 (Treatment group A) 
3   End of Cycle visit 
4   Imaging every 8 weeks irrespective of timing of treatment cycle 
 
5   Follow up visits will be performed at every 8-week interval


 
 
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1 Introduction 
1.1 
Background Information 
Pancreatic cancer, which is the 4th leading cause of cancer death in the United States 
(Jemal et al. 2008), is an indication with high need for improvement of systemic therapy. 
Less than 20% of pancreatic cancer patients are diagnosed with resectable and 
potentially curable disease while the vast majority of patients have advanced disease at 
the time of diagnosis with a median survival of approximately 6 months.  
FOLFIRINOX regimen is the standard first-line treatment for pancreatic cancer patients 
with good performance status. However, the optimal management strategy for patients 
who fail initial FOLFIRINOX remains undefined. There is still no standard of care in 
second-line therapy for patients with disease progression. 
Gemcitabine has been the standard systemic therapy for unresectable pancreatic cancer 
for the last decade, though 1-year survival rates ranging around 18% are still 
unsatisfactory (Burris et al. 1997; Moore et al. 2007). Numerous trials have aimed to 
demonstrate superiority of combinations of gemcitabine with other chemotherapeutics 
or targeted agents with disappointing results.  
Results of a controlled, randomized Phase 2 clinical trial comprising 200 patients 
indicate a considerable survival benefit for patients with advanced pancreatic cancer 
treated with EndoTAG-1 in combination with gemcitabine compared to gemcitabine 
monotherapy. 
The aim of this adaptive Phase 3 trial is to show a statistically significant superiority of 
EndoTAG-1 in combination with gemcitabine compared to gemcitabine monotherapy 
in patients with locally advanced/metastatic pancreatic cancer after FOLFIRINOX 
failure. 
1.2 
EndoTAG-1 
EndoTAG-1 is a novel formulation of cationic liposomes for the treatment of solid 
tumors, carrying paclitaxel embedded in the liposome membrane. Cationic liposomes 
are known to bind and internalize at tumor endothelial cells after intravenous 
administration, which is the basis for the new mode of action of EndoTAG-1. Using a 
cationic liposome formulation, the cytostatic and cytotoxic activities of paclitaxel are 
targeted to the activated tumor endothelial cells. Therefore, in contrast to conventional 
chemotherapy aiming at tumor-cell toxicity, EndoTAG-1 specifically displays 
antivascular and antiangiogenic activity. 
EndoTAG-1 was first developed by Munich Biotech AG (Germany) under the names 
LipoPac and MBT-0206 and by Medigene AG under the name of EndoTAG-1. Since 
2013, development and global commercialization of EndoTAG-1 is executed by 
SynCore Biotechnology Co., Ltd. 


 
 
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EndoTAG-1 is formed by the synthetic cationic lipid dioleoyl-trimethylammonium-
propane chloride (DOTAP-Cl) and the natural neutral phospholipid dioleoyl-
phosphatidylcholine (DOPC). In an aqueous solution of trehalose, liposomal 
membranes embedded with paclitaxel are assembled. 
1.2.1 Non-clinical studies using EndoTAG-1 
EndoTAG-1, when given intravenously in a variety of syngeneic and xenograft tumor 
models in mice and hamster, showed a pronounced higher uptake into tumor tissue 
compared to normal tissue. In all models tested, EndoTAG-1 led to a significantly 
reduced tumor growth activity compared to treatment with standard paclitaxel, 
independent of tumor type, animal species and immune status. In addition, the rate of 
metastasis was significantly decreased by EndoTAG-1 compared to standard paclitaxel. 
Furthermore, EndoTAG-1 was shown to be effective in paclitaxel-resistant tumors in 
animals. 
An increased anti-tumor activity in animals was observed when EndoTAG-1 was 
combined with other cytostatic or cytotoxic agents. Combination therapy (e.g. 
EndoTAG-1 + gemcitabine) showed enhanced tumor regression, reduction of lymph 
node metastases and absence of liver metastases compared to either monotherapy. In 
vitro, combination therapies of Endo TAG-1 with chemotherapeutics showed complete 
or concentration-dependent additivity, thus supporting the in vivo data. 
Mode-of-action studies in rodents demonstrated the neovascular targeting properties of 
EndoTAG-1. A strong decrease of the endothelial proliferation index in the tumor 
periphery as well as a reduction of the tumor perfusion index and an increase of 
endothelial cell apoptosis was observed. These results indicate a potential dual mode-
of-action of EndoTAG-1 by combining anti-neovascular and anti-tumor effects 
(Eichhorn et al 2010, Strieth et al 2008, Strieth et al 2004, Schmitt-Sody et al 2003). 
Toxicology 
The toxicological profile of EndoTAG-1 has been evaluated in single- and repeated-
dose toxicity studies in mice, rats and dogs covering treatment periods of up to 26 weeks. 
In an acute toxicity study in mice mortality was observed at 5.4 mg/kg BW liposomal 
paclitaxel. The same mortality was reported in the control group using empty liposomes 
and was most likely due to the large volumes of injected suspended lipid complexes. 
No other findings were reported in the acute toxicity studies. 
In subchronic toxicity studies in rats the high dose EndoTAG-1 group (1.5 mg/kg BW 
liposomal paclitaxel) showed slight weight loss and reduction of white blood cells. The 
main histopathological finding was hypocellularity of the hematopoetic bone marrow 
in about one third of the rats in this dose group. The effects were reversible and resolved 
during recovery. 
Acute, subchronic and chronic repeated dose toxicity studies have been performed in 
dogs. In the 14-day and 28-day studies liposomal paclitaxel doses up to 1.7 mg/kg BW 


 
 
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and 1.5 mg/kg BW, respectively, per application were given daily or every other day. 
At higher doses reduced food uptake accompanied by a moderate but continuous 
reduction in body weight was observed and lesions were found in the gastrointestinal 
tract - findings which are attributed to the action of paclitaxel. With daily treatment, 
lethal toxicity was observed in all dose groups. When dosed at 2-day intervals, 
treatment was tolerated better and only some animals of the higher dose groups died. 
In the 90-day and 180-day studies, doses up to 1.2 mg/kg BW were applied twice a 
week, resulting in a total of 22 to 27 and 46 applications, respectively. Due to severe 
toxicities including mortality observed in the high dose group, treatment was 
interrupted and, in part, reduced to one application per week. 
A "no observed adverse effect level" (NOAEL) could not be established in studies 
covering a treatment period of 3 or 6 months, which is common for cytostatic and 
cytotoxic drugs with low therapeutic index. The non-clinical toxicity studies indicate 
that the haematopoietic system, the gastrointestinal tract including the liver and the gall 
bladder and the male gonads are the potential target organs in humans. Microscopic 
lesions were seen mainly in areas of high tissue turn-over such as the gastrointestinal 
tract and the testes. Based on acute findings (hemorrhagic pulmonary edema) observed 
in a number of animals that died prematurely in the subchronic and chronic toxicity 
studies in dogs, the lung represents an additional target organ. During clinical 
application of EndoTAG-1 the function of these organ systems should be closely 
monitored. Other known side effects of standard paclitaxel were not observed during 
administration of EndoTAG-l. 
Pharmacokinetics 
The pharmacokinetic profile of EndoTAG-1 has been established in single dose studies 
in mice and rats and in repeated dose toxicokinetic studies in rats and dogs. The highest 
systemic exposure of paclitaxel from EndoTAG-1 was observed in humans and dogs, 
and the lowest in rats and mice. These findings were in line with the clearance rates 
observed, which were low for non-rodents (humans/ dogs) and high for rodents (rats/ 
mice). 
A linear pharmacokinetic relationship was determined for the administered EndoTAG-
1 dose and the Cmax and AUC of paclitaxel in rats and dogs. The pharmacokinetic 
profiles of paclitaxel from EndoTAG-1 compared to standard paclitaxel in rodents 
seemed to be almost identical at lower doses (1.1 mg/ kg BW liposomal paclitaxel), 
whereas at higher doses (5 mg/ kg BW liposomal paclitaxel) Cmax and AUC values of 
paclitaxel from EndoTAG-1 were markedly lower. No comparative studies have been 
performed in non-rodents. 
In vitro and in vivo studies demonstrated comparable metabolism of paclitaxel for 
EndoTAG-1 and standard paclitaxel. Both agents resulted in similar biodistribution 
patterns and kinetics in female rats. The highest concentration of paclitaxel was found 
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and adrenal gland. Paclitaxel was mainly excreted in bile (-88% of dose) and excretion 
was almost completed after 72 hours for both EndoTAG-1 and standard paclitaxel. 
The pharmacokinetic profile of the cationic liposomal constituent DOTAP is 
characterized by a linear relationship between the administered EndoTAG-1 dose and 
Cmax and AUC. In contrast to paclitaxel a later Cmax was observed for DOTAP. It 
appears to be slowly distributed and is incompletely cleared from systemic blood 
circulation. The results of the biodistribution study in female rats showed that a large 
amount of DOTAP is transiently distributed to the lungs and relatively high levels are 
maintained until a marked decrease of DOTAP occurred between 6-24 hours. In 
contrast, liver, kidneys and spleen showed a gradual increase of DOTAP levels up to 
6-24 hours. DOTAP was mainly excreted in the urine (78% of dose) and excretion 
occurred rather slowly. After 5 days, 9.2% of the dose was still present in the body. 
Consequently, accumulation of DOTAP was observed in the plasma of rats and dogs 
when EndoTAG-1 was administered twice per week for 26 weeks, but was not 
associated with a notable increase in toxicities. 
In vitro studies with human liver microsomes suggested either the absence of or only a 
weak Cytochrome P450 inhibition potential for DOTAP, whereas Cremophor EL, the 
excipient of standard paclitaxel, turned out to be a very potent Cytochrome P450 
inhibitor. 
1.2.2 Clinical studies using EndoTAG-1 
A total of 460 subjects with a variety of solid tumors have been treated with EndoTAG-
1 during participation in clinical studies. 
Nine clinical studies (phase 1/2) were initiated by the company Munich Biotech AG 
(MBT), which originally started the development of EndoTAG-1. Various doses (2.63 
- 66 mg/m2 liposomal paclitaxel), infusion speeds (up to 2.5 mL/min) and schedules 
(daily to weekly, for up to nine weeks) were examined in these studies. In these studies, 
a total of 163 subjects were treated with EndoTAG-1. EndoTAG-1 was usually given 
as a monotherapy except for one study in NSCLC (combination with carboplatin) and 
one study in gastrointestinal cancer (combination with 5-FU). 
At MediGene AG, three phase 2 trials have been conducted: 
• CT4001, an open-label, randomized, controlled Phase 2 study in 200 subjects with 
locally advanced or metastatic pancreatic cancer, was conducted to assess the safety 
and efficacy of a combination therapy of gemcitabine (Gemzar®) and EndoTAG-1 
at three different dose levels (corresponding to 11, 22 and 44 mg/m2 paclitaxel) 
versus gemcitabine monotherapy. EndoTAG-1 in combination with gemcitabine 
was generally well tolerated, corroborating the favorable safety profile observed in 
the Phase 1/2 studies. In terms of efficacy, the results indicate a survival benefit in 
subjects receiving EndoTAG-1 in combination with gemcitabine compared to 
gemcitabine alone, both for progression-free and overall survival. 


 
 
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• CT4002 was an open-label, randomized, controlled Phase 2 study to assess the 
efficacy and safety of treatment with infusions of EndoTAG-1 monotherapy 
(44mg/m² paclitaxel) twice per week or weekly infusions of EndoTAG-1 (22 mg/m² 
paclitaxel) in combination with standard paclitaxel (70 mg/m²) compared with 
paclitaxel monotherapy (90 mg/m² weekly) in 140 subjects with locally relapsed 
and/or metastatic triple receptor-negative breast cancer (TNBC). Treatment with 
EndoTAG-1 alone or in combination was well tolerated with manageable adverse 
events. The PFS rate at week 16, the primary efficacy endpoint, was 59.1% on 
combination therapy, 34.2% on EndoTAG-1 and 48.0% on paclitaxel. Exact one-
sided 95% CIs revealed that the hypothesis H0 (PFS rate ≤ 30%) could be rejected 
for the EndoTAG-1/paclitaxel combination group only. For a subgroup of subjects 
with confirmed TNBC, ECOG 0/1 at baseline and receiving first-line therapy for 
advanced disease, a median OS of 17.8, 11.9, and 10.1 months was achieved by the 
three treatment groups, respectively. These results indicate that EndoTAG-1 in 
combination with standard paclitaxel could be an efficacious and safe first-line 
therapy for patients with advanced TNBC. 
• CT4003 was an open-label, uncontrolled Phase 2 study evaluating the single-dose 
and steady-state pharmacokinetics of EndoTAG-1 and its effect on the blood supply 
and the angiogenesis of hepatic metastases in 20 subjects with a carcinomatous 
primary tumor other than hepatocellular (HCC), biliary or bile duct carcinoma. 
An investigator initiated trial (IJBNeoEndoTAG-1) was conducted at the Institute Jules 
Bordet in Brussels, Belgium. This study was an open-label, uncontrolled, single- center 
trial in 15 subjects with HER2-negative breast cancer who were candidates for surgery, 
including 6 subjects with TNBC. The objective of this study was to evaluate efficacy 
and safety of neoadjuvant EndoTAG-1 (22 mg/m² paclitaxel) in combination with 
standard paclitaxel (70 mg/m²) administered as 12 weekly infusions, followed by 
fluorouracil (500mg/m2), epirubicin (100mg/m2) and cyclophosphamide (500mg/m2) 
(FEC) administered every 3 weeks for a total of 9 weeks. The safety results were as 
expected from previous trials. Treatment with EndoTAG-1 plus paclitaxel resulted in 
significant reduction of MRI-estimated tumor volume and linear tumor size compared 
with baseline. Overall, a pathologic complete response (pCR) was achieved in 33% of 
the subjects. Of the 6 subjects with TNBC, 5 subjects achieved pCR. 
Safety 
Safety data of 163 subjects suffering from various solid tumors are available from phase 
1/2 studies. 138 (84.6%) subjects experienced one or more adverse events (AEs), 902 
AEs were reported in total. Most of these events were assessed as being causally related 
to study medication by the investigator (668 of 902, or 74%) and were classified as non-
serious (830 of 902, or 92%). The majority of these non-serious adverse drug reactions 
(ADR's) were of transient nature. Only 20 (2.2 %) AEs were assessed as serious and 
drug-related by the investigator. 


 
 
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In study CT 4001, AEs were reported in 92% to 100% of subjects in each treatment 
arm. No unexpected toxicities have been observed. During the first treatment cycle, 
severe hematological toxicities (grade 3/4 NCI-CTC) related to any study medication 
occurred in 22, 32 and 40% of subjects in the different GEM+Endo groups (11, 22 and 
44 mg/m2, respectively) compared to 24% on Gem monotherapy. Combination of 
EndoTAG-1 and Gem resulted in a dose dependent increase of grade 3/4 
thrombocytopenia reaching up to 16% and 14% in the two higher dose levels, albeit 
without clinical symptoms or bleeding complications. At the highest EndoTAG-1 dose 
level (44mg/m2 twice weekly), increased rates of grade 3/4 neutropenia (22%) and 
anemia (12%) were observed. During the first cycle, a total of 7 cases of febrile 
neutropenia were reported in the two higher GEM+Endo dose levels, including 4 cases 
of grade 3/4. During additional cycles with GEM+Endo therapy, none was observed. 
Infusion-related reactions, predominantly pyrexia and chills, were found to a higher 
extent in GEM+Endo groups, whereas the addition of EndoTAG-1 to Gem did not 
increase the known liver toxicity of Gem. In the GEM+Endo44 arm, one case of 
neuropathy was reported in a subject with diabetes, but was considered unrelated to 
study medication. 
AEs resulting in discontinuation of study medication were reported in 4 subjects (8%) 
in the GEM+Endo11 and 7 subjects (14%) in each of the GEM+Endo22 and 
GEM+Endo44 group. During the first cycle, 2 subjects (4%) in each of the 
GEM+Endo11 and GEM+Endo22 group, and 1 subject (2%) in the GEM+Endo44 
group died, but deaths were considered not related to study medication. During 
additional cycles, another 2 subjects of the GEM+Endo11 group had SAEs with fatal 
outcome. Both events, Staphylococcal sepsis and death from unknown cause, were 
considered unlikely to be related to study medication. 
In study CT4002 safety analysis revealed qualitatively and quantitatively the known 
toxicities of EndoTAG-1 and standard paclitaxel. AEs were reported in 91% to 100% 
of subjects in each treatment arm. No unexpected toxicities have been observed. 
EndoTAG-1 showed a similar safety profile to paclitaxel. On combination treatment, a 
slight increase in grade 3/4 adverse events was observed compared to either 
monotherapy, with uncomplicated neutropenia being the most predominant adverse 
event. Neutropenia was highest among subjects on combination therapy (40%), 
whereas anemia was predominantly observed in the standard paclitaxel study arm 
(36%). Grade 3/4 hematological toxicities, especially neutropenia and leucopenia, 
occurred more often in the combination arm (20% and 7%) compared to either agent 
alone (4% and 2% for EndoTAG-1 monotherapy, 7% and 0% for standard paclitaxel, 
respectively) (Awada et al, 2010). 
As was observed in CT4001, infusion-related reactions, predominantly pyrexia and 
chills were found to a higher extent in EndoTAG-1 treatment arms and increased at 
higher doses. Peripheral sensory neuropathy was observed in 13% of the combination 
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standard paclitaxel, respectively. Severe neurotoxicity was reported for 1 subject (4%) 
of the standard paclitaxel treatment arm.  
In study CT4003 all 20 subjects experienced at least one AE, with a total of 330 AEs 
reported. 33 AEs of grade 3/4 and 21 SAEs were observed and reported from 11 (55%) 
subjects. The most frequent AEs were abdominal pain, nausea, vomiting and fatigue in 
10 to 14 subjects (50-70%). Hypersensitivity and hyperhidrosis occurred in 8 subjects 
each (40%) and were mostly of mild to moderate severity. Hematological toxicities 
were observed in 4 subjects (20%), including 3 events of anemia and 1 event each of 
neutropenia and leucopenia (both of grade 3 severity). Peripheral sensory neuropathy 
was reported for 3 subjects (15%). No AE with a severity of grade 4 was reported. 
Pharmacokinetics 
The pharmacokinetic properties of EndoTAG-1 were determined in three phase 1/2 
dose escalation studies (CTLP01, CTLP05 and CTLP06) exploring several dose levels 
(2.63-66 mg/m2 paclitaxel) and application regimen (2-5 times per week) and in study 
CT4003. 
Results of studies CTLP01, CTLP05 and CTLP06 revealed that the maximum plasma 
concentrations and extents of exposure of paclitaxel and DOTAP, administered as 
EndoTAG-1, increased with the dose. Data were too limited to assess whether the 
increase is proportional. The clearance of paclitaxel and DOTAP remained constant 
with increasing doses, with higher clearance levels observed for paclitaxel compared to 
DOTAP. There was no indication for paclitaxel accumulation in plasma at any dose 
level or application regimen studied. Although DOTAP is cleared from the plasma 
slowly, there was also no evidence for accumulation of DOTAP. 
In study CT4003 reliable PK-profiles were obtained for paclitaxel and DOTAP after 
single dose and in steady state following intravenous infusion of EndoTAG-1 (22 
mg/m2 twice weekly for 25 days). The pharmacokinetic parameters observed for 
paclitaxel and DOTAP confirmed previous results with 22 mg/m2 EndoTAG-1 from 
early clinical trials (CTLP05, CTLP06). The mean maximum plasma concentration of 
paclitaxel was comparable after single dose and in steady state. The extent of exposure 
showed a small increase from the first to the last dose. The mean maximum plasma 
concentration of DOTAP increased from the first to the last dose and the extent of 
exposure increased more pronounced compared to paclitaxel. Distribution and 
elimination kinetics of EndoTAG-1 appear to be largely comparably to standard 
paclitaxel at lower dose levels. Only minor accumulation has been observed for 
paclitaxel and DOTAP, suggesting that no considerable saturation of distribution or 
elimination systems occurred. Finally, consistent gender-specific differences have not 
been observed with respect to the pharmacokinetics of paclitaxel and DOTAP (Fasol et 
al, 2011). 
The pharmacokinetic parameters of EndoTAG-1, paclitaxel and DOTAP were 
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(CTLP01, CTLP05 and CTLP06) and one phase 2 study (CT4003). The results are 
presented in report titled, Pooled Analyses of Human Pharmacokinetic data of 
EndoTAG-1 dated 28-Feb-2017. 
Efficacy 
In their phase 1/2 studies, Munich Biotech AG included patients with hormone-
refractory prostate cancer (CTLP01), unresectable locally advanced or metastatic 
gastrointestinal (CTLP05) or colorectal cancer (CTLP10) and metastatic breast cancer 
(CTLP09) applying doses between 2.63 and 66 mg/m2 liposomal paclitaxel in various 
regimen of up to 9 weeks treatment. Subjects were evaluated for overall tumor response 
only, survival data were not collected. Complete responses were not reported. Partial 
responses were observed in 3 (8%, CTLP09) and 1 (3%, CTLP010) subjects, stable 
disease was seen in 13 (36%, CTLP09), 3 (8%, CTLP010) and 4 (14%, CTLP05) of the 
subjects. Accordingly the clinical benefit rate was 44% and 11% in CTLP09 and 
CTLP10, respectively. The effect on tumor stabilization was most distinct in subjects 
with metastatic breast cancer (CTLP09) with a dose-dependent effect on the rate of 
subjects with non-progressive disease (33% at 22 mg/m2, 56% at 44 mg/m2). In study 
CTLP01, PSA levels remained stable in the majority of subjects during treatment, but 
increased during the follow-up period. 1/12 (8.33%) of subjects showed stable disease 
(reduction of PSA levels > 50%) after 43 days. 
In summary, disease stabilization and partial response has been observed in some of the 
subjects. However, subject numbers were small and studies were conducted without 
comparator(s). Phase II studies of MediGene AG were conducted in patients with 
advanced pancreatic cancer (CT4001), triple receptor-negative breast cancer (CT4002) 
and hepatic metastases from a carcinomatous primary tumor (CT4003). 
In study CT4001, 3 different dose levels of EndoTAG-1 (11, 22 and 44 mg/m2 
liposomal paclitaxel) in combination with gemcitabine (GEM+Endo) were compared 
to gemcitabine monotherapy (GEM) in 200 subjects (50 subjects in each study arm) 
with unresectable locally advanced or metastatic pancreatic adenocarcinoma. At the 
time of analysis 161 subjects have died. Median overall survival was 7.2 months on 
GEM monotherapy compared to 8.4, 8.7 and 9.4 months in the GEM+Endo cohorts (11, 
22 and 44 mg/m2, respectively). Median PFS reached 2.7 months compared to 4.1, 4.6 
and 4.4 months and the disease control rate after the first treatment cycle was 43% 
compared to 60, 65 and 52%, respectively. Accordingly, both the 6- and 12-month 
survival rates were higher in all GEM+Endo groups than in the GEM group (Löhr et al, 
2012). 
In study CT4002, 140 women with triple receptor negative metastatic or relapsed breast 
cancer have been randomized to 3 different study arms: EndoTAG-1 (22 mg/m2 
liposomal paclitaxel) in combination with standard paclitaxel (70 mg/m2), EndoTAG-
1 monotherapy (44 mg/m2 liposomal paclitaxel, twice per week), and standard 
paclitaxel monotherapy (90 mg/m2). Each treatment was given for 3 weeks, followed 
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59% on combination therapy compared to 34% in the EndoTAG-1 and 48% in the 
standard paclitaxel cohort (Awada et al, ESMO 2010). The clinical benefit rate 
(complete or partial response at any time and stable disease 2:6 months) on combination 
of EndoTAG-1 and paclitaxel (n=50 subjects) was 53% compared to 31 and 36% on 
EndoTAG-1 and paclitaxel monotherapies, respectively (Awada et al, SABCS 2011). 
PFS was 4.2 compared to 3.4 and 3.7 months, respectively. In the target population of 
the study, i.e. patients with TNBC, the overall survival was 13.0 months on combination 
of EndoTAG-1 and paclitaxel versus 11.9 and 10.1 months on EndoTAG-1 and 
paclitaxel monotherapies, respectively. Subgroup analysis in subjects with advanced 
TNBC, ECOG performance status 0 or 1 and first line therapy revealed an overall 
survival of 17.8 months on combination of EndoTAG-1 and paclitaxel versus 12.5 and 
10.1 months on EndoTAG-1 and paclitaxel monotherapies, respectively. However, the 
study was not powered for intergroup comparisons. 
Study CT4003 was conducted to evaluate pharmacokinetics of EndoTAG-1 (22 mg/m2 
liposomal paclitaxel, twice a week) and its effect on blood supply and angiogenesis of 
hepatic metastases in 20 subjects with a carcinomatous primary tumor other than 
hepatocellular, biliary or bile duct carcinoma. At the beginning of therapy all subjects 
had stable disease according to modified RECIST 1.1 criteria. The median PFS was 29 
days. The effect of EndoTAG-1 on target liver metastases perfusion assessed by CEUS 
was inhomogeneous, inflow coefficients showed a great intra-individual variability and 
a trend could not be elaborated. However, changes in perfusion parameters assessed by 
DCE-MRI were observed. By Day 29, 65% of subjects had decreases in ktrans, iAUC60, 
iAUC90 and iAUC120, supporting the hypothesis of a vascular targeting mode of 
action of EndoTAG-1 (Fasol et al, 2011). 
In conclusion, EndoTAG-1 has shown vascular targeting, vascular disrupting and anti-
tumor activity in different tumors in several nonclinical and clinical studies. 
Therapeutic efficacy was highest when EndoTAG-1 was administered in combination 
with other chemotherapeutics. Notably, both in pancreatic cancer and advanced TNBC, 
EndoTAG-1 has shown clinical benefit and the EndoTAG-1/paclitaxel and EndoTAG-
1/gemcitabine treatment combination was well tolerated. 
Based on the safety and efficacy data collected in these clinical trials, a positive benefit-
risk-profile was established for clinical use of EndoTAG-1. 
 
 


 
 
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2 Study Objectives and Endpoints 
2.1 
Study Objectives 
The objective of the study is to assess the safety and efficacy of a combination therapy 
of EndoTAG-1 plus gemcitabine vs. gemcitabine monotherapy in patients with locally 
advanced and/or metastatic adenocarcinoma of the pancreas eligible for second-line 
therapy after failing first-line therapy with FOLFIRINOX. 
2.1.1 Efficacy Objectives 
To assess the efficacy of twice weekly infusions of EndoTAG-1 with weekly infusions 
of gemcitabine versus gemcitabine monotherapy according to: 
• Assessment of survival (overall survival [OS], progression-free survival [PFS],) 
• Tumor response evaluation via Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v.1.1) 
2.1.2 Secondary Objective 
To assess the safety of twice weekly infusions of EndoTAG-1 with weekly infusions of 
gemcitabine versus gemcitabine monotherapy according to: 
• Incidence and percentage of subjects with treatment-emergent adverse events 
(TEAEs) 
• Laboratory abnormalities (hematology, coagulation parameters, clinical 
chemistry) 
• Dose reductions, pausing, and/or discontinuation of EndoTAG-1 and/or 
gemcitabine 
2.2 
Study Endpoints 
2.2.1 Primary Efficacy Endpoints 
There are two primary efficacy endpoints for this study:  
• Overall Survival (OS). 
Overall survival time is defined as time from randomization to death from any cause 
or last day known to be alive. 
• Progression Free Survival (PFS) 
Progression Free Survival time is defined as the time from randomization to either 
first observation of progressive disease or occurrence of death.  
2.2.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 


 
 
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• Percentage of subjects with Objective Response (OR) according to Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1)* 
Percentage of subjects with objective response is based on assessment of complete 
response (CR) or partial response (PR) according to RECIST v.1.1. 
• Duration of Response (DR)* 
Duration of Response is defined as the time from the first documentation of 
objective tumor response (date of the first CR or PR) to objective tumor progression 
or death due to any cause.  
• Percentage of subjects with disease control according to RECIST v.1.1* 
Percentage of subjects with disease control is based on assessment of complete 
response (CR) or partial response (PR) or stable disease (SD) according to RECIST 
v.1.1 
• Serum Carcinoma Antigen 19-9 (CA 19-9) response rate 
Responders are defined as subjects with a reduction in CA 19-9 levels by least 50% 
from baseline to the end of cycle 1 (or end of full treatment course). 
*The tumor measurement according to RECIST v.1.1 criteria will be reviewed by a 
qualified independent review board. The review is independent of the on-site tumor 
evaluation performed during study conduct. 
2.2.3 Safety Assessments: 
Safety will be assessed based on the following assessments: 
• Incidence and severity of treatment-emergent adverse events (TEAEs), including 
serious adverse events and adverse events resulting in permanent discontinuation of 
protocol-defined therapy.  
• Changes in selected laboratory test results (i.e.,  
o Serum chemistry including urea, serum creatinine, sodium, potassium, 
chloride, bicarbonate, glucose, bilirubin, albumin, ALT, AST, ALP, total 
protein; and  
o Full blood count (FBC) including hemoglobin, hematocrit, RBC count, 
Platelets count, total leukocyte count, differential leukocyte count and 
absolute neutrophil count)  
• Changes in vital signs including systolic and diastolic blood pressure and pulse  
• Changes in electrocardiogram (ECG) results  
• Changes in physical examination results 


 
 
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2.2.4 Exploratory Endpoints 
• Change from Baseline in European Organization for Research and Treatment of 
Cancer, Quality of Life Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, 
and social), global health status (GHS), symptom scales (fatigue, pain, 
nausea/vomiting), and single items (dyspnoea, appetite loss, insomnia, 
constipation/diarrhea, and financial difficulties). Most questions used 4- point scale 
(1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 
'Excellent'). Scores averaged, transformed to 0- 100 scale; higher score=better 
level of functioning or greater degree of symptoms. Change from 
baseline=Cycle/Day score minus baseline score. 
• Change from baseline in European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to disease symptoms, treatment 
(Tx) side effects and emotional issues specific to pancreatic cancer (PC). Questions 
include on altered bowel habits, pain, dietary changes, disease and Tx-related 
symptoms and issues related to the emotional and social well-being of participants 
with PC. All 26 Qs are answered on 4-point Likert scale ranging from '1=not at all' 
to 4='very much' and subsequently transformed into scales that range from 0-100; 
higher scores= greater degree of symptoms or treatment side effects and emotional 
issues. 
  


 
 
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3 Investigational Plan 
3.1 
Study Design 
This is a randomized controlled, open label, adaptive phase 3 study to evaluate the 
safety and efficacy of a combination regimen of twice weekly infusions of EndoTAG-
1 (Lipid Complexed Paclitaxel) with weekly administration of gemcitabine compared 
with gemcitabine monotherapy in subjects with measurable locally advanced and/or 
metastatic adenocarcinoma of the pancreas who are eligible for second-line therapy 
after failing first-line therapy with FOLFIRINOX. 
Eligible subjects will be randomized to one of the two treatment arms: 
 Arm A: Treatment with EndoTAG-1 22 mg/m2 twice weekly plus gemcitabine 
1000mg/m² once weekly, for 1 cycle (8 weeks) consisting of 3 weeks and 1 week 
rest followed by  3 weeks of treatment and 1 week rest until any one of the following 
occurs:  progressive disease or unacceptable toxicity or withdrawal of consent.  
Subjects will be eligible for continuing treatment beyond first cycle in absence of 
disease progression or unacceptable toxicity. Subsequent Treatment Cycles (8 
weeks/cycle) will be administered as 3 weeks of treatment and 1 week of rest 
followed by 3 weeks of treatment and 1 week rest. 
 Arm B: Treatment with gemcitabine 1000 mg/m² once weekly, for 1 cycle (8 weeks)  
consisting of 3 weeks of treatment and 1 week rest followed by 3 weeks of treatment 
and 1 week rest until any one of the following occurs:  progressive disease or 
unacceptable toxicity or withdrawal of consent. Subjects will be eligible for 
continuing treatment beyond in absence of disease progression of unacceptable 
toxicity. Subsequent Treatment Cycles (8 weeks/cycle) will be administered as 3 
weeks of treatment and 1 week reast followed by 3 weeks of treatment and 1 week 
rest. 
The randomization will be stratified by  
• Subjects with locally advanced vs metastatic pancreatic cancer 
• Subjects with ECOG performance status 0 vs 1 
The first treatment cycle will last at least 8 weeks and include 3 weeks of treatment and 
1 week rest followed by 3 weeks of treatment and 1 week rest. Subjects may continue 
to receive additional cycles of therapy until progressive disease or intolerable toxicity 
as per clinical judgment of the Investigator. 
Tumor response according to RECIST (version 1.1; Eisenhauer et al. 2009) will be 
evaluated on a scheduled basis every 8 weeks (±3 days) from randomization (regardless 
of the timing of treatment cycles) until disease progression is documented or until the 
cut-off date of the study, whichever comes earlier. Subjects will be monitored regularly 
for safety parameters and quality of life (EORTC QLQ-C30 and EORTC PAN-26).  


 
 
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After completing treatment, subjects who are not diagnosed with progressive disease 
(PD) will attend up to 6 Follow-up Visits every 8 weeks for 48 weeks, following which 
subjects will be followed-up by telephone every 8 weeks for survival. Subjects who 
experienced PD during Treatment Phase will undergo only one safety follow-up visit 
(4-8 weeks after the EOT visit), and then enter phone follow-up directly. Follow-up 
visits will be performed for the evaluation of survival status, safety parameters, QoL 
(EORTC QLQ-C30 and EORTC PAN-26) and administration of other anti-tumor 
treatment until death or end of the study, whichever comes first. 
Anti-tumor therapy after termination of study treatment will be at the discretion of the 
Investigator.  
A single, pre-planned Interim Analysis (IA) will be conducted when approximately 101 
subjects have died (60% of the expected 167 events). 
The cut-off date for the final analysis will be 12 months after the last subject was 
randomized or the last subject alive has been followed up for at least 48 weeks, 
whatever applies first. Subjects being still under treatment with study medication at this 
cut-off date will enter the extension phase of this trial. These subjects will be followed 
up until 28 days after the last administration of study medication.  
A Data and Safety Monitoring Board (DSMB), composed of independent 
representatives, will be in charge of reviewing the accrual, baseline, and safety data at 
periodic intervals. Representatives of the Sponsor will serve only as coordinating 
members of the committee, without having full member responsibilities or privileges. 
3.2 
Study Center(s) 
Up to 100 multinational centers 
3.3 
Study Population 
Study population includes patients with locally advanced and/or metastatic 
adenocarcinoma of the pancreas who are eligible for second-line therapy after failing 
first-line therapy with FOLFIRINOX. 
3.4 
Eligibility Criteria 
3.4.1 Inclusion Criteria 
Potential subjects are required to meet all of the following criteria for enrollment into 
the study and subsequent randomization: 
1. Age ≥ 18 years 
2. Written informed consent  
3. Histologically or cytologically confirmed adenocarcinoma of the pancreas 
4. Metastatic or locally advanced disease that is considered unresectable 


 
 
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5. Measurable / assessable disease according to RECIST v.1.1 
6. Documented disease progression on first line FOLFIRINOX   
7. Negative pregnancy test 
8. Both male and female patients and their partners of childbearing potential must 
agree to use two medically accepted methods of contraception (e.g., barrier 
contraceptives [male condom, female condom, or diaphragm with a spermicidal 
gel], 
hormonal 
contraceptives 
[implants, 
injectables, 
combination 
oral 
contraceptives, transdermal patches, or contraceptive rings], or one of the following 
methods of birth control (intrauterine devices, tubal sterilization or vasectomy) or 
must practice complete abstinence from intercourse of reproductive potential during 
the whole treatment duration and for at least 6 months after last treatment for arm 
A and arm B (excluding women who are not of childbearing potential and men who 
have been sterilized). 
9. ECOG performance status 0 or 1 
3.4.2 Exclusion Criteria 
Potential subjects meeting any of the following criteria will be excluded from 
enrollment and subsequent randomization: 
1. Cardiovascular disease, New York Heart Association (NYHA) III or IV 
2. History of severe supraventricular or ventricular arrhythmia 
3. History of coagulation or bleeding disorder  
4. History of acute myocardial infarction within 6 months before randomization 
5. History of congestive heart failure 
6. Acute or chronic inflammation (autoimmune or infectious) 
7. Significant active/unstable non-malignant disease likely to interfere with study 
assessments 
8. Laboratory tests (hematology, chemistry) outside specified limits: 
a) WBC ≤ 3 x 10³/mm³ 
b) ANC ≤ 1.5 x 10³/mm³ 
c) Platelets ≤ 100,000/mm³ 
d) Hb ≤ 9.0 g/dl (≤ 5.6 mmol/l) 
e) aPTT > 1.5 x ULN 
f) Serum creatinine > 2.0 mg/dl (> 176.8 µmol/l) 
g) AST and/or ALT > 2.5 x ULN; for patients with significant liver metastasis 
AST and/or ALT > 5 x ULN 
h) Alkaline phosphatase > 2.5 x ULN 
i) Total bilirubin > 2 x ULN 


 
 
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j) Albumin < 2.5 g/dL 
9. Clinically significant ascites 
10. Any anti-tumor treatment (except FOLFIRINOX as the first-line therapy) for 
pancreatic adenocarcinoma before enrollment. 
Note: Patients who have undergone surgical interventions for pancreatic 
adenocarcinoma will be eligible. 
11. Any radiotherapy for pancreatic adenocarcinoma before enrollment except for 
treatment of bone metastases if target lesions are not included in the irradiated field 
12. Major surgery < 4 weeks prior to enrollment 
13. Pregnant or nursing 
14. Investigational medicinal product < 4 weeks of enrollment 
15. Documented HIV history 
16. Active hepatitis B infection requiring acute therapy 
Note: Subjects infected by the hepatitis B virus will be eligible for the study if they 
have no signs of hepatic decompensation and meet the liver function tests eligibility 
criteria. 
17. Known hypersensitivity to any component of the EndoTAG-1 and/or gemcitabine 
formulations 
18. History of malignancy other than pancreatic cancer < 3 years prior to enrollment, 
except non-melanoma skin cancer or carcinoma in situ of the cervix treated locally 
19. Vulnerable populations (e.g. subjects unable to understand and give voluntary 
informed consent) 


 
 
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4 Study Schedule 
The study is divided into three phases: Screening, Treatment and Follow-up.  
• Screening Phase (Screening to Baseline): Up to 14 days 
• Treatment Phase:  
o First Treatment Cycle:  
 Treatment Group A: 8 weeks or potentially longer in the event of 
postponements (a total of 6 weekly infusions of gemcitabine and 12 twice 
weekly infusions of EndoTAG-1). 
 Treatment Group B: 8 weeks or potentially longer in the event of 
postponements (a total of 6 weekly infusions of gemcitabine).  
o Subsequent Treatment Cycles: Subjects will be eligible for continuing treatment 
with 3 weeks of treatment and 1 week rest followed by 3 weeks of treatment 
and 1 week rest until any one of the following occurs: progressive disease or 
unacceptable toxicity or withdrawal of consent. 
• Follow-Up Phase: Follow-up visits will be performed every 8 weeks until death or 
end of the study, whichever comes first. 
Procedures to be performed during each of these study phases are described below and 
provided as a Schedule of Assessments in Table 0-1 and Table 0-2. 
4.1 
Screening Visit 
The subject (or Legally Acceptable Representative (LAR)) will sign and date the 
informed consent form (ICF) and Health Insurance Portability Accountability Act 
(HIPAA) authorization (according to site policy and practices) prior to any study-
related procedures. A unique identification number (screening number) will be assigned 
to each subject who has provided written informed consent. The subject screening 
number will incorporate a two-digit region code (01, 02 or 03...), a three-digit Study 
Center number (001, 002 or 003….) and a three-digit numeric ID assigned in successive 
order of entering the study after signing the ICF at each center, beginning with 001 at 
each site (e.g. 01-001-001).  
 
Subject Screening 
#: 
XX - 
YYY 
- ZZZ 
 
XX=Region 
 
YYY=Study Center 
 
ZZZ=Subject Numeric ID 
All study centers will be instructed to maintain the study-specific pre-screening, 
screening and enrollment logs at their sites. If a subject initially fails to meet 
inclusion/exclusion criteria and is later reconsidered for participation, the subject will 
be re-consented and assigned a new screening number at the time of re-screening. 
Subjects who fail their first screening attempt may be re-screened a maximum of once 


 
 
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and may be enrolled if they are found to meet all inclusion and no exclusion criteria 
when re-screened.   
Patients with a clinical diagnosis of unresectable pancreatic adenocarcinoma may be 
screened. Prior to all screening procedures the investigator is responsible for explaining 
all aspects of this trial to the patient including potential side effects and alternative 
treatments available. The investigator must answer all questions by the patient 
according to his/her best knowledge and must give the patient ample time to consider 
his/her participation. If – after that - the patient wishes to participate in this trial, he/she 
must first give written informed consent. Only then may the investigator proceed with 
the screening procedure. 
The following evaluations and examinations have to be done within 14 days prior to 
randomization, if not stated otherwise: 
• Signed informed consent 
• Eligibility criteria 
• Demographic data, including date of birth, sex, and ethnic origin 
• Disease history, including date of first diagnosis and the history of the course 
of the disease 
• Medical and surgical history, including past or concurrent clinically significant 
disease(s) 
• Previous and concomitant medication 
• Physical examination, including evaluation of all body systems 
• Vital signs, including blood pressure (supine), heart rate, and body temperature 
(oral, axillary, tympanic or rectal), and weight and height. For measurement of 
body temperature, the same type of measurement is to be used throughout the 
study. 
• Performance status (ECOG Performance Status) 
• Blood samples for laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry 
o Coagulation parameters 
o Tumor marker CA 19-9 
o Urinalysis 
o Pregnancy test, if female of childbearing potential (serum or urine) 
• Tumor imaging: Abdominal CT-scan with i.v. and gastrointestinal contrasts (or 
MRI), and chest X-ray (or CT or MRI). Thoracic CT- or MRI-scans have to be 


 
 
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done additionally, if target lesions detected by chest X-ray are not clearly 
defined or not surrounded by aerated lung. Further imaging exams to be done if 
lesions are suspected in other areas. 
Note: Assessments of tumor imaging performed 4 weeks prior to randomization is 
acceptable. 
• Evaluation of detected lesions according to RECIST (version 1.1; Eisenhauer 
et al. 2009)  
• Electrocardiogram 
• Quality of Life Questionnaires 
All screening information will be fully documented in the subject’s medical records 
(i.e., source documents). If the patient fulfils all of the inclusion criteria and none 
of the exclusion criteria the patient may be randomized. 
• For consented subjects who do not meet eligibility criteria, a Screen Failure 
electronic Case Report Form (eCRF) will be completed. The Screen Failure 
eCRF will contain the following details: the subject identification number, the 
date of ICF signature, demographic information, and the reason for screen 
failure. No additional information will be required for subjects who fail 
screening.  
• For consented subjects who meet eligibility criteria, all required screening 
information will be transcribed onto the appropriate page of the eCRF. 
4.2 
Treatment Phase 
The treatment phase consists of eight weeks with seven visits for subjects in Arm B and 
13 visits for subjects in Arms A which will be performed according to the following 
time schedule: 
 
First Cycle 
VISIT 
NUMBER 
11 
1G2 
2 
2G 
3 
3G 
4  
5 
5G 
6 
6G 
7 
7G 
83/ 
EOT 
Week 
1 
1 
2 
2 
3 
3 
4 
5 
5 
6 
6 
7 
7 
8 
Day 
1 
4 
8 
11 
15 
18 
22 
29 
32 
36 
39 
43 
46 
53 
Arm A 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Arm B 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
1 Visit without suffix “G”: administration of EndoTAG-1 only; visit applies only to subjects of treatment group A 
2 Visits with suffix “G”: administration of gemcitabine (Treatment Groups A and B) +/- EndoTAG-1 (Treatment 
group A) 
3   End of Cycle visit 
 
However, in case of any non-hematological or hematological toxicities requiring 
postponement of the infusion, the subject may have up to four additional visits at 1-


 
 
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week intervals between the regular visits. In case a further postponement will be 
necessary after the fourth additional visit, the subject has to be withdrawn from active 
study treatment. In addition, the subject has to be withdrawn from active study 
treatment in case the total treatment time will exceed 26 weeks [from Visit 1 (Arm A) 
or Visit 1G (Arm B)]. 
4.2.1 Treatment Visit 1 (Baseline for Arm A) 
This visit applies to subjects in Arm A only and will be performed ≤ 7 working days 
after randomization. 
At Treatment Visit 1 the following examinations and assessments have to be done prior 
to treatment: 
• Any change in concomitant medication since last visit 
• Blood samples for immediate laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry 
o Coagulation parameters 
Note: Assessments of laboratory parameters performed 1 day prior to treatment is 
acceptable.  
• PK blood sample collection (within 3 hours prior to EndoTAG-1 treatment 
(predose), at the end of EndoTAG-1 i.v. infusion, and at 30 min, 1 hr, 2 hr, 4 hr 
and 6 hr post infusion) for first 50 subjects assigned to Arm A.  
• Physical examination, including evaluation of all body systems 
• Vital signs, including blood pressure (supine), heart rate, and body temperature 
(oral, axillary, tympanic or rectal), and weight 
• After all necessary exams have been finished the subject receives: 
 EndoTAG-1 infusion 
• Assessment of Adverse Events (AE) (performed post treatment) 
 
4.2.2 Treatment Visit 1G (Baseline for Arm B) 
These visits apply to subjects in all study arms (A and B). Visit 1 G is the baseline visit 
for subjects in Arm B. 
At Treatment Visit 1G the following examinations and assessments have to be done 
prior to treatment: 
• Any change in concomitant medication since last visit 


 
 
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• Adverse events and serious adverse events occurring since last visit (for Arm A 
only) 
Note: Assessment of Adverse Events will be performed post treatment for 
subjects assigned to Arm B 
• Blood samples for immediate laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry 
o Coagulation parameters 
Note: Assessments of laboratory parameters performed 1 day prior to treatment 
is acceptable. 
• PK blood sample collection (within 3 hours prior to EndoTAG-1 treatment 
(predose) [only for first 50 subjects assigned to Arm A]. 
• Physical examination, including evaluation of all body systems (for Arm B only) 
• Vital signs, including blood pressure (supine), heart rate, and body temperature 
(oral, axillary, tympanic or rectal), and weight 
• After all necessary exams have been finished the subject receives: 
 EndoTAG-1 infusion (Arm A) 
• After all necessary exams have been finished the subject receives: 
 gemcitabine infusion (Arm A and B) 
Note: For subjects in Arm A, EndoTAG-1 administration precedes the 
administration of gemcitabine. 
• Assessment of Adverse Events (AE) (performed post treatment for subjects 
assigned to Arm B) 
 
4.2.3 Treatment Visits 2, 3, 5, 6 and 7 
These visits apply to subjects in Arm A only. 
At each of these visits the following examinations and assessments have to be done 
prior to treatment: 
• Any change in concomitant medication since last visit 
• Adverse events and serious adverse events occurring since last visit 
• Vital signs, including blood pressure (supine), heart rate, and body temperature 
(oral, axillary, tympanic or rectal) and weight. For measurement of body 
temperature, the same type of measurement is to be used throughout the study. 


 
 
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• Blood samples for immediate laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry [only at Treatment Visit 5 (Day 29)] 
Note: Assessments of laboratory parameters performed 1 day prior to treatment 
is acceptable. 
• PK blood sample collection (within 3 hours prior to EndoTAG-1 treatment 
(predose)[only at Treatment Visits 2 (Day 8), 3 (Day 15), 5 (Day 29) and 7 (Day 
43)] for first 50 subjects assigned to Arm A. 
• After all necessary exams have been finished the subject receives: 
 EndoTAG-1 infusion 
 
4.2.4 Treatment Visits 2G, 3G, 5G, 6G and 7G 
These visits apply to subjects in all study arms (A and B).  
At each of these visits the following examinations and assessments have to be done 
prior to treatment: 
• Any change in concomitant medication since last visit 
• Adverse events and serious adverse events occurring since last visit 
• Blood samples for immediate laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry [only at Treatment Visit 5G (Day 32)] 
o Coagulation parameters 
Note: Assessments of laboratory parameters performed 1 day prior to treatment is 
acceptable. 
• Physical examination, including evaluation of all body systems 
• Vital signs, including blood pressure (supine), heart rate, and body 
temperature (oral, axillary, tympanic or rectal) and weight. For measurement 
of body temperature, the same type of measurement is to be used throughout 
the study 
• Depending on the results of the blood analyses subjects in Arm A receive after 
all necessary exams have been finished: 
 EndoTAG-1 infusion 
• Depending on the results of the blood analyses subjects in all Arms (A and B) 
receive after all necessary exams have been finished: 


 
 
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 gemcitabine infusion 
Note: For subjects in Arm A, EndoTAG-1 administration precedes the 
administration of gemcitabine 
 
 
 
 
4.2.5 Treatment Visit 8 / End of Treatment (EOT) Visit  
For all subjects the end of study treatment will be performed on day 53, 7 days after 
Visit 7G or when anyone of the criteria for early termination of study treatment is 
reached. 
At this visit the following examinations and assessments have to be done: 
• Any change in concomitant medication since last visit 
• Adverse events and serious adverse events occurring since last visit 
• Physical examination, including evaluation of all body systems 
• Vital signs, including blood pressure (supine), heart rate, and body 
temperature (oral, axillary, tympanic or rectal) and weight. For measurement 
of body temperature, the same type of measurement is to be used throughout 
the study 
• Performance status (ECOG Performance Status) 
• Blood samples for laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry 
o Tumor marker CA19-9 
o Urinalysis 
o Pregnancy test, if female of childbearing potential (serum or urine) 
• Tumor imaging: Abdominal CT-scan with i.v. and gastrointestinal contrasts 
(or MRI), and chest X-ray (or CT or MRI). Thoracic CT- or MRI-scans have 
to be done additionally, if target lesions detected by chest X-ray are not clearly 
defined or not surrounded by aerated lung. Further imaging exams to be done 
if lesions are suspected in other areas. 
• Evaluation of detected lesions according RECIST (version 1.1; Eisenhauer et 
al. 2009) 
• Electrocardiogram 


 
 
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• Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC PAN-26) 
 
4.2.6 Continuation of Treatment, Subsequent Cycles 
All subjects with complete/partial response or stable disease at Treatment Visit 8/End 
of Treatment visit who decide to continue study drug treatment will receive infusions 
according to the schedule performed during the study (EndoTAG-1 bi-weekly on days 
1 and 4; gemcitabine on Day 4), starting within one week of the Treatment Visit 8/End 
of Treatment visit. 
 
 
Subsequent Cycles 
VISIT 
NUMBER 
11 
1G2 
2 
2G 
3 
3G 
4  
5 
5G 
6 
6G 
7 
7G 
83/EOT 
Week 
1 
1 
2 
2 
3 
3 
4 
5 
5 
6 
6 
7 
7 
8 
Day 
1 
4 
8 
11 
15 
18 
22 
29 
32 
36 
39 
43 
46 
53 
Arm A 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Arm B 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
1 Visit without suffix “G”: administration of EndoTAG-1 only; visit applies only to subjects of treatment group A 
2 Visits with suffix “G”: administration of gemcitabine (Treatment Groups A and B) +/- EndoTAG-1 (Treatment 
group A) 
3   End of Cycle visit 
 
4.2.6.1 Subsequent Cycles, Treatment Visits 1, 2, 3, 5, 6 and 7 
These visits apply to subjects in Arm A only. 
At each of these visits the following examinations and assessments have to be done 
prior to treatment: 
• Any change in concomitant medication since last visit 
• Adverse events and serious adverse events occurring since last visit 
• Vital signs, including blood pressure (supine), heart rate, and body temperature 
(oral, axillary, tympanic or rectal) and weight. For measurement of body 
temperature, the same type of measurement is to be used throughout the study. 
• Blood samples for immediate laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry [only at Treatment Visit 1 (Day 1) and Treatment 
Visit 5 (Day 29)] 
• After all necessary exams have been finished the subject receives: 
 EndoTAG-1 infusion 


 
 
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4.2.6.2 Subsequent Cycles, Treatment Visits 1G, 2G, 3G, 5G, 6G and 7G 
These visits apply to subjects in all study arms (A and B).  
At each of these visits the following examinations and assessments have to be done 
prior to treatment: 
• Any change in concomitant medication since last visit 
• Adverse events and serious adverse events occurring since last visit 
• Blood samples for immediate laboratory analyses: 
o Hematology including differential hemogram  
o Clinical chemistry [only at Treatment Visit 1G (Day 4) and Treatment 
Visit 5G (Day 32)] 
o Coagulation parameters 
• Physical examination, including evaluation of all body systems 
• Vital signs, including blood pressure (supine), heart rate, and body temperature 
(oral, axillary, tympanic or rectal) and weight. For measurement of body 
temperature, the same type of measurement is to be used throughout the study 
• Depending on the results of the blood analyses subjects in Arm A receive after 
all necessary exams have been finished: 
 EndoTAG-1 infusion 
• Depending on the results of the blood analyses subjects in all Arms (A and B) 
receive after all necessary exams have been finished: 
 gemcitabine infusion 
Note: For subjects in Arm A, EndoTAG-1 administration precedes the 
administration of gemcitabine 
 
4.2.6.3 Subsequent Cycles, Treatment Visit 8 
These visits apply to subjects in all study arms (A and B). After each 7 weeks of 
continuation of treatment, the subject will attend Treatment Visit 8. These visits will be 
performed in 8-week intervals from the First Cycle, Treatment Visit 8. 
At this visit the following examinations and assessments have to be done: 
• Any change in concomitant medication since last visit 
• Adverse events and serious adverse events occurring since last visit 
• Physical examination, including evaluation of all body systems 


 
 
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• Vital signs, including blood pressure (supine), heart rate, and body temperature 
(oral, axillary, tympanic or rectal) and weight. For measurement of body 
temperature, the same type of measurement is to be used throughout the study 
• Performance status (ECOG Performance Status) 
• Blood samples for laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry 
o Tumor marker CA19-9 
o Urinalysis 
o Pregnancy test, if female of childbearing potential (serum or urine) 
• Tumor imaging: Abdominal CT-scan with i.v. and gastrointestinal contrasts (or 
MRI), and chest X-ray (or CT or MRI). Thoracic CT- or MRI-scans have to be 
done additionally, if target lesions detected by chest X-ray are not clearly 
defined or not surrounded by aerated lung. Further imaging exams to be done if 
lesions are suspected in other areas. 
• Evaluation of detected lesions according RECIST (version 1.1; Eisenhauer et 
al. 2009) 
• Electrocardiogram 
• Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC PAN-26) 
If the subject does not show progressive disease, subsequent treatment cycles can be 
started. Study treatment can be continued until progressive disease (according to 
RECIST) is documented. 
During the continuation of treatment, the administration of study drug will not be 
postponed; if the subject experiences toxicities that prevent the administration of drug, 
the dose will be omitted. 
4.3 
Follow-Up Phase 
All treated subjects will enter the Follow-Up Phase. The follow-up visits will be 
performed every eight weeks starting from the last study visit until the end of study or 
until death is reported.  
Subjects who drop out of the study before receiving study medication will not be 
followed up. 
4.3.1 Follow-Up Visit 1 (8 weeks after last study treatment) 
At this visit the following examinations and assessments have to be done: 
• Any change in concomitant medication since last visit 


 
 
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• Adverse events and serious adverse events occurring since last visit 
• Physical examination, including evaluation of all body systems 
• Vital signs, including blood pressure (supine), heart rate, and body temperature 
(oral, axillary, tympanic or rectal) and weight. For measurement of body 
temperature, the same type of measurement is to be used throughout the study 
• Performance status (ECOG Performance Status) 
• Blood samples for laboratory analyses: 
o Hematology including differential hemogram 
o Clinical chemistry 
o Coagulation parameters 
o Tumor marker CA19-9 
o Urinalysis 
o Pregnancy test, if female of childbearing potential (serum or urine) 
• Tumor imaging: Abdominal CT-scan with i.v. and gastrointestinal contrasts (or 
MRI), and chest X-ray (or CT or MRI). Thoracic CT- or MRI-scans have to be 
done additionally, if target lesions detected by chest X-ray are not clearly 
defined or not surrounded by aerated lung. Further imaging exams to be done if 
lesions are suspected in other areas. 
• Evaluation of detected lesions according RECIST (version 1.1; Eisenhauer et 
al. 2009) 
Note: Only for subjects with tumor status other than progressive disease at the 
End of Treatment visit. 
• Electrocardiogram 
• Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC PAN-26) 
4.3.2 Subsequent Follow-Up Visits 
At these subsequent follow-up visits (at clinic or over the phone) the investigator will 
request the following information: 
• Any change in concomitant medication since last visit / phone follow-up that 
was given due to an adverse event assessed as related to EndoTAG-1 
• Adverse events and serious adverse events occurring since last visit / phone 
follow-up assessed as related to EndoTAG-1 
• Any change in therapy for the pancreatic adenocarcinoma 
• Survival status / death 


 
 
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4.4 
Unscheduled Visits 
In the event that the subject returns to clinic at a time other than a regularly scheduled 
study visit, the visit will be regarded as an unscheduled visit. Assessments at 
unscheduled visits are at the discretion of the Investigator.  
 


 
 
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5 Subject completion and withdrawal 
5.1 
Subject Completion 
o A subject who completes at least the 48-week Follow-Up period after end (or 
discontinuation) of treatment, regardless of tumor response, will be 
considered as having completed the study. 
5.2 
Withdrawal of Subject from Therapy or Assessment 
A subject who enters the Treatment Phase but does not complete the study, as defined 
in Section 5.1, is considered to have prematurely withdrawn from the Study. All 
subjects have the right to withdraw at any point during treatment without prejudice to 
future care. It will be documented whether or not each subject completed the clinical 
study. If for any subject, study treatment or observations were discontinued, the 
reason(s) will be recorded. 
The Investigator can discontinue a subject at any time if it is considered medically 
necessary.  
In addition, subjects WILL be withdrawn from the study, in consultation with the 
Medical Monitor and the Investigator, if any of the following are met: 
• Withdrawal of consent by subject 
• A subject is significantly non-compliant with the requirements of the protocol. 
• The investigator determines that it is in the best interest of the subject. 
• Withdrawal by investigator due to safety or ethical concerns 
• Postponement of any administration of study drug for more than four consecutive 
weeks (only applicable for initial treatment cycle) 
• Initial treatment period (cycle) lasting longer than 26 weeks (6 months) 
• A subject becomes pregnant  
Note: The pregnancy will be followed to term for safety follow-up. Relevant safety 
information collected after the study has completed will be reported as 
supplemental information.  
• Discontinuation of study by Sponsor 
• Any major surgery 
• Chemotherapy 
Premature withdrawal from the study MAY occur if, in consultation with the Medical 
Monitor and the Investigator, any of the following are met: 
• A subject is treated with a prohibited medication 
• Major protocol violation 


 
 
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5.2.1 Discontinuation of Study Treatment 
If a subject discontinues treatment between two Treatment Visit-8, all assessments 
scheduled for the next Treatment Visit 8 should be performed. 
Additionally, a pregnancy test should be performed when the subject discontinues 
treatment, independent of the reason for discontinuing. 
5.2.2 Data Collected for Withdrawn Subjects 
Subjects may withdraw from the study or discontinue study treatment at any time; 
however, SynCore Biotechnology is dedicated to minimizing missing data in this study. 
An excessive rate of withdrawals can render the study non-evaluable; therefore, 
unnecessary withdrawal of subjects should be avoided. However, subjects must be 
removed if a safety concern occurs which is regarded as clinically relevant by the 
investigator. Should a subject decide to withdraw, every effort will be made to complete 
and report the observations as thoroughly as possible. 
All assessments scheduled for the End of Treatment visit have to be performed if a 
subject discontinues treatment before the End of Treatment visit. A subject prematurely 
ending active study treatment will enter the regular follow-up period. 
If a subject discontinues during the follow-up period, he/she should come in for one 
final follow-up visit and every attempt should be made to collect survival data over the 
phone. 
Investigators considering discontinuing study treatment should contact the medical 
monitor prior to such discontinuation. Subjects who have study treatment discontinued 
will continue to be followed, per protocol, whenever possible.  
Subjects who have study treatment discontinued due to a serious adverse event will be 
followed until resolution or stabilization of the event. 
In the event that a subject is withdrawn from the study at any time due to an adverse 
event or serious adverse event (SAE), the procedures stated in Section 8.2 or 8.4, 
respectively must be followed. 
Every attempt should be made to collect follow-up information. The reason for 
withdrawal from the study will be recorded in the source documents and on the 
appropriate page of the eCRF. 
Before a subject is identified as lost-to-follow up, the site should make all reasonable 
efforts to contact the subject. These attempts must be documented and should include 
at a minimum one phone call and one certified letter.  
For any subject who is lost to follow-up, the study site may attempt to ascertain survival 
information via following accesses but not limited to public database search, newspaper, 
hospital closed patient account. 
 


 
 
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5.3 
Screen Failures 
A subject who has signed a consent form, has been assigned a screening number, but is 
not treated is classified as a screen failure. Subject number, demographics and reason 
for screen failure will be recorded. 
If any of the screening assessments show a clinically relevant abnormal finding, in 
particular a significantly abnormal laboratory parameter, which is in contrast to the 
eligibility criteria and/or interferes with the requirements of the study in the opinion of 
the investigator, the patient will be classified as a screening failure, will not be 
randomized in the study. Nevertheless, the subject has the chance to be re-screened at 
a later time point. 
However, if a subject is dropped out of the study after randomization, he/she is not 
allowed to be re-screened and enter the study anew. 


 
 
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6 Study Treatments 
6.1 
Investigational Product (IP): EndoTAG-1 
The active pharmaceutical ingredient (API) in EndoTAG-1 is paclitaxel, which 
complies with the specifications of the European Pharmacopoeia (Ph.Eur.). 
Recommended International Non-proprietary Name (INN): Paclitaxel 
Compendial Name:   
 
Paclitaxel (USP, Ph.Eur.) 
CAS Registry Number: 
 
[33069-62-4] 
Molecular Weight:  
 
 
853.9 g/mol 
Formula:  
 
 
 
C47H51NO14 
 
Figure 6-1: 
Structural Formula - EndoTAG-1 (paclitaxel) 
 
EndoTAG-1 was first developed by Munich Biotech AG (Germany) under the names 
LipoPac and MBT-0206 and by Medigene AG under the name of EndoTAG-1. Since 
2013, development and global commercialization of EndoTAG-1 is executed by 
SynCore Biotechnology Co., Ltd. 
The Investigational Product (IP) is a powder for solution for infusion that appears as a 
white caked powder. It is reconstituted with water for injection prior to application. The 
resulting solution consists of small liposomal vesicles with an intensity weighted 
average particle size <300 nm. 
The aqueous phase is a solution of trehalose and citric acid as stabilizer. Trehalose is a 
natural, non-reducing disaccharide at about iso-osmolal concentration (284 mosmol, 98 
mg/mL), which needs to be taken into consideration when treating diabetic patients 
(insulin-dependent diabetes mellitus, IDDM). Citric acid is used at a concentration of 
60 µM in solution in order to maintain a low pH and therefore to increase the chemical 
stability of the API in the liquid phase. The IP contains less than 0.5% (w/w) ethanol 
and has a pH of 3 to 5. 
 
 


 
 
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Table 6-1: 
Excipients of EndoTAG-1 
Excipient: 
Formula: 
Molecular 
Weight: 
Function: 
DOTAP-Cl 
C42H80NO4Cl 
698.55 g/mol 
Membrane compound 
DOPC 
C44H84NPO8 
786.12 g/mol 
Membrane compound 
Trehalose dihydrate 
C12H22O11•2H2O 378.3 g/mol 
Cryoprotectant 
Citric acid, anhydrous 
C6H8O7 
192.12 g/mol 
Stabilizing acidifier 
6.2 
Comparator Product (IP): Gemcitabine 
Gemcitabine is used as a comparator with a marketing authorization (for pancreatic 
cancer at the dosage used in this protocol) in the respective countries. Further 
information on gemcitabine can be found in the Summary of Product Characteristics 
(SPC) of gemcitabine. 
6.3 
Packaging and Labeling of Investigational Product 
EndoTAG-1 is packed in 100 mL glass vials (hydrolytic class I) with bromobutyl 
stoppers fixed by standard color coded aluminum flip off caps.  
The Label information for the Primary Container (= immediate packaging) and 
Secondary Container (= outer packaging) will comply with the requirements of GMP 
Annex 13. If applicable, local labels will be further supplemented by further terms if 
requested by local law in the participating country. 
The label will contain the following information: 
Manufacturer: SynCore Biotechnology  
4F, No. 69, DongXing Rd., XinYi Dist., Taipei City 110, Taiwan, Tel.: +886-2-27603688  
EndoTAG-1: 6.4 mg  
Batch-Numbers.:  
Powder for solution for infusion  
1 vial contains 2.63 g lyophilised powder containing 6.40 mg liposomal paclitaxel  
For i.v. application after reconstitution  
Trial reference code: CT 4006  
For clinical trial use only  
Vial-No.:  
Store at 2-8°C, protected from light  
Handle and discard as required for cytotoxic drugs  
CAUTION: New drug - limited by United States law to Investigational Use (only for USA) 
6.4 
EndoTAG-1: Dose Justification 
Preclinical safety data obtained so far justify multiple administrations of EndoTAG-1 
up to a dose of 44 mg/m2 lipid complexed paclitaxel to patients. EndoTAG-1 has been 
investigated in several clinical studies and a favorable safety profile without major 
safety concerns at a dose of 44 mg/m2 lipid complexed paclitaxel has been assessed. 
Because of this and because of the complementary anti-neovascular mode of action of 
EndoTAG-1, it is expected that there is no interference in respect to safety and 
tolerability between EndoTAG-1 and gemcitabine. 


 
 
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However, due to the targeting mode of action of EndoTAG-1 lower doses might be as 
effective as higher doses with probably less side effects, especially when combined 
with standard chemotherapy. This assumption was confirmed with an exploratory 
analyses of CT 4001 study (A Controlled, Randomized, Open label Phase II Trial to 
Evaluate Safety and Efficacy of a 1st line Combination Treatment with Weekly Infusion 
of Gemcitabine and Twice Weekly Administration of Lipid Complexed Paclitaxel 
(EndoTAG-1) in Three Dose Levels Compared with Gemcitabine Monotherapy in 
Patients with Measurable Locally Advanced and/or Metastatic Adenocarcinoma of the 
Pancreas) with focus on a subpopulation of subjects with baseline ECOG grade of 0 
and 1. The results from the analyses demonstrated that hazard ratios (for PFS and OS) 
favor combination therapy of gemcitabine plus the EndoTAG-1 (for all three doses; 11 
mg/m², 22 mg/m² and 44 mg/m²) when compared to the gemcitabine monotherapy. 
However statistically significant differences were observed for the two endpoints (OS 
and PFS) between the gemcitabine monotherapy and EndoTAG-1 (22 mg/m²) plus 
gemcitabine.  
Based on the results of exploratory analyses of CT 4001 study, EndoTAG-1 (22 mg/m² 
lipid complexed paclitaxel) dose is selected for this Phase 3 study.  
6.5 
Study Dosing Schedule 
Arm A:  
• Treatment cycle 1: EndoTAG-1 will be given at a dose of 22 mg/m2 as an 
intravenous infusion which should be started slowly and increased to a maximum 
of 1.5 ml/min (15 min at 0.5 ml/min, 15 min at 1.0 ml/min. and thereafter 1.5 
ml/min.) on days 1, 4, 8, 11, 15, 18, 29, 32, 36, 39, 43 and 46 plus gemcitabine 1000 
mg/m², 30 min. i.v. infusion on days 4, 11, 18, 32, 39, and 46 of cycle 1 until any 
one of the following occurs:  progressive disease or unacceptable toxicity or 
withdrawal of consent 
• Subsequent treatment cycles: EndoTAG-1 on days 1, 4, 8, 11, 15, 18, 29, 32, 36, 
39, 43 and 46 plus gemcitabine on days 4, 11, 18, 32, 39, and 46 of all subsequent 
cycles, until any one of the following occurs:  progressive disease or unacceptable 
toxicity or withdrawal of consent 
Arm B: 
• Treatment cycle 1: gemcitabine 1000 mg/m², 30 min. i.v. infusion on days 4, 11, 18, 
32, 39, and 46 of cycle 1 until any one of the following occurs:  progressive disease 
or unacceptable toxicity or withdrawal of consent 
• Subsequent treatment cycles: gemcitabine on days 4, 11, 18, 32, 39, and 46 of all 
subsequent cycles, until any one of the following occurs: progressive disease or 
unacceptable toxicity or withdrawal of consent 
 


 
 
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6.6 
Dispensing, Storage and Accountability 
6.6.1 Preparation of EndoTAG-1 and i.v. administration 
EndoTAG-1 is delivered to the hospital pharmacy as a sterile, white powder for infusion 
(Lyophilisate) packaged in glass vials for single use. Until administration to the subject 
the investigational medicinal product has to be stored at 2-8°C, protected from light. 
The hospital pharmacy has to take care of the disposal of used vials and materials in 
contact with the study medication in compliance to the local regulations concerning 
hazardous (cytotoxic) waste. 
The stability of the reconstituted drug in the vial as the primary container system is 24 
hours when stored at 25°C ± 2°C. 
Prior to application, EndoTAG-1 has to be reconstituted with water for injection under 
aseptic conditions using a safety work bench for cytostatics or similar safety measures 
at the pharmacy. After transfer of the reconstituted drug to the infusion system, it is 
stable for a maximum of 4 hours. 
The solution is allowed to rest undisturbed at 2-8°C to allow complete reconstitution. 
The required application volume is calculated from the subject's body weight and the 
dose schedule. A sufficient number of reconstituted vials have to be prepared to cover 
the application volume. For large application volumes, the preparation is split into 
portions, which can be used one after the other and stored at 2-8°C until needed. The 
maximum volume for one portion should not exceed 200 ml to allow the administration 
within the time frame of 4 hours and ensure in-use stability throughout the application. 
The maximum infusion rate must not exceed 90 mL/hour = 1.5 mL/min and at the 
beginning of intravenous infusion the rate should be accelerated slowly from 0.5 
mL/min to 1.5 mL/min over a period of 30 min. The investigational medicinal product 
must not be stored and used a second time. 
After randomization and before start of treatment phase it can be considered to apply a 
central venous catheter to the subjects (if not already present) to facilitate 
administration of study medication. 
The investigator or pharmacist must maintain accurate records of the receipt of all 
investigational medicinal product provided by the sponsor, including date received, 
batch number, expiration date, subject number, amount received and disposition 
(dispensation date, amount of investigational medicinal product dispensed and subject 
identification number). 
All remaining unused investigational medicinal product has to be returned to the 
supplier after study termination or destroyed at the site's pharmacy after the written 
permission of the sponsor according to standard operating procedures. Destruction of 
investigational medicinal product has to be documented by the investigator and/or 
pharmacist. The respective documentation has to be sent to the Sponsor. 


 
 
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The pharmacist and the investigator have to follow the detailed information on 
preparation and administration of EndoTAG-1 provided by the sponsor in a separate 
document. 
6.6.2 Preparation of gemcitabine and i.v. administration 
The investigational sites have to buy the gemcitabine supply locally. Associated costs 
will be reimbursed by the sponsor. 
For reconstitution of the lyophilized gemcitabine please follow these instructions: 
• Calculate the amount of gemcitabine needed for administration of 1000 mg/m2. 
• To reconstitute, add 25 ml of 0.9% Sodium Chloride Injection to each required 1g 
vial or 5 ml of 0.9% Sodium Chloride Injection to each required 200 mg vial. 
• Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 
mg/ml. The total volume upon reconstitution will be 5.26 ml or 26.3 ml, 
respectively. 
• Complete withdrawal of the vial contents will provide 200 mg or 1g of gemcitabine, 
respectively. 
• Check that the solution is free from visible particles and that it is clear and colorless 
to light straw-colored. 
• Transfer the appropriate amount of reconstituted gemcitabine to an infusion bag. 
The drug may be administered as prepared or further diluted with 0.9% Sodium 
Chloride Injection to concentrations as low as 0.1 mg/ml. 
• Administer the gemcitabine solution as an intravenous infusion over a period of 30 
minutes. 
• Chemical and physical in-use stability of gemcitabine solution has been 
demonstrated for 24 hours at 30°C. From a microbiological point of view, the 
product should be used immediately. If not used immediately, in-use storage times 
and conditions prior to use are the responsibility of the user and would normally not 
be longer than 24 hours at room temperature. Gemcitabine solution must not be 
stored cold, as precipitation may occur. 
6.7 
Dose adjustments 
At the visit of a first infusion (Arm A: Visit 1, Arm B: Visit 1G), the subject has to 
receive 100% of the trial medication (Arm A: EndoTAG-1 and gemcitabine; Arm B: 
gemcitabine). If, for any reason it is clear that the subject will not be able to receive the 
full dose of trial medication at the first infusion, the treatment should not be initiated 
and the subject should be immediately withdrawn from the study. 
Important: For the purpose of dose adjustments due to clinical chemistry results 
(non-hematological toxicity) only basic parameters that can be analyzed without 


 
 
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longer waiting times (so called "emergency lab values") will be considered. These 
values are: AST, ALT and creatinine. The remainder of clinical chemistry will be 
assessed for safety issues, but not considered for the decision of dose adjustment. 
In case of hematological, non-hematological and special hematological toxicities, 
treatment might be reduced or postponed (during continuation of treatment: reduced or 
omitted) as specified in the following. In case of postponement, all examinations of the 
respective visit will be repeated one week later and study medication will be 
administered according to the specifications given in Section 6.7.1 and 6.7.2. 
6.7.1 Dose Modifications for EndoTAG-1 
Criteria for Dose Modifications 
• Grade 4 neutropenia lasting 7 or more days 
• Febrile neutropenia 
• Grade 4 thrombocytopenia  
• Grade 3 thrombocytopenia with significant bleeding or requiring transfusion 
• Grade ≥ 3 stomatitis/vomiting/diarrhea 
• Other ≥ Grade 3 and 4 toxicities a, b 
a Except Grade 3 fatigue/asthenia or transient arthralgia/myalgia for which no dose 
modification is required. 
b To be adjusted as medically indicated after discussion between Investigator and 
Sponsor 
If any of the above mentioned toxicity criteria are present, no study medication is to be 
administered at this visit. If the toxicity criteria are no longer fulfilled at the next 
scheduled visit, EndoTAG-1 is to be administered at a reduced dose of 11 mg/m². If the 
subject tolerates treatment at the reduced dose (i.e. does not develop any of the above 
mentioned toxicities), the EndoTAG-1 dose should be re-escalated to 22 mg/m². If re-
escalation is not tolerated by the subject, the dose is to be permanently reduced to 11 
mg/m². The attempt for re-escalation of the EndoTAG-1 dose is to be made only once 
throughout the study. Subjects not tolerating treatment even after dose reduction will 
be taken off study.  
6.7.2 Dose Modifications for Gemcitabine 
6.7.2.1 Dose Modifications for Hematologic Adverse Reactions  
Absolute granulocyte 
count 
(x 106/L) 
 
Platelet count 
(x 106/L) 
% of full dose 
≥ 1000 
And 
≥100,000 
100% 
500-999 
Or 
50,000 – 99,999 
75% 
<500 
Or 
<50,000 
Hold 


 
 
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6.7.2.2 Dose Modifications for Non-Hematologic Adverse Reactions  
Permanently discontinue Gemcitabine for any of the following:  
• Unexplained dyspnea or other evidence of severe pulmonary toxicity  
• Severe hepatic toxicity  
• Hemolytic-uremic syndrome  
• Capillary leak syndrome  
• Posterior reversible encephalopathy syndrome  
Note: Withhold gemcitabine or reduce dose by 50% for other severe (Grade 3 or 4) 
non-hematological toxicity until resolved. No dose modifications are recommended for 
alopecia, nausea, or vomiting. 
If a subject fails to meet criteria for retreatment on the day the next treatment is 
scheduled, treatment should be omitted and the subject will be re-evaluated at least 
weekly. Treatment may be omitted for a maximum of 2 weeks. If treatment is omitted 
for >1 week, a new cycle should be started upon continuation of treatment. Any subject 
who fails to recover from a treatment related adverse event to baseline or Grade 2  
within 2 weeks of scheduled retreatment will be withdrawn from the study with the 
exception of subjects who benefit from study treatment (non-progressive disease 
according to RECIST v.1.1), who may continue treatment on study after consultation 
and approval of the Sponsor. 
6.7.3 Dose Modification for Subjects Assigned to Arm A (EndoTAG-1 plus 
Gemcitabine) 
Subjects may start a new cycle of combination therapy if ANC is > 1,500/mm3, platelets 
are >100,000/mm3 and treatment-related non-hematologic adverse event including 
neuropathy has resolved to baseline or Grade 2. Subjects with Grade 2 neuropathy will 
not be retreated until resolved to Grade 1. 
Note: Subjects on treatment arm A who requires discontinuation of gemcitabine will 
not continue on single-agent EndoTAG-1 alone. However, subjects in Treatment Arm 
A who require discontinuation of EndoTAG-1 due to toxicity may continue on 
gemcitabine monotherapy. Subjects on Arm B (gemcitabine alone) will not be offered 
treatment with EndoTAG-1 at the time of discontinuation (no cross-over allowed). 
6.8 
Contraindications, Precautions, and Warnings for EndoTAG-1 
6.8.1 Contraindications 
EndoTAG-1 is contraindicated in patients with known severe hypersensitivity to 
paclitaxel or to any excipients. 
EndoTAG-1 should not be used in patients with baseline neutrophils < 1,000/mm3. 


 
 
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There is no experience of the use of EndoTAG-1 in pregnant women. Like other 
cytotoxic anticancer drugs, EndoTAG-1 could cause fetal harm when administered to 
a pregnant woman and, therefore, is contraindicated during pregnancy. Women of 
childbearing potential must be advised to avoid pregnancy while they or their male 
partner are receiving EndoTAG-1 and in the 90 days following discontinuation of 
EndoTAG-1 therapy. Should they become pregnant after all, they should inform the 
treating doctor immediately. 
It is not known whether EndoTAG-1 is excreted in human milk. EndoTAG-1 is 
contraindicated in nursing mothers. It is recommended that nursing be discontinued 
when receiving EndoTAG-1 therapy. 
6.8.2 Precautions and Warnings 
Sometimes infusion associated reactions may occur within minutes of starting the 
infusion of EndoTAG-1. These are characterized by symptoms including dyspnea, 
flushing, chest pain, hypertension, tachycardia, sweating, shortness of breath, chills, 
back pain, tightness in chest and throat as well as hypotension. Temporarily stopping 
the infusion usually resolves these symptoms without further therapy. However, 
medication 
to 
treat 
these 
symptoms 
(e.g. 
antihistamines, 
corticosteroids, 
catecholamines, see below) as well as emergency equipment should be available for 
immediate use. In most patients’ treatment can be resumed after all symptoms have 
resolved, without recurrence. To minimize the risk of infusion reactions, the infusion 
has to be started slowly and infusion rate should not exceed 1.5ml/min. The patient 
should be carefully monitored during infusion. 
Please follow the local procedures for handling of cytotoxic drugs. 
EndoTAG-1 contains the cytotoxic drug paclitaxel and, as with other potentially toxic 
compounds, caution should be exercised in handling EndoTAG-1. The use of gloves is 
recommended. If EndoTAG-1 solution contacts the skin, wash the skin immediately 
and thoroughly with soap and water. If EndoTAG-1 contacts mucous membranes, the 
membranes should be flushed immediately and thoroughly with water. 
Any unused product and all equipment used for the preparation and administration of 
EndoTAG-1 or contacting EndoTAG-1 must be disposed of in accordance with local 
requirements concerning cytotoxic drug products. 
6.8.3 Emergency Medication for infusion related toxicity 
• H2-receptor antagonist (e.g. cimetidine 300 mg i.v. or ranitidine 50 mg i.v.) 
• H1-antihistaminic (e.g. clemastine 2mg i.v.) 
together with other "state-of-the-art" emergency medications (e.g. corticoids, 
catecholamines) have to be kept handy on site. 
6.9 
Contraindications, Precautions, and Warnings for Gemcitabine 


 
 
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For contraindications, precautions, and warnings, refer to SPC of gemcitabine in details. 
 
Concomitant radiotherapy 
Concomitant radiotherapy (given together or ≤7 days apart): Toxicity associated with 
this multimodality therapy is dependent on many different factors, including dose of 
gemcitabine, frequency of gemcitabine administration, dose of radiation, radiotherapy 
planning technique, the target tissue, and target volume. Details and recommendations 
for use can refer to SPC of gemcitabine. 
 
Live vaccinations 
Yellow fever vaccine and other live attenuated vaccines are not recommended in 
patients treated with gemcitabine due to the risk of systemic, possibly fatal, disease, 
particularly in immunosuppressed patients. 
 
Fertility 
Men being treated with gemcitabine are advised not to father a child during and up to 
6 months after treatment and to seek further advice regarding cryoconservation of 
sperm prior to treatment because of the possibility of infertility due to therapy with 
gemcitabine. 
6.10 Other study medication 
No other study medication is allowed while the subject is participating in the trial. 
6.11 Prior and Concomitant Medication 
6.11.1 Prior Treatment 
Patients are not allowed to have received any chemotherapeutical treatment (except 
FOLFIRINOX as the first-line therapy) for pancreatic adenocarcinoma prior to 
enrollment. 
6.11.2 Permitted Treatment 
Premedication: 
In arm A group, Dexamethasone and anti-histamine drugs such as diphenhydramine (or 
its equivalent), cimetidine or ranitidine may be given as premedication for EndoTAG-
1 (liposomal paclitaxel). 
Paclitaxel-induced nausea and vomiting may be prevented by i.v. application of 
ondansetron (8 mg), granisetron (3 mg), tropisetron (4 mg) or dolasetron (100 mg) 
given 30 min prior to chemotherapy. Delayed nausea and vomiting may be treated with 
oral metoclopramide and dexamethasone. 
G-CSF or GM-CSF: 


 
 
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In case of observed severe hematotoxicity (i.e., maximal hematotoxicity with 
granulocytes < 0.5/µl or granulocytes < 1.0/ µl possibly accompanied by fever> 38.5° 
C, or hematotoxicity necessitating treatment delay), colony-stimulating factors should 
be given prophylactically starting on day 2 of the following cycles until recovery to 
prevent further episodes of hematotoxicity. 
Note: The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes 
CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel is 
concomitantly administered with known substrates (e.g., midazolam, buspirone, 
felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors 
(e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and 
carbamazepine) of CYP3A4.  
Caution should also be exercised when paclitaxel is concomitantly administered with 
known substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and 
inducers (e.g., rifampin) of CYP2C8.  
Potential interactions between paclitaxel, a substrate of CYP3A4, and protease 
inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates 
and/or inhibitors of CYP3A4, have not been evaluated in clinical trials. 
 
 


 
 
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7 Description of Study Assessments and Procedures 
7.1 
Informed Consent 
Written informed consent will be obtained for this study by the Investigator or designee 
from all subjects before the performance of any protocol-specific procedure. This study 
will be conducted in accordance with the provisions of the Declaration of Helsinki.  
In obtaining and documenting informed consent, the Investigator must comply with 
applicable regulatory requirements and must adhere to Good Clinical Practice (GCP). 
The Investigator, or designee, must fully inform subjects of all pertinent aspects of the 
study. Before informed consent may be obtained, the Investigator, or a person 
designated by the Investigator, must provide the subject ample time and opportunity to 
inquire about details of the study and to decide whether or not to participate in the trial. 
All questions about the trial must be answered to the satisfaction of the subject. Prior 
to the subject’s participation in the trial, the written informed consent must be signed 
and personally dated by the subject and by the person who conducted the informed 
consent discussion. Authorization for release of protected health information must also 
be obtained, as per local policies.  
7.2 
Assessment of Eligibility 
During the Screening Phase and prior to treatment administration, the Investigator must 
assess a subject’s continued suitability and eligibility for the trial. The Inclusion and 
Exclusion criteria of this Protocol are described in Sections 3.4.1 and 3.4.2. If the 
subject is not suitable or eligible for the trial then the subject will be a screen failure.  
7.3 
Disease History 
Disease history will be assessed at screening and will include the following: 
1. Date of first diagnosis and the history of the course of the disease 
2. Histologically or cytologically confirmed adenocarcinoma of the pancreas 
3. At least one measurable tumor lesion according to RECIST version 1.1 as assessed 
by the investigator (local radiological image assessment). 
4. Details of the prior chemotherapy, surgical or radiation therapy. 
7.4 
Medical History 
Medical history will be assessed at screening and will include the following: 
• Medical and surgical history, including past or concurrent clinically significant 
disease(s), or symptoms experienced during 30 days prior to screening are to be 
recorded, using the body system categories outlined below. For each history, the 
specific medical terminology for the disease/disorder/condition, the date of 
diagnosis, and the history status (resolved or ongoing) will be documented. 


 
 
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Cardiovascular 
 
 
Lymphatic 
Respiratory 
 
 
Hematologic 
Gastrointestinal  
 
Immunologic 
Renal 
 
 
 
Dermatologic 
Hepatic 
 
 
 
Psychiatric 
Neurological 
 
 
Genitourinary 
Endocrine 
 
 
Other 
7.5 
Demographic Information 
For the purposes of this study, demographic information will include: 
• Dates of ICF signature  
• Date of birth 
• Gender 
• Race (American Indian/Alaskan Native, Asian, Black/African American, 
Native Hawaiian/Pacific Islander, Caucasian, or other) 
• Ethnicity (Hispanic/Latino or Not Hispanic/Latino) 
7.6 
ECOG Performance Status 
The ECOG performance status will be documented at screening and at all Treatment 
Visit 8/End of Treatment visit. 
Table 7-1: 
ECOG Performance Status Scale1 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
                                                 
1 (Oken, Martin M., et al. 1982) 


 
 
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5 
Dead. 
 
 
7.7 
Physical Examination 
A complete physical examination will be performed to include a review of all systems. 
Each body system will be classified as being either normal or abnormal, with 
abnormalities for each body system noted. Subsequent physical examinations will 
identify changes from the baseline examination with both positive and negative changes 
being noted.  
The complete physical examination will include routine examinations for the following: 
• General Appearance 
• Head, Ears, Eyes, Nose, Throat (HEENT) 
• Lymph Nodes 
• Heart/Cardiovascular abnormalities 
• Respiratory 
• Abdomen 
• Genitourinary 
• Musculoskeletal and Extremities  
• Neurologic abnormalities Dermatologic abnormalities 
• Any other body system for which an abnormality is noted and which, in the 
opinion of the Investigator, is relevant to the safety of the subject or could 
impact safety or efficacy results for the subject; i.e., the abnormality is clinically 
significant (CS).  
7.8 
BSA Calculation 
BSA will be calculated on dosing days, using the formula (Mosteller, 1987) below: 
BSA (m2) = [Height (cm) x Body Weight (kg)/3600]½ 
The total dose (mg) will be calculated as:  
Total Dose 1/Dose 2 (mg/m2) x BSA (m2) 
7.9 
Vital Signs 
Vital signs, including 
• 
Height (cm) (only performed at screening) 
• 
Weight (kg) at each visit before a study treatment infusion 
• 
Blood pressure (supine),  
• 
Heart rate, and  
• 
Body temperature (oral, axillary, tympanic or rectal) 


 
 
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For measurement of body temperature, the same type of measurement is to be used 
throughout the study 
 
7.10 Laboratory Assessments 
The local laboratory for the study site will be used and all procedures will be performed 
following the standard operating procedure (SOP) of the local laboratory. 
The parameters assessed are detailed below: 
Hematology 
Hemoglobin, Hematocrit (Hct), Mean Corpuscular Volume (MCV), Mean Corpuscular 
Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), RBC 
count, WBC count, WBC Differential, Absolute neutrophil count and Platelet count 
Clinical Chemistry 
Total Bilirubin, Alkaline Phosphatase, ALT, AST, Gamma-glutamyl transferase (GGT), 
Albumin, Total Protein, Creatinine, Urea (BUN), Uric acid, Sodium, Potassium, 
Calcium, Chloride, Glucose and Triglycerides (TG). 
Coagulation 
INR, PT, aPTT, total Fibrinogen 
Urinalysis 
pH, Appearance, Color, Specific gravity, Viscosity, Turbidity, Ketones, Bilirubin, 
Blood, Glucose, Protein, Nitrites, Urobilinogen, Leukocyte esterases, Microscopic 
exam includes bacteria, cast, crystals, epithelial cells, RBC, and WBC.  
Pregnancy test 
A urine or serum pregnancy test for women of childbearing potential 
Tumor Marker 
CA 19-9 
7.11 PK Blood Sample Collection 
PK sample collection will only be performed from first 50 enrolled subjects assigned 
to Arm A.  
• Pharmacokinetic sampling on Day 1: Cmax, tmax, t½ term, VD, and CL for 
paclitaxel, 6α-OHpaclitaxel and DOTAP within 3 hours prior to EndoTAG-1 
treatment (predose), at the end of EndoTAG-1 i.v. infusion, and at 30 min, 1 hr, 2 
hr, 4 hr and 6 hr post infusion.   
• Pharmacokinetic sampling on Days 4, 8, 15, 29 and 43: trough levels of paclitaxel, 
6α-OH-paclitaxel and DOTAP within 3 hours prior to EndoTAG-1 treatment 
(predose). 


 
 
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7.12 Quality of Life Questionnaire 
The EORTC-QLQ-C30 [European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire], and PAN-26 module, which was specifically developed 
for clinical trials in pancreatic cancer, will be used to evaluate clinical benefit. 
7.13 Tumor Imaging 
Abdominal CT-scan with i.v. and gastrointestinal contrasts (or MRI), and chest X-ray 
(or CT or MRI). Thoracic CT- or MRI-scans have to be done additionally, if target 
lesions detected by chest X-ray are not clearly defined or not surrounded by aerated 
lung. Further imaging exams to be done if lesions are suspected in other areas. 
7.14 Tumor Response Evaluation 
7.14.1 Definition of lesions 
Tumor response will be assessed according to the RECIST (version 1.1; Eisenhauer et 
al. 2009). At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
7.14.1.1 Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 10mm by CT scan (CT scan slice thickness no greater than 5mm). 
• 10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable). 
• 20mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
7.14.1.2 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10mm or pathological 
lymph nodes with ≥10 to <15mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
7.14.1.3 Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 


 
 
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Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
Lesions with prior local treatment: 
• Tumour lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
7.14.2 Method of Assessment 
The same method of assessment and the same technique have to be used to characterize 
each identified and reported lesion at screening, at end of treatment and during follow-
up. 
Clinically detected lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI should be performed with contiguous cuts of 5 mm or less 
in slice thickness, if possible [minimum measurable lesion size: long axis ≥ 10 mm (CT 
+ MRI) and 2 x slice thickness, if the slice thickness is > 5 mm]. 
Ultrasound may only be used as a possible alternative to clinical measurements for 
superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules. 
 
 


 
 
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7.14.3 Baseline documentation of ‘target’ and ‘non-target’ lesions 
Only subjects with measurable disease at baseline should be enrolled in this study. For 
evaluation of tumor response, lesions present at screening will be separated into target 
and non-target lesions according to the following criteria: 
Target Lesions: 
• A maximum of five (5) target lesions in total (up to two (2) per organ)  
• Select largest reproducibly measurable lesions. If the largest lesion cannot be 
measured reproducibly, select the next largest lesion which can be measured  
• Add up longest diameters (LD) of non-nodal lesions (axial plane) and short axis 
diameters of nodes. This is the “sum of the longest diameters” (SLD) 
Non-Target Lesions  
• All other lesions present at screening. Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-
up. 
• It is possible to record multiple non-target lesions involving the same organ as a 
single item on the eCRF (e.g. “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”) 
7.14.4 Evaluation of target lesions 
• Measure LD (axial plane) for each target lesion  
• Measure short axis for target lymph nodes  
• Add these measurements to get the SLD  
• If too small to measure, a default value of 5 mm is assigned. If the lesion disappears 
completely, the measurement is recorded as 0 mm.  
• Splitting or coalescent lesions 
o If a target lesion fragments into multiple smaller lesions, the LDs of all 
fragmented portions are added to the sum  
o If target lesions coalesce, the LD of the resulting coalescent lesion is added to 
the sum 
 
 
 
 
 
 


 
 
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Table 7-2: 
Target Lesion Evaluation 
Response 
Definition 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered 
progression). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study 
 
7.14.5 Evaluation of non-target lesions 
Table 7-3: 
Non-Target Lesion Evaluation 
Response 
Definition 
Complete Response 
(CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes 
must be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease 
(PD) 
Unequivocal progression of existing non-target 
lesions. (Note: the appearance of one or more new 
lesions is also considered progression). 
 
7.14.6 Evaluation of Best Overall Response 
The best overall response is the best response recorded from start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the start of treatment). 


 
 
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The following table provides overall responses for all possible combinations of tumor 
responses in target and non-target lesions with or without the appearance of new lesions: 
Table 7-4: 
Time point response: subjects with target (± non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = inevaluable. 
7.15 Electrocardiogram 
A 12-lead ECG will be conducted at the Screening Visit (SV) and at all Treatment Visit 
8/End of Treatment visit.  
7.16 Concomitant Medication 
To avoid the use of concomitantly administered CYP3A4 and CYP2C8 inhibitors and 
inducers (see paclitaxel package insert). 
All medications and therapies administered or taken by the subject beginning 30 days 
prior to Screening Visit and throughout the study will be recorded in the source 
documents and, for randomized subjects, on the appropriate page of the electronic Case 
Report Form (eCRF). For each medication and non-study treatment, the following will 
be documented: 
• Medication/treatment name (generic name may be used if trade name is 
unknown) 
• Dose, unit, and frequency of dosing (individual dosages, not total daily dose).  
o Note: Each new dose of medication should be recorded as a separate 
entry, with the exception of medications that are given on a sliding scale. 
For these, it is acceptable to enter the range of the dosage, including the 
start and stop dates for which the specified dosage range was used. 
• Route of dosing 
• Indication for use 
• The start date  


 
 
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• The stop date (if medication/therapy is not ongoing) 
7.17 Randomization 
Subjects who are eligible to participate in the trial will be centrally randomized to 
receive either Arm A (EndoTAG-1 and gemcitabine) or Arm B (gemcitabine alone) in 
a 1:1 ratio using a stratified block randomization scheme. The stratification variables 
are the extent of disease (subjects with locally advanced and metastatic pancreatic 
cancer) and the performance status (ECOG performance status 0 and 1). Within each 
stratum, subjects will be allocated with equal probability to either treatment in Arm A 
or treatment in Arm B and the randomization system will be set up in such a way that 
there is a 1:1 balance between the treatment groups from the different strata. 
7.18 Study Treatment Administration 
Refer to Section 6 for details. 
7.19 Appropriateness of Measurements 
The measurements used in this in study are considered appropriate for the indication 
studied. Disease response is a common tool used in cancer trials to study the 
effectiveness of the study drug. Safety and tolerability of the study drug will be reported 
during the trial. 
 


 
 
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8 Adverse Events Definitions and Reporting 
The Investigator is responsible for the detection and documentation of events meeting 
the criteria and definition of an AE or SAE, as provided in this protocol. During the 
study when there is a safety evaluation, the Investigator or site staff will be responsible 
for detecting, documenting and reporting AEs and SAEs as detailed in this Section of 
the protocol.  
8.1 
Adverse Events (AE) 
An AE is any untoward medical occurrence that occurs in a patient or clinical 
investigation subject administered a pharmaceutical product, and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an IP, whether or not 
considered related to the medicinal product (definition per ICH E2A and E6 R1). 
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, 
must be recorded using medical terminology on the AE eCRF page. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology 
(e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as “upper respiratory infection”). All measures required for AE management must be 
recorded in the source document and reported according to Sponsor instructions. 
AEs will be elicited through direct questioning and subject reports. Any abnormality in 
physical examination findings or laboratory results that the investigator believes is 
clinically significant to the research subject and that occurred after initiation of the first 
study treatment will be reported as AEs. Abnormal findings that are NOT clinically 
significant should not be recorded as an AE. 
For all AEs, the Investigator must pursue and obtain information adequate to both 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as an SAE (see Section on SAEs) requiring immediate notification to the 
Sponsor or its designated representative. For all AEs, sufficient information should be 
obtained by the Investigator to determine the causality of the AE. 
Interventions for pre-treatment conditions (e.g., elective cosmetic surgery) or medical 
procedures that were planned before study enrolment are not considered AE. 
Laboratory results, which are out of range at the screening assessment (up to 14 days 
prior to randomization) do not fulfill the definition of an AE since these results 
represent the baseline information. 
Progression of the disease under investigation as well as an increase in CA19-9 values 
will not be regarded as adverse event during the course of this trial. Death due to disease 
progression has to be reported to the sponsor via the "Death due to Disease Progression" 
form. 


 
 
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8.1.1 Impact on Study Treatment 
The impact the event had on the study treatment will be assessed as either: none, study 
treatment interrupted, study treatment discontinued, or not applicable. The “not 
applicable” assessment will be used only when the subject is no longer in the treatment 
phase of the protocol or died. 
8.1.2 Intensity Assessment 
The severity of the AE will be graded according to the NCI Common Terminology 
Criteria for AEs (CTCAE) Grading Scale Version 4.03 (Publish Date: June 14, 2010, 
http://ctep.cancer.gov/reporting/ctc.html). 
The maximum severity (intensity) of the AE will be categorized by the Investigator as 
follows: 
Table 8-1:  
CTCAE v4.03 General Guidelines 
Grade 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL†. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE.‡ 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
†Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
‡Unlike the AE outcome assessment (see section 8.1.5), a subject may have more than one Grade 5 event. 
 
-Common Terminology Criteria for Adverse Events (CTCAE), v4.03: June 14, 2010 
For AEs not covered by NCI CTCAE, the severity will be characterized as “mild,” 
“moderate,” or “severe” according to the following definitions: 
• Mild events are usually transient and do not interfere with the subject’s daily 
activities 
• Moderate events introduce a low level of inconvenience or concern to the subject 
and may interfere with daily activities 
• Severe events interrupt the subject’s usual daily activities. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the experience should be noted. If the intensity category changes 
over a number of days, then those changes should be recorded separately (with distinct 
onset dates). All AEs, due to any cause that occurs during the investigation, whether or 
not related to the study drug, should be reported to the Safety Coordinator. 
 
 


 
 
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8.1.3 Causality Assessment 
The investigator will assign a relationship to the study drug (i.e. causality) for all AEs 
that occur during the study using the definitions below: 
• Unrelated: The AE is clearly related to other causes such as participant’s clinical 
state, environmental factors, or other therapies administered. 
• Unlikely to be related: The AE does not follow a reasonable temporal sequence 
from study drug administration; could readily have been produced by other causes 
such as the participant’s clinical state, environmental factors, or other therapies 
administered; does not follow a known response pattern to the study drug.  
• Possibly related: The AE follows a reasonable temporal sequence from study drug 
administration; follows a known response pattern to the study drug; could readily 
have been produced by other causes such as the participant’s clinical state, 
environmental factors, or other therapies administered.  
• Probably related: The AE follows a reasonable temporal sequence from study 
drug administration; follows a known response pattern to the study drug; cannot be 
reasonably explained by other factors such as the participant’s clinical state, 
environmental factors, or other therapies administered; improvement upon 
cessation of test drug.  
• Definitely related: The AE follows a reasonable temporal sequence from study 
drug administration; follows a known response pattern to the study drug; cannot be 
reasonably explained by other factors such as the participant’s clinical state, 
environmental factors, or other therapies administered; improvement upon 
cessation of test drug or reappears upon repeat exposure (if rechallenge occurs). 
8.1.4 Treatment Given as a Result of the Event 
The event impact in terms of treatment provided will be as either: none, medication 
administered, non-drug therapy administered, surgery performed, hospitalization, or 
other (with a specification). 
8.1.5 Outcome Assessment 
The outcome of the event will be assessed as either: resolved, resolved with sequelae, 
ongoing, or death. Only one AE per subject is allowed to have an outcome assessment 
as “death.” If there are multiple causes of death for a given subject, only the primary 
cause of death will have an outcome of death. 
8.2 
Adverse Event Reporting 
All AEs occurring during the study (from the time of the first study treatment until 
28 days after the last dose of study treatment) observed by the Investigator or reported 
by the subject (whether or not attributed to study drug), will be reported on the eCRF. 
Clinically significant AEs considered related or non-related to the IP by the Investigator 


 
 
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or the Sponsor will be followed until resolved or considered stable by the Investigator. 
The following information must be provided: description; dates of onset and resolution; 
severity; assessment of relatedness to IP; whether treatment was given as a result of the 
event and the outcome of the event. The investigator may be asked to provide follow-
up information. 
All AEs, serious or not, that result in the subject’s permanent withdrawal of IP or from 
the study will be discussed between the investigator and medical monitor. The eCRF 
for EOT/Early Withdrawal Visit should be completed including reason of withdrawal. 
It will be the investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the subject’s removal from study treatment. A subject may also 
voluntarily withdraw from study treatment due to what he or she perceives as an 
intolerable AE. If either of these occurs, the subject must undergo EOT assessment and 
be given appropriate care under medical supervision until symptoms cease or the 
condition becomes stable. 
8.3 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that at any dose (ICH E2A and 
E6 R1):  
• Results in death.  
• Is life-threatening.  
This means that the subject is at risk of death at the time of the event; it does not 
mean that the event hypothetically might have caused death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
• Results in persistent or significant disability or incapacity.  
• Is a congenital anomaly or birth defect.  
Other important medical events that may not be immediately life-threatening or result 
in death or hospitalization, based upon appropriate medical judgment, are considered 
SAEs if they are thought to jeopardize the subject and/or require medical or surgical 
intervention to prevent one of the outcomes defining a SAE. 
Since SAEs are critically important for the identification of significant safety problems, 
it is important to take into account both the Investigator’s and the sponsor’s assessment. 
If either the sponsor or investigator believes that the event is serious, the event must be 
considered serious and evaluated by the Sponsor for expedited reporting. 
All SAEs must be reported to the sponsor or sponsor designee immediately after the 
Investigator becomes aware of the event, along with a determination as to whether it is 
associated with the IP or any other study procedure. 
Disease progression should not be recorded as an AE or SAE term; instead, signs and 
symptoms of clinical sequelae resulting from disease progression will be reported if 
they fulfill the SAE definition.  


 
 
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8.4 
Serious Adverse Event Reporting 
All SAEs, irrespective of relationship to IP, must be reported within 24 hours of the 
Investigator knowledge of the event to Covance Patient Safety Services within 24 hours. 
CRO Covance 
Covance Patient Safety Services 
Email:      SAEIntake@covance.com 
Fax:          +1-888-887-8097 
Phone:     +61-2-88792000 (SAE hotline) 
A written SAE reports must include a full description of the event as described in 
Section 8.1 The Medical Monitor may request additional supporting documentation as 
it becomes available, such as lab reports, electrocardiogram [ECG] reports, discharge 
summary, hospital notes, etc, if applicable.  
Relevant medical records should be provided to the Sponsor or CRO as soon as they 
become available; autopsy reports should be provided for deaths if available. Should an 
Investigator be made aware of an SAE occurring any time after the reporting period, it 
must be promptly reported.  
The Investigator is also responsible for reporting all SAEs to the appropriate 
Institutional Review Board (IRB) in accordance with local laws and regulations. The 
Investigator is responsible for maintaining documentation in the study file that indicates 
the IRB has been properly notified.  
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of 
the following occurs:  
• The event resolves.  
• The event stabilizes.  
• The event returns to baseline, if a baseline value/status is available.  
• The event can be attributed to agents other than the IP or to factors unrelated to 
study conduct.  
• It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts).  
 
8.5 
SAE Follow-Up 
All subjects experiencing an SAE, including the discontinued subjects, must be closely 
followed until sufficient information is obtained to indicate a return to normal status or 
until the event stabilizes at a level acceptable to the investigator (i.e., recovery, return 
to baseline status, no further improvement expected, or death). 


 
 
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For each SAE indicated as an unresolved event on the initial report, regardless of 
whether the subject completed the study or withdrew, the site should submit a follow-
up report with updated information. 
8.6 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
Suspected Adverse Reaction (SAR)  
Suspected adverse reaction means any adverse event or adverse experience for which 
there is a reasonable possibility that the IP caused the adverse event. Inherent in this 
definition, and in the requirement to report them, is the need for the sponsor to evaluate 
the available evidence and make a judgment about the likelihood that the drug actually 
caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the IP and 
the adverse event. 
Unexpected 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the investigator brochure 
referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the investigator brochure listed only cerebral vascular accidents. 
8.7 
Expedited Reporting of SUSAR 
Sponsor (or designee) will provide written notification to the regulatory agencies i.e. 
FDA and all participating investigators of any suspected adverse reaction that is both 
serious and unexpected. Each notification should be submitted as specified below, 
depending on the type of event. Each written notification may be submitted on FDA 
form 3500A and/or CIOMS-I. 
• 7-Day Expedited Report: any serious and unexpected suspected adverse reaction 
that is fatal or life-threatening will be reported as soon as possible and no later than 
7 calendar days after the sponsor’s (or designee’s) initial receipt of the information. 
• 15-Day Expedited Report: any serious and unexpected suspected adverse reaction 
that is not fatal or life-threatening will be reported as soon as possible and no later 
than 15 calendar days after the sponsor (or designee) determines that the event 
qualifies for reporting (21 CFR 312.32). 
8.8 
Pregnancies 


 
 
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All initial reports of pregnancy must be reported to the Sponsor within 24 hours of the 
Investigator knowledge of the event using the appropriate pregnancy form.  
For IP, an exposure during pregnancy occurs if:  
• A female becomes, or is found to be, pregnant either while receiving or having been 
directly exposed (e.g., environmental exposure) to the IP, or the female becomes, 
or is found to be, pregnant after discontinuing and/or being directly exposed to the 
IP (maternal exposure) for 28 days after last dose of or exposure to IP.  
• A male partner of a pregnant female has been exposed to the IP, either due to 
treatment or environmental exposure, within 3 months prior to the time of 
conception and/or is exposed during his partner’s pregnancy (paternal exposure).  
If any study subject or study subject’s partner becomes or is found to be pregnant during 
the study subject’s treatment with the IP or exposure as defined above, the Investigator 
must submit this information on a Pregnancy form to the Sponsor (or its designated 
representative). In addition, the Investigator must submit information regarding 
environmental exposure to an IP in a pregnant woman (e.g., a subject reports that she 
is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) using 
the Pregnancy form. This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the pregnancy. The information submitted should 
include the anticipated date of delivery (see following information related to induced 
termination of pregnancy). 
Follow-up is conducted to obtain pregnancy outcome information on all exposure 
during pregnancy reports with an unknown outcome. The Investigator will follow the 
pregnancy until completion or until pregnancy termination (e.g., induced abortion) and 
then notify the Sponsor or its designated representative of the outcome as a follow-up 
to the initial Pregnancy form. In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth. In the event of a termination, the reason(s) 
for termination should be specified and, if clinically possible, the structural integrity of 
the terminated fetus should be assessed by gross visual inspection (unless pre-procedure 
test findings are conclusive for a congenital anomaly and the findings are reported).  
If the outcome of the pregnancy meets the criteria for immediate classification as an 
SAE (e.g., ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal 
death, or congenital anomaly [including that in a live born, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death]), the Investigator should follow the 
procedures for reporting SAEs.  
Additional information about pregnancy outcomes that are classified as SAEs follows:  
• “Spontaneous abortion” includes miscarriage and abortion.  
• All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after 1 month should be 


 
 
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reported as SAEs when the Investigator assesses the neonatal death as related to 
exposure to IP.  
Additional information regarding the exposure during pregnancy may be requested by 
the Investigator. Follow-up information regarding the outcome of the pregnancy and 
any postnatal sequelae in the infant will be required.  
 


 
 
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9 Statistical Considerations 
This section presents general information about statistical considerations and concepts 
such as randomization, stratification, statistical power, sample size, and a brief 
discussion on analysis methodology, as well as some data conventions. Detailed 
descriptions of the statistical analysis methods and data conventions that will be used 
in this study will be in a separate document; i.e., the Statistical Analysis Plan (SAP). 
9.1 
Treatment Groups  
The following treatment groups will be assessed: 
Group Description 
Arm A EndoTAG-1 22 mg/m2 twice weekly plus gemcitabine 1000 mg/m2 once weekly 
Arm B 
gemcitabine 1000 mg/m2 once weekly 
9.2 
Description of Study Endpoints  
9.2.1 Efficacy Endpoints 
9.2.1.1 Primary Efficacy Endpoints 
There are two primary endpoints for the study:    
• Overall survival (OS) 
Overall survival time is defined as time from randomization to death from any cause 
or last day known to be alive. 
• Progression Free Survival (PFS) 
Progression Free Survival time is defined as the time from randomization to either 
first observation of progressive disease or occurrence of death.  
 
9.2.1.2 Secondary Efficacy Endpoints 
The secondary endpoints for the study are: 
• Percentage of subjects with Objective Response (OR) according to Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1) 
• Percentage of subjects with objective response is based on assessment of complete 
response (CR) or partial response (PR) according to RECIST v.1.1. 
• Duration of Response (DR) 
• Duration of Response is defined as the time from the first documentation of 
objective tumor response (date of the first CR or PR) to objective tumor 
progression or death due to any cause.  
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• Percentage of subjects with disease control is based on assessment of complete 
response (CR) or partial response (PR) or stable disease (SD) according to 
RECIST v.1.1 
• Serum Carcinoma Antigen 19-9 (CA 19-9) response rate 
• Responders are defined as subjects with a reduction in CA 19-9 levels by least 
50% from baseline to the end of cycle 1 (or end of full treatment course). 
9.2.2 Safety Assessments 
Safety will be assessed based on the following assessments:  
• Incidence and severity of treatment-emergent adverse events (TEAEs), including 
serious adverse events and adverse events resulting in permanent discontinuation of 
protocol-defined therapy.  
• Changes in selected laboratory test results (i.e.,  
o Serum chemistry including urea, serum creatinine, sodium, potassium, 
chloride, bicarbonate, glucose, bilirubin, albumin, ALT, AST, ALP, total 
protein; and  
o Full blood count (FBC) including hemoglobin, hematocrit, RBC count, 
Platelets count, total leukocyte count, differential leukocyte count and 
absolute neutrophil count)  
• Changes in vital signs including systolic and diastolic blood pressure and pulse  
• Changes in electrocardiogram (ECG) results  
• Changes in physical examination results  
9.2.3 Exploratory Endpoints 
• Change From Baseline in European Organization for Research and Treatment of 
Cancer, Quality of Life Questionnaire Core-30 (EORTC QLQ- C30) Score  
EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, 
and social), global health status (GHS), symptom scales (fatigue, pain, 
nausea/vomiting), and single items (dyspnoea, appetite loss, insomnia, 
constipation/diarrhea, and financial difficulties). Most questions used 4- point scale 
(1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 
'Excellent'). Scores averaged, transformed to 0- 100 scale; higher score=better 
level of functioning or greater degree of symptoms. Change from 
baseline=Cycle/Day score minus baseline score. 
• Change from baseline in European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) Score  
QLQ-PAN26 consists of 26 questions (Qs) relating to disease symptoms, treatment 
(Tx) side effects and emotional issues specific to pancreatic cancer (PC). Questions 
include on altered bowel habits, pain, dietary changes, disease and Tx-related 
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with PC. All 26 Qs are answered on 4-point Likert scale ranging from '1=not at all' 
to 4='very much' and subsequently transformed into scales that range from 0-100; 
higher scores= greater degree of symptoms or treatment side effects and emotional 
issues. 
 
9.3 
Sample Size Determination and Rationale 
A total of 218 subjects will be enrolled and randomized in a 1:1 ratio to Arm A 
(EndoTAG-1 plus gemcitabine) and Arm B (gemcitabine monotherapy).  
The sample size is event-driven to collect a pre-specified number of primary efficacy 
outcomes. Based on the sample size calculation, the primary endpoint analysis for 
overall survival will require 167 events (deaths) from the 196 subjects. The primary 
endpoint analysis for progression-free survival will require 169 events (disease 
progression) from 182 subjects. This sample size is sufficient to detect a 40% reduction 
of overall survival in the risk of death in Arm A, as compared with Arm B (hazard ratio, 
0.60) using a 2-sided log-rank test with 90% power and an overall significance level of 
0.05 two sided test. This sample size is also sufficient to detect a 35% reduction of 
progression free survival in the risk of disease progression in Arm A, as compared with 
Arm B (hazard ratio, 0.647) using a 2-sided log-rank test with more than 80% power 
and an overall significance level of 0.05 two sided test. Sample size estimation for 
overall survival is depicted in Figure 9-1, total sample size requirement vs. the median 
survival time (month) in the treatment arm. Sample size is estimated using PASS (15) 
sample size software.  
Sample size estimation for progression-free survival is depicted in Figure 9-2, total 
sample size requirement vs. the median survival time (month) in the treatment arm. 
Sample size is estimated using PASS (15) sample size software. 
It is anticipated that there would be about 10% dropout in this study, to accommodate 
for the dropouts a total of 218 subjects would be randomized.  
The overall survival assumption for the sample size are based on published literature 
data comparing therapeutic effect of gemcitabine monotherapy and gemcitabine 
combination regimen on patients with advanced pancreatic cancer after previous 
FOLFIRINOX treatment. The hazard ratio for death of 0.60 with median overall 
survival of 4.4 months for gemcitabine monotherapy (Conroy et al. 2011) and 7.3 
months for gemcitabine + paclitaxel combination (Portal et al. 2015) was used for the 
sample size calculation. The progression-free survival assumption for the sample size 
are based on hazard ratio of 0.647 with median progression-free survival of 3.3 months 
for gemcitabine monotherapy (Conroy et al. 2011) and 5.1 months for gemcitabine + 
paclitaxel combination (Portal et al. 2015) was used for the sample size calculation. 
 
 


 
 
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Figure 9-1: 
Overall Survival Sample Size Plot: Total sample size requirement 
vs. the median survival time (month) in the treatment arm A.  
 
 
Figure 9-2:  Progression-Free Survival Sample Size Plot: Total sample size 
requirement vs. the median survival time (month) in the treatment arm A 
 
9.4 
Randomization and Stratification 


 
 
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This study will be conducted at approximately up to 100 sites. A total of 218 subjects 
are planned to be enrolled. All eligible subjects will be centrally randomized to receive 
either Arm A (EndoTAG-1 and gemcitabine) or Arm B (gemcitabine alone) in a 1:1 
ratio using a stratified block randomization scheme. The stratification variables are the 
extent of disease (subjects with locally advanced and metastatic pancreatic cancer) and 
the performance status (ECOG performance status 0 and 1). Within each stratum, 
subjects will be allocated with equal probability to either treatment in Arm A or 
treatment in Arm B and the randomization system will be set up in such a way that there 
is a 1:1 balance between the treatment groups from the different strata. 
9.5 
Blinding 
As this is an open label study, all study personnel will have knowledge of the treatment 
assignments after randomization and throughout the study. To avoid any susceptible 
selection bias, a stratified block randomization scheme with a mixed block size will be 
used and the blocks will be blinded until trial closure to all research personnel except 
the block generating statistician. The master randomization lists containing the 
treatment assignments will not be released to any study personnel prior to final database 
lock except for the DSMB meetings and at the time of the interim analysis.  
 
9.6 
Interim Analysis  
A single, pre-planned Interim Analysis (IA) will be conducted when approximately 101 
subjects have died (60% of the expected 167 events for the overall survival primary 
endpoint). 
The procedures for this IA will be based on a standard operating procedure (SOP) that 
has a well-established a firewall to protect the integrity of the trial. The IA will be 
performed by an independent statistician, who is not otherwise associated with the 
conduct of this trial. Details of the firewall will be outlined in the SOP. 
The results of the IA will be reviewed by an independent Data Safety and Monitoring 
Board (DSMB) who would assess the data for both safety (for the purposes of 
continuing the trial) and efficacy (for the purposes of sample size re-estimation). The 
DSMB responsibilities will be further elaborated in the DSMB charter. The DSMB will 
approve continuation of the study and recommend the sample size for remainder of the 
study. 
Goals:  
 
The objectives of this interim analysis are: 
• 
To evaluate the safety and efficacy of EndoTAG-1 plus gemcitabine in 
prolonging Overall Survival (OS) and Progression Free Survival (PFS) of 
subjects with locally advanced and/or metastatic adenocarcinoma of the 
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FOLFIRINOX.  
• 
Determine if it is necessary to evaluate the original sample size assumptions and 
to maintain study power. 
9.6.1 Metrics to be Calculated for the Interim Analysis 
9.6.1.1 Data for Safety Review 
At the time of the interim safety data review, all the data to be used along with the 
treatment assignment of each randomized subject will be given to the independent 
statistician. Using this data, the independent statistician will prepare descriptive 
summary and by subject listings of baseline and safety data including demographics, 
adverse events, serious adverse events, laboratory findings, physical examinations, vital 
signs, and ECG.   
9.6.1.2 Data for Efficacy Interim Analysis based on Overall Survival (OS) and 
Progression Free Survival (PFS) 
At the time of Interim Analysis, all the data to be used in the interim analysis along 
with the treatment assignment of each randomized subject will be given to the 
independent statistician. Using this data, the independent statistician will calculate the 
following metrics in addition to all the safety data that is to be prepared for the safety 
review: 
1. For the calculation of the conditional power: 
a. Proportion of subjects randomized to each Arm at the time of interim analysis 
b. The test statistic computed from the observed data using Cox proportional hazards 
model outlined in the Primary Efficacy Analysis as described in Section 9.8.3.1.  
c. The number of events at the time of the interim analysis 
2. For the re-estimation of the sample size, if necessary per Section 9.6.2: 
a. The median overall survival (OS) and median progression free survival (PFS) in Arm 
A and the observed number of subjects in the group, calculated using the Kaplan-Meier 
method, in months 
b. The median overall survival (OS) and median progression free  (PFS) in Arm B and 
the observed number of subjects in the group, calculated using the Kaplan-Meier 
method, in months 
3. The Conditional Power (CP) of the trial at the time of the IA based on items 1a. – 1c. and 
the formula provided below for both OS and PFS. 
 
Conditional Power (CP) using Differences in Overall Survival and Progression 
Free Survival 
The CP will be calculated for each primary endpoint (i.e., OS and PFS) according to 
the formula [Jenninson and Turnbull (2000) pages 205 to 208] per the metrics 


 
 
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calculated above using the formula:   
𝐶𝐶𝐶𝐶𝑘𝑘(𝜃𝜃) =  𝛷𝛷൭
𝑍𝑍𝑘𝑘ඥ𝐼𝐼𝑘𝑘−𝑧𝑧1−𝛼𝛼/2ඥ𝐼𝐼𝐾𝐾+ 𝜃𝜃(𝐼𝐼𝐾𝐾−𝐼𝐼𝑘𝑘)
ඥ𝐼𝐼𝐾𝐾−𝐼𝐼𝑘𝑘
൱
+ 𝛷𝛷൭
−𝑍𝑍𝑘𝑘ඥ𝐼𝐼𝑘𝑘−𝑧𝑧1−𝛼𝛼/2ඥ𝐼𝐼𝐾𝐾−𝜃𝜃(𝐼𝐼𝐾𝐾−𝐼𝐼𝑘𝑘)
ඥ𝐼𝐼𝐾𝐾−𝐼𝐼𝑘𝑘
൱ 
Where 
𝜃𝜃 =the observed treatment effect at the time of the interim analysis [log (HR) 
using OS and PFS data at the time of the IA] and: 
k=an interim stage at which the conditional power is computed  
K=the stage at which the study is terminated and the final test is computed  
Zk=the logrank test statistic calculated from the observed data that has been 
collected up to stage k, [ 𝑆𝑆𝑘𝑘ඥ𝐼𝐼𝑘𝑘෡
⁄
], where Sk is the logrank score statistic 
computed from the observed data]  
Ik=the information level at stage k; Ik= [Ek*Pc*(1-Pc); where Ek is the number of 
events at stage k and Pc is the proportion of subjects assigned to the control 
group (Arm B)] 
IK=the information level at the end of the study; IK= [E*Pc*(1-Pc); where E is 
the total number of events and Pc is the proportion of subjects assigned to the 
control group (Arm B)] 
Z1-α=the standard normal value for the test with at type I error rate of α 
The resulting Conditional Power (CP) from the two primary endpoints will be used to 
determine whether the sample size needs to be increased or remains unchanged. 
9.6.2 Rules and Methods for Decisions at the Time of the IA 
The re-estimation of the sample size plan will be performed while preserving alpha 
according to Mehta and Pocock (2010).  
The sample size for the study will be adjusted only if the Interim Analysis CP for at 
least one of the primary endpoints OS or PFS is less than 90% and greater than 35% 
(i.e., if CP for at least one of the primary endpoints is in the promising zone). In the 
event that both the CP from OS and PFS are in the promising zone, the lower CP will 
be used for adjustment of the sample size. The adjustment would be an increase in the 
target number of events (i.e., deaths or PD) needed in the study in order to bring the CP 
to at least 90% up to a maximum increase of 436 subjects (218 per group), using the 
observed effect size at the time of the interim analysis. 
If and only if the interim analysis CP is less than 90% and greater than 35% then the 
sample size will be re-estimated up to 436 subjects by suing the PASS sample size 
calculation in Section 3.2. The sample size calculations will be performed under the 
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the observed 1) hazard ratio of OS and median overall survival and 2) hazard ratio of 
PFS and median progression free survival in the treatment and control groups at the 
time of IA.      
The DSMB will make recommendations to sponsor on the continuation/modification/ 
termination and relevant comments based on the interim results. 
 
9.6.3 Rule and Method for Protection of Type I Error Rate 
Per the Mehta and Pocock (2010) paper, if one increases the sample size only when 
interim results are promising, a conventional hypothesis test can be performed without 
inflating the type-1 error. By following the procedure of Mehta and Pocock (2010), if 
the conditional power at the interim analysis is greater than 35%, performing an 
unblinded IA and sample size re-estimation will not have an effect on alpha and the 
overall type I error at the end of the study will be preserved. The cutoff value of 33% 
chosen based on the guidance from Mehta and Pocock (2010) with a maximum allowed 
re-estimation of two times the original sample size, an interim look when 60% of 
expected events occur, and a targeted conditional power of 90%.  
9.7 
General Statistical Considerations  
All collected study data will be presented in subject data listings or summarized. 
Statistical analyses will be performed using SAS® for Windows, version 9.4 or later. 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) 
will be calculated by treatment group for continuous variables. Frequencies and 
percentages will be presented by treatment group for categorical variables.  
All the efficacy analyses presented here will be conducted using both the ITT and PP 
populations. All safety analyses will be conducted using the Safety population. 


 
 
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9.7.1 Analysis Populations  
9.7.1.1 Intent-to-Treat (ITT) population 
The Intent-to-Treat (ITT) population is defined as all subjects randomized, regardless 
of actual treatment received. The ITT population will be the primary population for the 
analysis of primary and secondary endpoints.  
9.7.1.2 Per Protocol (PP) Population 
The Per Protocol (PP) population is defined as the set of subjects who meet the ITT 
population requirements, and were not associated with a major protocol violation. This 
population will be identified before the database lock.  
The PP analysis of primary and secondary endpoints will be considered supportive.  
9.7.1.3 Safety Population 
The Safety population is defined as any subject receiving the treatment after 
randomization. This population will be used for the analysis of safety parameters. 
9.7.2 Covariates  
In the efficacy analysis, the pre-specified stratification factors stated in Section 9.4 will 
be included in the model.  
9.7.3 Subgroups  
The following subgroups will be analyzed for the primary efficacy data of the study:   
• Age 
• Gender 
• Disease stage (Metastatic vs Locally advanced) 
• ECOG performance status (0 vs 1) 
• Region (United States, Taiwan, Korea, France, Russia, Hungary, Israel)  
9.7.4 Missing data  
For efficacy evaluation appropriate methods will be used to handle any missing data. 
The details of techniques for handling of missing data will be included in the SAP for 
the study which will be finalized prior to database lock.  
9.8 
Analysis Methods  
A detailed SAP accompanies the protocol and any amendments to the SAP will be 
developed and approved before the database is locked. The SAP will present the 
detailed statistical methodology to be used in analyzing the efficacy and safety data 
from this trial. 


 
 
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To maintain the trial-wise Type I error rate at 0.05, a hierarchical test procedure with 
fixed sequence will be used for the two primary endpoints and the secondary endpoints. 
The order of the endpoints is outlined in Section 9.8.3.1.  Each subsequent endpoint 
will not be tested unless the previous endpoint analysis in the hierarchy has rejected the 
null hypothesis. If an analysis of an endpoint fails to reject the null hypothesis, then no 
further analyses will be performed. All endpoints, if tested, will use a two-sided analysis 
at an α=0.05 significance level. 
9.8.1 Subject Disposition  
The disposition of all subjects who sign an ICF will be provided. The numbers of 
subjects screened, randomized, completed, and discontinued during the study, as well 
as the reasons for all post-randomization discontinuations will be summarized by 
treatment group, for all centers combined and each center separately. Disposition and 
reason for study discontinuation will also be provided as a by-subject listing.  
9.8.2 Demographic and Baseline Characteristics  
Demographics and baseline characteristics will be summarized by treatment group 
using appropriate descriptive statistics. Continuous variables will be summarized using 
the mean, median, standard deviation, minimum and maximum values by study 
treatment. Categorical variables will be summarized using frequency counts and 
percentages by study treatment. No inferential testing will be performed. 
9.8.3 Efficacy Analyses 
9.8.3.1 Primary Analysis  
The primary analysis will be conducted on the Intent-to-treat (ITT) population. PP 
population will be used for supportive analysis to show the robustness of the analysis. 
Primary Endpoints: 
To maintain the trial-wise Type I error rate at 0.05, a hierarchical test procedure with 
fixed sequence will be used for the two primary endpoints. The order of the endpoints 
will be as follows: 
1. Overall survival (OS) 
Overall survival time is defined as time from randomization to death from any cause 
or last day known to be alive. 
2. Progression Free Survival (PFS) 
Progression Free Survival time is defined as the time from randomization to either 
first observation of progressive disease or occurrence of death.  
 
 


 
 
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OS  and PFS will be compared between the treatment groups using stratified log-rank 
test with the stratification factors included in the model. The differences for treatment 
effect and its 95% CI will be estimated. 
In addition, the Kaplan-Meier method will also be used to depict the median time to 
death from any cause for the treatment groups.  
Secondary Endpoints:  
Similarly, to maintain the trial-wise Type I error rate at 0.05, a hierarchical test 
procedure with fixed sequence will be used for the secondary endpoints. The order of 
the endpoints will be as follows: 
1. Percentage of subjects with Objective Response (OR) according to Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1) 
2. Duration of Response (DR) 
3. Percentage of subjects with disease control according to RECIST v.1.1 
4. Serum Carcinoma Antigen 19-9 (CA 19-9) response rate 
Analysis of the secondary endpoints will be summarized according to the variable type:  
• Continuous data summaries will include:  
o If the Normality assumption is met, Analysis of Covariance (ANCOVA) or 
Mixed Model using the stratification factor in the model.  
o If the Normality assumption is not met, a non-parametric method or a rank 
–ANCOVA analysis i.e., an ANCOVA analysis on rank-transformed data 
will be used.  
• Categorical data summaries will be based on Logit model using the stratification 
factor in the model. 
Exploratory Endpoints: 
• Change From Baseline in European Organization for Research and Treatment of 
Cancer, Quality of Life Questionnaire Core-30 (EORTC QLQ- C30) Score  
• Change from baseline in European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) Score  
Similar analysis methods used for secondary endpoints will be applied to the analysis 
of the exploratory endpoints. Detailed analysis methods will be described in the SAP. 
9.8.3.2 Supportive Analysis  
To assess the consistency of the Primary Analysis results, supportive analysis will be 
conducted using the Per Protocol (PP) population. Statistical methodology for the 
supportive analyses will be the same as that of the primary analysis, with the exception 
of the analysis population used. The PP population will be used for the supportive 
analysis while ITT population will be used for the primary analysis.  


 
 
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9.8.3.3 Safety Analyses  
The Safety population will be used for the analysis of safety endpoints.  
For continuous variables data will be summarized by treatment using n, mean, SD, 
minimum and maximum values. For categorical variables data will be summarized by 
treatment using frequency and percentage. No inferential statistics are planned.  
Adverse Events: 
Adverse events will be coded using the most recent version of Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment Emergent AE’s (TEAE) are defined as 
events with an onset on or after the first randomized treatment. TEAEs will be 
summarized by treatment group, System Organ Class, and preferred term. The 
following TEAE summaries will be provided: 
 Overall (i.e., regardless of severity or relationship to treatment) 
 By severity grade (mild, moderate, severe, or life threatening for SAEs) 
 By relationship to clinical trial treatment according to the mapping scheme 
below: 
o Potentially related: will include all adverse events with a relationship rating 
of “definitely”, “probably” or “possibly”.  
o Unlikely/not related: will include all adverse events with a relationship 
rating of “unlikely” or “unrelated”. 
In addition, separate summaries of serious adverse events, and adverse events resulting 
in discontinuation of study treatment will be presented. 
Clinical Laboratory Data 
All laboratory values will be listed. Laboratory measurements will also be summarized 
as continuous variable and presented by treatment group and time point.  
Physical Examination  
All physical examination findings will be listed and/or summarized.  
Vital Signs 
All vital sign findings will be listed and summarized.  
 


 
 
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10 Direct Access to Source Data/Documentation 
Subjects will be identified on eCRFs by a unique subject identification number and on 
source documents by name and date of birth. No personal identifier will be used in any 
publication or communication used to support this research study. The subject 
identification number will be used if it becomes necessary to identify data specific to a 
single subject.  
The monitors, auditors, personnel authorized by the Sponsor, the local IRB, and the 
FDA are eligible to review medical and research records related to this study as a part 
of their responsibility to protect human subjects in clinical research and will be given 
direct access to source data and documentation (e.g., medical charts/records, printouts 
etc.) for source data verification, provided that subject confidentiality is maintained in 
accordance with local requirements. Access to electronic medical records may be 
governed by institution policy and each site will be required to ensure access while 
remaining compliant with institutional requirements. 


 
 
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11 Quality Control and Quality Assurance 
11.1 Monitoring Requirements 
In an effort to fulfil the obligations outlined in 21 Code of Federal Regulations (CFR) 
Part 312 and ICH guidelines which requires the Sponsor to maintain current personal 
knowledge of the progress of a study, the Sponsor's designated monitor will visit the 
center(s) during the study as well as maintain frequent telephone and written 
communication. The Investigator will permit the Sponsor to monitor the study as 
frequently as is deemed necessary and provide access to medical records to ensure that 
data are being recorded adequately, that data are verifiable and that protocol adherence 
is satisfactory.  
The Investigator will permit representatives of the Sponsor and/or designated CRO to 
inspect all eCRFs and corresponding study subject original medical records (source 
documents) at regular intervals throughout the study. Subject original medical records 
and other relevant data must be available to support all data recorded in the eCRF. In 
addition to the original medical records, these data may include but are not limited to, 
study, laboratory and diagnostic reports, quality of life questionnaire, etc.  
Site inspections serve to verify strict adherence to the protocol and the accuracy of the 
data being entered on the case report forms, in accordance with federal regulations. A 
Monitoring Log will be maintained at each study site which the monitor will sign, date 
and state the type of visit.  
The Investigator should be aware that the study site and subject records may be 
inspected by the Sponsor and or representatives of the designated CRO, FDA or other 
regional regulatory authority. 
For the IA, a cut-off date for data collection and monitoring will be determined and 
sites will be requested to provide current information up to the cut-off date. 
11.2 Acceptability of electronic Case Report Forms (eCRFs) 
eCRFs must be completed for each subject who has signed an informed consent form. 
For subjects who are screen failures, this would be limited to the screen failure eCRF 
page. All source documents and eCRFs will be completed as soon as possible after the 
subject's visit. Corrections to data on the eCRFs will be documented. The Investigator 
will review eCRFs to indicate that, to his/her knowledge, they are complete and 
accurate. eCRFs will be reviewed by the Sponsor’s or designated CRO’s monitor, who 
will make a decision as to their acceptability.  
11.3 Modification of Protocol 
The Investigator will not modify or alter this protocol without first obtaining the 
concurrence of the Sponsor. Approval by the Investigator’s IRB must also be obtained 
prior to implementation of the change, with two exceptions: 


 
 
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1. When necessary to eliminate apparent immediate hazard to the subject; or 
2. When the modification does not involve the subject’s participation in the trial. 
An amendment may also require modification of the informed consent form. The 
Investigator will provide an approval letter for the amendment and revised informed 
consent form, if applicable, to the Sponsor. An amendment must be in writing and it 
must be dated by both the Sponsor and the Investigator. If necessary, the Sponsor will 
submit protocol amendments to FDA and other appropriate regulatory authorities and 
notify other Investigators using this protocol. 
11.4 Reporting Protocol Deviations 
The Investigator is obligated to follow the protocol without departure from the 
requirements written in the protocol. If the Investigator deviates from the protocol 
requirements, the Sponsor will make the determination as to whether the subject will 
continue in the study. The Sponsor also has the right to discontinue the subject for 
protocol violations. The IRB may also have to be contacted if safety to the subject or if 
the scientific soundness of the study is involved. All protocol deviations must be 
documented in the eCRFs. 
11.4.1 Major Protocol Deviation or Violation 
A major protocol deviation or violation is a deviation from the IRB approved protocol 
that may affect the subject's rights, safety, or well-being and/or the completeness, 
accuracy and reliability of the study data. Examples of this include: 
• A research subject received the wrong treatment or incorrect dose. 
• A research subject met withdrawal criteria during the study but was not withdrawn. 
• A research subject received an excluded concomitant medication. 
• A research subject does not meet the protocol's eligibility criteria but was enrolled 
without prior approval from the sponsor. 
• Failure to obtain informed consent prior to initiation of study-related procedures  
• Failure to treat research subjects per protocol procedures that specifically relate to 
primary efficacy outcomes. 
• Changing the protocol without prior sponsor and IRB approval. 
• Multiple minor violations of the same nature after multiple warnings. 
11.4.2  Minor Protocol Deviation or Violation 
A minor protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that has not been approved by the IRB and 
which DOES NOT have a major impact on the subject's rights, safety or well-being, or 
the completeness, accuracy and reliability of the study data.  Examples of this include: 


 
 
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• Follow up visits that occurred outside the protocol required time frame because of 
the participant’s schedule. 
• Blood samples obtained at times close to but not precisely at the time points 
specified in the protocol. 


 
 
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12 Data and Safety Monitoring Board (DSMB) 
The study will be monitored by an independent DSMB to ensure patient safety 
and to assess efficacy. The CRO is responsible for the overall management of DSMB, 
including development of its charter and membership selection. The DSMB will 
be managed in conformance with the FDA guidelines for DSMB independence, 
management, and oversight. 
The DSMB will monitor the safety of the trial from the beginning and at 
approximately six month intervals based on enrolment thereafter. 
The DSMB will consist of three members and will review all unexpected AEs, all 
related AEs, all SAEs, and all deaths during the Treatment and Follow-Up Phases. 
All expedited safety reports will be provided in real time to the DSMB chair upon 
being reported to FDA. At each meeting, the DSMB will be authorized to unblind the 
study upon unanimous vote in the event of any concerns about safety or lack of 
efficacy. Unblinded CRO personnel, separate and independent of the blinded CRO 
personnel, will supply the DSMB with all necessary tables and listings to perform 
their independent review. The Sponsor will be invited to attend open sessions where 
data remain blinded, but will not attend closed sessions where data are discussed in 
more detail with potential unblinding. The DSMB will make the following 
recommendations at each safety evaluation: 
 Continue the study as planned; 
 Assess a specific aspect of safety that is not conclusive; 
 Gather more data to address a specific safety issue; and 
 Stop the study due to safety concerns. 
The DSMB will make the following additional recommendation at the efficacy 
evaluation: 
 Continue the study as planned; 
 Assess a specific aspect of efficacy that is not conclusive; 
 Gather more data to address a specific efficacy issue; and 
 Stop the study due to lack of efficacy. 
The Sponsor retains the responsibility to contact FDA and the final decision 
regarding the recommendation to continue or to terminate the study. 
A further description of the DSMB reporting requirements, meeting frequency, and the 
study stopping/continuation criteria can be found in the DSMB charter. 


 
 
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13 Ethics and Regulatory Requirements 
This study is to be conducted in accordance with the specifications of this protocol and 
in accordance with principles consistent with Declaration of Helsinki, GCP, 21 CFR 
Part 312, ICH E6, HIPAA regulations in 45 CFR Part 164 (US only), and the Belmont 
Principles of respect for persons, beneficence, and justice. No protocol changes will be 
implemented without the prior review and approval of the IRB, except when the 
modification does not involve the subject’s participation in the trial or where it may be 
necessary to eliminate an immediate hazard to a research subject. In the latter case, the 
change will be reported to the IRB as soon as possible, according to IRB regulations.  
Additionally, all study products used in this study are manufactured, handled and stored 
in accordance with applicable GMP and the products provided for this study will be 
used only in accordance with this protocol. 
13.1 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
The Principal Investigator (PI) at the site will provide the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) with all appropriate materials as 
required by their IRB/IEC, including but not limited to the clinical study protocol, 
informed consent form, and any advertising materials. The study will not be initiated 
until the IRB/IEC provides written approval of the aforementioned documents and until 
approval documents have been obtained by the Principal Investigator and Sponsor or 
Sponsor designee. The Investigator will not participate in the decision. If the 
Investigator is an IRB or IEC member, documentation must be provided indicating 
recusal from the approval process. Appropriate reports on the progress of this study by 
the Principal Investigator will be made to the IRB/IEC as required by local and 
applicable government regulations and in agreement with policy established by the 
Sponsor. The Investigator is required to maintain an accurate and complete record of 
all written correspondence to and received from the IRB/IEC, and must agree to share 
all such documents and reports with the Sponsor. 
No changes from the final approved protocol will be initiated without the IRB/IEC’s 
prior written approval or favorable opinion of a written amendment, except when 
necessary to eliminate immediate hazards to the subjects or when the modification does 
not involve the subject’s participation in the trial.  
13.2 Investigator’s Responsibilities 
The Investigators are responsible for performing the study in full accordance with the 
protocol and the current revision of the Declaration of Helsinki, the Good Clinical 
Practice: Consolidated Guideline, approved by the ICH, and any applicable national 
and local laws and regulations. Information regarding any study centers participating 
in this study that cannot comply with these standards will be documented. 
13.3 Subject Informed Consent Requirements 


 
 
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Written and oral information about the study in a language understandable by the 
subject will be given to all subjects by the Investigator and/or designee. Written 
informed consent will be obtained from each subject before any procedures or 
assessments that would not otherwise be required for the care of the subject are done 
and after the aims, methods, anticipated benefits, potential hazards, and insurance 
arrangements in force are explained and the subject has been given sufficient time to 
ask questions and consider participation in the study. It will also be explained to the 
subjects that they are free to refuse entry into the study and free to withdraw from the 
study at any time without prejudice to future treatment. It is permissible for a third 
person (e.g., a family member) to be present during the explanation of the study. 
The written Informed Consent Form ICF is to be in compliance with CFR 21 Part 50.27 
and GCP guidelines. The Sponsor and/or designated CRO will approve the ICF and all 
amendments to the ICF prior to submission to the IRB/IEC. A copy of the ICF to be 
used will be submitted by the Investigator to the IRB/IEC for review and approval prior 
to the start of the study. Each study site must provide the Sponsor with an unsigned 
copy of IRB/IEC-approved ICF along with applicable documentation to support this 
approval. The original signed ICF is retained in the subject's study records, and a copy 
is provided to the subject. A second copy may be filed in the subject’s medical record, 
if allowed by institutional policy.  
 


 
 
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14 Data Handling and Record Keeping 
14.1 Recording and Collection of Data 
The primary source document for this study will be the subject's medical record. If 
separate research records are maintained by the Investigator(s), the medical record and 
the research records will be considered the source documents for the purposes of 
auditing the study.  
Applicable source data will be manually transcribed to approve electronic case report 
forms (eCRF). The Investigator is ultimately responsible for the accuracy of the data 
transcribed on the forms. All source documents and eCRFs will be completed as soon 
as possible after the subject's visit. 
The Investigator will review eCRFs to indicate that, to his/her knowledge, they are 
complete and accurate. Designated source documents will be signed and dated by the 
appropriate study personnel. The Investigator must agree to complete and maintain 
source documents and eCRFs for each subject participating in the study. 
All research data will be entered, either electronically or manually, into a computerized 
database. The clinical database will be designed by the clinical data manager in 
accordance with 21 CFR Part 11 and based on protocol requirements defined by the 
Sponsor in association with the Lead Investigator.  
The Investigator will maintain a confidential list of study subjects that will include each 
subject’s study number, name, date of birth, and unique hospital identification number 
if applicable. This list will be kept by the Investigator and will not be collected by the 
Sponsor. A notation will be made in the subject’s case history/medical chart that he/she 
is participating in a clinical study and has provided a signed and dated ICF as well as a 
release for protected health information as required by local policies. The Investigator 
must also maintain a separate screening log of all the subjects screened for participation 
in the study; it should include gender, age, eligibility status, reason for ineligibility, if 
applicable; and study allocated subject number, if applicable.  
14.2 Clinical Data Management 
The Sponsor and/or designated CRO will be responsible for the processing and quality 
control of the data. Data management will be carried out as described in the Sponsor’s 
or CRO’s standard operating procedures (SOPs) for clinical studies. 
The handling of data, including data quality control, will comply with regulatory 
guidelines (e.g., ICH E6 GCP, and local regulations where applicable) and the 
Sponsor’s or the CRO’s SOPs as well as provisions of the study-specific Data 
Management Plan. 
 
14.3 Archiving 


 
 
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 All study documentation at the Investigator site and Sponsor site will be archived in 
accordance with ICH GCP E6 and the Sponsor’s quality standards and SOPs. 
The Investigator will maintain all research records, reports, and case history reports for 
a period of two years after regulatory approval of the investigational product. If no 
application is filed or if the application is not approved, records must be maintained for 
two years after all investigations have been completed, terminated or discontinued and 
the FDA has been notified.  
These documents should be retained for a longer period however, if required by the 
applicable regulatory requirements or if needed by Sponsor or its authorized 
representative (as per GCP 5.5.11). 
At the completion of the study, details of the archival process must be provided to the 
Sponsor. Study records are subject to inspection by applicable health and regulatory 
agencies at any time.  
Records to be retained by the Investigator include, but are not restricted to: 
• Source data and the primary records upon which they are based (e.g., subject’s 
progress notes, adverse event data, test results, and any other diagnostic 
procedures required to evaluate the progress of the study) 
• Completed eCRFs 
• Signed protocols and protocol amendments 
• Laboratory results, ranges, and certifications 
• Product (e.g., IP, Standard Care supplies) and accountability records 
• Study personnel signature log 
• Monitoring logs 
• Correspondence to and from the Sponsor, designee and IRB 
• Investigator and sub-investigator CVs 
• Signed informed consent and protected health information consent forms 
• Subject screening and randomization log 
• SAE reports 
• IRB approval and re-approval letters 
• Completed quality of life questionnaires 
• Other documents pertaining to the conduct of the study 
These documents must be maintained and kept on file by the Investigator so that the 
conduct of the study can be fully documented and monitored. 
At the completion of the study, details of the archival process must be provided to the 
Sponsor. Study records should not be transferred from site or destroyed without prior 
written agreement between the Sponsor and the study Investigator. Study records are 
subject to inspection by applicable health and regulatory agencies at any time.  


 
 
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15 Publication Plan 
All information supplied by SynCore Biotechnology in connection with this study 
and not previously published, is considered confidential information. This 
information includes, but is not limited to, the Investigator’s Brochure, clinical 
protocol, case report forms and other scientific data. Any data collected during the 
study are also considered confidential. This confidential information shall remain 
the sole property of SynCore Biotechnology, shall not be disclosed to others without 
the written consent of SynCore Biotechnology, and shall not be used except in the 
performance of this study. 
It is understood by the Investigator that the Sponsor will use the information collected 
in this clinical trial in connection with the development of EndoTAG-1. Therefore, this 
information may be disclosed as required to other Investigators or appropriate 
regulatory authorities. By agreeing to participate in this clinical trial, the Investigator 
understands that he/she has an obligation to provide the Sponsor with complete test 
results and all data developed during this trial. 
Publication and Disclosure: Because this is a multi-center trial, the site and 
Investigator shall not independently publish, publicly disclose, present or discuss any 
results of or information pertaining to the site’s and Investigator’s activities conducted 
under this protocol until such multi-center publication is released with the written 
approval and under the direction of Sponsor. Notwithstanding the foregoing, if a multi-
center publication is not released within eighteen (18) months after completion of 
analysis of all study data from all studies conducted within the multi-center trial, both 
the site and Investigator shall have the right to publish the results of and information 
pertaining to the site’s and Investigator’s activities conducted under this protocol and 
the clinical trial agreement, subject to the prior review and written approval of Sponsor. 
The site and Investigator agree to submit any proposed manuscript, presentation or 
other public disclosure regarding the study to Sponsor for review at least thirty (30) 
days prior to submitting such proposed manuscript to a publisher or delivering or 
making such presentation or other public disclosure to any third party. Within thirty (30) 
days of its receipt, Sponsor shall advise the site and/or Investigator, as the case may be, 
in writing of any information contained therein that is confidential information (other 
than research results included in a proposed manuscript) or that may impair Sponsor’s 
ability to obtain patent protection. Sponsor shall have the right to require the site and/or 
Investigator, as applicable, to remove specifically identified confidential information 
(but may not require removal of research results from a proposed manuscript) and/or to 
delay the proposed submission or delivery of the proposed manuscript or presentation, 
or other public disclosure, for an additional sixty (60) days to enable Sponsor to seek 
patent protection. The site and Investigator shall not publish, publicly disclose, present 
or discuss any results of or information pertaining to the site’s and Investigator’s 
activities prior to completion of the trial, even if the multi-center trial or the study is 


 
 
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terminated before its completion and the final clinical study report is signed off, or with 
respect to any endpoints or analyses other than those specified in this protocol. 


 
 
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16 References 
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. 
CA: a cancer journal for clinicians. 2008 Mar 1;58(2):71-96. 
 
Burris 3rd HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, 
Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R. Improvements in 
survival and clinical benefit with gemcitabine as first-line therapy for patients with 
advanced pancreas cancer: a randomized trial. Journal of clinical oncology. 1997 
Jun;15(6):2403-13. 
 
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, 
Walde D, Wolff RA, Campos D. Erlotinib plus gemcitabine compared with 
gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the 
National Cancer Institute of Canada Clinical Trials Group. Journal of clinical oncology. 
2007 May 20;25(15):1960-6. 
 
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). European journal of cancer. 
2009 Jan 31;45(2):228-47. 
 
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, 
Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J. FOLFIRINOX 
versus gemcitabine for metastatic pancreatic cancer. New England Journal of Medicine. 
2011 May 12;364(19):1817-25. 
 
Portal A, Pernot S, Tougeron D, Arbaud C, Bidault AT, De La Fouchardière C, Hammel 
P, Lecomte T, Dréanic J, Coriat R, Bachet JB. Nab-paclitaxel plus gemcitabine for 
metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective 
multicentre cohort. British journal of cancer. 2015 Sep 29;113(7):989-95. 
 
Eichhorn SJ, Dufresne A, Aranguren M, Marcovich NE, Capadona JR, Rowan SJ, 
Weder C, Thielemans W, Roman M, Renneckar S, Gindl W. Review: current 
international research into cellulose nanofibres and nanocomposites. Journal of 
materials science. 2010 Jan 1;45(1):1. 
 
Strieth S, Eichhorn ME, Werner A, Sauer B, Teifel M, Michaelis U, Berghaus A, 
Dellian M. Paclitaxel encapsulated in cationic liposomes increases tumor microvessel 
leakiness and improves therapeutic efficacy in combination with Cisplatin. Clinical 
cancer research. 2008 Jul 15;14(14):4603-11. 
 
Strieth S, Eichhorn ME, Sauer B, Schulze B, Teifel M, Michaelis U, Dellian M. 
Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes 
impairs functional tumor microvasculature. International journal of cancer. 2004 May 
20;110(1):117-24. 
 
Schmitt-Sody M, Strieth S, Krasnici S, Sauer B, Schulze B, Teifel M, Michaelis U, 
Naujoks K, Dellian M. Neovascular Targeting Therapy. Clinical Cancer Research. 
2003 Jun 1;9(6):2335-41. 
 


 
 
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Fasol U, Frost A, Büchert M, Arends J, Fiedler U, Scharr D, Scheuenpflug J, Mross K. 
Vascular and pharmacokinetic effects of EndoTAG-1 in patients with advanced cancer 
and liver metastasis. Annals of oncology. 2011 Jun 21:mdr300. 
 
Löhr JM, Haas SL, Bechstein WO, Bodoky G, Cwiertka K, Fischbach W, Fölsch UR, 
Jäger D, Osinsky D, Prausova J, Schmidt WE. Cationic liposomal paclitaxel plus 
gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a 
randomized controlled phase II trial. Annals of oncology. 2012 May 1;23(5):1214-22. 
 
Awada A, Bondarenko IN, Tarasova O, Bonneterre J, Nowara E, Ferrero J, Bakshi AV, 
Glasschroeder B, Elsasser U, Piccart M. Results of the first randomized phase II study 
of Cationic Liposomal Paclitaxel (EndoTAGTM-1) targeting tumor endothelial cells in 
advanced triple-negative breast cancer (TNBC). Ann Oncol. 2010 Oct 1;21(8s):viii5. 
 
Awada A, Bondarenko IN, Tarasova O, Bonneterre J, Nowara E, Ferrero JM, Bakshi 
AV, Weidenthaler H, Wilke C, Piccart MJ. P3-17-06: Final Results of a Controlled, 
Randomized 3-Arm Phase II Trial of EndoTAG”-1, a Cationic Liposomal Formulation 
of Paclitaxel Targeting Tumor Endothelial Cells, in Advanced Triple-Negative Breast 
Cancer (TNBC). 
 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. American 
journal of clinical oncology. 1982 Dec 1;5(6):649-56. 
 
Mosteller RD. Simplified calculation of body-surface area. The New England journal 
of medicine. 1987 Oct 22;317(17):1098. 
 
 
 


 
 
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17 Appendices 
17.1 Appendix-I: 
EORTC QLQ-C30 (version 3) 
 
 
 
 
 
 


 
 
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17.2 Appendix-II: EORTC  QLQ - PAN26 
 


 
 
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SAP_001.pdf: 
                            
 
     
 
 
 
 
 
Statistical Analysis Plan  
 
Study Title: 
A Randomized Controlled, Open label, Adaptive Phase-3 Trial to Evaluate 
Safety and Efficacy of EndoTAG-1 Plus Gemcitabine versus Gemcitabine 
alone in Patients with Measurable Locally Advanced and/or Metastatic 
Adenocarcinoma of the Pancreas Failed on FOLFIRINOX Treatment 
 
 
Protocol Number: 
Version  
CT 4006 
Version 4.2 / 28 Jan 2021 
 
 
Sponsor: 
SynCore Biotechnology Co., Ltd 
 
4F, No.69, DongXing Rd., XinYi Dist., 
Taipei City 110, Taiwan 
Tel:+886-2-2760-3688  
Fax: +886-2-2763-9287 
 
 
 
Prepared by: 
Amarex, Clinical Research 
 
20201 Century Boulevard 
 
Germantown, MD, 20874, USA 
 
 
Version No./Date 
Version 3.1, 07 June 2021 
 
Confidential Statement: The information contained herein is proprietary and no part of this 
information may be reproduced, photocopied, stored on a retrieval system, or transmitted without the 
express written consent of SynCore Biotechnology Co., Ltd. Any unauthorized use is prohibited. 
 
 
 


SynCore Biotechnology Co., Ltd 
CT 4006 
Statistical Analysis Plan 
 
 
 
Version 3.1 
                     
07 June 2021 
 
Page 2 of 53 
Confidential 
 
Signatory Page 
 
This Statistical Analysis Plan was reviewed and approved by: 
 
Author 
 
 
 
Statistician, Amarex 
 
Date  
 
 
 
Approval 
 
 
 
Muh-Hwan Su, PhD 
General Manager 
SynCore Biotechnology Co., Ltd. 
Date 
 
Approval 
 
 
 
Albert Lin  
Head of Quality Assurance 
SynCore Biotechnology Co. ltd 
Date 
 
 
 
 
 


SynCore Biotechnology Co., Ltd 
CT 4006 
Statistical Analysis Plan 
 
 
 
Version 3.1 
                     
07 June 2021 
 
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Confidential 
REVISION HISTORY 
 
Version No. 
Version Date 
Description of Modifications 
1.0 
01-Nov-2017 
Original Document  
2.0 
17-Jun-2020 
Editorial changes were made per Version 
4.0 of the protocol 
3.0 
28-Jan-2021 
Changes made based on FDA comments 
IND 
106057 
SynCore 
Advice-
Information 
Request 
IND_SDN36 
19Sep2020 (Reference ID: 4673002) 
3.1 
07-Jun-2021 
Changes made based on FDA comments 
IND 
106057 
SynCore 
Advice-
Information 
Request 
IND_SDN36 
23Apr2021 (Reference ID: 4683602) 
 
 


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TABLE OF CONTENTS  
 
Signatory Page ............................................................................................................................. 2 
1. 
List of abbreviations and acronyms ................................................................................. 6 
2. 
Introduction ........................................................................................................................ 9 
3. 
Study Overview ................................................................................................................ 10 
3.1 
Study Objectives................................................................................................... 10 
3.1.1 
Efficacy Objectives............................................................................... 11 
3.1.2 
Safety Objectives .................................................................................. 11 
3.2 
Study Design ......................................................................................................... 11 
3.2.1 
Sample Size Considerations ................................................................. 12 
3.2.2 
Randomization ..................................................................................... 15 
3.2.3 
Study Assessments Schedules ............................................................... 17 
4. 
Study Endpoints and Definitions .................................................................................... 20 
4.1 
Primary Efficacy Endpoint ................................................................................. 20 
4.2 
Secondary Efficacy Endpoints ............................................................................ 20 
4.3 
Exploratory Endpoints ........................................................................................ 20 
4.4 
Safety Endpoints .................................................................................................. 20 
4.5 
Definitions ............................................................................................................. 21 
4.5.1 
Study Day ............................................................................................. 21 
4.5.2 
Baseline and Change from Baseline .................................................... 21 
5. 
Statistical Analysis General Considerations .................................................................. 22 
5.1 
Analysis Populations ............................................................................................ 22 
5.2 
P-Values ................................................................................................................ 22 
5.3 
Procedures for Handling Missing Data.............................................................. 22 
5.4 
Interim Analysis ................................................................................................... 22 
5.4.1 
Purpose of the Interim Analysis ........................................................... 23 
5.4.2 
Safety Review ....................................................................................... 23 
5.4.3 
Adaptive Design: Re-estimation of Sample Size .................................. 23 
5.4.3.1 
Conditional Power Calculation ........................................ 24 
5.4.3.2 
Procedure for Re-estimation of the Sample Size .............. 25 
5.4.4 
Preservation of Type I Error Rate ....................................................... 25 
5.4.5 
Firewall for Protection Against Bias ................................................... 25 
5.5 
Subgroup Analysis ............................................................................................... 26 
5.6 
Covariates ............................................................................................................. 26 
5.7 
Multi-center Studies and Pooling of Centers..................................................... 26 
6. 
Statistical Analysis Methodology .................................................................................... 27 
6.1 
Study Subjects ...................................................................................................... 27 
6.1.1 
Subject Disposition .............................................................................. 27 


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6.1.2 
Protocol Deviations ............................................................................. 28 
6.1.3 
Demographics ...................................................................................... 29 
6.1.4 
Medical and Surgical History .............................................................. 29 
6.1.5 
Concomitant Medications .................................................................... 30 
6.2 
Efficacy Analysis .................................................................................................. 30 
6.2.1 
Primary Efficacy Analysis.................................................................... 30 
6.2.1.1 
Overall Survival ............................................................... 30 
6.2.1.2 
Progression Free Survival ................................................ 30 
6.2.1.3 
Null Hypothesis of the Primary Effiacy Analysis ............ 32 
6.2.1.4 
Primary Efficacy Analysis ................................................ 32 
6.2.2 
Secondary Efficacy Analyses ............................................................... 33 
6.2.2.1 
Objective Response .......................................................... 33 
6.2.2.2 
Duration of Response ....................................................... 34 
6.2.2.3 
Disease Control ................................................................ 34 
6.2.3 
Exploratory Analyses ........................................................................... 35 
6.2.3.1 
EORTC-QLQ-C30 Summary Score ................................. 35 
6.2.3.2 
EORTC-QLQ-PAN26 ...................................................... 36 
6.3 
Safety Analysis ..................................................................................................... 38 
6.3.1 
Exposure .............................................................................................. 38 
6.3.2 
Adverse Events ..................................................................................... 38 
6.3.3 
Clinical Laboratory Tests .................................................................... 39 
6.3.4 
Vital Signs ............................................................................................ 41 
6.3.5 
12-lead Electrocardiogram .................................................................. 42 
6.3.6 
Physical Exam ...................................................................................... 43 
6.4 
Pharmacokinetics ................................................................................................. 43 
7. 
Testing/Quality Control Plan and Software/System ..................................................... 44 
7.1 
Programming Specifications for TLFs............................................................... 44 
7.2 
Formatting Conventions ...................................................................................... 44 
7.3 
Standard Text Conventions ................................................................................ 45 
7.3.1 
Header.................................................................................................. 45 
7.3.2 
Title ...................................................................................................... 45 
7.3.3 
Footnotes.............................................................................................. 45 
7.3.4 
Footer ................................................................................................... 46 
7.4 
Statistical Conventions ........................................................................................ 46 
7.4.1 
Statistics Reported ............................................................................... 46 
7.4.2 
SAS Procedure Output ......................................................................... 47 
7.4.3 
Tables Summarizing Categorical Data ................................................ 47 
7.4.4 
Subject Data Listings ........................................................................... 47 
8. 
References ......................................................................................................................... 48 
9. 
Appendices ........................................................................................................................ 50 
9.1 
Planned Tables, Listings, and Figures ............................................................... 50 
9.2 
Rationale for changing PFS from secondary endpoint to primary endpoint . 53 
 


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1. LIST OF ABBREVIATIONS AND ACRONYMS 
Abbreviations   
Description 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
APTT 
Activated partial thromboplastin time  
AST 
Aspartate Aminotransferase 
CA 19-9 
Carbohydrate Antigen 19-9  
CDE 
Common Data Elements 
CDISC 
Clinical Data Interchange Standards Consortium 
CDMS 
Clinical Data Management System 
CFB 
Change From Baseline 
CI 
Confidence Interval 
cm 
centimeter 
CONSORT 
CONsolidated Standards Of Reporting Trials  
CP 
Conditional Power 
CR 
Complete Response 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DR 
Duration of Response 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EORTC-QLQ-C30 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 
EORTC-QLQ-PAN26 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Pancreatic Module 
FBC 
Full Blood Count 


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FDA 
Food and Drug Administration 
H 
High 
HCT 
Hematocrit 
HR 
Heart Rate 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
INR 
Internation Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
kg 
kilogram 
L 
Low 
m 
meter 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration  
MCV 
Mean Corpuscular Volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
NINDS 
National Institute of Neurological Disorders and Stroke 
ODS 
Output Delivery System 
OR  
Objective Response 
OS 
Overall Survival 
PCFB 
Percent Change From Baseline 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Partial Response 
PT 
Prothrombin Time  
QC 
Quality Control 
QoL 
Quality of Life 
Qs 
Questions 


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RBC 
Red Blood Cell  
RECIST v1.1 
Response Evaluation Criteria In Solid Tumors Version 1.1 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressue 
SD 
Standard Deviation 
SD 
Stable Disease 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings and Figures 
WBC 
White Blood Cell  
WHODrug 
World Health Organization Drug Dictionary 


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2. INTRODUCTION 
This Statistical Analysis Plan (SAP) is prepared to provide a more technical and detailed elaboration 
of the principal statistical features stated in the protocol. The SAP will ensure that the tables, listings, 
and figures that will be produced and statistical methods that will be used are complete and accurate 
and will allow valid conclusions to be drawn. In the development of this SAP, the following documents 
were used: 
• CT 4006 (version 4.2),  28 Jan 2021 
 
The principles in the following guidance documents are followed in preparation of this SAP: 
• International Conference on Harmonisation (ICH) E3 (1995): Structure and Content of 
Clinical Study Reports 
• ICH E6 R2 (2016): Guideline for Good Clinical Practice 
• ICH E9 (1998): Statistical Principles for Clinical Trials 
In the event that a discrepancy is found between the descriptions in the statistical section of the protocol 
and this document, the description in this document supersedes the descriptions in the statistical section 
of the protocol. 
 
 


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3. STUDY OVERVIEW 
EndoTAG-1 is a novel formulation of cationic liposomes for the treatment of solid tumors, carrying 
paclitaxel embedded in the liposome membrane. Cationic liposomes are known to bind and internalize 
at tumor endothelial cells after intravenous administration, which is the basis for the new mode of 
action of EndoTAG-1. Using a cationic liposome formulation, the cytostatic and cytotoxic activities 
of paclitaxel are targeted to the activated tumor endothelial cells. Therefore, in contrast to conventional 
chemotherapy aiming at tumor-cell toxicity, EndoTAG-1 specifically displays antivascular and 
antiangiogenic activity. 
 
Based on the results of preclinical studies and clinical phase 1/2 studies and its new therapeutic concept, 
EndoTAG-1 represents a promising candidate for the treatment of solid malignancies, both for taxane-
sensitive and taxane-insensitive tumors. 
 
Pancreatic cancer, which is the 4th leading cause of cancer death in the United States (Jemal et al. 
2008), is an indication with high need for improvement of systemic therapy. Less than 20% of 
pancreatic cancer patients are diagnosed with resectable and potentially curable disease while the vast 
majority of patients have advanced disease at the time of diagnosis with a median survival of 
approximately 6 months. 
 
FOLFIRINOX regimen is the standard first-line treatment for pancreatic cancer patients with good 
performance status. However, the optimal management strategy for patients who fail initial 
FOLFIRINOX remains undefined. There is still no standard of care in second-line therapy for patients 
with disease progression. 
 
Gemcitabine has been the standard systemic therapy for unresectable pancreatic cancer for the last 
decade, though 1-year survival rates ranging around 18% are still unsatisfactory (Burris et al. 1997; 
Moore et al. 2007). Numerous trials have aimed to demonstrate superiority of combinations of 
gemcitabine with other chemotherapeutics or targeted agents with disappointing results. 
 
Results of a controlled, randomized Phase 2 clinical trial comprising 200 patients indicate a 
considerable survival benefit for patients with advanced pancreatic cancer treated with EndoTAG-1 in 
combination with gemcitabine compared to gemcitabine monotherapy. 
 
The aim of this adaptive Phase 3 trial is to show a statistically significant superiority of EndoTAG-1 
in combination with gemcitabine compared to gemcitabine monotherapy in patients with locally 
advanced/metastatic pancreatic cancer after FOLFIRINOX failure. 
 
3.1 Study Objectives 
The objective of the study is to assess the safety and efficacy of a combination therapy of EndoTAG-
1 plus gemcitabine vs. gemcitabine monotherapy in patients with locally advanced and/or metastatic 


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adenocarcinoma of the pancreas eligible for second-line therapy after failing first-line therapy with 
FOLFIRINOX. 
 
3.1.1 Efficacy Objectives 
To assess the efficacy of twice weekly infusions of EndoTAG-1 with weekly infusions of gemcitabine 
versus gemcitabine monotherapy according to: 
• Assessment of survival (overall survival [OS], progression-free survival [PFS]) 
• Tumor response evaluation via Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST v.1.1) 
 
3.1.2 Safety Objectives  
To assess the safety of twice weekly infusions of EndoTAG-1 with weekly infusions of gemcitabine 
versus gemcitabine monotherapy according to: 
• Incidence and percentage of subjects with treatment-emergent adverse events (TEAEs) 
• Laboratory abnormalities (hematology, coagulation parameters, clinical chemistry) 
• Dose reductions, pausing, and/or discontinuation of EndoTAG-1 and/or gemcitabine 
 
3.2 Study Design 
This is a randomized controlled, open label, adaptive phase-3 study to evaluate the safety and efficacy 
of a combination regimen of twice weekly infusions of EndoTAG-1 (Lipid Complexed Paclitaxel) 
with weekly administration of gemcitabine compared with gemcitabine monotherapy in subjects with 
measurable locally advanced and/or metastatic adenocarcinoma of the pancreas who are eligible for 
second-line therapy after failing first-line therapy with FOLFIRINOX. 
 
Eligible subjects will be randomized to one of the two treatment arms: 
• Arm A: Treatment with EndoTAG-1 22 mg/m2 twice weekly plus gemcitabine 1000mg/m² 
once weekly, for 1 cycle (8 weeks) consisting of 3 weeks and 1 week rest followed by 3 weeks 
of treatment and 1 week rest until any one of the following occurs: progressive disease or 
unacceptable toxicity or withdrawal of consent. Subjects will be eligible for continuing 
treatment beyond first cycle with 3 weeks of treatment and 1 week rest in absence of disease 
progression or unacceptable toxicity. 
• Arm B: Treatment with gemcitabine 1000mg/m² once weekly, for 1 cycle (8 weeks) consisting 
of 3 weeks and 1 week rest followed by 3 weeks of treatment and 1 week rest until any one of 
the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. 
Subjects will be eligible for continuing treatment beyond first cycle with 3 weeks of treatment 
and 1 week rest in absence of disease progression or unacceptable toxicity. 
 
The randomization will be stratified by: 


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• Subjects with locally advanced vs metastatic pancreatic cancer 
• Subjects with Eastern Cooperative Oncology Group (ECOG) performance status 0 vs 1 
 
The first treatment cycle will last at least 8 weeks and include 3 weeks of treatment and 1 week rest 
followed by 3 weeks of treatment and 1 week rest. Subjects may continue to receive additional cycles 
of therapy until progressive disease or intolerable toxicity as per clinical judgment of the Investigator. 
 
Tumor response according to RECIST (version 1.1; Eisenhauer et al. 2009) will be evaluated on a 
scheduled basis every 8 weeks (±3 days) from randomization (regardless of the timing of treatment 
cycles) until disease progression is documented or until the cut-off date of the study, whichever comes 
earlier. Subjects will be monitored regularly for safety parameters, pain and quality of life. 
 
After completing treatment, subjects who are not diagnosed with progressive disease (PD) will attend 
up to 6 Follow-up Visits every 8 weeks for 48 weeks, following which subjects will be followed-up 
by telephone every 8 weeks for survival. Subjects who experienced PD during Treatment Phase will 
undergo only one safety follow-up visit (4-8 weeks after the EOT visit), and then enter phone follow-
up directly. Follow-up visits will be performed for the evaluation of survival status, safety parameters, 
QoL (EORTC QLQ-C30 and EORTC PAN-26) and administration of other anti-tumor treatment until 
death or end of the study, whichever comes first. 
 
Anti-tumor therapy after termination of study treatment will be at the discretion of the Investigator. 
An Interim Analysis (IA) will be conducted when approximately 101 deaths have occurred on study. 
 
The cut-off date for the final analysis will be 12 months after the last subject was randomized or the 
last subject alive has been followed up for at least 48 weeks, whatever applies first. Subjects being still 
under treatment with study medication at this cut-off date will enter the extension phase of this trial. 
These subjects will be followed up until 28 days after the last administration of study medication. 
 
A Data and Safety Monitoring Board (DSMB), composed of independent representatives, will be in 
charge of reviewing the accrual, baseline, and safety data at periodic intervals. Representatives of the 
Sponsor will serve only as coordinating members of the committee, without having full member 
responsibilities or privileges. 
 
The Schedule of Assessments can be found in Table 1-1 and Table 1-2 in Section 3.2.3 
 
3.2.1 Sample Size Considerations  
A total of 218 subjects will be enrolled and randomized in a 1:1 ratio to Arm A (EndoTAG-1 plus 
gemcitabine) and Arm B (gemcitabine monotherapy). The sample size is event-driven to allow for 
collection of a pre-specified number of primary efficacy outcomes. Based on the sample size 


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calculation, the primary endpoint analysis for overall survival will require 167 events (deaths) from 
196 subjects. The primary endpoint analysis for progression-free survival will require 169 events 
(disease progression) from 182 subjects.  
This sample size is sufficient to detect a 40% reduction of overall survival in the risk of death in Arm 
A, as compared with Arm B (hazard ratio, 0.60) using a 2-sided log-rank test with 90% power and an 
overall significance level of 0.05 two sided test.  
This sample size is also sufficient to detect a 35% reduction of progression-free survival in the risk of 
death in Arm A, as compared with Arm B (hazard ratio, 0.647) using a 2-sided log-rank test with more 
than 80% power and an overall significance level of 0.05 two sided test. 
Sample size estimation for overall survival is depicted in Figure 1, total sample size requirement vs. 
the median survival time (month) in the treatment arm. Sample size is estimated using PASS (15) 
sample size software. 
Sample size estimation for progression-free survival is depicted in Figure 2, total sample size 
requirement vs. the median survival time (month) in the treatment arm. Sample size is estimated using 
PASS (15) sample size software. 
It is anticipated that there would be about 10% dropout in this study, to accommodate for the dropouts 
a total of 218 subjects would be randomized. The overall survival assumption for the sample size are 
based on published literature data comparing therapeutic effect of gemcitabine monotherapy and 
gemcitabine combination regimen on patients with advanced pancreatic cancer after previous 
FOLFIRINOX treatment. The hazard ratio for death of 0.60 with median overall survival of 4.4 months 
for gemcitabine monotherapy (Conroy et al. 2011) and 7.3 months for gemcitabine + paclitaxel 
combination (Portal et al. 2015) was used for the sample size calculation. 
The progression-free survival assumption for the sample size are based on hazard ratio of 0.647 with 
median progression-free survival of 3.3 months for gemcitabine monotherapy (Conroy et al. 2011) and 
5.1 months for gemcitabine + paclitaxel combination (Portal et al. 2015) was used for the sample size 
calculation. 
 
 
 
 
 


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Figure 1: Overall Survival Sample Size Plot: Total Sample size Requirement vs. the Median 
Survival Time (month) in the Treatment Arm A. 
 
 
 
Figure 2: Progression-Free Survival Sample Size Plot: Total Sample size Requirement vs. the 
Median Survival Time (month) in the Treatment Arm A. 
 


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During the interim analysis, the sample size will be re-evaluated. Detals of this procedure are given in 
Section 5.4. 
 
3.2.2 Randomization 
Subjects who are eligible to participate in the trial will be centrally randomized to receive either Arm 
A (EndoTAG-1 and gemcitabine) or Arm B (gemcitabine alone) in a 1:1 ratio using a stratified block 
randomization scheme. The stratification variables are the extent of disease (subjects with locally 
advanced and metastatic pancreatic cancer) and the performance status (ECOG performance status 
0 and 1). Within each stratum, subjects will be allocated with equal probability to either treatment in 
Arm A or treatment in Arm B and the randomization system will be set up in such a way that there 
is a 1:1 balance between the treatment groups from the different strata. 
The randomization schedule generated will include sufficient assignments to randomize the 
maximum number of subjects possible in the case of sample size re-estimation after the interim 
analysis (Section 5.4).    


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As this is an open label study, all study personnel will have knowledge of the treatment assignments 
after randomization and throughout the study. To avoid any susceptible selection bias, a stratified 
block randomization scheme with a mixed block size will be used and the blocks will be blinded 
until trial closure to all research personnel except the block generating statistician. The master 
randomization lists containing the treatment assignments will not be released to any study personnel 
prior to final database lock except for the DSMB meetings and at the time of the interim analysis. 


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3.2.3 Study Assessments Schedules   
Study assessments are described in detail in the protocol, and summarized below in Table 1-1 and Table 1-2. 
 
 
 


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Table 1-1: Schedule of Assessments – Screening and Treatment Phase 
 


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Table 1-2 Schedule of Assessments – Subsequent Treatment Cycles and Follow-up Phase 
 
 


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4. STUDY ENDPOINTS AND DEFINITIONS 
4.1 Primary Efficacy Endpoint 
• 
Overall survival (OS) 
Overall survival time is defined as time from randomization to death from any cause or last day 
known to be alive.  
• 
Progression Free Survival (PFS) 
Progression Free Survival time is defined as the time from randomization to either first 
observation of progressive disease or occurrence of death. 
 
4.2 Secondary Efficacy Endpoints 
The following are the secondary efficacy endpoints: 
• Percentage of subjects with Objective Response (OR) according to Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST v.1.1) 
• Duration of Response (DR) 
• Percentage of subjects with disease control according to RECIST v.1.1 
• Serum Carbohydrate Antigen 19-9 (CA 19-9) response rate 
 
4.3 Exploratory Endpoints 
• Change From Baseline in European Organization for Research and Treatment of Cancer, 
Quality of Life Questionnaire Core-30 (EORTC QLQ- C30) Score 
• Change from baseline in European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) Score 
 
4.4 Safety Endpoints 
The following are the endpoints that will be used to assess safety: 
• Incidence and severity of treatment-emergent adverse events (TEAEs), including serious 
adverse events and adverse events resulting in permanent discontinuation of protocol-defined 
therapy. 
• Changes in selected laboratory test results (i.e., 
o Serum  chemistry  including  urea,  serum  creatinine,  sodium,  potassium,  chloride, 
bicarbonate, glucose, bilirubin, albumin, ALT, AST, ALP, total protein; and 
o Full blood count (FBC) including hemoglobin, hematocrit, RBC count, Platelets count, 
total leukocyte count, differential leukocyte count and absolute neutrophil count) 
• Changes in vital signs including systolic and diastolic blood pressure and pulse 
• Changes in electrocardiogram (ECG) results 
• Changes in physical examination results 


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4.5 Definitions  
4.5.1 Study Day  
For purposes of describing days on study drug in data listings, data will be assigned a study day relative 
to the first dose of the first cycle of the Treatment Phase (for Arm A, where a subject receives first 
administration EndoTAG-1 + gemcitabine [listed as first cycle D1 in Table 1-1] and for Arm B, where 
a subject receives the first administration of gemcitabine monotherapy [listed as first cycle D4 in Table 
1-1]). This day will be known as “First Cycle First Dose.” A given visit’s Study Day will be assigned 
according to the following rules (this numbering of days differs from the “Day” as described in the 
Tables 1-1 and 1-2): 
 
For events that occurred up to and including First Cycle First Dose: 
Study Day = Visit date – date of First Cycle First Dose + 1 
For events prior to First Cycle First Dose: 
Study Day = Visit date – date of First Cycle First Dose 
 
Visit numbers as designated on the study eCRFs (Electronic Case Report Forms) will be used. For 
selected parameters, visit windows will also be calculated for use in descriptive statistics by time. 
 
4.5.2 Baseline and Change from Baseline  
Baseline assessments for efficacy and safety endpoints will be identified in Section 6.2 and 6.3, 
respectively.  
 
Unless indicated otherwise, change from baseline (CFB) will be calculated as follows: 
CFB = Value at Visit - Baseline 
Percent change from baseline (PCFB) will be calculated as follows: 
PCFB (%) = 100*(Value at Visit - Baseline)/Baseline  
 
 
 
 


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5. STATISTICAL ANALYSIS GENERAL CONSIDERATIONS  
5.1 Analysis Populations  
Screened Population: The Screened Population will include all subjects who signed the informed 
consent form and were screened for participation in this study.  This population will be used when 
describing disposition in the study. 
 
Intent-to-Treat Population:  The Intent-to-Treat (ITT) population is defined as all subjects 
randomized, regardless of actual treatment received. The ITT population will be the primary 
population for the analysis of primary, secondary and exploratory endpoints. 
 
Per Protocol Population: The Per Protocol (PP) population is defined as the set of subjects who meet 
the ITT population requirements, and were not associated with a major protocol violation. This 
population will be identified before the database lock. 
The PP analysis of primary and secondary endpoints will be considered supportive. 
 
Safety Population: 
The Safety Population is defined as any subject receiving any treatment after randomization. For Arm 
A, this consists of subjects that received any portion of the first administration EndoTAG-1 + 
gemcitabine. For Arm B, this consists of subjects that received any portion of the first administration 
of gemcitabine monotherapy. This population will be used for the analysis of all safety endpoints. 
 
 
5.2 P-Values 
To maintain the trial-wise Type I error rate at 0.05, a hierarchical test procedure with fixed sequence 
will be used for the two primary endpoints and the secondary endpoints. The order of the endpoints is 
outlined in Section 6.2. Each subsequent endpoint will not be tested unless the previous endpoint 
analysis in the hierarchy has rejected the null hypothesis. If an analysis of an endpoint fails to reject 
the null hypothesis, then no further analyses will be performed. All secondary endpoints, if tested, will 
use a two-sided analysis at an α=0.05 significance level. 
 
5.3 Procedures for Handling Missing Data 
For categorical secondary efficacy endpoints, if a subject died while on-study, the endpoint will be 
imputed as a failure. Details are in the respective subsections in Section 6.2. Unless otherwise noted, 
no imputation of other endpoints or safety data will occur.  
5.4 Interim Analysis 
A single, pre-planned Interim Analysis (IA) will be conducted when approximately 101 subjects 
have died (60% of the expected 167 events) for the overall survival primary endpoint.  
 


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The results of the IA will be reviewed by an independent Data Safety and Monitoring Board (DSMB) 
who will assess the data for both safety (for the purposes of continuing the trial) and efficacy (for the 
purposes of sample size re-estimation). The DSMB responsibilities will be further elaborated in the 
DSMB charter. The DSMB will approve continuation of the study and recommend the sample size 
for remainder of the study. 
 
5.4.1 Purpose of the Interim Analysis  
The objectives of the interim analysis are to: 
• 
Evaluate the safety of EndoTAG-1 plus gemcitabine in prolonging Overall Survival (OS) 
and Progression Free Survival (PFS) of subjects with locally advanced and/or metastatic 
adenocarcinoma of the pancreas eligible for second-line therapy after failing first-line 
therapy with FOLFIRINOX. 
• 
Determine if it is necessary to evaluate the original sample size assumptions and maintain 
study power using adaptive design for sample size reassessment. 
 
5.4.2 Safety Review 
At the time of the interim safety data review, all the data to be used along with the treatment 
assignment of each randomized subject will be given to the independent statistician. Using this data, 
the independent statistician will prepare descriptive summary and by subject listings of baseline and 
safety data including demographics, adverse events, serious adverse events, laboratory findings, 
physical examinations, vital signs, and ECG. 
 
5.4.3 Adaptive Design: Re-estimation of Sample Size 
At the time of Interim Analysis, all the data to be used in the interim analysis along with the treatment 
assignment of each randomized subject will be given to the independent statistician. Using this data, 
the independent statistician will calculate the following metrics in addition to all the safety data that 
is to be prepared for the safety review: 
 
1. For the calculation of the conditional power: 
a. Proportion of subjects randomized to each Arm at the time of interim analysis 
b. The test statistic computed from the observed data using Cox proportional hazards 
model outlined in the Primary Efficacy Analysis Section 6.2.1 
c. The number of events at the time of the interim analysis 
 
2. For the re-estimation of the sample size, if necessary per Section 5.4.3.2: 
a. The median overall survival (OS) and median progression free survival (PFS) in Arm 
A and the observed number of subjects in the group, calculated using the Kaplan-
Meier method, in months 
b. The median overall survival (OS) and median progression free survival (PFS) in Arm 


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B and the observed number of subjects in the group, calculated using the Kaplan-
Meier method, in months 
 
3. The Conditional Power (CP) of the trial at the time of the IA based on items 1a. – 1c. and the 
formula provided for both OS and PFS in Section 5.4.3.1.  
 
5.4.3.1 Conditional Power Calculation 
The CP will be calculated for each primary endpoint (i.e. OS and PFS) according to the formula 
(Jenninson and Turnbull [2000] pages 205 to 208) per the metrics calculated above using the 
formula: 
 
 
where:  
o Θ = the observed treatment effect at the time of the interim analysis [log(HR) using 
OS and PFS data at the time of the IA]  and: 
o k = an interim stage at which the conditional power is computed 
o K = the stage at which the study is terminated and the final test is computed Zk = the 
logrank test statistic calculated from the observed data that has been collected up to 
stage k, 
𝑆𝑆𝑘𝑘
ඥ𝐼𝐼𝑘𝑘
෢ , where Sk  is the logrank score statistic computed from the observed data 
and 𝐼𝐼𝑘𝑘෡ is the estimated information at stage k 
 
o Ik = the information level at stage k; Ik= [Ek*Pc*(1-Pc); where Ek is the number of 
events at stage k and Pc is the proportion of subjects assigned to the control group 
(Arm B)] 
o IK = the information level at the end of the study; IK= [E*Pc*(1-Pc); where E is the 
total number of events and Pc is the proportion of subjects assigned to the control 
group (Arm B)] 
 
o Z1-α = the standard normal value for the test with at type I error rate of α 
 
The resulting Conditional Power (CP) from the two primary endpoints will be reported to the DSMB 
and used to determine whether the sample size needs to be increased or remains unchanged. 
 
 


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5.4.3.2 Procedure for Re-estimation of the Sample Size 
The re-estimation of the sample size plan will be performed while preserving alpha according to Mehta 
and Pocock (2010).  
 
The sample size for the study will be adjusted only if the Interim Analysis CP for at least one of the 
primary endpoints OS or PFS is less than 90% and greater than 33% (i.e., if CP for at least one of the 
primary endpoints is in the promising zone). In the event that both the CP from OS and PFS are in the 
promising zone, the lower CP will be used for adjustment of the sample size. The adjustment would 
be an increase in the target number of events (i.e., deaths or PD) needed in the study in order to bring 
the CP to at least 90% up to a maximum increase of 436 subjects (218 per group), using the observed 
effect size at the time of the interim analysis. If the sample size is increased to the maximum of 436 
subjects, it is expected that the trial duration will be increased by 2.5 years. 
 
If and only if the interim analysis CP is less than 90% and greater than 33% then the sample size will 
be re-estimated, up to 436 subjects. The sample size calculation will be performed under the same 
assumptions as the initial sample size calculation, with the exception of inserting the observed 1) 
hazard ratio of OS and median overall survival and 2) hazard ratio of PFS and median progression free 
survival in the treatment and control groups at the time of the interim analysis.  
 
The sample size will be maintained at the original sample size if the CP is greater than or equal to 90% 
or if the CP is less than or equal 33%. If a sample size re-estimate is required, the re-estimated sample 
size will be reported to the DSMB. Regardless of the size of the CP at IA, the original sample size will 
not be reduced nor will the trial be stopped early for efficacy. 
 
The DSMB will make recommendations to sponsor on the continuation/modification/ termination 
based on the interim safety and conditional power results. 
 
5.4.4 Preservation of Type I Error Rate 
Per the Mehta and Pocock (2010) paper, if one increases the sample size only when interim results 
are promising, a conventional hypothesis test can be performed without inflating the type-1 error. By 
following the procedure of Mehta and Pocock (2010), if the conditional power at the interim analysis 
is greater than 33%, performing an unblinded interim analysis and sample size re-estimation will not 
have an affect on alpha and the overall type I error at the end of the study will be preserved. The 
cutoff value of 33% chosen based on the guidance from Mehta and Pocock (2010) with a maximum 
allowed re-estimation of two times the original sample size, an interim look when 60% of expected 
events occur, and a targeted conditional power of 90%.  
 
5.4.5 Firewall for Protection Against Bias  
The procedures for this IA will be based on a standard operating procedure (SOP) that has a well-
established a firewall to protect the integrity of the trial. The IA will be performed by an independent 


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statistician, who is not otherwise associated with the conduct of this trial. Since the study is an open 
label study after the blinded randomized assignment to study arm, SynCore and the CRO will be 
provided all results of the interim analysis and the decision of the DSMB to a) stop the trial due to 
safety, b) continue the trial with the original sample size, without p-value adjustment of the final 
analyses, c) continue the trial with a re-estimated sample size.  
 
In order to prevent unauthorized persons from accessing the unblinded interim analysis materials 
and results, a restricted, secure web-based system will be created. This system will centrally store 
the interim analysis results and reports, DSMB agenda and meeting minutes, and any other relevant 
DSMB materials. Team members granted access to the restricted system based on their role in the 
study. No person who is involved in the conduct of the study will be granted access to the restricted 
system. 
 
To ensure that no bias will be introduced into the conduct of the trial, SynCore, the CRO, nor any 
other entity associated with the conduct of the trial will perform any unblinded analyses until the 
trial is completed and the database is locked. 
 
5.5 Subgroup Analysis 
The following subgroups will be analyzed for the primary efficacy data of the study:   
• Age 
• Gender 
• Disease stage (Metastatic vs Locally advanced) 
• ECOG performance status (0 vs 1) 
• Region (United States, Taiwan, Korea, France, Russia, Hungary, Israel)  
 
5.6 Covariates 
 In the efficacy analysis, the pre-specified stratification factors stated in Section 3.2.2 will be included 
in the model. 
 
5.7 Multi-center Studies and Pooling of Centers 
There are expected to be up to 100 study sites in this study. Due to the large number of study sites and 
the small numbers of subjects per site, the analysis of efficacy endpoints will not include adjustments 
for specific study site. However, subgroup analysis by Region (United States, Taiwan, Korea, France, 
Russia, Hungary and Israel) will be peformed. 
 


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6. STATISTICAL ANALYSIS METHODOLOGY  
All data collected for this study will be presented in summary tables, listings, and figures (TLFs) as 
indicated in Appendix 1 of this SAP.  Shells for TLFs with enough detail for programming will be 
provided as a guide to develop the programming SAS codes. These shells will be in sufficient detail 
to simulate the actual TLFs when they are created from the locked database.    
 
Tabulations for continuous data will use a standard set of summary statistics: number of observations 
available (n), mean, standard deviation (SD), median, and range (minimum, maximum).   
 
Categorical or dichotomous data will be tabulated using counts and percentages. The numerator and 
denominator for each percentage calculation will be specified in the footnotes of table shells.   
 
Data listings will present all information recorded in eCRFs and any derived variable(s) included in 
the analysis datasets for all subjects and visits. 
 
6.1 Study Subjects 
6.1.1 Subject Disposition  
The final study disposition of each subject will be captured in the eCRF. For those subjects who do 
not complete the study as planned, all potential reasons for discontinuation will be provided, with one 
indicated as primary. 
 
The following categories will be used in the summaries as the number of subjects by treatment arm 
(with the excpetion of Screened) for all centers combined and for each center separately. 
• Screened 
• Randomized (Intent-to-Treat Population) 
• Randomized and Discontinued before receiving study drug 
o Reason for Discontinuation before receiving study drug 
• Randomized and received at least a partial first dose of study drug (Safety Population) 
• Discontinued after receving study drug 
o Reason for Discontinuation after receving study drug 
• Per Protocol Population  
• Completed Study, defined as a subject who completes at least the 48-week Follow-Up period 
after end (or discontinuation) of treatment, regardless of tumor response 
 
A listing of subject disposition will be prepared, inclusive of dates of last dose and last contact, and 
any investigator comments regarding reason for discontinuation. A summary table will tabulate overall 
disposition of the subjects by the categories above. An additional summary table will summarize 


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number of screen failure subjects and reasons for screen failure. A CONsolidated Standards Of 
Reporting Trials (CONSORT) figure will summarize subject disposition from screening to completion. 
 
6.1.2 Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedure 
defined in the protocol.  
 
The following categories will be used to group protocol deviations  
1. Eligibility/Enrollment 
2. Out of Visit Window 
3. Protocol Procedure/Assessment 
4. Investigational Product Administration 
5. Other 
 
The following are categorical reasons used to document why a protocol deviation occurred: 
1. Subject illness 
2. Subject unable to comply 
3. Subject refusal 
4. Clinical error 
5. Pharmacy error 
6. Laboratory error 
7. Investigator/staff decision 
8. Sponsor decision 
9. Other  
 
A subset of the protocol deviations can be identified as a major protocol deviation as described below: 
Major Protocol Deviation: A Major protocol deviation that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject’s rights, safety, or well-being.  
 
Major protocol deviations include but are not limited to: 
• A research subject received the wrong treatment or incorrect dose. 
• A research subject met withdrawal criteria during the study but was not withdrawn. 
• A research subject received an excluded concomitant medication. 
• A research subject does not meet the protocol's eligibility criteria but was enrolled without prior 
approval from the sponsor. 


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• Failure to obtain informed consent prior to initiation of study-related procedures 
• Failure to treat research subjects per protocol procedures that specifically relate to primary 
efficacy outcomes. 
• Changing the protocol without prior sponsor and IRB approval. 
• Multiple minor violations of the same nature after multiple warnings. 
 
Upon soft lock of database, all documented protocol deviations in the study will be reviewed to identify 
all important protocol deviations by a data review team including representatives from clinical 
operations, medical, data management, and statistics, and sent to the sponsor for approval. Final 
decisions will be documented and databased.  
 
A summary table of post-randomization protocol deviations will be presented by treatment arm and 
overall. The number and proportion of subjects with protocol deviations (major/minordeviations) will 
be tabulated by protocol deviation category.  
 
6.1.3 Demographics 
Descriptive summaries of the Safety Population will be prepared for the demographic and baseline 
(Screening) parameters listed below. Categorical variables will be described with counts and 
percentages and continuous variables with mean and standard deviation (SD). These variables will 
also be summarized for the ITT population if it differs from the safety population by more than 10% 
in overall sample size). 
• Age (years) 
• Age Group (<65 vs. ≥65) 
• Gender 
• Race/ethnicity 
• Disease State (Metastatic vs. Locally Advanced) 
• ECOG Performance Status (0 vs. 1) 
• Country 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
 
6.1.4 Medical and Surgical History 
At the Screening visit, the general medical and surgical procedures history will be recorded on the 
eCRF, Medical History data will be summarized in a table by MedDRA version 23.0 System Organ 
class (SOC) and Preferred Term (PT). Data listings for medical history and surgical history will be 
provided. 


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6.1.5 Concomitant Medications 
All prior and concomitant medications, interventions and procedures will be tabulated. Prior and 
concomitant medications will be coded to the therapeutic drug classes and generic drug names using 
the World Health Organization Drug (WHODrug) classifications version March 1 2020. 
 
A by-subject listing comprehensive of prior and concomitant medications will be generated, inclusive 
of verbatim and coded terms, doses and routes, and start and stop dates. Prior medications will be 
flagged. Prior and concomitant status with respect to study drug treatment will be determined based 
on imputed dates. Prior medications used within 30 days of Screening will be provided in a separate 
listing. 
 
6.2 Efficacy Analysis 
6.2.1 Primary Efficacy Analysis 
The primary efficacy endpoints for the study are: 
1. Overall Survival 
2. Progression Free Survival 
As discussed in Section 5.2, to maintain the trial-wise Type I error rate at 0.05, a hierarchical test 
procedure with fixed sequence will be used. PFS will only be compared if the primary analysis of 
OS rejects the null hypothesis. 
 
6.2.1.1 Overall Survival 
Overall survival (OS) is defined as the time from randomization to death from any cause or last day 
known to be alive. OS will be defined in months, where: 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 = (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑ℎ 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑 𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘 𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
–  𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 +  1)/30 
The below dates will be used in order to determine the date of death or last day known to be alive 
used for Overall Survival calculation: 
Table 6-1: Date of Death or Censoring for Overall Survival Situation 
Order 
Situation  
Date of Death or Censoring  
Outcome  
1 
Subject died 
Date of Death 
Dead 
2 
Subject known to be alive in the survival 
follow-up 
Date of last day known to be alive 
Censored 
3 
Subject completed the study  
Date of study completion 
Censored 
4 
Subject withdrew from the study or was lost 
to follow-up after randomization  
Date of withdraw from the study or 
lost to follow-up 
Censored 
5 
Subject did not withdrawal nor lost to 
follow-up and is still in the study  
Date of last visit 
Censored 
6.2.1.2 Progression Free Survival 


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Progression Free Survival (PFS) is defined as the time from randomization to either first observation 
of progressive disease or occurrence of death. To assess progression, it is necessary to estimate the 
overall tumour burden at baseline. The tumor imaging as the Screening Visit will be used as the 
baseline measurement. Tumor imaging will be completed every 8 weeks irrespective of the timing of 
the treatment cycle. When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. A sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters in millimeters.  
 
At baseline, all other non-target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurement of these lesions will be as follows: 
Response 
Definition 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non- 
pathological in size (<10mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also 
considered progression). 
  
At the post-baseline tumor imaging assessments, the sum of diameters will be measured. Progressive 
disease will be considered at least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum of diameters or any other post-
baseline calculated sum of diameters before a respective imaging visit). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters. 
Additionally, the appearance of one or more new lesions compared to the baseline assessment is also 
considered progression at any post-baseline visit.  
 
Following any post-baseline imaging, the investigator will determine if the disease is progressive based 
on the above criteria and record the response in the eCRF. 
 
The date of progression free survival will be considered the date of first observation of progressive 
disease or the last known day to be alive, whichever is first. For the calculation of the end of 
progression free survival, in months, the following formula will be used: 
 
 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆  
= (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑  𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑 𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘 


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 𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏 𝑎𝑎𝑙𝑙𝑖𝑖𝑖𝑖𝑖𝑖 –  𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 +  1) / 30 
The below dates will be used in order to determine the first observation of progressive diease or last 
day known to be alive used for Progression Free Survival calculation: 
Table 6-2: Date of Death or Censoring for Progression Free Survival Situation 
Order 
Situation  
Date of Progression or Censoring  
Outcome  
1 
Incomplete or no baseline tumor 
assessments 
Randomization 
Censored 
2 
Subjects died or disease progressed 
Date of Death or Date of first 
observation of progressive disease, 
whichever is first 
Progressed 
3 
Subjects completed the study with 
no disease progression 
Date of study completion 
Censored 
4 
Subjects did not withdrawal nor lost 
to follow-up and are still in the 
study with no disease progression 
Date of last visit 
Censored 
5 
Subjects who have two or more 
consecutive missing tumor 
assessments before a PFS event 
Date of last visit prior to the PFS event 
Censored 
6 
Subjects who receive a new anti-
cancer therapy with no 
documented progression 
Date of last visit prior to the initiation 
of new anti-cancer therapy 
Censored 
7A 
Treatment discontinuation for 
toxicity or other reason 
Date of last progression with no 
documented progression 
Censored 
7B 
 
Treatment discontinuation for 
toxicity or other reason 
Date of documented progression with 
protocol specified continued follow-up 
in all treatment arms 
Progressed 
 
 
6.2.1.3 Null Hypothesis of the Primary Effiacy Analysis 
For PFS, the null hypothesis is that there is no difference in PFS between the treatment groups Arm A 
and Arm B. The alternative hypothesis is that there is a difference in PFS between treatment groups 
Arm A and Arm B.  
For OS, the null hypothesis is that there is no difference in overall survival between the treatment 
groups Arm A and Arm B. The alternative hypothesis is that there is a difference in overall survival 
between treatment groups Arm A and Arm B.  
 
6.2.1.4 Primary Efficacy Analysis 
Primary efficacy endpoints will be compared between the treatment arms using stratified log-rank 
test with the factors ECOG status (0 vs. 1) and disease stage (Metastatic vs. Locally Advanced) 


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included as stratification. The differences between treatment arms, its 95% Confidence Interval (CI), 
and p-value will be reported.  
 
 
 
In addition, the Kaplan-Meier method will also be used to depict the median, the 1st quartile, and 3rd 
quartile time to PD or death from any cause for the treatment arms. A Kaplan-Meier plot will present 
the non-parametric function by treatment arm. 
 
The Primary Efficacy Analyses will be tested on the Intent-to-Treat Population. In addition, it will be 
carried out on the Per Protocol Population and will be considered supportive analysis. 
 
6.2.2 Secondary Efficacy Analyses 
To maintain the trial-wise Type I error rate at 0.05, a closed test procedure will be used for the 
secondary endpoints. The order of the endpoints will be as follows: 
 
 
1. Percentage of  subjects  with  Objective  Response  (OR)  according to  Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST v.1.1) 
 
2. Duration of Response (DR) 
 
3. Percentage of subjects with disease control according to RECIST v.1.1 
 
 
4. Serum Carbohydrate Antigen 19-9 (CA 19-9) response rate 
 
Any Secondary Efficacy Analyses that are carried out will be tested on the Intent-to-Treat Population. 
In addition, they will be carried out on the Per Protocol Population and will be considered supportive 
analyses. 
 
 
6.2.2.1 Objective Response 
The percentage of subjects with Objective Response (OR) during the course of the study according 
to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1) will be summarized.  
 
To assess objective response, it is necessary to estimate the overall tumour burden at baseline. The 
tumor imaging as the Screening Visit will be used as the baseline measurement. Tumor imaging will 
be completed every 8 weeks irrespective of the timing of the treatment cycle. When more than one 
measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a 


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maximum of two lesions per organ) representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters in millimeters.  
 
At any post-baseline imaging assessment, the investigator will determine and record in the eCRF 
whether there is a complete response (CR) or partial response (PR) where: 
o Complete Response = Disappearance of all target lesions 
o Partial Response = At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters 
 
If a subject has a CR or PR at any visit during treatment or follow-up, they will be considered as having 
an objective response. 
The number and frequency of subjects who have an objective response by treatment arm will be 
presented. To test the difference in proportions between the two groups, a logistic regression model 
will be used. The model will include factors ECOG status (0 vs. 1) and disease stage (Metastatic vs. 
Locally Advanced). The p-value for the treatment arm variable will be reported.  
 
6.2.2.2 Duration of Response 
Duration of Response (DR) is defined as the time from the first documentation of objective tumor 
response to objective tumor progression or death due to any cause. The date of objective response and 
the date of progression are defined as in Section 6.2.2.1 and 6.2.1.1, respectively. The earliest date 
with CR or PR will be considered the date of objective response. The date of tumor progression will 
be considered the earliest date that PD is objectively documented after the objective response date, 
taking as reference for PD the smallest measurements recorded since the treatment started. The 
duration of response, in months, will be calculated as: 
 
           𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 
                    = (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑ℎ
− 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 (𝐶𝐶𝐶𝐶 𝑜𝑜𝑜𝑜 𝑃𝑃𝑃𝑃) +  1) / 30 
Date of tumor progression or death will be determined following Table 6-2.  
This endpoint will only be evaluated in subjects with objective response of CR or PR. The analysis 
of duration of responses will only be used as a descriptive analysis. 
In addition, the Kaplan-Meier method will also be used to depict the median, the 1st quartile, and 3rd 
quartile Duration of Response for the treatment arms.  
 
6.2.2.3 Disease Control 
Percentage of subjects with disease control will be summarized. Disease control is based on 
assessment of complete response (CR) or partial response (PR) or stable disease (SD) according to 
RECIST v.1.1. 


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CR and PR are defined as in Section 6.2.2.1. Stable disease is defined as neither sufficient shrinkage 
to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. If a subject is classified as CR, PR, or SD at their last imaging visit, they 
will be considered to have disease control. If a subject died while on study, they will be classified as 
failed to have disease control irregardless of previous imaging assessments.  
 
The number and frequency of subjects who have a disease control by treatment arm will be presented. 
To test the difference in proportions between the two groups, a logistic regression model will be used. 
The model will include factors ECOG status (0 vs. 1) and disease stage (Metastatic vs. Locally 
Advanced). The p-value for the treatment arm variable will be reported.  
 
6.2.2.4 Serum Carbohydrate Antigen 19-9 (CA 19-9) response rate 
Serum Carbohydrte Antigen 19.9 (CA 19-9) will be collected as part of the laboratory assessments at 
Screening, on week 8 of treatment cycles, and at Follow-up Visit 1. The Screening assessment will 
be considered the baseline assessment. Responders are defined as subjects with a reduction in Serum 
Carbohydrate Antigen 19.9 (CA 19-9) levels by least 50% from baseline to the end of cycle 1 (or end 
of full treatment course). If a subject died while on study, they will be classified as a failure, 
irregardless of previous assessments.  
 
The number and frequency of subjects who have a disease control by treatment arm will be presented. 
To test the difference in proportions between the two groups, a logistic regression model will be used. 
The model will include factors ECOG status (0 vs. 1) and disease stage (Metastatic vs. Locally 
Advanced). The p-value for the treatment arm variable will be reported.  
 
6.2.3 
Exploratory Analyses 
1. Change from Baseline in European Organization for Research and Treatment of Cancer, 
Quality of Life Questionnaire Core-30 (EORTC QLQ- C30) Score 
 
2. Change from baseline in European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) Score 
 
 
6.2.3.1 EORTC-QLQ-C30 Summary Score 
Change  from  Baseline  in  European  Organization  for  Research  and  Treatment  of  Cancer, Quality 
of Life Questionnaire Core-30 (EORTC QLQ- C30) Summary Score will be performed. The 
assessment at the Screening visit will be considered the baseline assessment.  
 
EORTC QLQ-C30 score will be evaluated for the following domains: 


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• Global health QoL: 
 (items 29 and 30)  
 
• Functional scales including: 
 Physical (items 1 to 5),  
 Role (items 6 and 7),  
 Cognitive (items 20 and 25),  
 Emotional (items 21 to 24) and,  
 Social (items 26 and 27). 
 
•         Symptom scales including:  
 Fatigue (items 10, 12, and 18), 
 Pain (items 9 and 19) and, 
 Nausea/vomiting (items 14 and 15). 
 
•         Side effect scales and overall side effect bother scales including: 
 Dyspnoea (item 8), 
 Appetite loss (item 13), 
 Insomnia (item 11) and, 
 Constipation/diarrhea (items 16 and 17). 
 
All scales in the summary score consist of questions that use a 4- point scale (1 'Not at All' to 4 'Very 
Much').   
EORTC-QLQ-C30 change from baseline for each category will be calculated at Follow-up Visit 1 and 
will be summarized by treatmentgroup (n, mean, standard deviation, median, minimum and 
maximum).  
 
To test for the difference in change from baseline between treatment groups, the following methods 
will be used, as appropriate: 
o If the normality assumption is met, Analysis of Covariance (ANCOVA). The model 
will consist of the Follow-up Visit 1 value as the dependent variable and with the 
baseline value, time, time x treatment interaction, and the covariates from Section 5.6 
in the model, as necessary.  
 
o If the Normality assumption is not met, a rank–ANCOVA analysis i.e., an ANCOVA 
analysis on rank-transformed data will be used. 
 
The p-values for the appropriate analysis will be presented. 
 
6.2.3.2 EORTC-QLQ-PAN26 


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Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) Scorewill be performed. The assessment at the 
Screening visit will be considered the baseline assessment. 
 
QLQ-PAN26 consists of 26 questions (Qs) relating to disease symptoms, treatment side effects and 
emotional issues specific to pancreatic cancer (PC). Questions include on altered bowel habits, pain, 
dietary changes, disease and Tx-related symptoms and issues related to the emotional and social well-
being of participants with PC. All 26 Qs are answered on 4-point Likert scale ranging from '1=not at 
all' to 4='very much' and subsequently transformed into scales that range from 0-100; higher scores= 
greater degree of symptoms or treatment side effects and emotional issues. 
PAN26 score will be evaluated for 7 domain scores as below: 
•       Pancreatic pain (item 31, 33, 34 and 35) 
•       Digestive (item 36 and 37),  
•       Altered bowel habit (item 46 and 47), 
•       Hepatic (item 44 and 45),  
•       Body image (item 48 and 49), 
•       Health care satisfaction (item 53 and 54) and,  
•       Sexuality (item 55 and 56). 
 
The mean of the each domain will be calculated and will be considered the EORTC-QLQ-PAN26 
score for a given visit. EORTC-QLQ-PAN26 change from baseline for each domain will be calculated 
at Follow-up Visit 1 and will be summarized by treatmentgroup (n, mean, standard deviation, median, 
minimum and maximum).  
 
To test for the difference in change from baseline between treatment groups, the following methods 
will be used, as appropriate: 
o If the normality assumption is met, Analysis of Covariance (ANCOVA). The model 
will consist of the Follow-up Visit 1 value as the dependent variable and with the 
baseline value, time, time x treatment interaction, and the covariates from Section 5.6 
in the model, as necessary.  
 
o If the Normality assumption is not met, a rank–ANCOVA analysis i.e., an ANCOVA 
analysis on rank-transformed data will be used. 
 
The p-values for the appropriate analysis will be presented. 
 
 
 


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6.3 Safety Analysis 
6.3.1 Exposure 
Summary statistics will be presented for the time on treatment in months by study arm, where the time 
on treatment will be calculated as: 
Time on Treatment = (Date of Last Dose – Date of First Dose) / 30 
 
The time on treatment will be summarized by treatment arm for the ITT Population, the Per Protocol 
Population, and the Safety Population. 
6.3.2 Adverse Events 
All adverse events will be coded using version 23.0 of MedDRA, which will be noted in the CSR. 
 
A treatment-emergent adverse experience (TEAE) is defined as any event that only occurred after 
the first dose of the study drug (Day 1 of the first cycle for Arm A and Day 4 of the first cycle for 
Arm B) or that existed before drug administration but increased in severity or treatment attribution.  
 
The duration of an AE will be calculated as: 
 
Duration = (AE End Date – AE Onset Date) + 1 
 
 
The incidence of TEAEs and treatment emergent serious adverse events (SAEs) will be 
summarized.  
 
An overall summary of TEAEs will include: 
o Incidence of subjects with one or more TEAE 
o Incidence of TEAEs by highest relationship 
o Incidence of TEAEs by highest severity 
o Incidence of TEAEs by action taken 
o Incidence of TEAEs by outcome 
o Incidence of treatment-emergent SAEs 
 
The incidence of TEAEs will be presented by the following separately: 
• System Organ Classification and Preferred Term 
• Preferred Term in descending order of frequency of events overall 
• System Organ Classification and Preferred Term by maximum intensity 
• System Organ Classification and Preferred Term by highest relationship,  


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• Treatment-related TEAE by System Organ Classification and Preferred Term by highest 
relationship (possibly, probably, definitely) 
• TEAE leading to discontinuation by System Organ Classification and Preferred Term 
 
In addition, separate summaries of TEAEs will be prepared with subjects categorized by System 
Organ Classification and Preferred Term and by sex, age, and race. 
 
The incidence of treatment-emergent serious adverse events (SAEs) will be presented by system 
organ classification and preferred terms, by treatment-related status (possibly, probably, certainly), 
and for those that are fatal. 
Adverse events will be listed for all subjects, including verbatim and coded terms. 
 
6.3.3 Clinical Laboratory Tests 
Serum chemistry laboratory tests will be collected at Screening, Visits 1G, 2G, and 8 of the First Cycle 
Treatment Phase, Visit 8 of Subsequent Cycle Treatment Phases, and Follow-up Visit 1 after the last 
treatment cycle. The following serum chemistry parameters will be used for safety analysis: 
• Urea 
• Serum Creatinine  
• Sodium  
• Potassium  
• Chloride  
• Bicarbonate  
• Glucose  
• Bilirubin  
• Albumin  
• Alanine Aminotransferase (ALT) 
• Aspartate Aminotransferase (AST) 
• Alkaline Phosphatase (ALP) 
• Total protein 
 
Hematology laboratory tests will be collected at Screening, every non-rest visit during the Treatment 
Phases, and Follow-up Visit 1 after the last treatment cycle. The following hematology parameters will 
be used for safety analysis: 
• Hemoglobin  
• Hematocrit (HCT) 
• Mean Corpuscular Volume (MCV) 


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• Mean Corpuscular Hemoglobin (MCH) 
• Mean Corpuscular Hemoglobin Concentration (MCHC) 
• Red Blood Cell (RBC) count  
• Platelets count  
• White Blood Cell (WBC) count  
• WBC Differential 
• Differential Leukocyte count  
• Absolute Neutrophil count 
 
Coagulation laboratory tests will be collected at Screening, Visits 1G, 2G, 3G, 5G, 6G, 7G, and 8 of 
treatment phases for each cycle, and Follow-up Visit 1 after the last treatment cycle. The following 
coagulation parameters will be used for safety analysis: 
• International Normalized Ratio (INR) 
• Prothrombin Time (PT) 
• Activated partial thromboplastin time (APTT) 
• Total Fibrinogen 
 
Urinalysis laboratory tests will be collected at Screening, Visit 8 of treatment phase for each cycle, 
and Follow-up Visit 1 after the last treatment cycle. The following urinalysis parameters will be used 
for safety analysis: 
• pH 
• Appearance 
• Color 
• Specific Gravity 
• Viscosity 
• Turbidity 
• Ketones 
• Bilirubin 
• Blood 
• Glucose 
• Protein 
• Nitrites 
• Urobilinogen 
• Leukocyte Esterases 
• Microscopic Exam: 


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o Bacteria 
o Cast 
o Crystals 
o Epithelial cells 
o RBC 
o WBC 
 
Baseline for each lab parameter will be considered the last assessment before the dose administration 
on Study Day 1 (date of First Cycle First Dose as described in Section 4.5.1) for serum chemistry, 
hematology, and coagulation and as the Screening assessment for urinalysis.  
 
For continuous endpoints, summary statistics for the outcome at each available week’s assessment and 
its change from baseline will be tabulated separately for chemistry, hematology, coagulation, and 
urinalysis parameters. Additionally, number and propotion of subjects with investigator-determined 
abnormal lab results will be tabulated as a shift table by treatment arm with baseline vs. respective 
week presented for each parameter. Number and proportion of subjects with clinically significant 
abnormal results will also be presented by week and by treatment arm in a table. For summary tables, 
the visits will be presented as Screening, “Treatment Phase X, Visit Y,” and Follow-Up Phase. The 
Follow-up Phase will present the Follow-up Visit 1 for all subjects, regardless of the number of 
treatment cycles completed. 
 
Clinical laboratory results will be listed for all subjects, inclusive of flags for whether or not the value 
is outside laboratory normal range or considered significant by the Investigator.  Normal ranges will 
be noted in the listing. Values outside laboratory normal ranges as well as those considered clinically 
significant by the Investigator will be flagged as L (low) and H (high).  
 
Pregnancy Tests and Tumor Marker CA 19-9 collected throughout the study will also be presented in 
listings. 
 
6.3.4 Vital Signs 
Vital Signs are collected at Screening, all Treatment Phase visits for each cycle, and Follow-up Visit 
1 after the last treatment phase. The following vital signs parameters will be collected: 
• Systolic Blood Pressure (SBP) 
• Diastolic Blood Pressure (DBP) 
• Heart Rate 
• Body Temperature 
• Weight 
 


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Summary statistics for the parameters at each available week’s assessment and its change from 
baseline will be tabulated SBP, DBP, and Heart Rate. Additionally, number and propotion of subjects 
with investigator-determined abnormal vital sign results will be tabulated as a shift table by treatment 
arm with baseline vs. respective visit presented for each parameter. Number and proportion of subjects 
with clinically significant abnormal results will also be presented by week and by treatment arm in a 
table. For summary tables, the visits will be presented as Screening, “Treatment Phase X, Visit Y,” 
and Follow-Up Phase. The Follow-up Phase will present the Follow-up Visit 1 for all subjects, 
regardless of the number of treatment cycles completed. 
 
All vital sign results will be listed for all subjects, inclusive of flags for whether or not the value is 
outside normal range or considered significant by the Investigator.  Normal ranges will be noted in the 
listing. Values outside laboratory normal ranges as well as those considered clinically significant by 
the Investigator will be flagged as L (low) and H (high).  
 
6.3.5 12-lead Electrocardiogram 
Electrocardiograms will be performed at Screening and every 8 weeks regardless of treatment 
cycle. Parameters to be summarized include:  
• Heart Ratet (HR) 
• PR Interval 
• RR Interval 
• QRS 
• QT 
• QTc with the Bazett correction (QTcB= QT/(RR)½) 
• QTc with the Fridericia correction (QTcF = QT/(RR)⅓) 
 
All triplicate results will be averaged for summary and analysis purposes.   
 
ECG results will be summarized by treatment arm and week. Descriptive statistics will include mean, 
standard deviation, median, minimum, and maximum. Continuous ECG parameters will be 
summarized as change from Baseline (Screening Assessment).  For the summary of change statistics, 
the Baseline mean and standard deviation will be provided for the subset of subjects with available 
data for the change summary. Clinical interpretations will also be summarized by visit and treatment 
arm. For summary tables, the visits will be presented as Screening, “Treatment Phase X, Visit 8,” and 
Follow-Up Phase. The Follow-up Phase will present the Follow-up Visit 1 for all subjects, regardless 
of the number of treatment cycles completed. 
 
ECG results, including clinical interpretation and a flag for whether or not the value meets criteria 
for being possibly clinically significant, will be listed for all subjects. Any ECG abnormalities, 
based on clinical interpretation, will be listed. 


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6.3.6 Physical Exam 
Complete physical examination is to be performed at Screening, Visits 1G, 2G, 3G, 5G, 6G, 7G, and 
8 of treatment phases for each cycle, and Follow-up Visit 1 after each treatment cycle. The complete 
examination will consist of evaluation of the following: 
• Skin 
• Head 
• Eyes 
• Ears 
• Nose 
• Throat 
• Neck 
• Thyroid 
• Lungs 
• Heart 
• Lymph nodes 
• Abdomen 
• Extremities 
  
Descriptive statistics will be provided for proportions of subjects with abnormalities on physical 
examination by treatment arm at each week. Physical examination findings will be listed.   
 
6.4 Pharmacokinetics 
A separate SAP will be prepared that describes the methodology to be used in analyzing 
pharmacokinetic (PK) data. 
 
 


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7. TESTING/QUALITY CONTROL PLAN AND SOFTWARE/SYSTEM 
All statistical programs will be written in SAS® version 9.3 or higher [6].  Statistical programs will be 
tested and reviewed for Quality Control (QC) by a second programmer/biostatistician not involved in 
the programming as per DP Clinical (CRO)’s standard operating procedure (SOP). In addition, CRO’s 
SOP will be followed to ensure that the information is complete, consistent, and accurately reflects the 
data stored in Clinical Data Management System (CDMS) database.  Further all tables, listings, and 
figures (TLFs) will undergo a QC process by an independent biostatistician/programmer to ensure that 
the information is complete, consistent, and accurately reflects the data stored in CDMS.  
 
7.1 Programming Specifications for TLFs 
Appendix 1 provides a list of all the TLFs that are planned to be produced. 
 
7.2 Formatting Conventions 
The following formatting conventions will be used to output TLFs:  
• TLFs are outputted by SAS Output Delivery System (ODS) into Rich Text Files (RTF) 
format. 
• Tables and Listings will include borders around all headings and data cells. 
• Output will be in landscape orientation with margins of 1.5 inches on top, and 1 inch 
for right, left, and bottom. 
• The default font to be in tables/listings/figures will be Courier New.  
• Preferred and minimum font size: 
 
Portion of Output 
Preferred 
Minimum 
Page Header 
10 pt 
8 pt 
Title 
10 pt  
8 pt 
Column header 
10 pt  
8 pt 
Cells 
10 pt 
8 pt 
Footnote 
10 pt  
8 pt 
Page Footer 
10 pt 
8 pt 
 
• Data will be centered within columns when the maximum length of the data being 
displayed is less than or equal to the maximum width of the column heading. When the 
maximum length of the data being displayed exceeds the maximum width of the column 
heading, the data will be left-justified. 
• Column headings should be in initial capital characters.  For numeric variables, include 
“unit” in the column heading when appropriate. 


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• In figures, axes will be labeled appropriately. 
  
7.3 Standard Text Conventions 
7.3.1 Header 
All output (table, listing, or figure) will have the following header: 
 
SynCore Biotechnology Co., Ltd. 
Protocol: CT 4006 
 
      
 
 
 
Page xx of XX 
[Output Type] 
 
where [Output Type] is “Interim Analysis,” “Clinical Study Report,” etc as appropriate. All output will 
have the date and time (date and time output was generated) and internal page number in the footer.  
Tables/Listings/Figures should be internally paginated (i.e., page numbers should appear sequentially 
within each output). 
 
7.3.2 Title 
At least three (3) lines, in general, will be reserved for the entire title.  
• The first line is for the table/listing/figure number;  
• The second line is for the actual title; and  
• The third line is reserved for the analysis population descriptor.  
 
All titles will be centered, as shown in the following example: 
 
Table 14.3.1.1 
Topline Summary of Safety Events 
Safety Population 
 
7.3.3 Footnotes 
Unless otherwise specified, footnotes will appear on all pages within the tables and listings as follows: 
• Footnotes will be in the format of  “Note: followed by 2 spaces, then the 
footnotes”, as shown in the following example:  
 
Note:  SD = Standard Deviation; SEM = Standard Error of the Mean. 
 
• Each line of a complete footnote should end with a period. 
• When an abbreviation (e.g. AE, SAE, etc.) appears first time in the whole set of 
TLFs for a study, a footnote should be provided at least once; and it is up to the 


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study statistician, to decide whether there is a need to repeat the same footnote 
for the rest of TLFs.  
• A footnote serves as a brief explanation/clarification /definition /concept of a 
flag symbol or a character, an abbreviation, a terminology, etc., that appears in 
or relates directly to the displayed content of a table/listing/figure.  
• Footnotes will not contain detailed/technical elaboration of, for example, a 
mathematical/statistical formula, a statistical term/test, or an algorithm for 
deriving a parameter value, which should be addressed in the text of the SAP. 
• All footnotes will be at the lowest line of the page immediately above the footer.  
There will be one space between the last footnote and the footer. 
• For Tables, first footnote will provide source listings and/or analysis datasets 
names for cross-referencing. 
 
7.3.4 Footer 
The following footer should appear at the very bottom of each page of a table, a listing, or a figure 
generated in SAS in the lower left corner: 
 
Program: PGNAME.sas; Creation Date and Time: MMDDDYYYY HH:MM 
Data Cutoff: DDMMMYY:HH:MM:SS – Listing Generated MMM  DD, YYYY  
 
where PGNAME = SAS program name. 
 
7.4 Statistical Conventions 
7.4.1 Statistics Reported  
• Unless otherwise specified, the mean and standard deviation (SD) will be displayed to one more 
decimal place than the original value, while minimum and maximum will be reported in the 
format of the original data, e.g.:   
 
Original: xx 
Mean and SD: xx.x 
Minimum and maximum: xx 
 
• Descriptive statistics in this template include: Mean, Median, Standard Deviation (SD), 
Minimum, Maximum, and N. In addition, 95% CI will be presented when appropriate.  
 
• Unless specified in the actual TLF shells for a study, all percentages will be rounded to 1 decimal 
place in all tables/listings/figures.  Rounding will take place after all calculations have been 
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• Use of N versus n: 
N = total number of subjects or subjects in the population. 
n = total number of subjects or subjects in the specific category. 
 
7.4.2 SAS Procedure Output 
If appropriate, SAS procedure output may be formatted and saved as source for references and will be 
included in Appendix.  
 
7.4.3 Tables Summarizing Categorical Data 
The following specifications apply to tables that summarize categorical data: 
• Percent of events should be left blank (including the parentheses) if the number 
of events is zero. 
• If the categories of a parameter are ordered, then all categories between the 
maximum possible category and the minimum category will be included, even 
if n=0 for a given category between the minimum and maximum level for that 
parameter. 
• If the categories are not ordered, then only those categories for which there is at 
least one subject represented will be included. 
• A missing category will be added to any parameter for which information is not 
available for any subjects. 
 
7.4.4 Subject Data Listings 
In general, individual subject data listings should include all subjects with data.  However, if a subject 
data listing includes only subjects who met a certain condition, and there were no subjects who met 
that condition, then a “message” will appear indicating that no subjects met the condition for inclusion 
in that listing. 
 
 
 


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8. REFERENCES 
 
Burris 3rd HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, 
Portenoy RK, Storniolo AM, Tarassoff P, Nelson R (1997). Improvements in survival and clinical 
benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized 
trial. Journal of clinical oncology.;15(6):2403-13. 
 
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, 
Gourgou-Bourgade S, de la Fouchardière C, Bennouna J. FOLFIRINOX versus gemcitabine for 
metastatic pancreatic cancer (2011). New England Journal of Medicine. ;364(19):1817-25. 
 
Cui L, Hung HM, Wang SJ (1999). Modification of sample size in group sequential clinical trials. 
Biometrics; 55:853–7. 
 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC 
Quality of Life Group (2001). The EORTC QLQ-C30 Scoring Manual (3rd Edition). European 
Organisation for Research and Treatment of Cancer, 
. 
ICH E3 (1995): Structure and Content of Clinical Study Reports. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
 
ICH E6 (R2) (2016): Guideline for Good Clinical Practice. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
 
ICH E9 (1998): Statistical Principles for Clinical Trials. International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
 
ICH E9 (R1) (2017): Estimands and Sensitivity Analysis in Clinical Trials (ICH). 
 
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008). Cancer statistics. CA: a cancer 
journal for clinicians. 2008 Mar 1;58(2):71-96. 
 
MedDRA Version XX.X (MMM YYYY). International Federation of Pharmaceutical Manufacturers 
and Associations (IFPMA). 
 
Mehta, C.R. and Pocock, S.J. (2010). Adaptive increase in sample size when interim results are 
promising: A practical guide with examples. Statistics in Medicine. Volume 30, Issue 28; pp. 3267–
3284. 


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Portal A, Pernot S, Tougeron D, Arbaud C, Bidault AT, De La Fouchardière C, Hammel P, Lecomte 
T, Dréanic J, Coriat R, Bachet JB. Nab-paclitaxel plus gemcitabine for metastatic pancreatic 
adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort (2015). British 
journal of cancer;113(7):989-95. 
.. 
SAS® for Windows® Version 9.3. SAS Inc. Cary, North Carolina USA. 
 
The WHO Drug Dictionary (WHO-DD) (Mar 2017). World Health Organization (WHO) Uppsala 
Monitoring Center (UMC). 


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9.  APPENDICES 
9.1 Planned Tables, Listings, and Figures  
Output Number 
Output Name 
Study Population 
Table 14.1.1.1 
Screen Failure Summary  
Screened 
Population 
Table 14.1.1.2 
Subject Disposition 
Screened 
Population 
Table 14.1.2 
Protocol Deviations 
Safety Population 
Table 14.1.3.1 
Demographics and Baseline Characteristics 
Safety Population 
Table 14.1.3.2 
Demographics and Baseline Characteristics 
ITT Population 
Table 14.1.4.1 
Medical History 
Safety Population 
Table 14.1.4.2 
Prior Medications 
Safety Population 
Table 14.1.4.3 
Concomitant Medications 
Safety Population 
Table 14.1.5 
Study Drug Exposure 
Safety Population 
Table 14.2.1.1A 
Progression Free Survival by Treatment Arm 
ITT Population 
Table 14.2.1.1B 
Progression Free Survival by Treatment Arm 
Per Protocol 
Population 
Table 14.2.1.2A 
Overall Survival by Treatment Arm 
ITT Population 
Table 14.2.1.2B 
Overall Survival by Treatment Arm 
Per Protocol 
Population 
Table 14.2.2.1A 
Objective Response by Treatment Arm 
ITT Population 
Table 14.2.2.1B 
Objective Response by Treatment Arm 
Per Protocol 
Population 
Table 14.2.2.2A 
Duration of Response by Treatment Arm 
ITT Population 
Table 14.2.2.2B 
Duration of Response by Treatment Arm 
Per Protocol 
Population 
Table 14.2.2.3A 
Disease Control by Treatment Arm 
ITT Population 
Table 14.2.2.3B 
Disease Control by Treatment Arm 
Per Protocol 
Population 
Table 14.2.2.4A 
EORTC QLQ-C30 Summary Score Change from Baseline by 
Treatment Group 
ITT Population 
Table 14.2.2.4B 
EORTC QLQ-C30 Summary Score Change from Baseline by 
Treatment Group 
Per Protocol 
Population 
Table 14.2.2.5A 
EORTC QLQ-PAN26 Summary Score Change from Baseline by 
Treatment Group 
ITT Population 
Table 14.2.2.5B 
EORTC QLQ-PAN26 Summary Score Change from Baseline by 
Treatment Group 
Per Protocol 
Population 
Table 14.2.2.6A 
Serum Carbohydrate Response by Treatment Group 
ITT Population 
Table 14.2.2.6B 
Serum Carbohydrate Response by Treatment Group 
Per Protocol 
Population 
Table 14.3.1.1 
Topline Summary of Treatment Emergent Adverse Events 
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Table 14.3.1.2 
Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Population 
Table 14.3.1.3 
Treatment Emergent Adverse Events by Preferred Term in 
Descending Order of Frequency 
Safety Population 
Table 14.3.1.4 
Treatment Emergent Adverse Events by Maximum Severity 
Safety Population 
Table 14.3.1.5 
Treatment Emergent Adverse Events by Highest Relationship to 
Study Drug 
Safety Population 
Table 14.3.1.6 
Treatment Emergent Treatment Related Adverse Events by Highest 
Relationship to Study Drug 
Safety Population 
Table 14.3.1.7 
Treatment Emergent Adverse Events Leading to Discontinuation 
Safety Population 
Table 14.3.1.8.1 
Treatment Emergent Adverse Events by XX Subgroup 
Safety Population 
Table 14.3.1.8.2 
Treatment Emergent Adverse Events by XX Subgroup 
Safety Population 
Table 14.3.1.8.3 
Treatment Emergent Adverse Events by XX Subgroup 
Safety Population 
Table 14.3.2.1 
Treatment Emergent Serious Adverse Events by System Organ 
Class and Preferred Term 
Safety Population 
Table 14.3.2.2 
Treatment Emergent Treatment Related Serious Adverse Events by 
Highest Relationship to Study Drug 
Safety Population 
Table 14.3.3 
Treatment Emergent Fatal Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety Population 
Table 14.3.4.1.1 
Summary of Vital Signs 
Safety Population 
Table 14.3.4.1.2 
Abnormal Vital Signs Shift Table 
Safety Population 
Table 14.3.4.1.3 
Number and Proportion with Clinically Significant Abnormal Vital 
Signs Results 
Safety Population 
Table 14.3.4.2.1 
Summary of Hematology Laboratory Results 
Safety Population 
Table 14.3.4.2.2 
Abnormal Hematology Shift Table 
Safety Population 
Table 14.3.4.2.3 
Number and Proportion with Clinically Significant Abnormal 
Hematology Results 
Safety Population 
Table 14.3.4.3.1 
Summary of Chemistry Laboratory Results 
Safety Population 
Table 14.3.4.3.2 
Abnormal Chemistry Shift Table 
Safety Population 
Table 14.3.4.3.3 
Number and Proportion with Clinically Significant Abnormal 
Chemistry Results 
Safety Population 
Table 14.3.4.4.1 
Summary of Coagulation Laboratory Results 
Safety Population 
Table 14.3.4.4.2 
Abnormal Coagulation Shift Table 
Safety Population 
Table 14.3.4.4.3 
Number and Proportion with Clinically Significant Abnormal 
Coagulation Results 
Safety Population 
Table 14.3.4.5.1 
Summary of Urinalysis Laboratory Results 
Safety Population 
Table 14.3.4.5.2 
Abnormal Urinalysis Shift Table 
Safety Population 
Table 14.3.4.5.3 
Number and Proportion with Clinically Significant Abnormal 
Urinalysis Results 
Safety Population 
Table 14.3.4.6.1 
Summary of 12-Lead Electrocardiogram Parameters 
Safety Population 
Table 14.3.4.6.2 
Clinical Interpretation and Categorical Results of 12-Lead 
Electrocardiogram  
Safety Population 


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Figure 14.1.1.2.1 
Subject Disposition 
Screened 
Population 
Figure 14.2.1.1.1 
Overall Survival by Treatment Arm 
ITT Population 
Figure 14.2.1.2.1 
Overall Survival by Treatment Arm 
Per Protocol 
Population 
Figure 14.2.2.1.1 
Progression Free Survival by Treatment Arm 
ITT Population 
Figure 14.2.2.2.1 
Progression Free Survival by Treatment Arm 
Per Protocol 
Population 
Figure 14.2.4.1.1 
Duration of Response by Treatment Arm 
ITT Population 
Figure 14.2.4.2.1 
Duration of Response by Treatment Arm 
Per Protocol 
Population 
 
Listing 16.1.7 
Randomization Scheme 
All Enrolled 
Listing 16.2.1.1 
Subject Eligibility  
All Enrolled 
Listing 16.2.1.2 
Subject Disposition 
All Enrolled 
Listing 16.2.1.3 
Identification of Analysis Sets 
All Enrolled 
Listing 16.2.2 
Protocol Deviations 
All Enrolled 
Listing 16.2.4.1 
Demographics 
All Enrolled 
Listing 16.2.4.2.1 Medical History 
All Enrolled 
Listing 16.2.4.2.2 Surgical History 
All Enrolled 
Listing 16.2.4.2.3 Disease History 
All Enrolled 
Listing 16.2.4.3 
Prior and Concomitant Medications 
All Enrolled 
Listing 16.2.5 
Dose Administration 
All Enrolled 
Listing 16.2.6.1 
Tumor Imaging 
All Enrolled 
Listing 16.2.6.2 
RECIST 1.1 Assessments 
All Enrolled 
Listing 16.2.6.3 
Carbohydrate Antigen 19-9 
All Enrolled 
Listing 16.2.6.4.1 EORTC QLQ-C30  
All Enrolled 
Listing 16.2.6.4.2 EORTC QLQ-PAN26 
All Enrolled 
Listing 16.2.6.5 
ECOG Performance Status 
All Enrolled 
Listing 16.2.6.6 
Derived Time-to-Event Efficacy Endpoints 
All Enrolled 
Listing 16.2.7.1 
Adverse Events 
All Enrolled 
Listing 16.2.7.2 
Serious Adverse Events 
All Enrolled 
Listing 16.2.8.1 
Hematology Laboratory 
All Enrolled 
Listing 16.2.8.2 
Chemistry Laboratory 
All Enrolled 
Listing 16.2.8.3 
Coagulation Laboratory 
All Enrolled 
Listing 16.2.8.4 
Urinalysis Laboratory 
All Enrolled 
Listing 16.2.8.5 
Pregnancy Test 
All Enrolled 
Listing 16.2.9 
Vital Signs 
All Enrolled 


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Listing 16.2.10 
12-Lead Electrocardiogram 
All Enrolled 
Listing 16.2.11 
Physical Examination 
All Enrolled 
Listing 16.2.X 
Pharmacokinetics (Not Applicable to This SAP) 
All Enrolled 
 
9.2 Rationale for changing PFS from secondary endpoint to primary endpoint 
 
Based on a systematic electronic search using MEDLINE, EMBASE, and the Cochrane Central 
Register of Controlled Trials, Fausto P. et al.(1) and Tsuyoshi Hamada et al.(2) have identified 30 
randomized controlled trials from 2002 to 2013 and 50 randomized controlled phase II and III trials 
from 1995 to 2015 in the first-line chemotherapy for patients with advanced pancreatic cancer(PC), 
respectively. Through a correlation approach to evaluate potential surrogate end-points, PFS, for OS, 
they found PFS was strongly correlated with OS (correlation coefficient were 0.75 and 0.76 
respectively). Weighted linear regression models revealed the greatest determinant coefficient of 0.78 
and 0.84 between the hazard ratio (HR) of the experimental arms compared with the control arms of 
PFS and that of OS. Both of the analytical results implied that PFS can serve as the most suitable 
surrogate end-point for OS, facilitating early study completion and cost reduction.  
Thomas et. al. (3) also mentioned that among all patients receiving first-line chemotherapy for MPC, 
49% went on to receive second-line therapy and 19% received third-line therapy; the trend is showing 
more and more pancreatic cancer patients were given sequential treatments than before. Furthermore, 
in NCCN guidelines on metastatic pancreatic cancer (4), a wide variety of first and second-line 
treatments are recommended. Although there is no recommendation for third-line treatments, first and 
second-line treatments could be selected according to patient’s performance status (PS). Both 
increasing acceptance of physicians to continue treatments and more PC combination treatments 
available have largely impacted the OS of MPC patients.   
As Fausto P. et al. pointed out that an ideal surrogate endpoint (e.g.PFS) would correlate with the true 
endpoint (OS), and should totally capture the actual treatment effect on the true endpoint. Based on 
the evidence mentioned above, we change PFS from secondary endpoint to primary endpoint. 
 
REFERENCES FOR RATIONALE  
(1) Fausto Petrelli, Andrea Coinu, Karen Borgonovo, Mary Cabiddu and Sandro Barni, “Progression-
free survival as surrogate endpoint in advanced pancreatic cancer: meta-analysis of 30 randomized 
first-line trials”, Hepatobiliary Pancreat Dis Int, 14(2):124-131, 2015. 
(2) Tsuyoshi Hamada, Yousuke Nakai, Hiroyuki Isayama, Hideo Yasunaga, Hiroki Matsui, 
Naminatsu Takahara, Suguru Mizuno, Hirofumi Kogure, Saburo Matsubara, Natsuyo Yamamoto, 
Minoru Tada, Kazuhiko Koike, “Progression-free survival as a surrogate for overall survival in first-
line chemotherapy for advanced pancreatic cancer”, Eur. J. Cancer, 65: 11-20, 2016.  
(3) Thomas A. Abrams, Gary Meyer, Jeffrey A. Meyerhardt, Brian M.Wolpin, Deborah Schrag, 
Charles S. Fuchs, OPatterns of Chemotherapy Use in a U.S.-Based Cohort of Patients with 
Metastatic Pancreatic Cancer”, The Oncologist, 22:925–933, 2017. 
(4) NCCN Guidelines for patients, Pancreatic Cancer, 2019.