Clinical trial NCT04083235
Conditions: Metastatic Adenocarcinoma of the Pancreas
Sponsor: Ipsen
Start date: 2020-02-11; Completion date: 2025-02-18
Enrollment: 770 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to look at the efficacy and safety of Irinotecan liposome injection in combination with other approved drugs used for cancer therapy, namely 5 fluorouracil/leucovorin (5FU/LV) plus oxaliplatin compared to nab-paclitaxel + gemcitabine treatment in improving the overall survival of patients not previously treated for metastatic pancreatic cancer.

Detailed description:

Arms: arm 1: Irinotecan liposome injection, oxaliplatin, 5 FU/LV, will be administered on Days 1 and 15 of each 28-day cycle (until progression or unacceptable toxicity). arm 2: Nab-paclitaxel and gemcitabine will be administered on Days 1, 8 and 15 of each 28-day cycle (until progression or unacceptable toxicity).
Interventions: intervention 1: Irinotecan Liposomal Injection intervention 2: Oxaliplatin intervention 3: 5Fluorouracil intervention 4: Leucovorin intervention 5: Nab-paclitaxel intervention 6: Gemcitabine
Intervention descriptions: intervention 1: Irinotecan liposome injection is irinotecan in the form of the sucrosofate salt, encapsulated in liposomes for i.v. infusion. It is supplied in sterile, single-use vials containing 10 mL of irinotecan liposome injection at a concentration of 4.3 mg/mL free base equivalent (FBE). intervention 2: Oxaliplatin injection, USP is supplied in single-dose vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. intervention 3: Fluorouracil injection, USP is a colorless to faint yellow, aqueous, sterile, nonpyrogenic injectable solution available in 50 mL and 100 mL pharmacy bulk package. Each mL contains 50 mg fluorouracil in water for injection, USP. intervention 4: Leucovorin Calcium for Injection is supplied in vials ranging from 50-500 mg and available as an injectable solution or lyophilized powder for reconstitution. intervention 5: Nab-paclitaxel is a lyophilised powder containing 100 or 250 mg of paclitaxel formulated as albumin-bound particles in single-use vials for re-constitution. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. intervention 6: Gemcitabine for injection is a lyophilised powder for solution for infusion, with each single use vial containing 200 mg, 1 g or 2 g of gemcitabine.

Protocol documents:
Prot_002.pdf: 
IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 1
 
PROTOCOL TITLE: An open-label, randomised, multicentre, phase III study of irinotecan 
liposome injection, oxaliplatin, 5-fluorouracil/leucovorin versus nab-paclitaxel plus 
gemcitabine in subjects who have not previously received chemotherapy for metastatic 
adenocarcinoma of the pancreas 
 
STUDY PROTOCOL 
STUDY NUMBER: D-US-60010-001 
Irinotecan liposome injection (IPN60010) 
EudraCT number: 2018-003585-14 
ClinicalTrials.gov number: NCT04083235. 
Version 5.0 (with Amendment 4): 19 August 2021  
 
Study Sponsor: 
Ipsen Bioscience, Ipsen Group  
650 E Kendall Street, Cambridge, MA 02142, USA 
Tel: 
 
 
Sponsor Signatory:  
 
 
Ipsen Bioscience Inc.,  
650 E Kendall Street,  
Cambridge, MA 02142, USA 
Tel: 
 
 
Emergency Contact: 
Global Patient Safety Head 
Ipsen Innovation 
Zone Industrielle de Courtaboeuf, 5 avenue du Canada, 91940 Les Ulis, France 
Mobile:  
 (for emergency contact) 
Tel:  
 (USA only) 
For serious adverse event (SAE) and pregnancy reporting if the eCRF is unavailable: 
E-mail: 
 
If email reporting is not possible: 
Fax: 
  
Fax: 
 (USA and Latin America) 
Persons supplied with this information must understand that it is strictly confidential. Information contained 
herein cannot be disclosed, submitted for publication or used for any purpose other than that contemplated 
herein without the sponsor’s prior written authorisation. 
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D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 2
 
INVESTIGATOR’S AGREEMENT 
Investigator Agreement and Signature: 
I have read and agree to Protocol D-US-60010-001 entitled ‘An open-label, randomised, 
multicentre, 
phase 
III 
study 
of 
irinotecan 
liposome 
injection, 
oxaliplatin, 
5-fluorouracil/leucovorin versus nab-paclitaxel plus gemcitabine in subjects who have not 
previously received chemotherapy for metastatic adenocarcinoma of the pancreas.’ I am aware 
of my responsibilities as an investigator under the guidelines of Good Clinical Practice (GCP), 
local regulations (as applicable) and the study protocol. I agree to conduct the study according 
to these guidelines and to appropriately direct and assist the staff under my control, who will 
be involved in the study. 
 
NAME: [ ] 
TITLE: 
[PRINCIPAL] 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
Sponsor’s Representative Signature: 
NAME: 
  
TITLE: 
        SIGNATURE: 
 
DATE: 
OFFICE: 
Ipsen Bioscience Inc.  
650 East Kendal Street  
Cambridge, Massachusetts 02142  
USA  
 
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D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 3
 
COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol D-US-60010-001 entitled ‘An open-label, randomised, 
multicentre, 
phase 
III 
study 
of 
irinotecan 
liposome 
injection, 
oxaliplatin, 
5-fluorouracil/leucovorin versus nab-paclitaxel plus gemcitabine in subjects who have not 
previously received chemotherapy for metastatic adenocarcinoma of the pancreas.’ I am aware 
of my responsibilities as a coordinating investigator under the guidelines of Good Clinical 
Practice (GCP), local regulations (as applicable) and the study protocol. I agree to conduct the 
study according to these guidelines and to appropriately direct and assist the staff under my 
control, who will be involved in the study. 
 
NAME: 
TITLE: 
COORDINATING 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
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D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 4
 
SUMMARY OF CHANGES 
The initial version of the protocol dated 03 October 2019 was amended four times. The current 
version of the protocol was released on 19 August 2021 and includes all amendments (see 
Table 1).  
All changes from the United Kingdom (25 February 2020) and Germany (27 March 2020) 
protocol addenda produced in response to the country-specific requests from the regulatory 
authorities received during the clinical trial submission process were included in the protocol 
version 3.0 (amendment 2).  
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
28 November 2019 
Appendix 9 
2 
20 May 2020 
Appendix 10 
3 
03 June 2020 
Appendix 11 
4 
19 August 2021 
Appendix 12 
 
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CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 5
 
SYNOPSIS 
Name of sponsor/company: Ipsen Bioscience 
Name of finished product: Irinotecan liposome injection  
Name of active ingredient(s): Irinotecan in the form of sucrosofate salt 
Title of study: An open-label, randomised, multicentre, phase III study of irinotecan 
liposome injection, oxaliplatin, 5-fluorouracil/leucovorin versus nab-paclitaxel plus 
gemcitabine in subjects who have not previously received chemotherapy for metastatic 
adenocarcinoma of the pancreas. 
Study number: D-US-60010-001 
Number of planned centres: approximately 200 to 245 sites worldwide  
Planned study period: 
The study will be completed once all subjects 
have died, withdrawn consent or are lost to 
follow-up. 
Phase of development: 
Phase III  
Study type: interventional, open-label, randomised, multicentre, efficacy and safety study  
Study Objectives: 
Primary Objective: 
The primary objective of this study is to evaluate the efficacy of the regimen of irinotecan 
liposome injection + oxaliplatin + 5-fluorouracil (5-FU)/leucovorin (LV) versus 
nab-paclitaxel + gemcitabine in improving overall survival (OS) in subjects who have not 
previously received chemotherapy for metastatic adenocarcinoma of the pancreas. 
Secondary Objectives: 
The secondary objectives of this study are as follows: 
• 
To evaluate progression free survival (PFS) according to Response Evaluation Criteria 
in Solid Tumours (RECIST) Version 1.1 guidelines 
• 
To evaluate the overall response rate (ORR) according to RECIST Version 1.1 
guidelines  
• 
To evaluate the safety of this regimen in this patient population. 
Exploratory Objectives: 
• 
To evaluate time to deterioration or worsening of subjects physical functioning, 
disease related symptoms and treatment related symptoms of interest using patient-
reported outcome (PRO) data collected using the European Organisation for Research 
and Treatment of Cancer quality-of-life-core questionnaire (EORTC QLQ-C30), 
specific pancreatic cancer module (QLQ-PAN26) questionnaire and PRO of Common 
Terminology Criteria of Adverse Events (PRO-CTCAE) as well as the 
EuroQol 5 dimension health status questionnaire (5 level) (EQ-5D-5L). 
• 
To evaluate the pharmacokinetics (PK), and the relationship between PK exposure and 
efficacy 
and 
safety, 
of 
the 
regimen 
of 
irinotecan 
liposome 
injection+oxaliplatin+5-FU/LV (Arm 1) in this patient population 
• 
To compare time to treatment failure (TTF) between treatment arms 
• 
To compare duration of response (DOR) between treatment arms 
• 
To compare time to response (TTR) between treatment arms 
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PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 6
 
• 
To describe the possible association between genotypes to include but not be limited 
to UGT1A1*28 and other UGT1A genotypes, SN-38 concentration (only for subjects 
treated with irinotecan liposome injection+oxaliplatin+5-FU/LV) and safety 
• 
To explore the pharmacodynamic biomarker CA 19-9 for the regimen of irinotecan 
liposome injection+oxaliplatin+5-FU/LV compared with nab-paclitaxel+gemcitabine 
in this patient population.  
• 
To conduct biobanking of samples for future analysis of biomarkers amongst subjects 
who consent to optional biobanking. 
• 
To collect gene mutation and genomic alteration status associated with pancreatic 
adenocarcinoma of subjects determined prior to screening (if available). 
Study hypothesis: Irinotecan liposome injection+oxaliplatin+5-FU/LV has superior efficacy 
over nab-paclitaxel+gemcitabine, demonstrated by a 3-month improvement in OS, in the 
treatment of subjects who have not previously received chemotherapy for metastatic 
adenocarcinoma of the pancreas. 
Methodology:  
This is an open-label, randomised, multicentre, phase III study. Subjects will be randomised 
in a 1:1 ratio to one of the following treatment regimens: 
• 
Arm 1: irinotecan liposome injection+oxaliplatin+5-FU/LV 
• 
Arm 2: nab-paclitaxel+gemcitabine 
There is no pre-defined duration of treatment for each subject. It is intended that subjects will 
be treated until radiologically determined progressive disease per RECIST Version 1.1, 
unacceptable study medication related toxicity or withdrawal from study. 
Number of subjects planned: 
Approximately 750 subjects are planned to be randomised (approximately 375 subjects per 
arm). 
Diagnosis and criteria for inclusion:  
Inclusion criteria: 
A subject will be eligible for inclusion in this study only if all the following criteria are met: 
General inclusion criteria 
(1) 
Subject has been informed about the nature of the study, and has agreed to participate 
in the study, and signed the informed consent form (ICF) prior to participation in any 
study-related activities. 
(2b) Male or non-pregnant and non-lactating female and ≥18 years of age: 
(a) 
Females of child-bearing potential (i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy) must test negative for pregnancy at the time of screening based 
on a urine or serum pregnancy test. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. Female subjects of 
reproductive potential must agree to use a highly effective method of birth 
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PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 7
 
control, during the study and for 7 months following the last dose of study 
medication (see also Appendix 4 and Section 4.3.3). 
(b) 
Male subjects must agree to use condoms during the study and for 6 months 
following the last dose of study medication. 
Disease specific inclusion criteria 
(3) 
Histological or cytologically confirmed adenocarcinoma of the pancreas that has not 
been previously treated in the metastatic setting. 
(4) 
Initial diagnosis of metastatic disease (as per American Joint Committee on Cancer 
8th Edition [AJCC 2017]) must have occurred ≤6 weeks prior to screening. 
(5a) Subject has one or more metastatic lesions measurable by computed tomography (CT) 
scan (or magnetic resonance imaging (MRI), if the subject is allergic to CT contrast 
media) according to RECIST Version 1.1 criteria. 
(6a) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at 
screening and within 7 days prior to randomisation.  
Haematological, biochemical and organ function inclusion criteria 
(7a) Subject has adequate biological parameters as demonstrated by the following blood 
counts: 
(a) 
Absolute neutrophil count (ANC) ≥2000/mm3 without the use of hemopoietic 
growth factors within the last 7 days prior to randomisation 
(b) 
Platelet count ≥100,000/mm3 
(c) 
Haemoglobin (Hgb) ≥9 g/dL obtained ≤14 days prior to randomisation.  
(8) 
Adequate hepatic function as evidenced by: 
(a) 
Serum total bilirubin ≤1.5x upper limit of normal (ULN) (biliary drainage is 
allowed for biliary obstruction), and 
(b) 
Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase 
(ALT) ≤2.5x ULN (≤5x ULN is acceptable if liver metastases are present). 
(9) 
Adequate renal function with a creatinine clearance (CLCR) of >30 mL/min. Actual 
body weight should be used for calculating CLCR using the Cockcroft-Gault Equation: 
CLCR (mL/min) = ((140–Age [years]) * (Weight [kg]/(Serum Creatinine [mg/dL]*72).  
Multiply the result by 0.85 if the subject is female. For subjects with a body mass index 
(BMI) >30 kg/m2, adjusted body weight should be used instead. 
(10a) Electrocardiogram (ECG) without any clinically significant findings (QT interval 
 
corrected by Fridericia’s formula (QTcF) ≤450 msec and no known arrhythmias) and 
 
per the investigator’s assessment. 
(11) Adequate coagulation studies (obtained ≤14 days prior to randomisation) as 
demonstrated by prothrombin time and partial thromboplastin time within normal
limits (≤1.5 x ULN). (Subjects on warfarin or other vitamin K antagonists should be 
discussed with the sponsor). 
(12) Subject has no clinically significant abnormalities in urinalysis results (obtained within 
the last 7 days prior to randomisation), per the investigator’s assessment. 
(13) Subjects infected with human immunodeficiency virus (HIV) are eligible if they meet 
all the following criteria: 
(a) 
CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibited 
cytochrome (CYP)-interacting medications 
(b) 
Probable long-term survival with HIV if cancer were not present 
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CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 8
 
(c) 
Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks 
and willing to adhere to their HAART regimen with minimal overlapping 
toxicity and drug-drug interactions with the experimental agents in this study 
(d) 
HIV is not multi-drug resistant 
(e) 
Taking medication and/or receiving antiretroviral therapy that does not interact 
or have overlapping toxicities with the study medication. 
Exclusion criteria: 
Subjects must meet all the inclusion criteria listed above and none of the following exclusion 
criteria: 
General exclusion criteria 
(1) 
Any other medical or social condition deemed by the investigator to be likely to 
interfere with a subject’s ability to sign informed consent, cooperate and participate in 
the study, or interfere with the interpretation of the results. 
(2a)  Unwilling or unable to comply with study procedures and/or study visits, including 
long-term follow-up for survival. 
Disease specific exclusion criteria 
(3) 
Prior treatment of pancreatic cancer in the metastatic setting with surgery, 
radiotherapy, chemotherapy or investigational therapy: 
(a) 
Palliative radiotherapy is permitted 
(b) 
Placement of biliary stent/tube is permitted. 
(4) 
Prior treatment of pancreatic adenocarcinoma with chemotherapy in the adjuvant 
setting, except those where at least 12 months have elapsed since completion of the 
last dose and no persistent treatment-related toxicities are present.  
(5) 
Subject has only localised advanced disease. 
(6a) Documented serum albumin <3 g/dL within 7 days prior to randomisation. 
(7) 
Known history of central nervous system (CNS) metastases. (Subjects on a stable or 
decreasing dose of steroids and deemed clinically stable as per the investigator’s 
assessment are eligible). 
(8) 
Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, 
inflammation, occlusion, diarrhoea >Grade 1, malabsorption syndrome, ulcerative 
colitis, inflammatory bowel disease or partial bowel obstruction.  
(9) 
History of any second malignancy in the last 2 years; subjects with prior history of 
in-situ cancer or basal or squamous cell skin cancer are eligible. Subjects with a history 
of other malignancies are eligible if they have been continuously disease free for at 
least 2 years prior to screening. Subjects who have a concurrent malignancy that is 
clinically stable and does not require tumour-directed treatment are eligible. 
Haematological, biochemical and organ function exclusion criteria 
(10) Known hypersensitivity to any of the components of irinotecan liposome injection, 
other liposomal products, or any components of 5-FU, LV or oxaliplatin. 
(11) Known hypersensitivity to any of the components of nab-paclitaxel or gemcitabine.  
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PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 9
 
(12) 
Concurrent illnesses that would be a relative contraindication to trial participation 
such as active cardiac or liver disease, including:  
(a) 
Severe arterial thromboembolic events (myocardial infarction, unstable angina 
pectoris, stroke) less than 6 months before screening 
(b) 
High cardiovascular risk, including, but not limited to, recent coronary stenting 
or myocardial infarction in the past year prior to screening 
(c) 
New York Heart Association (NYHA) Class III or IV congestive heart failure, 
ventricular arrhythmias or uncontrolled blood pressure  
(d) 
Known historical or active infection with hepatitis B, or active infection with 
hepatitis C (note that subjects with hepatitis C who have been clinically cured, 
defined as persistent absence of hepatitis C ribonucleic acid (RNA) detected by 
polymerase chain reaction (PCR) test in serum 12 weeks after completing 
antiviral treatment, are eligible for this study) 
(13) Active infection or an unexplained fever >38.5°C during screening visits or on the first 
scheduled day of dosing (at the discretion of the investigator, subjects with tumour 
fever may be enrolled), which in the investigator’s opinion might compromise the 
subject’s participation in the study or affect the study outcome. 
(14) Major surgery, other than diagnostic surgery, within 4 weeks prior to randomisation. 
(15) Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1 (please refer 
to Appendix 1). Subjects are ineligible if:  
- 
they are unable to discontinue the use of strong inhibitors of CYP3A, 
CYP2C8 and UGT1A1 at least 1 week prior to randomisation  
- 
they are unable to discontinue the use of strong CYP3A and CYP2C8 
inducers at least 2 weeks prior to randomisation. 
(16) There is presence of any contraindications outlined in the Contraindications or 
Warnings and Precautions sections of the investigator brochure (IB) for irinotecan 
liposome injection, or in the prescribing information for 5-FU, LV or oxaliplatin. 
(17) There is presence of any contraindications outlined in the Contraindications or Special 
Warnings and Precautions sections of the product prescribing information for 
nab-paclitaxel or gemcitabine.  
(18) Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma. 
(19) Subjects who, in the opinion of the investigator, have symptoms or signs suggestive of 
clinically unacceptable deterioration of the primary disease at the time of screening. 
(20a) History of systemic connective tissue disorders (e.g. lupus, scleroderma, arteritis 
nodosa). 
(21) History of interstitial lung disease, history of slowly progressive dyspnoea and 
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary 
hypersensitivity pneumonitis or multiple allergies. 
(22) History of peripheral artery disease (e.g. claudication, Leo Buerger's disease). 
(23) Subjects who have received a live vaccine within 4 weeks prior to randomisation. 
(24) Known low or absent dihydropyrimidine dehydrogenase (DPD) activity. Where 
required by local regulations, testing for DPD deficiency must be performed using a 
validated method which is recommended by local health authorities.  
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PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 10
 
Test product, dose and mode of administration: 
Irinotecan liposome injection (also known as Nal-IRI, BAX2398, PEP02, liposomal 
irinotecan and MM-398) is irinotecan in the form of the sucrosofate salt, encapsulated in 
liposomes for intravenous (i.v.) infusion. The liposome is a unilamellar lipid bilayer vesicle, 
approximately 110 nm in diameter, which encapsulates an aqueous space containing 
irinotecan in a gelated or precipitated state as the sucrosofate salt. It is supplied in sterile, 
single-use vials containing 10 mL of liposome irinotecan injection at a concentration of 
4.3 mg/mL free base equivalent (FBE). Irinotecan liposome injection must be stored 
refrigerated (2 to 8°C, 36 to 46°F) with protection from light and must not be frozen.  
Irinotecan liposome injection dose will be expressed as FBE. 
The test product irinotecan liposome injection is administered in combination with 
oxaliplatin and 5-FU/LV. 
Arm 1: Doses and administration of irinotecan liposome injection, oxaliplatin, 5-FU/LV, on 
Days 1 and 15 of each 28-day cycle will be: 
• 
Irinotecan liposome injection administered at 50 mg/m2 (FBE) i.v. over 90 minutes 
(±10 minutes) 
• 
Oxaliplatin administered at 60 mg/m2 i.v. over 120 minutes (±10 minutes) 
• 
LV (l+d racemic form-generic form) 400 mg/m2, i.v. over 30 minutes (±5 minutes) 
• 
5-FU administered 2400 mg/m2 i.v. over 46-hours (±120 minutes) 
Dose level reductions required due to toxicity related to irinotecan liposome injection, 
oxaliplatin, LV and 5-FU should be made following the guidelines outlined in Appendix 2. 
Reference therapy, dose and mode of administration: 
Arm 2: Doses and administration of nab-paclitaxel and gemcitabine and on Days 1, 8 and 15 
of each 28-day cycle will be: 
• 
Nab-paclitaxel administered at 125 mg/m2 i.v. over 35 minutes (±5 minutes)  
• 
Gemcitabine administered at 1000 mg/m2 i.v. over 30 minutes (±5 minutes) 
Dose level reductions required due to toxicity related to nab-paclitaxel and gemcitabine 
should be made following the guidelines outlined in Appendix 3. 
Duration of treatment: 
Both regimens are 28-day cycles unless cycle duration is modified by toxicity. 
The toxicity of each dose must be recorded prior to the administration of a subsequent dose 
and graded according to the National Cancer Institute (NCI) CTCAE (Version 5.0). All dose 
modifications for all arms should be based on the worst preceding toxicity. 
Dosing may be delayed to allow for recovery from toxicity related to the study treatment. If 
the time required for recovery from toxicity is more than 14 days in Arm 1 or 21 days in 
Arm 2, consideration should be given to discontinuing the subject from further treatment, 
unless the subject is demonstrating benefit overall, in which case the possibility of remaining 
on study medication should be discussed between investigator and sponsor, after review of 
the associated risks and benefits. However, if oxaliplatin is not well tolerated in subjects 
randomised to Arm 1, oxaliplatin may be discontinued and subjects may continue to receive 
irinotecan liposome injection+5-FU/LV at the discretion of the investigator and continue in 
the study.  
If a subject’s dose is reduced during the study due to toxicity, it should remain reduced for 
the duration of the study; dose re-escalation is not permitted (with exception, see 
Appendix 3). In Arm 1 any subject who has three dose reductions and experiences an adverse 
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D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 11
 
event (AE) that would require a fourth dose reduction must be discontinued from study 
treatment. In Arm 2, any subject who has two dose reductions and experiences an AE that 
would require a third dose reduction must be discontinued from study treatment. Toxicity 
requiring discontinuation of any of the drugs in either regimen (apart from oxaliplatin) will 
result in discontinuation from the study treatment. 
A subject who discontinues study medication and has not withdrawn from the study must 
continue with all ongoing protocol requirements until confirmed radiographic disease 
progression or until the start of alternative anti-cancer therapy. 
A follow-up clinic visit is required approximately 30 days after last dose of study treatment 
to complete the final safety assessments. Subsequently, subjects will be followed for survival 
once every 2 months via telephone, email, or clinic visit until death or study closure, 
whichever occurs first.  
Criteria for evaluation (endpoints): 
Primary and Key Secondary Efficacy Endpoints and main evaluations:  
Efficacy Assessments 
Subjects will have CT scans (or MRI if the subject is allergic to CT contrast media) performed 
every 8 weeks that will be evaluated by the investigator site using RECIST guidelines 
Version 1.1 for complete response, partial response, stable disease or progressive disease.  
Subjects will be followed in the study until death to assess OS time. Subjects who have 
terminated study medication treatment will have follow-up every 2 months to determine 
survival status. 
Efficacy: 
Primary Endpoint(s) and Evaluation(s): 
Primary Efficacy 
The primary efficacy endpoint is the OS of subjects treated with irinotecan liposome 
injection+oxaliplatin+5-FU/LV 
compared 
to 
subjects 
treated 
with 
nab-paclitaxel+gemcitabine. 
Secondary Endpoints(s) and Evaluation(s): 
Secondary Efficacy 
The secondary efficacy endpoints (PFS and ORR) will only be evaluated if the primary 
efficacy 
endpoint 
demonstrates 
superiority 
for 
irinotecan 
liposome 
injection+oxaliplatin+5-FU/LV over nab-paclitaxel+gemcitabine. Investigator-assessed 
tumour response will be used in efficacy analysis. 
Pharmacokinetics:  
Plasma concentrations of total irinotecan and SN-38 will be used to characterise their 
corresponding PK parameters, in co-administration with 5-FU and oxaliplatin, using a 
nonlinear mixed effects approach. Individual PK parameters will be estimated if warranted 
by the data. Oxaliplatin and/or 5-FU concentrations might be used for further PK 
characterisation if more investigations are required. 
Graphical exploration will be performed to investigate any relationship between PK and PD 
endpoints. If a trend is shown, PK/PD modelling will be performed and reported separately. 
Safety: 
Safety will be monitored through continuous reporting of AEs and serious adverse events 
(SAEs), laboratory abnormalities, and incidence of subjects experiencing dose modifications 
(including dose reductions, dose omissions and dose delays) and/or premature 
discontinuation of study medication (and reason for discontinuation).  
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IPSEN GROUP 
D-US-60010-001 
 
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PAGE 12
 
The safety evaluations include: 
• 
AEs 
• 
Clinical laboratory assessments 
• 
ECG findings 
• 
Complete physical examination including the evaluation of ECOG, vital signs, 
measurements and body weight. 
These safety evaluations will be performed from ICF signature, throughout the study to 
30 days after the last study treatment administration. 
An independent data and monitoring committee (IDMC) will be established for this study to 
operate as an independent expert advisory group with the primary responsibility of 
monitoring the safety of enrolled subjects by reviewing the clinical data at scheduled time 
points described in the IDMC Charter, as well as on an ad hoc basis, as needed. The IDMC 
will additionally review the safety and efficacy of the interim analysis and make appropriate 
recommendations based on those results. 
Statistical Methods: 
Method of Randomisation:  
• 
Randomisation ratio 1:1 
• 
Stratification factors: 
- 
ECOG Performance Status (0 or 1) 
- 
Region (North America/East Asia/Rest of the World) 
- 
Liver metastases (Yes/No) 
Sample Size and Power Considerations:  
The study sample size required to demonstrate an improvement in OS of irinotecan liposome 
injection+oxaliplatin+5-FU/LV compared with nab-paclitaxel+gemcitabine has been 
calculated using the following assumptions: 
• 
expected median OS on nab-paclitaxel+gemcitabine arm of 9 months 
• 
expected median OS on irinotecan liposome injection+oxaliplatin+5-FU/LV arm of 
12 months  
• 
for detection of a true HR of 0.75 
• 
one-sided test 
• 
overall type I error rate = 0.025 
• 
power = 90%  
• 
randomisation allocation ratio 1:1 (Arm 1: Arm 2). 
Approximately 750 subjects will be randomised in a 1:1 ratio to the two treatment arms. 
Accounting for the planned interim analysis, follow-up until at least 543 OS events are 
observed across the two treatment arms provide at least 90% power to detect a true HR ≤0.75 
(modified OS: 9 versus 12 months), using a stratified log-rank test with overall 1-sided 
significance level of 0.025 (adjusted for interim analysis). 
Assuming enrolment over 16 months increasing to approximately 62 subjects per month and 
lost-to-follow-up rate of 5% across both treatment arms, the timing of the interim analysis is 
expected to be at 24 months after the first subject treated and the timing of the final analysis 
is expected to be at 36.5 months after the first subject treated. 
If blinded projection of the accumulating OS events suggests that the number required for 
the final analysis will not be reached (due to censoring) within 32 months of study initiation, 
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IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 13
 
the sample size may be increased up to 800 subjects or until prespecified events are met, 
whichever comes earlier. The projection to inform the decision to potentially increase the 
number of subjects will be carried out within 3 months prior to expected completion of 
planned enrolment of 750 subjects. 
Primary Efficacy Analyses 
The final analysis will be performed using the intention to treat (ITT) population. The OS for 
each treatment arm will be summarised by median survival time (including 95% confidence 
intervals (CI)) from Kaplan-Meier estimation. The Kaplan-Meier curve for survival will be 
presented for each treatment arm. Stratified analyses based on the randomisation stratification 
factors from the IWRS data will be used for treatment comparisons. Differences in the OS 
curves will be tested using a stratified log-rank test. The estimated treatment effect for Arm 1 
will be summarised by the HR (including 95% CI) from stratified Cox regression analysis. 
There are two planned analyses of OS: interim analysis and final analysis. The interim 
analysis is planned when at least 272 OS events (i.e. 50% information time) have been 
observed in the ITT population. If that analysis does not indicate futility or efficacy, then the 
final analysis is planned at 543 OS events when 100% of the planned number of subjects 
have been enrolled. The overall type I error is controlled at 1-sided significance level of 0.025 
(adjusted for interim analysis). To control type I and type II errors, the planned interim 
analysis will utilise Hwang-Shi-Decani (HSD) alpha and (non-binding) beta spending 
function with γ parameter equal to -4 for type I error type and γ equal to -1 for type II error. 
If interim analysis does not indicate futility or efficacy, the final analysis is planned when 
543 OS events are observed.  
Secondary Efficacy Analyses 
Secondary efficacy endpoints will be tested no more than once. If the primary endpoint of 
OS is declared significant at the interim analysis, secondary efficacy endpoints will be tested 
at the interim; otherwise at the final analysis if OS is found to be statistically significant at 
that analysis. Hypothesis testing of secondary efficacy endpoints will be conducted in a 
stagewise hierarchical manner incorporating alpha spending for each endpoint using HSD 
γalpha= -4, similar to that specified for the primary efficacy analysis. The nominal level for the 
comparison will depend on whether the analysis is carried out at the OS interim or at the 
planned OS final analysis.  
The first endpoint in the hierarchy of secondary endpoints will be PFS. If OS and PFS are 
both significant, then ORR would be tested. Any parameter which is not formally tested for 
significance (per the hierarchy) will be regarded as descriptive and exploratory. 
Safety Analyses 
Safety analyses will be performed using the safety population. All safety data will be included 
in the subject data listings.  
Tabular summaries will present incidence by treatment arm for all treatment-emergent 
adverse events (TEAEs), SAEs, TEAEs leading to treatment discontinuation, TEAEs leading 
to death, TEAEs related to study medications. All the safety data will be described by grade 
(all grades and Grade 3 and higher). All events will be summarised by Medical Dictionary 
for Regulatory Activities (MedDRA) Version 22.0 or later by system organ class and 
preferred term. 
Laboratory data will be presented by treatment arm. Abnormal laboratory values will be 
assessed using all available tests results and toxicity grading will be assigned according to 
NCI CTCAE (Version 5.0) toxicity scale, where criteria are available to do so. Laboratory, 
vital signs, and ECG data will be summarised according to parameter type. 
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IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 14
 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...................................................................................... 2 
COORDINATING INVESTIGATOR’S AGREEMENT..................................................... 3 
SUMMARY OF CHANGES ................................................................................................... 4 
SYNOPSIS ................................................................................................................................ 5 
TABLE OF CONTENTS ....................................................................................................... 14 
LIST OF ABBREVIATIONS ................................................................................................ 20 
1 
BACKGROUND INFORMATION ............................................................................ 24 
1.1 
Introduction ................................................................................................................... 24 
1.1.1 
Pancreatic Cancer Treatment ..................................................................... 24 
1.1.1.1 
Description of 5-Fluorouracil and Leucovorin ........................................... 25 
1.1.1.2 
Description of Oxaliplatin ........................................................................... 25 
1.1.1.3 
Description of Gemcitabine ......................................................................... 25 
1.1.1.4 
Description of Nab-paclitaxel ...................................................................... 26 
1.2 
Irinotecan Liposome Injection ..................................................................................... 26 
1.2.1 
Irinotecan Liposome Injection Pre-Clinical Experience .......................... 26 
1.2.1.1 
Irinotecan Liposome Injection Pre-Clinical Pharmacokinetics .................. 27 
1.2.2 
Irinotecan Liposome Injection Clinical Experience.................................. 27 
1.2.2.1 
Ongoing MM-398-07-02-03 Phase II Study ................................................ 28 
1.2.2.2 
Irinotecan Liposome Injection Safety in Humans ........................................ 29 
1.2.2.3 
Irinotecan Liposome Injection Clinical Efficacy in Pancreatic Cancer ...... 30 
1.3 
Known and Potential Risks and Benefits to Human Subjects .................................. 30 
1.3.1 
Risks ............................................................................................................. 30 
1.3.1.1 
Lack of Efficacy ............................................................................................ 30 
1.3.1.2 
Safety Risks .................................................................................................. 31 
1.3.2 
Benefits ........................................................................................................ 33 
1.4 
Selection of Investigational Medicinal Products and Dosages .................................. 33 
1.5 
Population to be Studied .............................................................................................. 34 
1.6 
Compliance Statement .................................................................................................. 34 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 36 
2.1 
Purpose of the Study ..................................................................................................... 36 
2.1.1 
Study Rationale ........................................................................................... 36 
2.1.1.1 
Unmet Clinical Need .................................................................................... 36 
2.1.1.2 
Targeting a Validated Target: Topoisomerase I ......................................... 37 
2.1.1.3 
Clinical Data Generated in Metastatic Pancreatic Adenocarcinoma with 
Irinotecan Liposome Injection ..................................................................... 37 
2.1.1.4 
Irinotecan+5-FU/LV+Oxaliplatin (FOLFIRINOX) .................................... 37 
2.1.1.5 
Clinical Data for the CA19-9 Biomarker ..................................................... 39 
2.1.1.6 
Clinical Data in UGT1A1*28 Homozygous Patients .................................. 39 
2.2 
Study Objectives ........................................................................................................... 41 
2.3 
Study Hypothesis ........................................................................................................... 41 
3 
STUDY DESIGN ........................................................................................................... 42 
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IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 15
 
3.1 
General Design and Study Schema ............................................................................. 42 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 42 
3.2.1 
Primary Efficacy Endpoint and Evaluations ............................................. 42 
3.2.2 
Secondary Efficacy Endpoint and Evaluations ......................................... 42 
3.2.2.1 
Tumour Assessments .................................................................................... 42 
3.2.3 
Safety Endpoints and Evaluations ............................................................. 43 
3.2.3.1 
Safety Assessments ....................................................................................... 43 
3.3 
Exploratory Endpoints ................................................................................................. 43 
3.3.1 
Patient-Reported Outcomes ........................................................................ 43 
3.3.2 
Pharmacokinetics ........................................................................................ 44 
3.3.3 
Time to Treatment Failure ......................................................................... 44 
3.3.4 
Duration of Response .................................................................................. 44 
3.3.5 
Time to Response ........................................................................................ 44 
3.3.6 
Genotyping: UGT1A1 and SN-38 ............................................................... 44 
3.3.7 
Biomarkers CA 19-9 .................................................................................... 44 
3.3.8 
Biobanking .................................................................................................. 44 
3.3.9 
Gene Mutations and Genomic Alterations ................................................. 44 
3.4 
Randomisation and Blinding ....................................................................................... 45 
3.5 
Maintenance of Randomisation and Blinding ............................................................ 45 
3.6 
Study Treatments and Dosage ..................................................................................... 45 
3.7 
Study Duration .............................................................................................................. 46 
3.8 
Source Data Recorded on the Case Report Form ...................................................... 46 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 48 
4.1 
Inclusion Criteria .......................................................................................................... 48 
4.2 
Exclusion Criteria ......................................................................................................... 49 
4.3 
Stopping Rules, Discontinuation and Withdrawal Criteria and Procedures .......... 51 
4.3.1 
Discontinuation of Study Treatment .......................................................... 51 
4.3.2 
Withdrawal from the Study ......................................................................... 52 
4.3.3 
Procedures Following Study Medication Discontinuation or Study 
Withdrawal .................................................................................................. 52 
4.3.4 
Study Termination ....................................................................................... 53 
5 
STUDY PROCEDURES .............................................................................................. 54 
5.1 
Study Schedule .............................................................................................................. 54 
5.2 
Study Visits .................................................................................................................... 59 
5.2.1 
Procedures for Screening and Enrolment ................................................. 59 
5.2.2 
Procedures During Study Treatment Phase .............................................. 59 
5.2.3 
Procedures After Study Treatment (Follow-up Phase) ............................. 59 
5.2.3.1 
End of Treatment Visit ................................................................................. 59 
5.2.3.2 
Follow-up Visits ........................................................................................... 59 
5.3 
Laboratory Assessments ............................................................................................... 60 
5.4 
Imaging .......................................................................................................................... 60 
6 
TREATMENT OF SUBJECTS ................................................................................... 61 
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PAGE 16
 
6.1 
Study Medication Preparation, Storage, Security and Accountability .................... 61 
6.1.1 
Study Medication Storage and Security ..................................................... 61 
6.1.2 
Investigational Medicinal Product Preparation ........................................ 61 
6.1.3 
Investigational Medicinal Product Accountability .................................... 61 
6.2 
Study Medications Administered ................................................................................ 61 
6.2.1 
Irinotecan Liposome Injection+Oxaliplatin+5-FU/LV (Arm 1) ............... 61 
6.2.1.1 
Irinotecan Liposome Injection, Dose, Mode of Administration: ................. 62 
6.2.1.2 
Oxaliplatin, Leucovorin, 5-Fluorouracil ..................................................... 62 
6.2.2 
Nab-paclitaxel+Gemcitabine (Arm 2) ........................................................ 62 
6.2.2.1 
Nab-paclitaxel and Gemcitabine ................................................................. 62 
6.2.3 
Combination Therapy Study Cycles ........................................................... 63 
6.2.4 
Management of Infusion Reactions ........................................................... 63 
6.2.4.1 
Allergic Reaction ......................................................................................... 63 
6.2.4.2 
Anaphylaxis .................................................................................................. 64 
6.2.4.3 
Treatment Guidelines ................................................................................... 64 
6.2.5 
Dose Modifications ..................................................................................... 65 
6.2.5.1 
Dose Modifications and Omissions Arm 1: Irinotecan Liposome 
Injection+Oxaliplatin+5-FU/LV ................................................................. 65 
6.2.5.2 
Dose Modifications and Omissions Arm 2: Nab-paclitaxel+Gemcitabine . 66 
6.2.5.3 
UGT1A1*28 Monitoring .............................................................................. 67 
6.3 
Concomitant Medication/Treatment/Therapy ........................................................... 67 
6.3.1 
Pre-Medication ............................................................................................ 67 
6.3.1.1 
Arm 1: Irinotecan Liposome Injection+Oxaliplatin+5-FU/LV ................... 67 
6.3.1.2 
Arm 2: Nab-paclitaxel+Gemcitabine .......................................................... 68 
6.3.2 
Prohibited Therapy and Therapy to be Monitored Closely ....................... 68 
6.3.3 
Permitted Concomitant Medication/Therapy ............................................. 69 
6.3.3.1 
Granulocyte Colony-Stimulating Factors .................................................... 69 
6.3.3.2 
Therapy for Diarrhoea ................................................................................. 69 
6.4 
Lifestyle Restrictions/Recommendations .................................................................... 70 
6.5 
Procedures for Monitoring Subject Compliance ....................................................... 70 
7 
ASSESSMENT OF EFFICACY .................................................................................. 71 
7.1 
Primary Efficacy Endpoint and Evaluation ............................................................... 71 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 71 
7.2.1 
Time to Event Endpoints ............................................................................. 71 
7.3 
Exploratory Efficacy Endpoints and Evaluations ..................................................... 71 
7.4 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data.......... 72 
8 
ASSESSMENT OF SAFETY ....................................................................................... 73 
8.1 
Adverse Events .............................................................................................................. 73 
8.1.1 
Definition of an Adverse Event .................................................................. 73 
8.1.2 
Categorisation of Adverse Events ............................................................... 73 
8.1.2.1 
Intensity Classification ................................................................................. 73 
8.1.2.2 
Causality Classification ............................................................................... 74 
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IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 17
 
8.1.2.3 
Assessment of Expectedness ......................................................................... 74 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 74 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 74 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 74 
8.1.3 
Adverse Events of Special Interest ............................................................. 74 
8.1.4 
Recording and Follow-up of Adverse Events ............................................. 74 
8.1.5 
Reporting of Serious Adverse Events ......................................................... 75 
8.1.6 
Pregnancy .................................................................................................... 76 
8.1.7 
Deaths .......................................................................................................... 77 
8.1.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 77 
8.1.9 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 77 
8.2 
Clinical Laboratory Tests ............................................................................................ 77 
8.2.1 
Haematology ................................................................................................ 78 
8.2.2 
Blood Biochemistry ..................................................................................... 78 
8.2.3 
UGT1A1*28 Genotyping ............................................................................. 78 
8.2.4 
CA19-9 Biomarker ...................................................................................... 78 
8.2.5 
Pregnancy Test ............................................................................................ 78 
8.2.6 
Urinalysis ..................................................................................................... 78 
8.2.7 
Dihydropyrimidine Dehydrogenase Testing .............................................. 78 
8.3 
Physical Examination ................................................................................................... 79 
8.4 
Vital Signs ...................................................................................................................... 79 
8.5 
Electrocardiography ..................................................................................................... 79 
8.6 
Performance Status ....................................................................................................... 79 
9 
ASSESSMENTS OF PHARMACOKINETICS ......................................................... 80 
9.1 
Pharmacokinetics .......................................................................................................... 80 
9.1.1 
Sample Collection ....................................................................................... 80 
9.1.2 
Analytical Procedures ................................................................................. 81 
9.1.3 
Use of Samples After Study Completion .................................................... 81 
10 
EXPLORATORY BIOMARKERS AND BIOBANKING ....................................... 82 
11 
STATISTICS ................................................................................................................. 84 
11.1 Analysis Populations ..................................................................................................... 84 
11.1.1 
Populations Analysed .................................................................................. 84 
11.1.2 
Reasons for Exclusion from the Analyses ................................................. 84 
11.2 Sample Size Determination .......................................................................................... 84 
11.3 Significance Testing and Estimations ......................................................................... 85 
11.4 Statistical/Analytical Methods ..................................................................................... 86 
11.4.1 
Demographic and Other Baseline Characteristics .................................... 86 
11.4.2 
Subject Disposition and Withdrawals ......................................................... 86 
11.4.3 
Pharmacokinetic Data ................................................................................ 87 
11.4.3.1 
Listings and Summary Statistics of Concentrations ..................................... 87 
11.4.3.2 
Pharmacokinetic Data Analysis ................................................................... 87 
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11.4.3.3 
Pharmacokinetics/Pharmacodynamics Relationship ................................... 88 
11.4.4 
Efficacy Evaluation ..................................................................................... 88 
11.4.4.1 
Primary Efficacy Analysis ............................................................................ 88 
11.4.4.2 
Secondary Efficacy Analysis ........................................................................ 89 
11.4.4.3 
Patient-Reported Outcomes Analysis .......................................................... 89 
11.4.5 
Safety Evaluation ........................................................................................ 90 
11.5 Subgroup Analyses ....................................................................................................... 90 
11.6 Independent Data Monitoring Board and Interim Analysis .................................... 91 
12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 92 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 93 
13.1 Protocol Amendments and Protocol Deviations ........................................................ 93 
13.1.1 
Protocol Amendments ................................................................................. 93 
13.1.2 
Protocol Deviations and Exceptions........................................................... 93 
13.2 Information to Study Personnel .................................................................................. 94 
13.3 Study Monitoring .......................................................................................................... 94 
13.4 Investigator’s Regulatory Obligations ........................................................................ 94 
13.5 Audit and Inspection .................................................................................................... 95 
13.6 Data Quality Assurance ................................................................................................ 95 
14 
ETHICS ......................................................................................................................... 96 
14.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 96 
14.2 Informed Consent for Participation in the Study ...................................................... 96 
14.2.1 
Optional Informed Consent for Biobanking .............................................. 96 
14.3 Contractual and Financial Details ............................................................................... 97 
14.4 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 97 
14.5 Confidentiality Regarding Study Subjects ................................................................. 97 
15 
DATA HANDLING AND RECORD KEEPING ....................................................... 99 
15.1 Recording of Study Data .............................................................................................. 99 
15.2 Data Management ......................................................................................................... 99 
15.3 Record Archiving and Retention ............................................................................... 100 
15.4 Use of Data After Study Completion ......................................................................... 100 
16 
FINANCING AND INSURANCE ............................................................................. 101 
16.1 Insurance, Indemnity and Compensation ................................................................ 101 
17 
REPORTING AND PUBLICATION OF RESULTS .............................................. 102 
17.1 Publication Policy ....................................................................................................... 102 
17.2 Clinical Study Report ................................................................................................. 103 
18 
REFERENCES ............................................................................................................ 104 
19 
LIST OF APPENDICES ............................................................................................ 108 
 
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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Summary of Grade 3 or Higher Adverse Events in NAPOLI-1 Study .......... 29 
Table 3 
Summary of Subject Karnofsky Performance Score at Baseline (MPACT 
Study) .................................................................................................................... 34 
Table 4 
Summary of Comparisons between Clinical Studies ....................................... 39 
Table 5 
Study Procedures and Assessments ................................................................... 55 
Table 6 
Estimates of Blood Volume Drawn Throughout the Study ............................. 60 
Table 7 
Summary of Pharmacokinetic Sampling Timepoints ...................................... 80 
Table 8 
Type I (α) and Type II (β) Error Spending for the Planned Analyses ........... 85 
Table 9 
Arm 1 (Irinotecan liposome injection+oxaliplatin+5-FU/LV) Dose 
Modifications for Haematological Toxicities .................................................. 111 
Table 10 
Arm 1 (Irinotecan liposome 
injection+oxaliplatin+5-FU/LV) Dose 
Modifications for Diarrhoea ............................................................................. 112 
Table 11 
Dose Modifications for Non-Haematological Toxicities Other than 
Diarrhoea, Asthenia and Grade 3 Anorexia ................................................... 113 
Table 12 
Dose Level Reductions for Nab-paclitaxel and Gemcitabine ........................ 115 
Table 13 
Nab-paclitaxel and Gemcitabine Dose Modifications at the Start of Each 
Cycle or Within a Cycle for Neutropenia and/or Thrombocytopenia .......... 115 
Table 14 
Nab-paclitaxel and Gemcitabine Dose Modifications for Other Adverse 
Drug Events ........................................................................................................ 116 
Table 15 
Recommendations for Management of Chemotherapy Induced Diarrhoea 119 
 
LIST OF FIGURES 
Figure 1 
Tissue Distribution of Irinotecan Liposome Injection in an HT-29 
Xenograft Study. .................................................................................................. 27 
Figure 2 
Study Design ........................................................................................................ 42 
Figure 3 
CONSORT Flow Diagram .................................................................................. 87 
 
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LIST OF ABBREVIATIONS 
 
ABBREVIATION 
Wording Definition  
5-FU 
5-fluorouracil 
ACS 
American Cancer Society 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ARID1A 
AT-Rich Interaction Domain 1A gene 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUCTau 
Area under the concentration time curve over the dosing interval 
BMI 
Body mass index 
BOR 
Best overall response 
BRCA 1 
Breast Cancer 1 gene 
BRCA 2 
Breast Cancer 2 gene 
BSA 
Body surface area 
C#D# 
Cycle #, Day # 
CA 
Competent Authority 
CA19-9 
Carbohydrate antigen 19.9  
CDKN2  
Cyclin-Dependent Kinase inhibitor 2A 
CFR 
Code of Federal Regulations (United States of America) 
CI 
Confidence interval 
(CLCR) 
Creatinine clearance 
Cmax 
Maximum observed plasma drug concentration 
CMO 
Contract Manufacturing Organisation 
CNS 
Central nervous system 
CRO 
Contract research organisation 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome 
DHFR 
Dihydrofolate reductase 
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Competent Author
petent Author
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ABBREVIATION 
Wording Definition  
DL 
Dose level 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DPD 
Dihydropyrimidine dehydrogenase  
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of Cancer 
EoT 
End of treatment 
EPAR 
European Public Assessment Report 
EPCAM 
Epithelial Cell Adhesion Molecule 
ePRO 
Electronic patient-reported outcome 
EQ-5D-5L 
EuroQol 5 dimension health status questionnaire (5 level) 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FBE 
Free base equivalent 
FDA 
Food and Drug Administration 
FOLFIRINOX 
Irinotecan+oxaliplatin+5-FU/LV 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
GNAS 
Guanine nucleotide-binding protein, alpha-stimulating activity 
polypeptide 1 
HAART 
Highly active antiretroviral therapy 
HAS 
Haute Autorité de Santé (French National Authority for Health)
HCG 
Human chorionic gonadotrophin 
Hgb 
Haemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Hazard Ratio 
HSD 
Hwang-Shi-Decani 
i.v. 
Intravenous 
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ABBREVIATION 
Wording Definition  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IDMC 
Independent data monitoring committee 
IEC 
Independent ethics committee 
IMP 
Investigational Medicinal Product 
INCa 
Institut National du Cancer (French National Cancer Institute) 
IRB 
Institutional review board 
ITT 
Intention to treat 
IWRS 
Interactive Web Response System 
KRAS 
Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LC 
Liquid chromatography 
LV 
Leucovorin 
MDD 
Medical Development Director 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLH1 
Human MutL homolog 1 
MRI 
Magnetic resonance imaging 
MSH2 
Human MutS homolog 2 
MSH6 
MutS (E.coli) homolog 6 
NCCN 
National Comprehensive Cancer Network 
NCI-CTC 
National Cancer Institute – Common Toxicity Criteria 
NOS 
Not otherwise specified 
ORR 
Overall response rate 
OS 
Overall survival 
PALB2 
Partner and localizer of the BRCA2 gene 
PBRM1 
Polybromo 1 gene 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PP 
Per protocol 
PRO 
Patient Reported Outcome 
QLQ-C30 
Quality-of-life core 30 questionnaire 
QLQ-PAN26 
Quality-of-life questionnaire pancreatic cancer module 
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ABBREVIATION 
Wording Definition  
QoL 
Quality of life 
QTcF 
QT interval corrected by Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RNA 
Ribonucleic acid 
RNF43 
Ring Finger Protein 43 gene 
RREB1   
Ras Responsive Element Binding Protein 1 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System® 
SCLC 
Small cell lung cancer 
SD 
Standard deviation 
SMAD4 
Mothers against decapentaplegic homolog 4 
SmPC 
Summary of Product Characteristics 
SN-38 
Irinotecan active metabolite 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TGFbR2 
Transforming Growth Factor Beta Receptor 2 
tmax 
Time to maximum observed drug concentration 
TOP 1 
Topoisomerase I 
TP53 
Tumour Protein p53 
TTF 
Time to treatment failure 
TTR 
Time to Response 
UDP 
Human uridine diphosphate 
UGT 
UDP-glucuronosyltransferase 
UGT1A1 
Uridine diphosphate glucuronosyl transferase 1A1 
UGT1A1*28 
UGT1A1 pharmacogenetic variant *28 
ULN 
Upper limit of normal 
US(A) 
United States (of America) 
USPI 
United States package insert 
WBC 
White blood cell(s) 
WOCBP 
Women of child-bearing potential 
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1 
BACKGROUND INFORMATION  
1.1 
Introduction  
Pancreatic adenocarcinoma and its variants account for over 90% of pancreatic malignancies 
and is one of the most difficult to treat cancers [NCCN 2020, Lambert 2019]. Compared with 
most other cancers, pancreatic cancer is associated with a poor prognosis; it is one of the 
tumours with the least favourable outlook in terms of survival: mortality from pancreatic cancer 
is almost identical to its incidence with a mortality to incidence ratio of 0.94 [Bray 2018]. 
Pancreatic cancer is often diagnosed late in the natural history of the disease due to lack of 
screening tests, symptoms being largely nonspecific and not usually appearing until the disease 
has progressed [Evans 2014, Saftoiu 2020, Henrikson 2019]. Owing to the lack of early 
symptoms and the aggressive nature of the disease, up to 80% of patients with pancreatic 
adenocarcinoma receive a diagnosis at an advanced stage, by which time the tumour is 
unresectable [Martinez-Bosch 2018, Lambert 2019]. 
Despite recent advances in the management of pancreatic adenocarcinoma, poor survival rates 
continue, with a median overall survival (OS) of less than 1 year and a 5-year survival rate of 
0-11% depending upon the geographic location. However, for patients with metastatic disease 
who comprise the majority of patients with pancreatic adenocarcinoma at the time of diagnosis, 
the 5-year survival is only 3% [ACS 2020, Rawla 2019, Cancer statistics in Japan 2017, 
Lambert 2019]. 
The American Cancer Society (ACS) estimated about 56,770 new cases of pancreatic cancer 
and about 45,750 deaths from pancreatic cancer in the United States (US) in 2019. Although 
pancreatic cancer constitutes only 3% of all new cases of cancers in the US, it is the fourth 
leading cause of cancer deaths, estimated that in 2019 it was responsible for 7% and 8% of all 
cancer-related mortalities in men and women respectively [Siegel 2019]. Similar trends have 
been observed in the European Union (EU) - an estimated 90,700 deaths from pancreatic cancer 
have been predicted for 2019 making it the fourth leading cause of cancer deaths and being 
responsible for 6.7% of all cancer-related mortalities[Malvezzi 2019]. Projections of the 
number of deaths from cancer indicate that pancreatic cancer will become the second leading 
cause of cancer related mortality by the year 2030 [Rahib 2014]. 
1.1.1 
Pancreatic Cancer Treatment 
Gemcitabine monotherapy was the major first-line metastatic pancreatic cancer treatment 
proven to prolong OS over 5-fluorouracil (5-FU) [Burris 1997], leading to the Food and Drug 
Administration (FDA) and European Medicines Agency (EMA) approvals in 1996. Various 
gemcitabine-based combination therapies were then assessed with the aim of improving 
survival. 
Attempts to improve on gemcitabine single agent activity by combining it with other available 
chemotherapies have been largely unsuccessful [Borazanci 2014, Teague 2015, Ko 2015]. Two 
combination chemotherapy regimens have emerged as new standards of care for first-line 
treatment of metastatic pancreatic cancer: 
• 
5-FU/leucovorin (LV)+irinotecan+oxaliplatin (FOLFIRINOX) and 
• 
nab-paclitaxel+gemcitabine 
These demonstrate median OS of 11.1 months (PRODIGE study) and 8.5 months (MPACT), 
respectively, in separate phase III studies [Conroy 2011, von Hoff 2013].  
Given the poor prognosis and the low median survival rates of less than one year for patients 
with metastatic disease, new treatment options are still needed. In addition, research into novel 
and predictive biomarkers is important to manage this disease [Ko 2015].  
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Irinotecan liposome injection has been studied in a randomised, phase III, international study 
(NAPOLI-1), in which the regimen of irinotecan liposome injection and 5-FU/LV significantly 
prolonged OS compared to 5-FU/LV treatment alone in metastatic pancreatic cancer patients 
who had progressed following gemcitabine-based therapy [Wang Gillam 2016].  
Irinotecan liposome injection in combination with 5-FU/LV was approved by the FDA, the 
EMA and other regulatory agencies worldwide for the treatment of patients with metastatic 
adenocarcinoma of the pancreas after disease progression following gemcitabine-based 
therapy. 
Irinotecan liposome injection is also being studied in an ongoing phase II study to assess the 
safety, tolerability and efficacy in combination with oxaliplatin and 5-FU/LV in subjects with 
unresectable, locally advanced and metastatic adenocarcinoma of the pancreas who have not 
previously received chemotherapy in the metastatic setting (preliminary results in the 
Investigator’s Brochure (IB) and summarised in Section 1.3.2). 
The goal of the present study is to assess the efficacy and safety of irinotecan liposome injection, 
in combination with other anticancer therapies (i.e. 5-FU/LV and oxaliplatin) in subjects not 
previously treated for metastatic pancreatic cancer, compared to a nab-paclitaxel+gemcitabine 
control. Descriptions of the anticancer therapies to be used in combination regimens in this 
study are briefly described below.  
1.1.1.1 
Description of 5-Fluorouracil and Leucovorin 
5-Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid biosynthesis. The 
deoxyribonucleotide of the drug inhibits thymidylate synthase, thus inhibiting the formation of 
thymidylic acid from deoxyuridylic acid, thus interfering in the synthesis of deoxyribonucleic 
acid (DNA). It also interferes with ribonucleic acid (RNA) synthesis and is used in the treatment 
of carcinoma of the colon, rectum, breast, stomach and pancreas. 
Leucovorin acts as a biochemical cofactor for 1-carbon transfer reactions in the synthesis of 
purines and pyrimidines. Leucovorin does not require the enzyme dihydrofolate reductase 
(DHFR) for conversion to tetrahydrofolic acid. The effects of methotrexate and other 
DHFR-antagonists are inhibited by LV. Leucovorin can potentiate the cytotoxic effects of 
fluorinated pyrimidines (i.e., 5-FU and floxuridine). After 5-FU is activated within the cell, it 
is accompanied by a folate cofactor, and inhibits the enzyme thymidylate synthase, thus 
inhibiting pyrimidine synthesis. Leucovorin increases the folate pool, thereby increasing the 
binding of folate cofactor and active 5-FU with thymidylate synthase. 
1.1.1.2 
Description of Oxaliplatin 
Oxaliplatin is a platinum-based drug that acts as a DNA cross-linking agent to effectively inhibit 
DNA replication and transcription, resulting in cytotoxicity which is cell-cycle non-specific. 
Oxaliplatin is typically used in combination with infusional 5-FU/LV and is approved for use 
in advanced colorectal cancer (refer to reference information for oxaliplatin for more details). 
1.1.1.3 
Description of Gemcitabine 
Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumour activity and is 
approved for treatment of ovarian cancer in combination with carboplatin, breast cancer in 
combination with paclitaxel, non-small cell lung cancer in combination with cisplatin, and for 
pancreatic cancer as a single-agent or in combination with nab-paclitaxel (refer to reference 
information for gemcitabine for more details). 
Gemcitabine acts on cells undergoing DNA synthesis and blocks the progression of cells 
through the G1/S-phase boundary, which ultimately results in the initiation of apoptotic cell 
death. 
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1.1.1.4 
Description of Nab-paclitaxel 
Nab-paclitaxel (trade name Abraxane®) is an albumin-bound form of paclitaxel, a microtubule 
inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilises 
microtubules by preventing depolymerisation. Paclitaxel induces abnormal arrays or “bundles” 
of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. 
The inhibition of normal microtubule network interferes with essential interphase and cellular 
functions. It is approved for the treatment of metastatic breast cancer, non-small cell lung cancer 
in combination with carboplatin, and adenocarcinoma of the pancreas in combination with 
gemcitabine (refer to reference information for nab-paclitaxel for more details). 
1.2 
Irinotecan Liposome Injection 
Irinotecan liposome injection (also known as Nal-IRI, BAX2398, PEP02, liposomal irinotecan 
and MM-398) is encapsulated in a nanoliposome drug delivery system. This is referred to as 
liposomal irinotecan in Europe and has tradename Onivyde® in the USA and Onivyde pegylate 
liposomal® in Europe. The active ingredient of the irinotecan liposome injection is a member 
of the topoisomerase I inhibitor class of drugs and is a semi-synthetic and water-soluble 
analogue of the naturally-occurring alkaloid, camptothecin. Topoisomerase I inhibitors work to 
arrest uncontrolled cell growth by preventing the unwinding of DNA and therefore preventing 
replication. The pharmacology of irinotecan is complex, with extensive metabolic conversions 
involved in the activation, inactivation, and elimination of the drug [Garcia-Carbonero 2002, 
Vanhoefer 2001, Drummond 2006]. Irinotecan is a pro-drug that is converted by nonspecific 
carboxylesterases into a 100 to 1000-fold more active metabolite, SN-38 [Kang 2014]. SN-38 
is cleared via glucuronidation, (for which major pharmacogenetic differences have been 
shown), and biliary excretion. These drug properties contribute to the marked differences in 
efficacy and toxicity observed in clinical studies with irinotecan [Kalra 2014, Tsai 2011]. 
Drug carrier technologies represent a rational strategy to improve the pharmacokinetics (PK) 
and biodistribution of irinotecan while protecting it from premature metabolism. Irinotecan 
liposome injection employs a novel intraliposomal drug stabilisation technology for 
encapsulation of irinotecan into long-circulating liposome-based nanoparticles with high drug 
load and high in vivo stability. The stable nanoliposome formulation of irinotecan has several 
attributes that may provide an improved therapeutic index.  The controlled and sustained release 
should improve activity of this schedule-dependent drug by increasing duration of exposure of 
tumour tissue to drug, an attribute that allows it to be present in a higher proportion of cells 
during the more sensitive S-phase of the cell cycle. The improved PK, high intravascular drug 
retention in the liposomes and enhanced permeability and retention effect may potentially result 
in site-specific drug delivery to solid tumours. Stromal targeting results from the subsequent 
depot effect, where liposomes accumulating in tumour associated macrophages release their 
payload, which is then converted locally to the substantially more cytotoxic SN-38. The 
preferentially local bioactivation should result in reduced exposure to potential sites of toxicity 
and increased exposure to neighbouring cancer cells within the tumour. 
1.2.1 
Irinotecan Liposome Injection Pre-Clinical Experience  
Irinotecan liposome injection has been shown in pre-clinical settings to have a broad spectrum 
of activity in a wide range of solid tumours including colon, pancreatic, gastric, cervical, 
non-small cell lung, small cell lung, ovarian, thyroid, and breast cancers, as well as glioma, 
Ewing’s sarcoma, and neuroblastoma, often with a high degree of anti-tumour activity against 
resistant or difficult to treat cancer models [Drummond 2006, Kang 2014, Kalra 2014]. 
Irinotecan liposome injection has also shown potent antitumour activity, including durable 
tumour regressions, and was markedly superior to the equivalent dose of free drug in a 
bioluminescent-based orthotopic xenograft pancreatic model [Tsai 2011]. 
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1.2.1.1 
Irinotecan Liposome Injection Pre-Clinical Pharmacokinetics 
The PK properties of irinotecan liposome injection were evaluated in an HT-29 colon cancer 
subcutaneous xenograft model, as reported by [Kalra 2014]. Both irinotecan and SN-38 were 
cleared very rapidly (within 8 hours) from the plasma following non-liposomal irinotecan 
administration; however, irinotecan liposome injection clearance was demonstrated to be 
considerably slower and remained in circulation for over 50 hours. SN-38 plasma exposure was 
also greater though maximum observed plasma drug concentration (Cmax) levels were reduced 
following irinotecan liposome injection administration, suggesting the advantage of the 
irinotecan liposomal formulation in prolonging exposure and half-life via the ability of the lipid 
bilayer to protect the conversion of prodrug CPT-11 to SN-38. Further, both irinotecan and 
SN-38 accumulated in tissues for extended time (at least 1 week after administration of 
irinotecan liposome injection), yet there were relatively higher levels of prolonged 
accumulation in the tumour compared to normal tissue, where the metabolites are at very low 
levels after 48 hours (Figure 1).  
Activation of irinotecan to SN-38 by the liver is the primary path for SN-38 tumoural 
accumulation when non-liposomal irinotecan is administered. In contrast, these data suggest 
that accumulation of irinotecan liposome injection in the tumour and subsequent liposome 
breakdown and local conversion of irinotecan to SN-38 is responsible for the enhanced tumour 
exposure to SN-38 when irinotecan liposome injection is administered. These preclinical data 
demonstrating longer retention time in tumour lesions with irinotecan liposome injection 
administration compared to non-liposomal irinotecan administration formed the basis for 
clinical development. 
Figure 1 Tissue Distribution of Irinotecan Liposome Injection in an HT-29 Xenograft Study.   
 
Levels of SN-38 in various tissues following a single irinotecan liposome injection (20 mg/kg) dose are shown. 
Prolonged accumulation of SN-38 (~168 h) seen in tumour compared to other organs (~48 h). 
 
1.2.2 
Irinotecan Liposome Injection Clinical Experience 
Irinotecan liposome injection has been studied in subjects with solid tumours, including cervical 
cancer, gastric cancer, pancreatic cancer, and colorectal cancer. Disease areas currently being 
studied include glioma (intravenous (i.v.) and convection-enhanced local delivery), breast 
cancer and several paediatric solid tumours, including Ewing's sarcoma, rhabdomyosarcoma, 
neuroblastoma, osteosarcoma and small cell lung cancer (SCLC). Clinical studies of irinotecan 
liposome injection have been completed to date, with over 600 subjects across multiple tumour 
types exposed to various dosing regimens, with other studies actively recruiting subjects across 
multiple tumour types (see IB).  
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1.2.2.1 
Ongoing MM-398-07-02-03 Phase II Study 
Study MM-398-07-02-03 (
, EudraCT Number: 2015-003086-28) is an 
ongoing open-label, phase II study to assess the safety, dose-limiting toxicities (Part 1A only), 
tolerability and efficacy of irinotecan liposome injection in combination with oxaliplatin and 
5 FU/LV in subjects with unresectable, locally advanced and metastatic adenocarcinoma of the 
pancreas who have not previously received chemotherapy in the metastatic setting.  
Study MM-398-07-02-03 comprises a complete initial dose exploration (Part 1A) followed by 
dose expansion (Part 1B: ongoing) of the irinotecan liposome injection+oxaliplatin+5‑FU/LV 
regimen. 
Subjects were enrolled in cohorts following a 3+3 dose escalation design in Part 1A, (n=31), to 
select the dose level of the combination of oxaliplatin and irinotecan liposome injection. 
Following four dose exploration cohorts (Part 1A), a recommended dose (irinotecan liposome 
injection 50 mg/m2, oxaliplatin 60 mg/m2, LV 400 mg/m2, 5-FU 2400 mg/m2 every 2 weeks - 
Cohort B) for expansion (Part 1B) was selected based on dose-limiting toxicities and 
cumulative safety. The expansion phase enrolled an additional 25 subjects at the selected dose 
level. A total of 56 patients have been enrolled and treated in Parts 1A and 1B. 
An interim data analysis for safety and efficacy was performed with data cut-off 
19 February 2019 after all subjects in the dose-expansion cohort had completed the second 
scheduled tumour evaluation at 16 weeks.  
The pooled population (n=32) included all subjects treated at the recommended dose for 
expansion (irinotecan liposome injection 50 mg/m2, oxaliplatin 60 mg/m2, LV 400 mg/m2, 
5-FU 2400 mg/m2 every 2 weeks - Cohort B of Part 1A n=7; Part 1B n=25). The best overall 
response in the pooled analysis was complete response (CR) in one subject (diagnosed with 
locally advanced Stage III disease), partial response (PR) in 10 subjects, and stable disease (SD) 
in 15 patients (sum of CR+PR+SD: 81.3%), with an overall response rate (ORR) of 34%. 23 of 
32 patients (71.9%) achieved disease control at 16 weeks. At the time of data cut-off, 15 of 
32 subjects in the pooled population analysis remained on treatment.  
For the 56 subjects treated, all (100.0%) had TEAEs. There were nine TEAEs that were defined 
as dose limiting toxicities (DLTs) that were reported by five subjects across the four dose 
exploration cohorts (diarrhoea, n=2; vomiting, anal fissure, anal inflammation, proctalgia, 
neutropenic infection, neutropenic sepsis, and febrile neutropenia, all n=1), including one 
subject treated in Part 1A Cohort B who was included in the pooled analysis (febrile 
neutropenia). 
Treatment-related TEAEs Grade 3 or higher were reported by 39 of 56 subjects, including 
20 subjects from the pooled analysis of 32 subjects treated with irinotecan liposome injection 
50 mg/m2 + LV 400 mg/m2 + 5-FU 2400 mg/m2, and oxaliplatin 60 mg/m2. The TEAEs 
included: neutropenia, n=9; febrile neutropenia, hypokalaemia, both n=4; diarrhoea, nausea, 
both n=3; anaemia, vomiting, both n=2, with no reported Grade 3 or higher fatigue or peripheral 
neuropathy. 
SAEs were reported by 31 of the 56 treated subjects, including 14 of the 32 subjects in the 
pooled analysis, with 23 subjects reporting treatment-related SAEs. In the pooled analysis, 10 
of the 32 subjects had treatment-related SAEs: nausea, febrile neutropenia, both n=3; diarrhoea, 
vomiting, both n=2; colitis, enterocolitis, stomatitis, anaemia, pneumonia, and pyrexia, all n=1. 
At the data cut-off there were no treatment-related TEAEs leading to death. 
More data from this study are provided in the Investigator’s Brochure. 
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1.2.2.2 
Irinotecan Liposome Injection Safety in Humans 
Preliminary safety results for Study MM-398-07-02-03, where subjects with pancreatic cancer 
were given first line treatment with irinotecan liposome injection in a combination regimen 
with 5-FU/LV and oxaliplatin are presented in Section 1.2.2.1 and also in the IB. 
The NAPOLI-1 study was the pivotal study for obtaining marketing approval for the treatment 
of patients with metastatic adenocarcinoma of the pancreas after disease progression following 
gemcitabine-based therapy with irinotecan liposome injection in a combination regimen with 
5-FU/LV (i.e. no regimen in the NAPOLI-1 study included oxaliplatin). With respect to 
irinotecan liposome injection, when used in combination with 5-FU and LV, the most common 
adverse reactions (≥20 %) observed in clinical trials considered to be related to the regimen are: 
diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, anaemia, stomatitis and 
pyrexia. The overall safety profile of irinotecan liposome injection is presented in detail in the 
IB. Table 2 summarises ≥ Grade 3 safety data from the NAPOLI-1 trial comparing irinotecan 
liposome injection+5-FU/LV (at a dose of 70 mg/m2 (FBE) given on an every 2 week schedule), 
or irinotecan liposome injection monotherapy (at a dose of 100 mg/m2 (FBE) given on an every 
3 week schedule), with 5-FU/LV alone (given weekly for 4 weeks followed by 2 weeks of rest) 
in the same population of subjects who had received prior gemcitabine therapy.  
Table 2 
Summary of Grade 3 or Higher Adverse Events in NAPOLI-1 Study  
 
Irinotecan 
liposome 
injection + 
5-FU/LV[a] 
(N=117) 
Irinotecan 
liposome 
injection[b] 
(N=147) 
5-FU/LV[c] 
(N=134) 
Grade ≥3 non-haematologic AEs in >5% subjects, % 
Fatigue 
14 
6 
4 
Diarrhoea 
13 
21 
5 
Vomiting 
11 
14 
3 
Nausea 
8 
5 
3 
Asthenia 
8 
7 
7 
Abdominal pain 
7 
8 
6 
Decreased appetite 
4 
9 
2 
Hypokalemia 
3 
12 
2 
Hypernatremia 
3 
6 
2 
Grade ≥3 haematologic AEs based on laboratory values, % [d, e] 
Neutrophil count decreased    
20 
16 
2 
Haemoglobin decreased 
6 
7 
5 
Platelet count decreased 
2 
1 
0 
AE=adverse event, FBE=free base equivalent, 5-FU=5-fluorouracil, LV=leucovorin 
Data from phase III NAPOLI study of nal-IRI+5-FU/LV vs. 5-FU/LV [Wang-Gillam 2016] 
a Irinotecan liposome injection at 70 mg/m2 FBE, oxaliplatin followed by LV 400 mg/m² over 30 min, then 5-FU 2400 
mg/m² over 46 h, every 2 weeks. 
b Irinotecan liposome injection 100 mg/m² FBE every 3 weeks. 
c LV 200 mg/m² as a 30-min infusion followed by an infusion of 5-FU 2000 mg/m² over 24 h, every week for the first 4 
weeks of each 6-week cycle. 
d Per CTCAE Version 4 
e Includes only subjects who had at least one post-baseline assessment 
 
It has been shown in animal and human PK studies that once irinotecan is released from the 
irinotecan liposome injection liposomes, the conversion of irinotecan to SN-38 is similar to that 
of the unencapsulated irinotecan. The safety of irinotecan liposome injection, therefore, may be 
indirectly compared with the safety of non-liposomal irinotecan, primarily based on a 
qualitative comparison of adverse reactions, as reported in the Camptosar® United States 
package insert (USPI) for irinotecan [Camptosar® USPI 2016]. The comparison is qualitative, 
as both irinotecan and irinotecan liposome injection have been used in different doses and 
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schedules as monotherapy and combination therapy with other chemotherapeutic agents; 
therefore, quantitative comparisons are difficult. The most common adverse reactions of 
irinotecan and irinotecan liposome injection are similar and are mainly gastrointestinal events 
and myelosuppression.  
The common adverse reactions (>30%) observed in clinical studies with irinotecan in 
combination with other agents are: nausea, vomiting, abdominal pain, diarrhoea, constipation, 
anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anaemia, 
thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, and alopecia. The 
common adverse reactions (>30%) observed in single agent irinotecan therapy in clinical 
studies are: nausea, vomiting, abdominal pain, diarrhoea, constipation, anorexia, neutropenia, 
leukopenia (including lymphocytopenia), anaemia, asthenia, fever, body weight decreasing, 
and alopecia see Camptosar® USPI [Camptosar® USPI 2016]. 
1.2.2.3 
Irinotecan Liposome Injection Clinical Efficacy in Pancreatic Cancer 
Clinical 
efficacy 
of 
irinotecan 
liposome 
injection 
has 
been 
demonstrated 
in 
gemcitabine-refractory metastatic pancreatic cancer subjects: in a randomised, phase III, 
international study (NAPOLI-1), in which irinotecan liposome injection was given as a 
monotherapy, or in combination with 5-FU/LV, compared to the control arm of 5-FU/LV alone 
[Wang-Gillam 2016]. The majority of subjects enrolled in this study had received prior 
chemotherapy in the metastatic setting (others received gemcitabine as neoadjuvant or adjuvant 
therapy). Approximately one half of subjects were categorised as second-line, and 
approximately a third of subjects were post-second line in the metastatic setting. The irinotecan 
liposome injection+5-FU/LV combination significantly prolonged OS compared to 5-FU/LV 
treatment alone. The median OS for the irinotecan liposome injection+5-FU/LV regimen arm 
was 6.1 months compared to 4.2 months for the 5-FU/LV alone control arm with an unstratified 
hazard ratio (HR) of 0.67 (95% confidence interval (CI): 0.49 to 0.92, p=0.012). The irinotecan 
liposome injection monotherapy arm demonstrated a median OS of 4.9 months (compared to 
4.2 months in the control arm); although this was not a statistically significant difference, there 
was numerical improvement in overall response rate (ORR) and CA19-9 response, suggesting 
activity of irinotecan liposome injection alone. Further, in subjects who received ≥80% of the 
protocol defined treatment during the first 6 weeks of treatment (the per protocol (PP) analysis), 
the irinotecan liposome injection+5-FU/LV regimen arm achieved a median OS of 8.9 months 
versus 5.1 months for the control arm (HR 0.57, 95% CI: 0.36 to 0.88, p=0.0117). The ORR in 
the irinotecan liposome injection+5-FU/LV regimen arm was 16% versus 1% on the control 
arm (p<0.001) [Chen 2015]. The results from this study are very promising and provide 
motivation for testing irinotecan liposome injection in pancreatic cancer patients not previously 
treated with gemcitabine. 
A more detailed description of the product is provided in Section 6.1. 
1.3 
Known and Potential Risks and Benefits to Human Subjects 
1.3.1 
Risks 
1.3.1.1 
Lack of Efficacy  
While there is a potential risk of lack of efficacy of irinotecan liposome injection, as this 
irinotecan formulation has not been studied in a phase III study in subjects with untreated 
metastatic pancreatic adenocarcinoma, it is considered to be low. Activity of non-liposomal 
irinotecan in this setting has been observed in the FOLFIRINOX clinical study [Conroy 2011] 
and irinotecan liposome injection has demonstrated activity in this disease supported by the 
NAPOLI-1 trial [von Hoff 2014]. 
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1.3.1.2 
Safety Risks  
Irinotecan liposome injection in combination with 5-FU/LV has been approved in 39 countries 
since 2015 for the treatment of patients with metastatic adenocarcinoma of the pancreas after 
disease progression following gemcitabine-based therapy. The safety profile has been described 
in the IB and in labelling (e.g. the USPI). 
The results for 56 subjects treated in the ongoing phase II Study MM-398-07-02-03 with the 
regimen irinotecan liposome injection+oxaliplatin+ 5-FU/LV can be found in the IB and are 
summarised in Section 1.2.2.1. As seen from these results, the overall safety risks for the 
combination regimen irinotecan liposome injection+oxaliplatin+5-FU/LV are similar to those 
observed in the PRODIGE phase III study in pancreatic cancer [Von Hoff 2013], which include 
neutropenia, hypokalaemia, diarrhoea, nausea, anaemia and vomiting. No new safety signals 
were observed when compared to the Onivyde® USPI [Onivyde® USPI 2017]. 
Caution should be exercised when using irinotecan liposome injection in subjects with body 
mass index <18.5 kg/m2. 
Specific safety risks for 5-FU, LV and oxaliplatin, separately, in Arm 1 and nab-paclitaxel and 
gemcitabine in Arm 2, are described below. 
Potential Toxicities with 5-Fluorouracil (Arm 1 only) 
Stomatitis and esophago-pharyngitis (which may lead to sloughing and ulceration), diarrhoea, 
anorexia, nausea, emesis and myelosuppression are commonly seen with treatment; alopecia 
and dermatitis, in the form of pruritic rash usually appearing on the extremities, may also be 
seen (see the reference information for 5-FU). Very common adverse events (AEs) (≥20%) that 
were observed with irinotecan liposome injection in combination with 5-FU/LV in clinical trials 
considered to be related were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, 
fatigue, anaemia, stomatitis and pyrexia. 
Part of the toxicities following treatment with 5-FU may be related to deficiency in the activity 
of the main enzyme enabling elimination of 5-FU, dihydropyrimidine dehydrogenase (DPD). 
This deficiency can be low (around 3 to 8% of individuals) or absent (between 0.01 and 0.5% 
of individuals). 
In March 2020, the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) has 
recommended that patients should be tested for deficiency of DPD before starting cancer 
treatment with 5-FU. PRAC recommends that patients with a known complete DPD deficiency 
must not be given 5-FU intravenously as a complete lack of working DPD puts them at higher 
risk of severe and life-threatening side effects. In addition, for patients with a partial DPD 
deficiency, PRAC recommends a reduced starting dose of 5-FU; since the effectiveness of a 
reduced dose has not been established, following doses may be increased if there are no serious 
side effects [PRAC Guidelines 2020]. 
Given the heterogeneity in clinical practice and lack of consensus clinical guidelines for starting 
dose modifications, subjects with known low or absent DPD activity will be excluded from this 
study. 
Potential Toxicities with Oxaliplatin (Arm 1 only) 
The following AEs are relatively common (≥40%) with oxaliplatin treatment in combination 
with 5-FU/LV and are to be expected with the irinotecan liposome injection containing 
regimen: peripheral sensory neuropathy, neutropenia, thrombocytopenia, anaemia, nausea, 
increases in transaminases and alkaline phosphatase, diarrhoea, fatigue, emesis, and stomatitis. 
In a phase III study of the FOLFIRINOX regimen (5-FU/LV+irinotecan+oxaliplatin), the most 
common (>5%) Grade 3 or 4 AEs were: neutropenia, fatigue, vomiting, diarrhoea, 
thrombocytopenia, sensory neuropathy, anaemia, elevated alanine aminotransferase (ALT) 
level, thromboembolism, and febrile neutropenia [Conroy 2011]. Grade 3 or 4 hypersensitivity 
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reactions, including anaphylactic reactions, have been observed in 2 to 3% of colon cancer 
patients receiving oxaliplatin. See Section 6.2.4 for guidelines on the management of infusion 
reactions. Additional AEs such as nausea, fever and injection site reaction, may be anticipated, 
as described in the reference information for oxaliplatin. There needs to be caution if oxaliplatin 
is co-administered with other medicinal products known to cause QT interval prolongation or 
rhabdomyolysis. 
Potential Toxicities with Nab-paclitaxel and Gemcitabine (Arm 2 only) 
The most common adverse reactions (≥20%) for single agent gemcitabine are nausea/vomiting, 
anaemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, 
hematuria, rash, thrombocytopenia, dyspnea, and peripheral oedema. 
The following AEs are relatively common (≥20%) with nab-paclitaxel and gemcitabine 
combination treatment: neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, 
peripheral oedema, diarrhoea, pyrexia, vomiting, decreased appetite, rash, and dehydration. 
Severe hypersensitivity reactions with fatal outcome have been reported with nab-paclitaxel 
treatment; see Section 6.2.4 for guidelines on the management of infusion reactions. Additional 
AEs may be anticipated, as described in the reference information for nab-paclitaxel and 
gemcitabine. 
Other Toxicities Requiring Special Attention 
For both treatment arms, QTc prolongation that occurs in the setting of diarrhoea induced 
electrolyte imbalance should be treated with appropriate electrolyte repletion. Once the 
underlying abnormality is corrected and the electrocardiogram (ECG) abnormalities have 
reversed, treatment may continue under careful monitoring and with appropriate dose 
modification for diarrhoea as described in Section 6.3.3.2. 
Care of Intravenous Site: 
Care should be taken to avoid extravasation, and the infusion site should be monitored for signs 
of inflammation. Should extravasation occur, flushing the site with sterile saline and 
applications of ice are recommended, or as per institutional standard of care. 
NAPOLI-1 Study Risk Assessment 
Safety results from the NAPOLI-1 study, which was the pivotal study for obtaining marketing 
approval for second line treatment of pancreatic cancer with irinotecan liposome injection in a 
combination regimen with 5-FU/LV, are summarised in Section 1.2.2.2 and the IB. 
Irinotecan hydrochloride trihydrate is a known active substance, with a well-established safety 
profile. In the NAPOLI-1 study, most of the treatment-emergent adverse events (TEAEs) in 
combination with 5-FU/LV were manageable with supportive therapy, dose delays or both 
[Onivyde European Public Assessment Report (EPAR)]. The following adverse reactions, 
considered to be possibly or probably related to the administration of irinotecan liposome 
injection, were reported in 264 subjects with metastatic adenocarcinoma of the pancreas and 
listed in the EU Summary of Product Characteristics (SmPC), 147 of whom received irinotecan 
liposome injection in monotherapy (100 mg/m2 FBE) and 117 subjects received irinotecan 
liposome injection (70 mg/m2 FBE) in combination with 5-FU/LV. The most common adverse 
reactions (incidence ≥20%) with combination treatment were: diarrhoea, nausea, vomiting, 
decreased appetite, neutropenia, fatigue, asthenia, anaemia, stomatitis and pyrexia. The most 
common serious adverse reactions (≥2%) of irinotecan liposome injection therapy were 
diarrhoea, vomiting, febrile neutropenia, nausea, pyrexia, sepsis, dehydration, septic shock, 
pneumonia, acute renal failure, and thrombocytopenia. The EPAR states that ‘no unexpected 
safety findings emerged so far from the liposomal irinotecan development program to challenge 
what is previously known from standard irinotecan’. 
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The EU Risk Management Plan lists potential risks (embryotoxicity or teratogenicity, 
hypersensitivity reactions, medication errors related to drug/dose confusion with non-liposomal 
irinotecan and interstitial lung disease) as well as missing information (use in patients with 
hepatic impairment and patients with renal impairment) [Onivyde EPAR 2016]. Subjects with 
metastatic adenocarcinoma of the pancreas, who will receive irinotecan liposome injection in 
this study might be exposed to the same potential safety risks. These are listed in the irinotecan 
liposome injection IB and considered or mitigated in the different sections of the study protocol, 
e.g. exclusion criteria (Section 4.2), description of study medications including investigational 
medicinal products (IMPs) (Section 6.2) and use of concomitant therapies (Section 6.3). 
1.3.2 
Benefits 
Based on current clinical experience, it is considered that irinotecan liposome 
injection+oxaliplatin+5-FU/LV represents a novel therapeutic approach for first-line treatment 
of patients with metastatic pancreatic cancer, which is currently a high unmet clinical need. By 
adding oxaliplatin to irinotecan liposome injection and 5-FU/LV the potential to increase DNA 
damage and potentiate efficacy exists. In addition, due to the prolonged PK properties of 
irinotecan liposome injection and sustained tumour exposure, it is thought that using irinotecan 
liposome injection instead of conventional irinotecan would improve upon the efficacy and 
tolerability of the standard FOLFIRINOX regimen. Building on prior experience from the 
standard FOLFIRINOX regimen, the objective is to demonstrate a 3-month improvement in OS 
versus the approved regimen of gemcitabine+nab-paclitaxel.  
The IB gives efficacy (and safety) results from the ongoing phase II Study MM-398-07-02-03, 
during which subjects received first-line treatment for metastatic pancreatic cancer with 
irinotecan liposome injection+oxaliplatin+5-FU/LV. Overall 56 subjects were enrolled and 
treated, and as of data cut off 32 subjects had been treated (in both parts of the study) at the 
selected dose level (see Section 1.2.2.1).The best overall response (BOR) in the pooled analysis 
for 32 subjects treated with irinotecan liposome injection 50 mg/m2 + oxaliplatin 60 mg/m2+ 
5-FU/LV 2400/400 mg/m2 was: complete response in one subject (diagnosed with locally 
advanced Stage III disease), partial response in 10 subjects, and stable disease in 15 subjects 
(sum of complete response +partial response +stable disease: 81.3%), with an ORR of 34%. 
1.4 
Selection of Investigational Medicinal Products and Dosages 
The rationale for the proposed combination regimen is based on the clinical results of 
Study MM-398-07-02-03. This study included an initial dose exploration (Part 1A) followed 
by dose expansion (Part 1B) of the irinotecan liposome injection+oxaliplatin+5-FU/LV 
regimen as detailed in Section 1.2.2.1. This preliminary safety analysis provides reassurance 
that the safety profile of each of the drugs is in line with the expected safety profile of each of 
the drugs within the regimen and can be administered to subjects with pancreatic cancer. 
The proposed study design regimen for Arm 1 includes irinotecan liposome injection at a dose 
of 50 mg/m2 (FBE), the recommended starting dose for subjects homozygous for the 
UGT1A1*28 allele; hence, there is no reason to suggest a different starting dose for subjects 
homozygous for the UGT1A1*28 allele. As part of this study, pharmacogenomic data will be 
collected on all subjects for determination of UGT1A1*28 status at baseline. As per the 
scheduled assessments, all subjects will be monitored closely for haematological toxicities, with 
specific guidance for full blood count thresholds prior to dosing and dose modifications for 
haematological toxicities, which will also be monitored and evaluated by the Independent Data 
Monitoring Committee (IDMC) (see Section 11.6 for information about the IDMC).  
Nab-paclitaxel (tradename: Abraxane®) in combination with gemcitabine has been chosen as 
the control arm based on its approval in the US, in the EU and in other territories for first-line 
treatment of patients with metastatic adenocarcinoma of the pancreas, its robust OS benefit 
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demonstrated in the same patient population intended to be enrolled in the study (ECOG 
performance status 0 or 1, which is similar to Karnofsky Performance Status  ≥70, 
[Oken 1982]), on its inclusion in clinical practice guidelines and on its widespread clinical use 
in this disease setting. 
• 
An OS benefit was demonstrated in this patient population in the registration study for 
nab-paclitaxel (the MPACT study). The median OS was 8.5 months in the 
gemcitabine+nab-paclitaxel arm compared with 6.7 months in the gemcitabine arm 
(HR 0.72, 95% CI: 0.62 to 0.83, p<0.001). [von Hoff 2013] 
• 
The administration of nab-paclitaxel in combination with gemcitabine is recommended 
by the National Comprehensive Cancer Network (NCCN) [NCCN Guidelines Pancreatic 
Adenocarcinoma, Version 1.0 2020] and European Society for Medical Oncology 
(ESMO) Clinical Practice Guidelines [Ducreux 2015 with 2019 update] as a category 1 
(preferred) option for patients with metastatic adenocarcinoma of the pancreas 
• 
There is widespread clinical use of nab-paclitaxel in combination with gemcitabine in 
this disease setting. [Abrams 2017].  
Further details on administration procedures and dosage are provided in Section 6.2. 
1.5 
Population to be Studied 
The study will enrol adult subjects with metastatic adenocarcinoma of the pancreas who have 
not previously received chemotherapy. Because subjects will be randomised to either of the two 
arms, the inclusion and exclusion criteria (Sections 4.1 and 4.2) reflect contraindications and 
restrictions for both regimens. 
Similar to the population included in the MPACT study of first-line treatment of subjects with 
metastatic adenocarcinoma of the pancreas, subjects will be enrolled with ECOG performance 
status 0 or 1 (similar to Karnofsky performance status ≥70 [von Hoff 2013]). Table 3 
summarises the Karnofsky performance status of subjects at baseline in the MPACT study. 
Table 3 
Summary of Subject Karnofsky Performance Score at Baseline (MPACT Study) 
Karnofsky Performance 
Status 
Nab-
paclitaxel+gemcitabine 
(N=431) 
n/N (%) 
Gemcitabine alone 
 
(N=430) 
n/N (%) 
Total 
 
(N=861) 
n/N (%) 
100 
69/429 (16) 
69/429 (16) 
138/858 (16) 
90 
179/429 (42) 
199/429 (46) 
378/858 (44) 
80 
149/429 (35) 
128/429 (30) 
277/858 (32) 
70 
30/429 (7) 
33/429 (8) 
63/858 (7) 
60 
2/429 (<1) 
0/429 
2/858 (<1) 
Data Source: [von Hoff 2013] Table 1 
1.6 
Compliance Statement 
The study will adhere to all local regulatory requirements and relevant company policies. The 
sponsor will ensure that the countries where the data are transferred provide an adequate level 
of protection to the data. 
The study will be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) 
Guidelines. Any episode of noncompliance will be documented. 
In case of data transfer outside the EU, the sponsor will either ensure that the countries where 
the data are transferred provide an adequate level of data protection or that the company 
receiving the data has joined the EU-US Privacy Shield Framework or will put in place a 
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contract including standard contractual clauses adopted by the European Commission to ensure 
that the transfer of study information complies with applicable data protection legislation. Such 
a contract can be made available upon request. 
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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
This study is designed to evaluate the efficacy of the regimen of irinotecan liposome 
injection+oxaliplatin+5-FU/LV versus nab-paclitaxel+gemcitabine in improving OS in 
subjects with metastatic adenocarcinoma of the pancreas who have not previously received 
chemotherapy. 
Nab-paclitaxel+gemcitabine has been selected as the comparator arm treatment, as it is FDA 
and EMA approved and widely used regimen for first-line treatment of a well characterised and 
identifiable population of adult patients with metastatic adenocarcinoma of the pancreas. 
2.1.1 
Study Rationale 
Given the limited options for patients, the overall poor prognosis and the low median survival 
rates of less than one year for patients with metastatic disease, development of new treatments 
is still a necessity. In addition, research into novel and predictive biomarkers is important to 
manage this disease [Ko 2015, Garrido-Laguna 2015]. 
2.1.1.1 
Unmet Clinical Need 
Pancreatic cancer is associated with an extremely poor prognosis for several reasons. It is 
usually diagnosed at an advanced stage, which is often due to presentation with non-specific or 
no symptoms, a lack of sensitive and specific biomarkers, and difficulties in imaging early stage 
disease. Pancreatic cancer is also very aggressive, with perineural and vascular early growth 
and early distant metastases which preclude curative surgery in most cases. It is also 
characterised by a remarkable resistance to most conventional treatment options, including 
chemotherapy, radiotherapy and molecularly targeted therapy. Finally, pancreatic cancer 
harbours multiple genetic and epigenetic alterations and have dense tumour microenvironments 
shown to impede drug delivery. Despite some incremental progress in areas of research and 
patient care, the overall effect on the prognosis of patients with advanced pancreatic cancer has 
been marginal and these factors result in low observed OS rates. Thus, the development of 
improved systemic treatments remains a top priority for pancreatic cancer.  
During the last two decades since gemcitabine approval, two gemcitabine combination 
regimens emerged as FDA approved therapies for first-line treatment of metastatic pancreatic 
cancer: nab-paclitaxel+gemcitabine, and erlotinib+gemcitabine. Erlotinib+gemcitabine was not 
chosen for the control arm due to modest improvements in the OS and limited clinical use in 
the disease setting. The median OS in the gemcitabine+erlotinib arm was 6.4 months compared 
with 6.0 months in the gemcitabine+placebo arm (HR 0.81, 95% CI: 0.68 to 0.97, p=0.028). 
[Erlotinib 2010].  
Since the approval of gemcitabine in 1997, no phase III trial in advanced/metastatic disease had 
demonstrated a clinically and statistically significant improvement in OS over gemcitabine 
monotherapy until recently. The treatment landscape for metastatic disease has evolved to 
include two key regimens: irinotecan, oxaliplatin and 5-FU/LV (FOLFIRINOX) and 
nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine. [von Hoff 2013, 
Conroy 2011] The nab-paclitaxel plus gemcitabine regimen is the only FDA and EMA 
approved regimen for this patient population. Currently, the NCCN [NCCN Clinical Guidelines 
Pancreatic Adenocarcinoma, Version 1.0 2020] and ESMO [Ducreux 2015 with 2019 update] 
recommend treatment with FOLFIRINOX or nab-paclitaxel+gemcitabine as standards of care 
for patients with metastatic pancreatic cancer. Age, performance status and other clinical factors 
are considered when deciding which regimen is appropriate. Gemcitabine monotherapy is 
currently reserved for patients who are not eligible to receive combination chemotherapy. 
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2.1.1.2 
Targeting a Validated Target: Topoisomerase I  
Irinotecan is an antineoplastic agent of the topoisomerase I (TOP 1) inhibitor class. DNA 
topoisomerases are a class of enzymes involved in the regulation of DNA supercoiling. Type I 
topoisomerases change the degree of supercoiling of DNA by causing single-strand breaks and 
relegation. Inhibition of TOP I stabilises the complex between TOP I and DNA which collides 
with moving DNA replication forks, eventually leading to double stranded DNA damage and 
ultimately cell death. It is a well-established fact that increased cytotoxicity of TOP I inhibitors 
is associated with sustained exposure.  
TOP I is a validated drug target in metastatic adenocarcinoma of the pancreas. Irinotecan and 
irinotecan liposome injections are both referred to in guidelines for the treatment of metastatic 
adenocarcinoma of the pancreas as per the FOLFIRINOX regimen mentioned above for 
irinotecan and as part of a combination with 5-FU/LV for irinotecan liposome injection. 
Irinotecan and its active metabolite SN-38 bind to the TOP I - DNA complex and prevent 
relegation of the single-strand breaks. Liposomal delivery of irinotecan provides a mechanism 
for sustained inhibition of TOP I and prolong the duration of active therapy at the site of tumour 
cells to inhibit tumour growth. 
2.1.1.3 
Clinical Data Generated in Metastatic Pancreatic Adenocarcinoma with Irinotecan 
Liposome Injection 
Clinical 
efficacy 
of 
irinotecan 
liposome 
injection 
has 
been 
demonstrated 
in 
gemcitabine-refractory metastatic pancreatic cancer patients: in a randomised, phase III, 
international study (NAPOLI-1), irinotecan liposome injection was given as a monotherapy, or 
in combination with 5-FU/LV, compared to the control arm of 5-FU/LV alone 
[Wang-Gillam 2016]. The majority of subjects enrolled in this study had received prior 
chemotherapy in the metastatic setting (others received gemcitabine as neoadjuvant or adjuvant 
therapy). Approximately half of subjects were categorised as second-line, and approximately 
one third of subjects were post-second line in the metastatic setting. The irinotecan liposome 
injection+5-FU/LV regimen significantly prolonged OS compared to 5-FU/LV treatment alone. 
The median OS for the irinotecan liposome injection+5-FU/LV regimen arm was 6.1 months 
compared to 4.2 months for the 5-FU/LV alone control arm with an unstratified HR of 0.67 
(95% CI: 0.49 to 0.92, p=0.012). The irinotecan liposome injection monotherapy arm 
demonstrated a median OS of 4.9 months (compared to 4.2 months in the control arm); although 
this was not a statistically significant difference, there was numerical improvement in ORR and 
CA19-9 response, suggesting activity of irinotecan liposome injection alone. Further, in 
subjects who received ≥80% of the protocol defined treatment during the first 6 weeks of 
treatment (the per protocol analysis), the irinotecan liposome injection+5-FU/LV regimen arm 
achieved a median OS of 8.9 months versus 5.1 months for the control arm (HR 0.57, 95% CI: 
0.36 to 0.88, p=0.0117). The ORR in the irinotecan liposome injection+5-FU/LV regimen arm 
was 16% versus 1% on the control arm (p <0.001). The results from this study were very 
promising and provide motivation for testing irinotecan liposome injection in pancreatic cancer 
patients not previously treated with gemcitabine.  
2.1.1.4 
Irinotecan+5-FU/LV+Oxaliplatin (FOLFIRINOX)  
The regimen of 5-FU/LV+irinotecan+oxaliplatin (the FOLFIRINOX regimen) has been studied 
in multiple clinical trials. As mentioned previously, FOLFIRINOX has become a standard of 
care regimen for patients with good performance status based on the results of a single phase III 
trial conducted in France with 342 subjects showing median OS of 11.1 months 
versus 6.8 months for the gemcitabine alone control arm (HR 0.57, 95% CI: 0.45 to 0.73, 
p<0.001) [Conroy 2011]. The FOLFIRINOX regimen has been recommended by the NCCN 
and ESMO as a preferred option for first-line metastatic disease since 2011 [NCCN 2020, 
Ducreux 2015 with 2019 update]. 
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In the current study, a modified FOLFIRINOX regimen will evaluate irinotecan liposome 
injection instead of conventional irinotecan, in order to improve the safety, tolerability and 
ultimately efficacy of the original FOLFIRINOX regimen. With irinotecan liposome injection 
dosing, the Cmax of SN-38 is predicted to be lower than would be expected for standard dosing 
with non-liposomal irinotecan. Additionally, in a small phase II study in colorectal cancer, data 
suggest that irinotecan liposome injection+5-FU/LV may have less toxicity than non-liposomal 
irinotecan+5-FU/LV (the FOLFIRI regimen) [Chibaudel 2016]. Therefore, toxicity of the 
irinotecan liposome injection-containing triplet regimen is not expected to be greater than that 
seen with FOLFIRINOX. 
In humans, the standard dose regimen of FOLFIRINOX which demonstrated efficacy is 
85 mg/m2 oxaliplatin, 180 mg/m2 irinotecan (non-liposomal), LV infusion 400 mg/m2 followed 
by 5-FU at a dose of 400 mg/m2 administered by i.v. bolus followed by a continuous infusion 
of 2400 mg/m2 [Conroy 2011]. Yet due to toxicity, modified FOLFIRINOX regimens are often 
used (e.g. elimination of the 5-FU bolus) with unknown effects on the efficacy and safety of 
modified schedules [Ducreux 2015]. In the current study, a modified triplet regimen is 
proposed, whereby no bolus of 5-FU will be administered. The doses of oxaliplatin and 
irinotecan liposome injection determined from the phase II combination regimens will be 
combined with the standard continuous infusion dose of 5-FU (excluding the bolus)/LV.  
In the current study, the nab-paclitaxel+gemcitabine regimen will be compared to a regimen 
containing 
irinotecan 
liposome 
injection+oxaliplatin+5-FU/LV. 
While 
many 
gemcitabine-based combination regimens have been tested in clinical trials, nab-paclitaxel plus 
gemcitabine is the only approved standard of care regimen that offers significant benefit for 
first-line treatment of metastatic pancreatic cancer. The nab-paclitaxel+gemcitabine regimen is 
a preferred first-line treatment option according to the NCCN recommendations and ESMO 
Clinical Practice Guidelines [NCCN 2020, Ducreux 2015 with 2019 update]. In a phase III, 
international study of 861 subjects (MPACT trial), nab-paclitaxel+gemcitabine demonstrated a 
median OS of 8.5 months versus 6.7 months for gemcitabine alone (HR 0.72, 95% CI: 0.62 to 
0.83, p; <0.001) [von Hoff 2013]. While nab-paclitaxel+gemcitabine is generally thought to be 
more tolerable than FOLFIRINOX, this regimen is associated with neuropathy and neutropenia, 
and has not been compared directly with FOLFIRINOX (Table 4) including the modified triplet 
regimen which substitutes irinotecan liposome injection instead of irinotecan. 
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Table 4 
Summary of Comparisons between Clinical Studies 
Regimens 
Nal-IRI+5-FU-LV[a] 
FOLFIRINOX[b] 
Nab-
paclitaxel+gemcitabine[c] 
Setting 
Post-gemcitabine 
Front-line Metastatic Disease 
Efficacy 
 
 
 
Hazard Ratio 
0.67 
0.57 
0.72 
Median OS  
6.1 months 
11.1 months 
8.5 months 
Change versus Control 
1.9 months 
4.3 months 
1.8 months 
Adverse Events ≥ Grade 3  
 
 
 
Neutropenia 
20% 
45% 
38% 
Febrile neutropenia 
2% 
5% 
3% 
Fatigue 
14% 
24% 
17% 
Vomiting 
11% 
15% 
<5% 
Diarrhoea 
13% 
13% 
6% 
Neuropathy 
None 
9% 
17% 
5-FU=5-fluorouracil, LV=leucovorin, Nal-IRI=irinotecan liposome injection, OS=overall survival 
a Data from phase III NAPOLI study of nal-IRI+5-FU/LV vs. 5-FU/LV [Wang-Gillam 2016]  
b Data from phase III PRODIGE study of FOLFIRINOX vs. gemcitabine [Conroy 2011] 
c Data from phase III MPACT study of nab-paclitaxel+gemcitabine vs. gemcitabine [von Hoff 2013]  
2.1.1.5 
Clinical Data for the CA19-9 Biomarker 
Carbohydrate antigen 19.9 (CA19-9), is a prognostic tumour marker used to detect and monitor 
adenocarcinoma of the pancreas [Reni 2009, Chan 2014].  
During the MPACT study, A total of 379 subjects in the nab-paclitaxel+gemcitabine group and 
371 subjects in the gemcitabine group had a baseline CA19-9 measurement [von Hoff 2013]. 
A total of 61% of the subjects in the nab-paclitaxel+gemcitabine group, as compared with 44% 
of those in the gemcitabine group, had a decrease from baseline of at least 20% (p<0.001), and 
31% versus 14% had a decrease of at least 90% (p<0.001). Subjects in the two treatment groups 
who had a decrease of at least 90% in the CA19-9 level had a median survival of 13.5 months, 
as compared with 8.2 months among those with a decrease of less than 90% (HR for death, 
0.53; 95% CI, 0.43 to 0.67; p<0.001). A higher percentage of subjects in the 
nab-paclitaxel+gemcitabine group than in the gemcitabine group had a reduction of at least 90% 
in the CA19-9 level. 
During the NAPOLI-I study, serial imaging studies and assessment of CA19-9 were undertaken 
at baseline and every 6 weeks until either disease progression, a new antineoplastic treatment 
was started, or withdrawal of consent [Wang-Gillam 2016]. There were 28 (29%) of 97 subjects 
allocated nanoliposomal irinotecan plus 5-FU/LV who achieved a CA19-9 response (≥50% 
decrease from abnormal baseline) versus seven (9%) of 81 assigned 5-FU/LV (p=0.0006). 
2.1.1.6 
Clinical Data in UGT1A1*28 Homozygous Patients 
Human uridine diphosphate (UDP) glucuronosyltransferase (UGT) 1A1 is the enzyme that 
detoxifies neurotoxic bilirubin by conjugating it with glucuronic acid. Human UGT1A1 plays 
a critical role in the detoxification and excretion of endogenous and exogenous lipophilic 
compounds mainly in the liver and gastrointestinal tract. UGT1A1 is responsible for the 
glucuronidation of SN-38 to SN-38G as part of the mechanism of SN-38 clearance. Variation 
in TA-repeat length of a critical TATA box in the UGT1A1 promoter significantly contributes 
to enzyme activity with longer TA-repeat lengths showing lower expression than the wild-type. 
UGT1A1*28 (TA7) 7/7 homozygosity results in reduced UGT enzymatic activity and may 
result in elevated SN-38 levels and thereby contribute to increased SN-38 mediated toxicity 
following treatment with non-liposomal irinotecan.  
Multiple studies have evaluated the association between UGT1A1*28 7/7 homozygosity, 
SN-38 concentration and safety in patients treated with non-liposomal irinotecan and suggest 
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the associations are dose-dependent. Much higher SN-38 concentrations were observed for 
UGT1A1*28 6/7 and 7/7 (compared to 6/6) when irinotecan was administered at a high dose 
of 300 mg/m2 than when it was administered at a low dose of 15 to 75 mg/m2 daily for 5 days 
for 2 consecutive weeks (41 to 159% versus 10 to 40%, respectively) [Iyer 2002, Stewart 2007]. 
In a study of 66 subjects who received single-agent non-liposomal irinotecan (350 mg/m2 every 
3 weeks), the incidence of Grade 4 neutropenia in subjects heterozygous (UGT1A1*28 6/7) and 
homozygous (7/7) for the UGT1A1*28 was 12.5% and up to 50% respectively [Camptosar® 
USPI 2016]. In a subsequent study, association between UGT1A1*28 homozygosity and 
haematological toxicity was observed only in subjects treated with >150 mg/m2 non-liposomal 
irinotecan. By contrast, at lower dose of non-liposomal irinotecan (100 to 125 mg/m2 every 
week) similar haematological toxicities were observed for both homozygous and 
non-homozygous subjects [Hoskins 2007]. However, more recent publications from 
prospective trials studying the FOLFIRI regimen (irinotecan dose of 180 mg/m2) and the role 
of UGT1A1*28 polymorphism in toxicity and efficacy further suggest that the data are 
insufficient for recommending different dose adjustments in UGT1A1*28 homozygous patients 
[Toffoli 2006]. 
In patients treated with irinotecan liposome injection, the association between 
UGT1A1*28 homozygosity, SN-38, and haematologic toxicity is primarily obtained from 
study NAPOLI-1, where UGT1A1*28 homozygous subjects were treated at reduced dose 
(50 versus 70 mg/m2 (FBE) every 2 weeks in combination with 5-FU/LV, or 70 versus 
100 mg/m2 (FBE) every 3 weeks monotherapy). The NAPOLI-1 study Population PK results 
are described in the IB and together with safety data confirms that the predicted Grade 3 or 
higher neutropenia was also similar if treated at 70 mg/m2 (FBE) monotherapy (8.7% versus. 
7.4%, respectively), or if treated at 100 mg/m2 (FBE) monotherapy (15% versus 13%, 
respectively). An additional Population PK study presented in the IB showed that overall 
exposure to SN-38 was deemed similar between Japanese and non-Japanese populations with 
unrecognisable influence of UGT1A genotypes. Additionally, in a phase I study (UCSF 8103), 
no differences in toxicity were seen in cohorts of UGT1A1*28 6/7 (n=18) or 6/6 (n=16) 
subjects, and similar rates of dose limiting toxicities were seen in both cohorts. Based on these 
data, patients homozygous for UGT1A1*28, administered with the same dose of irinotecan 
liposome injection administration as non-homozygous patients, do not appear to be at 
significant clinical risk of increased Grade 3 or higher neutropenia. 
Mechanistically, these data indicate that the association of UGT1A1*28 polymorphism to 
SN-38 concentration and to haematological toxicity appear to depend on the incoming load of 
SN-38 to be metabolised by UGT enzymes. The dose-dependent association of UGT1A1*28 
and SN-38 or neutropenia observed with non-liposomal irinotecan administration is consistent 
with this hypothesis. Furthermore, liposomal encapsulation appears to spread out the incoming 
load of SN-38 by controlling the release of irinotecan. This is supported by a study in subjects 
with advanced gastric cancer in which 100 mg/m2 irinotecan liposome injection administration 
resulted in five times lower plasma SN-38 Cmax as compared to 300 mg/m2 non-liposomal 
irinotecan (PEP0206) [Roy 2013]. Reduced load of SN-38 may allow for metabolism by 
UGT enzymes even in patients with reduced UGT enzyme activities (for example, 
UGT1A1*28 homozygous patients). 
Despite the lack of associations between UGT1A1*28 homozygosity, safety, and PK, the 
irinotecan liposome injection USPI [Onivyde® USPI 2017] followed the NAPOLI-1 protocol 
that started homozygous patients at a lower dose due to the comparatively small number of 
patients with UGT1A1*28 homozygous treated with irinotecan liposome injection. Therefore, 
the absence of a relationship between UGT1A1*28 homozygosity and increased SN-38 
exposure or toxicity following irinotecan liposome injection administration warrants further 
study. In this study, the starting dose of irinotecan liposome injection will be the same 
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regardless of UGT1A1*28 genotype. UGT1A1*28 genotype will be collected on all subjects as 
a safety biomarker to further analyse the association between UGT1A1*28 homozygosity, 
SN-38 concentration and toxicity. Irinotecan liposome injection dose reduction will follow the 
same dose reduction rules for all subjects regardless of UGT1A1*28 genotype. Regular safety 
monitoring of subjects will be conducted by the sponsor medical monitor(s) and by the IDMC 
during the study. The safety and any available PK of UGT1A1*28 homozygous subjects will 
be compared to those who are non-homozygous for UGT1A1*28 to determine whether any 
different dosing strategy (such as a lower starting dose and/or different dose reduction for 
irinotecan liposome injection) is required for subjects who are homozygous. 
2.2 
Study Objectives 
The primary objective of the study is to evaluate the efficacy of the regimen of irinotecan 
liposome injection+oxaliplatin+5-FU/LV versus nab-paclitaxel+gemcitabine in improving OS 
in subjects who have not previously received chemotherapy for metastatic adenocarcinoma of 
the pancreas. 
The secondary objectives of the study are as follows: 
• 
To evaluate progression free survival (PFS) according to Response Evaluation Criteria 
in Solid Tumours (RECIST) Version 1.1 guidelines 
• 
To evaluate the overall response rate (ORR) according to RECIST Version 1.1 guidelines  
• 
To evaluate the safety of this regimen in this patient population. 
The exploratory objectives of the study are as follows: 
• 
To evaluate time to deterioration or worsening of subjects physical functioning, disease 
related symptoms and treatment related symptoms of interest using patient-reported 
outcome (PRO) data collected using the European Organisation for Research and 
Treatment of Cancer quality-of-life-core questionnaire (EORTC QLQ-C30) and, specific 
pancreatic cancer module (QLQ-PAN26) questionnaire and patient reported outcomes 
Common Terminology Criteria of Adverse Events (PRO-CTCAE) and the EuroQol 5 
dimension health status questionnaire (5 level) (EQ-5D-5L) 
• 
To evaluate the pharmacokinetics (PK), and the relationship between PK exposure and 
efficacy 
and 
safety, 
of 
the 
regimen 
of 
irinotecan 
liposome 
injection+oxaliplatin+5-FU/LV (Arm 1) in this patient population 
• 
To compare time to treatment failure (TTF) between treatment arms 
• 
To compare duration of response (DOR) between treatment arms 
• 
To compare time to response (TTR) between treatment arms 
• 
To describe the possible association between genotypes to include but not be limited to 
UGT1A1*28 and other UGT1A genotypes, SN-38 concentration (only for subjects 
treated with irinotecan liposome injection+oxaliplatin+5-FU/LV) and safety 
• 
To explore the pharmacodynamic biomarker CA 19-9 for the regimen of irinotecan 
liposome injection+oxaliplatin+5-FU/LV compared with nab-paclitaxel +gemcitabine in 
this patient population. 
• 
To conduct biobanking of samples for future analysis of biomarkers amongst subjects 
who consent to optional biobanking. 
• 
To collect gene mutation and genomic alteration status associated with pancreatic 
adenocarcinoma of subjects determined prior to screening (if available). 
2.3 
Study Hypothesis 
Irinotecan 
liposome 
injection+oxaliplatin+5-FU/LV 
has 
superior 
efficacy 
over 
nab-paclitaxel+gemcitabine, demonstrated by a 3-month improvement in OS, in the treatment 
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of subjects who have not previously received chemotherapy for metastatic adenocarcinoma of 
the pancreas. 
3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is an open-label, randomised, multicentre, phase III study to evaluate the efficacy and 
safety of the irinotecan liposome injection+oxaliplatin+5-FU/LV combination regimen versus 
nab-paclitaxel+gemcitabine in adult subjects with metastatic adenocarcinoma of the pancreas. 
After informed consent is obtained and subjects have been successfully screened, subjects will 
be randomised in a 1:1 ratio to one of the following treatment regimens: 
• 
Arm 1: irinotecan liposome injection+oxaliplatin+5-FU/LV 
• 
Arm 2: nab-paclitaxel+gemcitabine. 
Approximately 750 subjects are planned to be randomised (1:1 approximately 375 subjects per 
arm).  
Subjects will be stratified according to: 
• 
ECOG performance status (0/1) 
• 
Region (North America/East Asia/Rest of the World) 
• 
Liver metastases (Yes/No). 
Dose adjustment is permitted as described in Section 3.6. 
An IDMC will be established for this study to operate as an independent expert advisory group 
with the responsibility of evaluating cumulative safety and other clinical trial data at regular 
intervals (see Section 11.6). 
Figure 2 Study Design 
 
 
  
3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoint and Evaluations 
The primary efficacy endpoint is the OS of subjects treated with irinotecan liposome 
injection+oxaliplatin+5-FU/LV compared to subjects treated with nab-paclitaxel+gemcitabine.  
Survival will be defined, in the standard way for OS evaluation, as time from the date of 
randomisation to the date of death (any cause). Subjects who do not have a date of death 
recorded at the time of the final analysis will be censored at the last known time that the subject 
was alive. 
3.2.2 
Secondary Efficacy Endpoint and Evaluations 
3.2.2.1 Tumour Assessments 
Tumour assessments are obtained by imaging, as described in Section 5.4. 
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Tumour response will be evaluated according to the Response Evaluation Criteria in Solid 
Tumours (RECIST) Version 1.1 [Eisenhauer 2009], to establish disease progression by 
computed tomography (CT) or magnetic resonance imaging (MRI) if the subject is allergic to 
CT contrast media. In addition, other imaging procedures, as deemed appropriate by the 
investigator, will be performed to assess sites of neoplastic involvement. The same method of 
assessment for each lesion must be used throughout the study. Investigators should select target 
and non-target lesions in accordance with RECIST Version 1.1 guidelines. Follow-up 
measurements and overall response should also be in accordance with these guidelines. 
Tumour assessments should be completed until it has been determined that the subject has 
progressive disease (in accordance with RECIST Version 1.1). For subjects who do not have 
documented disease progression per RECIST Version 1.1 at the time of treatment termination, 
imaging studies should continue to be performed into the follow-up period every 8 weeks until 
radiological disease progression is documented or until the start of another anti-cancer 
treatment, whichever comes first. Continued imaging follow-up on schedule is recommended 
to reduce potential bias in the evaluation of the impact of the experimental treatments on disease 
[Fleming 2009]. 
The PFS is the time from randomisation to the first documented objective disease progression 
using RECIST Version 1.1 or death due to any cause, whichever occurs first. Determination of 
PFS will be per investigator assessment. 
The ORR is defined as the proportion of subjects with a BOR characterised as either a complete 
response or partial response. BOR is defined as the best response as recorded from 
randomisation until documented objective disease progression using RECIST Version 1.1. To 
classify BOR as stable disease, there should be a qualifying stable disease assessment at least 
8 weeks after randomisation. ORR of irinotecan liposome injection+oxaliplatin+5-FU/LV arm 
will be compared to the nab-paclitaxel+gemcitabine arm. Differences in ORR between Arm 1 
and Arm 2 will be provided with 95% CIs and compared using a Cochran-Mantel-Haenszel 
test, adjusting by randomisation strata. 
3.2.3 
Safety Endpoints and Evaluations 
3.2.3.1 
Safety Assessments  
Safety will be monitored through continuous reporting of AEs and serious adverse events 
(SAEs), laboratory abnormalities, incidence of subjects experiencing dose modifications 
(including infusion interruptions, dose omissions and dose delays) and/or premature 
discontinuation of study medication (and reason for discontinuation). 
These safety evaluations will be performed from ICF signature, throughout the study to 30 days 
after the last study treatment administration (see Table 5). 
3.3 
Exploratory Endpoints 
3.3.1 
Patient-Reported Outcomes  
The PRO exploratory endpoints are as follows: 
• 
Assess time to deterioration or worsening of subjects physical functioning, disease 
related symptoms and treatment related symptoms of interest using the European 
Organisation for Research and Treatment of Cancer quality-of-life-core questionnaire 
(EORTC-QLQ-C30) 
and 
specific 
pancreatic 
cancer 
module 
(QLQ-PAN26) 
questionnaire and PRO of Common Terminology Criteria of Adverse Events (CTCAE)  
• 
Assess time to deterioration or worsening on remaining quality of life (QoL) subscales 
of QLQ-C30 and QLQ-PAN26 
• 
Compare % of subjects with stable, improved or worsened QoL scores as assessed by 
QLQ-C30, QLQ-PAN26 and PRO-CTCAE 
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• 
Summarise HRQoL score at each visit as assessed by QLQ-C30, QLQ-PAN26, 
PRO-CTCAE and EQ-5D-5L. 
3.3.2 
Pharmacokinetics 
The pharmacokinetics (PK), and the relationship between PK exposure and efficacy and safety, 
of the regimen of irinotecan liposome injection+oxaliplatin+5-FU/LV (Arm 1) in this patient 
population will be evaluated. 
3.3.3 
Time to Treatment Failure 
The time to treatment failure (TTF) between treatment arms will be compared. The TTF is 
defined as the time from randomisation to treatment discontinuation for any reason, including 
disease progression, treatment toxicity, subject preference, or death. 
3.3.4 
Duration of Response 
Duration of response (DOR) is defined as the time of initial response (complete response or 
partial response) until documented tumour progression using RECIST guidelines Version 1.1 
or death. For subjects who do not have documented tumour progression or death, DOR will be 
censored at the time of the last evaluable tumour assessment.  
3.3.5 
Time to Response 
Time to response (TTR) will be computed only for subjects who achieved complete response 
or partial response. The TTR is the time from randomisation to the first objective tumour 
response.  
3.3.6 
Genotyping: UGT1A1 and SN-38 
The possible association between genotypes to include but not limited to UGT1A1*28 and other 
UGT1A genotypes, SN-38 concentration (only for subjects treated with irinotecan liposome 
injection+oxaliplatin+5-FU/LV) and safety will be described. 
3.3.7 
Biomarkers CA 19-9 
The biomarker CA 19-9 will be measured and concentrations compared between treatment 
arms.  
3.3.8 
Biobanking  
The exploratory endpoint comprises biobanking of samples for future analysis, among subjects 
who consent. Analysis of biobank samples will be performed outside the scope of the main 
study and reported separately. 
Instructions for collection, processing, handling and shipment of the biobanking samples will 
be outlined in the laboratory manual. 
3.3.9 
Gene Mutations and Genomic Alterations 
The exploratory endpoint comprises of collection of gene mutation and genomic alteration 
status associated with pancreatic adenocarcinoma of the subjects, determined prior to screening 
where available. Several genes are associated with an increased risk of developing PDAC. 
Those of key interest include: 
• 
Germline mutations and genomic alterations: BRCA1, BRCA2, PALB2, ATM, 
CDKN2A, MLH1, MSH2, MSH6, TP53 and EPCAM [Rainone 2020]. 
• 
Somatic mutations and genomic alterations: KRAS, TP53, CDKN2A, SMAD4, RNF43, 
ARID1A, TGFβR2, GNAS, RREB1 and PBRM1 [Raphael 2017]. 
Gene mutations and genomic alteration may be used for exploration of potential predictive 
biomarkers and correlation with clinical outcome; the results may be reported separately.  
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3.4 
Randomisation and Blinding 
This is an open-label study and there is no blinding. 
The sponsor’s randomisation manager or a designee, who is a statistician independent from the 
study, will prepare a list of randomisation numbers. It will be produced in blocks, on a balanced 
ratio [1:1] and will be stratified according to: 
• 
ECOG performance status (0/1) 
• 
Region (North America/East Asia/Rest of the World) 
• 
Liver metastases (Yes/No). 
The randomisation and treatment arm assignation will be managed by interactive web response 
system (IWRS). After eligibility is confirmed, at Day 1 of Cycle 1 (or within 4 days prior to 
Cycle 1 Day 1 where required by local procedures) subjects will be assigned a randomisation 
number and to the associated treatment arm, in sequential order at each centre and within each 
level of strata. 
The quantity of treatment kits will be also allocated by IWRS each time drug is dispensed, 
according to the allocated treatment group and subject body surface area (BSA). The IWRS 
will also manage all the logistical aspects of treatments (e.g. drug supplies, replacement of lost, 
damaged, quarantined, expiring and expired kits).  
This service provides investigators, site co-ordinators and project team members with a 24-hour 
per day, 7-day per week service. In case of medical or technical randomisation or dispensation 
queries, a 24-hour helpline is available. See supporting information in the IWRS reference 
manual. 
The investigator will under no circumstances change the randomisation number or the treatment 
group allocated to the subject. Recruitment will stop once approximately 750 subjects (or up to 
800 subjects in the circumstance that over enrolment is necessary to meet 543 OS events, due 
to heavy censoring) have been randomised (see Section 11.2). However, subjects in screening 
at that time will be allowed to proceed in the study if they are eligible for entry, and subject 
data will be used in the analysis. 
Randomised subjects who terminate their study participation for any reason before 
administration of the first dose of randomised study medication will retain their randomisation 
number (i.e. this number will not be reused). The next subject will be assigned another 
randomisation number, even if he/she should receive the same treatment. Subjects who leave 
the study early will not be replaced. 
The sponsor’s randomisation manager will keep the master randomisation list. A copy of this 
list will be also confidentially supplied to the IWRS vendor. The master list and the copy 
supplied to the IWRS vendor will be kept confidential in a secure location. Access to the 
randomisation list must be restricted until authorisation is given to release it for final analysis. 
3.5 
Maintenance of Randomisation and Blinding 
This is an open-label study and there is no blinding. 
3.6 
Study Treatments and Dosage 
Irinotecan liposome injection will be administered in combination with oxaliplatin and 
5-FU/LV, as follows: 
Arm 1: Doses and administration of irinotecan liposome injection, oxaliplatin, 5-FU/LV, on 
Days 1 and 15 of each 28-day cycle: 
• 
Irinotecan liposome injection will be administered at 50 mg/m2 (FBE) i.v. over 
90 minutes (±10 minutes) 
• 
Oxaliplatin will be administered at 60 mg/m2 i.v. over 120 minutes (±10 minutes) 
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• 
LV (l+d racemic form-generic form) 400 mg/m2, i.v. over 30 minutes (±5 minutes) 
• 
5-FU will be administered 2400 mg/m2 i.v. over 46-hours (±120 minutes). 
A more detailed description of administration procedures for Arm 1 is given in Section 6.2.1. 
The comparator treatment will be administered as follows. 
Arm 2: Doses and administration of nab-paclitaxel and gemcitabine (established doses as per 
USPI and EU SmPC nab-paclitaxel), on Days 1, 8 and 15 of each 28-day cycle: 
• 
Nab-paclitaxel will be administered at 125 mg/m2 i.v. over 35 minutes (±5 minutes) 
• 
Gemcitabine will be administered at 1000 mg/m2 i.v. over 30 minutes (±5 minutes). 
A more detailed description of administration procedures for Arm 2 is given in Section 6.2.2. 
For all drugs listed above a variation of 5% between the dose calculated by the IWRS and the 
total dose administered is permitted. 
The label text for all study medication provided by the sponsor will be translated and/or 
adjusted, to be in compliance with applicable regulatory requirements (e.g. Good 
Manufacturing Practice guidelines (Volume 4 Annex 13)), national laws in force and in 
accordance with the local languages.  
The investigator or designee will only dispense study medication to subjects included in this 
study. Each subject will only be given the regimen for the treatment group that the subject has 
been randomised to. The regimen administration for each subject will be documented in the 
electronic case report form (eCRF). 
Both regimens are 28-day cycles unless cycle duration is modified by toxicity. (see 
Section 6.2.5 for details on dose modifications). 
It is intended that subjects will be treated until radiologically determined progressive disease 
per RECIST Version 1.1 or unacceptable study medication related toxicity. However, a subject 
may discontinue study treatment at any other time (see Section 4.3.1).  
3.7 
Study Duration 
For each subject, this study will consist of a 28-day screening period followed by 28-day cycles 
of treatment until radiologically determined progressive disease per RECIST Version 1.1, 
unacceptable study medication related toxicity or withdrawal from study. An EoT clinic visit is 
required approximately 30 days after last dose of study treatment to complete the final safety 
assessments of the treatment phase (see Section 8.1.4 for follow-up of AEs). Subsequently, 
subjects will be followed for survival once every 2 months via telephone, email, or clinic visit 
until death or study closure, whichever occurs first (see Section 4.3.3). 
The subject’s participation in the treatment phase of the study will be considered to have ended: 
• 
at the time of the last visit 
• 
in the case that the subject does not attend the last visit, 30 days after last study 
medication intake  
• 
the death of the subject, if this occurs within 30 days after last study medication intake. 
The overall duration of the study will be approximately 2.5 years. The study will be considered 
to have started when the first subject has provided signed informed consent.  
The study will be completed once all subjects have discontinued the study treatment and at least 
543 OS events have occurred in the randomised subjects. 
3.8 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 CFR Part 11. As required by 
GCP guidelines, the sponsor assigned monitor will verify, by direct reference to the source 
documents, that the data required by the protocol are accurately reported on the eCRF.  
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The source documents must, as a minimum, contain a statement that the subject is included in 
a clinical study, the date that informed consent was obtained prior to participation in the study, 
the identity of the study, diagnosis and eligibility criteria, visit dates, study medication 
administration and any AEs and associated concomitant medication. 
As required by Section 6.4.9 of the International Conference on Harmonisation (ICH) Guideline 
E6(R2) [ICH E6(R2) 2016], if some items are recorded directly on the eCRF and are considered 
as source data, the identification of these data must be documented and agreed between the 
investigator and the sponsor. 
Definition for source data and source documents are given below: 
• 
Source data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and evaluation 
of the study. Source data are contained in source documents (original records or certified 
copies). 
• 
Source documents: Original documents, data and records (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays, subject files and records 
kept at the pharmacy, at the laboratories and at medicotechnical departments involved in 
the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel and by local and possibly foreign, competent authorities (CAs). This 
information is included in the subject’s information and ICF. 
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
A subject will be eligible for inclusion in this study only if all the following criteria are met: 
General Inclusion Criteria 
(1) 
Subject has been informed about the nature of the study, and has agreed to participate in 
the study, and signed the ICF prior to participation in any study-related activities. 
(2b) Male or non-pregnant and non-lactating female and ≥18 years of age: 
(a) 
Females of child-bearing potential (i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilisation 
methods 
include 
hysterectomy, 
bilateral 
salpingectomy 
and 
bilateral 
oophorectomy) must test negative for pregnancy at the time of screening based on 
a urine or serum pregnancy test. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. Female subjects of reproductive potential 
must agree to use a highly effective method of birth control, during the study and 
for 7 months following the last dose of study medication (see also Appendix 4 and 
Section 4.3.3). 
(b) 
Male subjects must agree to use condoms during the study and for 6 months 
following the last dose of study medication. 
Disease Specific Inclusion Criteria 
(3) 
Histological or cytologically confirmed adenocarcinoma of the pancreas that has not 
been previously treated in the metastatic setting. 
(4) 
Initial diagnosis of metastatic disease (as per American Joint Committee on Cancer 8th 
Edition [AJCC 2017]) must have occurred ≤6 weeks prior to screening. 
(5a) Subject has one or more metastatic lesions measurable by CT scan (or MRI, if the subject 
is allergic to CT contrast media) according to RECIST Version 1.1 criteria. 
(6a) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening 
and within 7 days prior to randomisation. 
Haematological, Biochemical and Organ Function Inclusion Criteria 
(7a) Subject has adequate biological parameters as demonstrated by the following blood 
counts: 
(a) 
Absolute neutrophil count (ANC) ≥2000/mm3 without the use of hemopoietic 
growth factors within the last 7 days prior to randomisation 
(b) 
Platelet count ≥100,000/mm3  
(c) 
Haemoglobin (Hgb) ≥9 g/dL obtained ≤14 days prior to randomisation.  
(8) 
Adequate hepatic function as evidenced by: 
(a) 
Serum total bilirubin ≤1.5x upper limit of normal (ULN) (biliary drainage is 
allowed for biliary obstruction), and  
(b) 
Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase 
(ALT) ≤2.5x ULN (≤5x ULN is acceptable if liver metastases are present). 
(9) 
Adequate renal function with a creatinine clearance (CLCR) of >30 mL/min. Actual body 
weight should be used for calculating CLCR using the Cockcroft-Gault Equation: CLCR 
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CCI


IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 49
 
(mL/min) = ((140–Age [years]) * (Weight [kg]/(Serum Creatinine [mg/dL]*72). 
Multiply the result by 0.85 if the subject is female. For subjects with a body mass index 
(BMI) >30 kg/m2, adjusted body weight should be used instead. 
(10a) Electrocardiogram (ECG) without any clinically significant findings (QT interval 
corrected by Fridericia’s formula (QTcF) ≤450 msec and no known arrhythmias) and per 
the investigator’s assessment. 
(11) Adequate coagulation studies (obtained ≤14 days prior to randomisation) as 
demonstrated by prothrombin time and partial thromboplastin time within normal limits 
(≤1.5 x ULN). (Subjects on warfarin or other vitamin K antagonists should be discussed 
with the sponsor). 
(12) Subject has no clinically significant abnormalities in urinalysis results (obtained within 
the last 7 days prior to randomisation), per the investigator’s assessment. 
(13) Subjects infected with human immunodeficiency virus (HIV) are eligible if they meet all 
the following criteria: 
(a) 
CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibited 
cytochrome (CYP)-interacting medications 
(b) 
Probable long-term survival with HIV if cancer were not present 
(c) 
Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks 
and willing to adhere to their HAART regimen with minimal overlapping toxicity 
and drug-drug interactions with the experimental agents in this study 
(d) 
HIV is not multi-drug resistant 
(e) 
Taking medication and/or receiving antiretroviral therapy that does not interact or 
have overlapping toxicities with the study medication (Section 6.3.2). 
4.2 
Exclusion Criteria 
Subjects must meet all the inclusion criteria listed above in Section 4.1 and none of the 
following exclusion criteria: 
General Exclusion Criteria 
(1) 
Any other medical or social condition deemed by the investigator to be likely to interfere 
with a subject’s ability to sign informed consent, cooperate and participate in the study, 
or interfere with the interpretation of the results.  
(2a)  Unwilling or unable to comply with study procedures and/or study visits, including long-
term follow-up for survival. 
Disease Specific Exclusion Criteria 
(3) 
Prior treatment of pancreatic cancer in the metastatic setting with surgery, radiotherapy, 
chemotherapy or investigational therapy: 
(a) 
Palliative radiotherapy is permitted 
(b) 
Placement of biliary stent/tube is permitted. 
(4) 
Prior treatment of pancreatic adenocarcinoma with chemotherapy in the adjuvant setting, 
except those where at least 12 months have elapsed since completion of the last dose and 
no persistent treatment-related toxicities are present. 
(5) 
Subject has only localised advanced disease. 
(6a) Documented serum albumin <3 g/dL within 7 days prior to randomisation 
(7) 
Known history of central nervous system (CNS) metastases. (Subjects on a stable or 
decreasing dose of steroids and deemed clinically stable as per the investigator’s 
assessment are eligible). 
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CCI


IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 50
 
(8) 
Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, 
inflammation, occlusion, diarrhoea > Grade 1, malabsorption syndrome, ulcerative 
colitis, inflammatory bowel disease, or partial bowel obstruction. 
(9) 
History of any second malignancy in the last 2 years; subjects with prior history of in-situ 
cancer or basal or squamous cell skin cancer are eligible. Subjects with a history of other 
malignancies are eligible if they have been continuously disease free for at least 2 years 
prior to screening. Subjects who have a concurrent malignancy that is clinically stable 
and does not require tumour-directed treatment are eligible. 
Haematological, Biochemical and Organ Function Exclusion Criteria 
(10) Known hypersensitivity to any of the components of irinotecan liposome injection, other 
liposomal products, or any components of 5-FU, LV or oxaliplatin. 
(11) Known hypersensitivity to any of the components of nab-paclitaxel or gemcitabine. 
(12) Concurrent illnesses that would be a relative contraindication to trial participation such 
as active cardiac or liver disease, including: 
(a) 
Severe arterial thromboembolic events (myocardial infarction, unstable angina 
pectoris, stroke) less than 6 months before screening 
(b) 
High cardiovascular risk, including, but not limited to, recent coronary stenting or 
myocardial infarction in the past year prior to screening 
(c) 
New York Heart Association (NYHA) Class III or IV congestive heart failure, 
ventricular arrhythmias or uncontrolled blood pressure  
(d) 
Known historical or active infection with hepatitis B, or active infection with 
hepatitis C (note that subjects with hepatitis C who have been clinically cured, 
defined as persistent absence of hepatitis C RNA detected by polymerase chain 
reaction (PCR) test in serum 12 weeks after completing antiviral treatment, are 
eligible for this study)  
(13) Active infection or an unexplained fever >38.5°C during screening visits or on the first 
scheduled day of dosing (at the discretion of the investigator, subjects with tumour fever 
may be enrolled), which in the investigator’s opinion might compromise the subject’s 
participation in the study or affect the study outcome. 
(14) Major surgery, other than diagnostic surgery, within 4 weeks prior to randomisation. 
(15) Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1 (please refer to 
Appendix 1 and Section 6.3.2). Subjects are ineligible if:  
- 
they are unable to discontinue the use of strong inhibitors of CYP3A, CYP2C8 
and UGT1A1 at least 1 week prior to randomisation  
- 
they are unable to discontinue the use of strong CYP3A and CYP2C8 inducers 
at least 2 weeks prior to randomisation. 
(16) There is presence of any contraindications outlined in the Contraindications or Warnings 
and Precautions sections of the IB for irinotecan liposome injection, or in the prescribing 
information for 5-FU, LV or oxaliplatin. 
(17) There is presence of any contraindications outlined in the Contraindications or Special 
Warnings and Precautions sections of the product prescribing information for 
nab-paclitaxel or gemcitabine. 
(18) Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma. 
(19) Subjects who, in the opinion of the investigator, have symptoms or signs suggestive of 
clinically unacceptable deterioration of the primary disease at the time of screening. 
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CCI


IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 51
 
(20a) History of systemic connective tissue disorders (e.g. lupus, scleroderma, arteritis 
nodosa). 
(21) History of interstitial lung disease, history of slowly progressive dyspnoea and 
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary 
hypersensitivity pneumonitis or multiple allergies. 
(22) History of peripheral artery disease (e.g. claudication, Leo Buerger's disease). 
(23) Subjects who have received a live vaccine within 4 weeks prior to randomisation. 
(24) Known low or absent dihydropyrimidine dehydrogenase (DPD) activity. Where required 
by local regulations, testing for DPD deficiency must be performed using a validated 
method which is recommended by local health authorities. 
4.3 
Stopping Rules, Discontinuation and Withdrawal Criteria and Procedures 
4.3.1 
Discontinuation of Study Treatment  
It is intended that subjects will be treated until radiologically determined progressive disease 
per RECIST Version 1.1 or unacceptable study medication related toxicity. However, a subject 
may discontinue study treatment at any other time. Reasons for discontinuation of study 
treatment include, but are not limited to the following: 
• 
Radiologically determined progressive disease, per RECIST Version 1.1 
• 
Clinical deterioration sufficient to prevent further radiological assessment 
• 
A study medication related AE, prior to disease progression, which: 
- 
in the opinion of the investigator, precludes further treatment with all study 
medication 
- 
requires treatment regimen to be withheld (see maximum durations described in 
Section 6.2.5), unless in the opinion of the investigator the subject is receiving 
benefit overall from the study treatment 
- 
would result in more dose reductions than allowed in the study protocol (details 
can be found in Appendix 2 and 3 
- 
requires discontinuation of irinotecan liposome injection, 5-FU or LV in Arm 1 or 
nab-paclitaxel or gemcitabine in Arm 2 
• 
Development of an intercurrent medical condition or need for concomitant therapy that 
precludes further treatment with all study medications 
• 
Withdrawal of consent for further treatment 
• 
Withdrawal of consent for further treatment and survival follow-up 
• 
Discretion of the treating physician 
• 
Pregnancy. 
Subject may be permitted to continue study treatment after RECIST v1.1 criteria for progressive 
disease are met if in the investigator’s opinion that subject is receiving clinical benefit from 
study treatment. Documented evidence of clinical benefit must include all of the following 
criteria: absence of symptoms and signs (including worsening of laboratory values) indicating 
unequivocal progression of disease, meaningful reduction from baseline of tumour biomarker 
CA19-9, and no decline in ECOG performance status. At the time of initial progression 
investigator must discuss with the subject deferring any standard treatment options and 
possibility of continuing study treatment. Decision made by the investigator and the subject 
should be documented in the clinic notes. Investigator must receive written sponsor or sponsor’s 
delegate approval before subject with radiologically confirmed progressive disease by RECIST 
v1.1. continues any study treatment.  
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IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 52
 
Dosing may be delayed from when it was scheduled (permitting a total of 28 days between the 
scheduled Day 1 and Day 15 doses for Arm 1 and up to 21 days for Arm 2, Section 6.2.5 – note 
that Arm 2 has scheduled Day 1, Day 8 and Day 15 dosing and the maximum delay between a 
missed scheduled dose and the next one, whichever dose was missed, should not be longer than 
21 days) to allow for recovery from toxicity related to the study treatment. If the time required 
for recovery from toxicity is more than described in Section 6.2.5, consideration should be 
given to discontinuing the subject from further treatment, unless the subject is demonstrating 
benefit overall, in which case the possibility of remaining on study medication should be 
discussed between investigator and sponsor, or delegate after review of the associated risks and 
benefits. However, if oxaliplatin is not well tolerated in subjects randomised to Arm 1, 
oxaliplatin may be discontinued and subjects may continue to receive irinotecan liposome 
injection+5-FU/LV at the discretion of the investigator and continue in the study (see Sections 
6.2.1 and 6.2.5.1). Toxicity requiring discontinuation of any of the drugs in either regimen 
(apart from oxaliplatin) will result in discontinuation from the study treatment. 
An EoT clinic visit is required approximately 30 days after last dose of study treatment to 
complete the final safety assessments. Subsequently, subjects will be followed for survival once 
every 2 months via telephone, email, or clinic visit until death or study closure, whichever 
occurs first. A subject who discontinues study medication but has not withdrawn from the study 
should also continue the disease evaluation assessment (CT/MRI) until confirmed radiographic 
disease progression as described in Section 5 or until the subject starts alternative anti-cancer 
therapy, whichever comes first. 
4.3.2 
Withdrawal from the Study 
Reasons for withdrawal from treatment, but continuation in follow-up in the study are described 
in Section 4.3.1. Withdrawal from the study (including withdrawal from both treatment and 
follow-up) include, but are not limited to the following: 
• 
Death of the subject 
• 
Subject is lost to follow-up (see Section 4.3.3) 
• 
Withdrawal of consent  
• 
Study termination by the sponsor 
• 
Significant noncompliance with the protocol, per investigator’s assessment. 
4.3.3 
Procedures Following Study Medication Discontinuation or Study Withdrawal 
The date the subject discontinues study treatment or withdraws from the study, the primary 
reason for study treatment discontinuation, study termination, and/or termination of 
participation (e.g. withdrawal of consent) will be captured within the eCRF. 
Following study medication discontinuation all procedures and evaluations required at the 
30-day EoT visit should be completed. All subjects who discontinue study medication as a 
result of an AE must be followed until resolution or stabilisation of the AE. Subjects who 
discontinue study medication prior to radiologically determined disease progression should 
continue to be assessed radiologically, according to the protocol-specified schedule, until 
radiologically determined progressive disease per RECIST Version 1.1, has been documented 
or until the subject starts alternative anti-cancer therapy, whichever comes first. 
Subjects are instructed to continue using highly effective methods of birth control (females) 
and condoms (males) for the duration of the study and for 7 months (females) and 6 months 
(males) months after receiving the last dose of any study treatment. 
The OS follow-up contacts should continue every 2 months from the 30-day EoT visit until 
death or study closure, whichever comes first. If a subject does not return to the clinic or respond 
to follow-up visit telephone calls, attempts should be made to contact the subject or their family 
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CCI


IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 53
 
via phone, email, or mail. At least three documented attempts, including one via certified mail, 
should be made to contact the subject before declaring a subject potentially lost to follow-up. 
If the subject is considered potentially lost to follow-up, the date of death may be captured from 
public records or all other means allowed per local regulations. No subject can be considered 
as lost to follow-up before final study closure. 
If a subject withdraws from the study treatment at any point, a complete final evaluation at the 
time of the subject’s withdrawal should be made with an explanation of the reason for 
withdrawal. At the time of discontinuation from the study treatment, it should be clarified with 
the subject that they will continue to be assessed radiologically, according to the 
protocol-specified schedule, until radiologically determined progressive disease per RECIST 
Version 1.1, has been documented or until the subject starts alternative anti-cancer therapy, 
whichever comes first.  
Afterwards, the subject will be followed up for survival status (including where appropriate 
through publicly available records).  
Subjects participating to the optional research biobanking program have the right to withdraw 
their consent at any time and for any reason during the study or during the period of sample 
storage (i.e. the entire 15 years during which the sample is kept). If a subject wishes to withdraw 
consent for biobanking, and the samples are still at the investigator site or at the central 
laboratory at this time, the investigator must inform the study monitor in writing of the subject’s 
decision and destroy the samples. If the samples are in the sponsor’s central biorepository, the 
investigator must inform Ipsen directly of the withdrawal using the e-mail address, 
, mentioning only the patient ID in this e-mail. Ipsen will ensure 
the destruction of the samples and all corresponding aliquots and issue confirmation of the 
destruction, which will be forwarded to the investigator. Analyses conducted before withdrawal 
will not be affected. 
4.3.4 
Study Termination 
The sponsor reserves the right to terminate the study at any site and at any time. Reasons for 
study termination may include, but are not limited to, the following: 
• 
Investigator non-compliance with the protocol, GCP or regulatory requirements 
• 
Insufficient enrolment 
• 
Safety concerns 
• 
Drug supply or manufacturing issues 
• 
The sponsor’s decision to modify or discontinue the development of irinotecan liposome 
injection 
• 
A request to discontinue the study by the relevant regulatory authorities. 
The sponsor will promptly inform all investigators and the relevant regulatory authorities if the 
study is suspended or terminated for any reason. The investigator will promptly notify their 
IRB/EC if the study is suspended or terminated. 
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CCI


IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 54
 
5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 5. 
If the COVID-19 pandemic prevents subjects from coming to the site, subjects can have their 
study visit assessments performed remotely as judged appropriate by the investigator. This must 
be discussed with the sponsor (or delegate) before being implemented. In such a case, the 
investigator will perform a telemedicine visit and will make every effort to confirm all 
important medical information and safety event(s) occurring since the last visit are collected. 
Guidance on how to collect protocol-planned assessments is provided in Appendix 8. 
Independent ethics committees (IECs)/institutional review boards (IRBs) will be notified of the 
changes as applicable locally. Of note, as the adapted visit deviates from the regular protocol 
plan, the changes will be recorded as protocol deviations related to COVID-19. 
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CCI


IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 55
 
Table 5 
Study Procedures and Assessments 
 
Screening 
Treatment Phase: 28 Day cycle (unless modified due to toxicity) 
Follow-up Phase 
 
D-28 to 
Randomisation 
 
Cycle 1 
Additional Cycles 
Q8W after 
randomisation 
EoT Visit 
(30±14 
days after 
last dose) 
Q2M after 
EoT visit 
D1 
D3 
(A1) 
D8 
(A2) 
D15 
D17 
(A1) 
D1 
D3 
(A1) 
D8 
(A2) 
D15 
D17 
(A1) 
 
 
 
Informed consent[a] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility[b] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation[c] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history[d] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics[d] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, physical 
exam[e] 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
ECOG performance status[f] 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
QLQ-C30, QLQ-PAN26, 
EQ-5D-5L[g] 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
PRO-CTCAE[g] 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
ECG[h] 
X 
X 
 
 
X(A1) 
 
X(A2) 
 
 
 
 
 
X 
 
Haematology [i] 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
Blood biochemistry[j] 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
Urinalysis[j] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
UGT1A1*28 [k] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
DPD testing [z] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CA19-9[l] 
X 
X 
 
 
 
 
X[l] 
 
 
 
 
 
 
 
Pregnancy test [m] 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Plasma for PK (Arm 1 only) 
[n] 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
Disease evaluation 
(CT/MRI) [o] 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Pre-medication/ Check 
blood results[p] 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
Arm 1: Nal-IRI +oxaliplatin 
+5-FU/LV [q] 
 
X 
 
 
X  
 
X 
 
 
X 
 
 
 
 
Arm 1: Removal of 5-FU 
pump [r] 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
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YHG
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Y
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SU
SU
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SUR
X
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SURY
SS
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X
SUR
SUR
SU
SU
SUR
SSUR
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X(A1)
SU
SU
SS
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SU
SU
$SSU
$S
$SS
$S
X
S
$S
$S
$SS
SS
SS
$SS
$S
$SS
$S
X
X
S
$S
$S
$SS
SS
SS
$SS
$S
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$S
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SS
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IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 56
 
 
Screening 
Treatment Phase: 28 Day cycle (unless modified due to toxicity) 
Follow-up Phase 
 
D-28 to 
Randomisation 
 
Cycle 1 
Additional Cycles 
Q8W after 
randomisation 
EoT Visit 
(30±14 
days after 
last dose) 
Q2M after 
EoT visit 
D1 
D3 
(A1) 
D8 
(A2) 
D15 
D17 
(A1) 
D1 
D3 
(A1) 
D8 
(A2) 
D15 
D17 
(A1) 
 
 
 
Arm 2: gemcitabine 
+nab-paclitaxel [s] 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
Prior and concomitant meds 
and procedures[u] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE/SAEs [v] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall survival [w] 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Further anticancer therapy 
[w(i)] 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Archival tumour tissue[x] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking blood and stool 
[y] 
 
X 
 
 
 
 
X[y] 
 
 
 
 
 
X 
 
Abbreviations and Footnotes 
Note: All cycles are 28-day cycles, unless modified due to toxicity 
Note: pre-dose assessments can be completed 2 days prior to dosing according to local standard of care  
5-FU=5-flurouracil, A1=Arm 1, A2=Arm 2, AE=adverse event, βHCG=β human chorionic gonadotropin, BSA=body surface area, C=cycle, CT=computed tomography, D=day, 
DNA=deoxyribonucleic acid, DPD= Dihydropyrimidine dehydrogenase, ECG=electrocardiogram, EORTC= European Organisation for Research and Treatment of Cancer, EoT=End of Treatment, 
EQ-5D-5L=EuroQol 5 dimension health status questionnaire (5 level), HRQL= health-related quality of life, Nal-IRI=irinotecan liposomal injection, LV=leucovorin, MRI=magnetic resonance 
imaging, OS=overall survival, QLQ-PAN26=quality of life questionnaire pancreatic cancer module, PK=pharmacokinetics, QLQ-C30=quality-of-life core 30 questionnaire, Q2M=every 2 months, 
Q8W=every 8 weeks, RECIST= Response Evaluation Criteria in Solid Tumours, RNA=ribonucleic acid, SAE=serious adverse event, SmPC=summary of product characteristics. 
a 
Informed consent: Informed consent to be signed before any screening activities take place. Additional optional biobanking informed consent to be signed for subjects who are willing to 
participate in the biobanking sampling. 
b 
Eligibility: To be checked against the inclusion and exclusion criteria. 
c 
Randomisation: Only to be performed when a subject has been successfully screened. Randomisation to be performed on C1D1, or within 4 days prior to C1D1 where required by local 
procedures. Date of randomisation must be entered in the eCRF. 
d 
Medical history and demographics: To be completed during the screening process i.e. within 28 days prior to randomisation. Gene mutation status and genomic alterations of the subjects 
determined prior to screening will be collected at Screening (if available) and will be recorded as part of the disease history in the eCRF (See Section  3.3.9 for list of associated genes for 
collection). 
e 
Vital signs and physical examination: Procedures to be completed within 7 days prior to randomisation. Vital signs will include height (at screening only) weight, resting blood pressure, 
pulse and temperature. BSA is calculated within 2 days before D1 and D15 of each cycle before treatment administration. Physical examination must include neurological examination on 
D1 of each cycle. 
f 
ECOG performance status: To be assessed within 7 days prior to randomisation. 
g 
HRQL questionnaires: On D1 of treatment cycles, HRQL questionnaires must be completed before study treatment administration.  
Note: Every effort should be made for the QoL to be completed within 24 hours prior to the planned visit date. QoL does not need to be repeated if the QoL was completed on the planned 
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PAGE 57
 
visit date and the visit was subsequently postponed. If a subject is unable to complete the QoL on the planned visit date, then this can be performed on the new postponed visit date. QoL 
should always be completed prior to study assessments. 
h 
ECG: For screening, ECG to be measured within 28 days prior to randomisation. Arm 1 only: ECG to be performed pre and post oxaliplatin infusion on D1 and D15 of C1 only and repeated 
as clinically indicated during the study. Arm 2 only: ECG to be performed pre infusion of nab-paclitaxel and gemcitabine on D1 of Cycles C1, C2, C3 and C4 and repeated as clinically 
indicated during the study. In addition, ECG to be repeated as clinically indicated during the study. 
i 
Haematology: For the screening sample, collection should occur within 7 days before randomisation. Routine or historical samples taken before signing ICF within this timeframe can be 
used for the screening sample. Day 8 collections are required for Arm 2 only. Results of samples taken must be obtained and reviewed prior to dosing (D1, D8 and D15). Refer to Section 8.2.1 
for the required results, e.g. coagulation testing. 
j 
Biochemistry and Urinalysis: For the screening sample, collection should occur within 7 days before randomisation. Serum biochemistry must be assessed centrally but can also be analysed 
locally in the case of requiring timely results for medical management. Screening central biochemistry results must be obtained prior to randomisation. Urinalysis will be performed locally. 
Refer to the eCRF completion guideline for the required results. 
k 
UGT1A1*28: Sample to be collected within 7 days prior to randomisation. Biomarker result not required prior to enrolment in the study or prior to dosing on C1D1. 
l 
CA19-9: First sample to be collected within 7 days prior to randomisation. Sample to be collected at D1 of every other cycle, i.e. C1D1, C3D1, C5D1, etc. 
m 
Pregnancy test (urine or serum βHCG):  Sample to be collected and results reviewed prior to randomisation and before treatment on D1 of each cycle. Any positive urine pregnancy test 
must be confirmed via serum β-HCG. 
n 
PK sampling (Arm 1 only): C1D1: Samples collected at the following timepoints: pre-dose (within 24 hours prior to irinotecan liposome injection infusion); at the end of the irinotecan 
liposome injection infusion (+15 mins) and at the end of the oxaliplatin infusion (+5 mins). C1D3: Sample collected within 2 hours prior to the completion of the 5-FU infusion. C1D15: 
Sample collected just prior to dosing with irinotecan liposome injection (within 24 hours). If subject is seen in clinic between C1D3 and C1D15 then an additional PK sample should be 
collected at the time of the visit (subject does not need to come to clinic for this sample only). 
o 
Disease evaluation: For screening to be performed within 28 days before randomisation. CT (or MRI if the subject is allergic to CT contrast media) according to RECIST Version 1.1. 
Routine or historical scans taken before signing ICF within this timeframe can be used to perform the screening assessment according to RECIST Version 1.1. Scan schedule is Q8W after 
randomisation. The scan schedule of every 8 weeks (± 7 days) after randomisation is to be adhered to, regardless of whether the subject has a treatment delay. EoT visit: Disease evaluation 
to be performed unless completed in the 8 weeks before the EoT visit. Q2M after EoT visit: For subjects who discontinue the study treatment for reasons other than radiologically confirmed 
disease progression per RECIST version 1.1 and have not started any further anti-cancer treatment (e.g. subjects who are removed due to adverse events). 
p 
Pre-medication Arm 1: Dexamethasone and a 5-HT3 antagonist, or equivalent other anti-emetics. Atropine may be prescribed as per standard of care and/or prophylactically for subjects 
who experienced acute cholinergic symptoms. Arm 2: As per standard practice or Prescribing Information/SmPC. Prior to each dosing for Arm 1 and prior to each cycle for Arm 2, subjects 
must comply with the relevant blood count criteria (see Section 6.2.3). 
q 
Arm 1: Nal-IRI +oxaliplatin+5-FU/LV: Infusions to be administered ±2 days from scheduled date of administration in the following order: irinotecan liposome injection, followed by 
oxaliplatin infusion, followed by LV (30 minutes after oxaliplatin end) and then 5-FU infusion (within 60 minutes after LV). On D1 of every cycle, treatment experience during the previous 
cycle(s) will be reviewed in case dose modification(s) are required. 
r 
Arm 1: Removal of 5-FU pump: Pump removal might occur at a home visit, rather than a visit to site except at C1D3. For C1D3 the subject will visit the site and a PK sample will be taken 
2 hours before the pump finishes delivering 5-FU. Time of PK sample and time of finishing pump infusion must be recorded.   
s 
Arm 2: gemcitabine+nab-paclitaxel: Infusions to be administered ±2 days from scheduled date. There must always be at least 6 days between Day 1 and Day 8 and Day 8 and Day 15. 
Administration in the following order: administration of nab-paclitaxel first, followed by gemcitabine. On D1 of every cycle, treatment experience during the previous cycle(s) will be 
reviewed in case dose modification(s) are required. 
u 
Prior and concomitant medications and procedures: To be recorded in the eCRF during the screening period (i.e. within 28 days before randomisation) and then as an ongoing process 
throughout the study. 
v 
AEs/SAEs: Subjects must be followed for AEs/SAEs, regardless of relationship, from the time they signed the informed consent until at least 30 days after the last dose of study treatment. 
w 
Overall survival: Follow-up contacts should be made Q2M (±7 days) until death or study completion; data collected should include OS status.  
w(i) Further anticancer therapy: Follow-up contacts should be made Q2M (±7 days) until death or study completion; data collected should include any subsequent anti-cancer treatment 
information.  
x 
Biobanking: Archival tumour samples: Archived samples to be collected for those individuals who have signed the optional biobanking informed consent. 
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y  
Biobanking: Blood and stool: Only to be collected for those individuals who have signed the optional biobanking informed consent. Whole blood (samples for RNA, circulating free DNA, 
plasma), and stool samples will be collected prior to treatment dosing on C1D1 and every other cycle after that (i.e. C3D1, C5D1, etc). Whole blood for DNA samples will be collected on 
C1D1 only. 
z 
DPD testing: Where required by local regulations, testing for DPD activity must be performed using a validated method which is recommended by local health authorities (Appendix 7). 
Result to be received and reviewed prior to randomisation.
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5.2 
Study Visits 
5.2.1 
Procedures for Screening and Enrolment 
The screening phase will begin once the subject signs the ICF. All procedures for screening are 
outlined in Table 5. 
For further descriptions of the clinical and laboratory assessments required, please refer to 
Section 8.2.  
Subjects will be offered to participate in an optional research biobanking programme. Subjects 
who agree to participate will be requested to sign a separate informed consent. Subjects can 
participate in the study even if they are not participating in the optional biobanking programme. 
After informed consent is obtained, all subjects will be allocated a subject number. Screened 
subjects must be identifiable throughout the study. The investigator will maintain a list of 
subject numbers and names to enable records to be found at a later date if required. 
Under no circumstances will subjects be screened more than once, however, on discussion with 
the sponsor medical monitor (or delegate), it may be required that some assessments need to be 
repeated, such as safety assessments and blood sampling. 
Following confirmation of eligibility for the study, subjects will be given a randomisation 
number and allocated to one of the dosing groups specified in Section 3.6. 
In the event that the subject does not receive study medication, the primary reason will be 
recorded.  
5.2.2 
Procedures During Study Treatment Phase 
Procedures will be performed during the study treatment phase as per Table 5.  
5.2.3 
Procedures After Study Treatment (Follow-up Phase) 
5.2.3.1 
End of Treatment Visit 
Subjects will continue to receive treatment until radiologically determined progressive disease 
per RECIST Version 1.1, unacceptable study medication related toxicity or withdrawal. An 
EoT visit is required approximately 30 days (±14 days) after last dose of study treatment to 
complete the final safety assessments.  
For subjects who withdraw prematurely from the study, final evaluations will be performed at 
the EoT visit (30±14 days after the last dose).  
Subjects with ongoing AEs or clinically significant laboratory test abnormalities (as determined 
by the investigator) will be monitored as described in Section 8.1.4 and Section 8.1.2.5, 
respectively.  
All procedures and assessments are outlined in Table 5. 
Subjects are to use contraception throughout the study, as well as after they stop receiving study 
medication, as described in Section 4.3.3. 
5.2.3.2 
Follow-up Visits 
After the EoT visit, subjects should continue to be followed for survival status once every 
2 months (±7 days) via telephone, email, clinic visit, or medical record review until death, 
withdrawal of consent or study closure, whichever occurs first. Additionally, data on 
subsequent anti-cancer treatments should be collected during these contacts and documented in 
the eCRF. In the case of subjects who are discontinued from treatment for reasons other than 
progressive disease per RECIST Version 1.1, disease evaluations (including imaging studies) 
should continue into the follow-up period, as described in Section 4.3.3. 
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If a subject does not respond to the OS follow-up contacts, at least three documented attempts, 
including one via certified mail, should be made to contact the subject before declaring a subject 
potentially lost to follow-up. If the subject does not respond to these requests, the date of death 
may be captured from public records or all other means allowed by local regulations. 
5.3 
Laboratory Assessments 
The total volume of blood drawn for all evaluations throughout this study is dependent on the 
numbers of cycles of treatment completed and is estimated in Table 6 (see Section 10 for 
biobanking sample volumes, which are not included in this estimate).  
Table 6 
Estimates of Blood Volume Drawn Throughout the Study  
Study Phase 
Arm 1 
Arm 2 
Screening 
20 mL 
20 mL 
Cycle 1 
70 mL 
25 mL 
Per subsequent cycle 
20 mL 
25 mL 
Pregnancy test for women  
(Screening and Day 1 of each cycle) 
3.5 mL per test 
3.5 mL per test 
Notes: Estimates given to the nearest +5mL 
An additional 16.5 to 19 mL of blood will be collected from subjects who have signed the optional biobanking informed 
consent. 
Technical instructions will be provided in a separate laboratory manual. 
The following samples will be analysed locally: 
• 
Haematology samples will be assessed at the site’s local laboratory (see Section 8.2.1) 
• 
Blood biochemistry samples can be assessed at the site’s local laboratory only if needed 
to allow for immediate decision-making (see Section 8.2.2 and also note that centrally 
assessed biochemistry results are required to confirm eligibility). Blood biochemistry 
samples will be assessed at central laboratory (in the list below). 
• 
Dipstick urinalysis 
• 
Pregnancy test (see Section 8.2.5). 
• 
DPD testing will be performed using a validated method which is recommended by local 
health authorities at the site’s local laboratory (See Section 8.2.7 and Appendix 7). 
The following samples will be sent for central analysis: 
• 
Blood biochemistry (see Section 8.2.2) 
• 
CA19-9 (see Section 8.2.4) 
• 
UGT1A1*28 (see Section 8.2.3)  
• 
PK samples (see Section 9.1). 
5.4 
Imaging 
Subjects will have CT scans (or MRI if the subject is allergic to CT contrast media) performed 
every 8 weeks (see Table 5) that will be evaluated by the investigator using RECIST guidelines 
Version 1.1 for complete response, partial response, stable disease or progressive disease.  
The sponsor will collect and store all tumour assessment images for all subjects throughout the 
study.  
For subjects who discontinue the study treatment for reasons other than radiologically 
confirmed disease progression per RECIST version 1.1 and have not started any further 
anti-cancer treatment, will have follow-up Q2M after EoT for disease evaluation. 
Technical instructions will be provided in separate image acquisition guidelines. 
The CT scans (or MRI) will be retained by the sponsor for central independent assessment, 
should this be required. 
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6 
TREATMENT OF SUBJECTS 
6.1 
Study Medication Preparation, Storage, Security and Accountability 
All medication provided to the subject (i.e. irinotecan liposome injection, oxaliplatin, 5-FU, 
LV, nab-paclitaxel and gemcitabine) is classed as study medication. The study medication that 
is provided to the clinical site by the sponsor is also referred to as IMP. All IMP is study 
medication but not all study medication may be defined as IMP. 
6.1.1 
Study Medication Storage and Security 
The investigator or an approved representative (e.g. pharmacist) will ensure that all study 
medication (i.e. irinotecan liposome injection, oxaliplatin, 5-FU, LV, nab-paclitaxel and 
gemcitabine) is stored in a secured area, under recommended temperature monitored storage 
conditions, in accordance with applicable regulatory requirements and the pharmacy manual. 
Temperature of storage for irinotecan liposome injection is described in Section 6.2.1.1 and 
accompanying packaging information provides the relevant storage conditions for the other 
study medications. 
6.1.2 
Investigational Medicinal Product Preparation 
The investigator or an approved representative (e.g. pharmacist) will ensure that all study 
medication is prepared and dispensed by qualified staff members. 
6.1.3 
Investigational Medicinal Product Accountability 
All IMP sourced by the sponsor is to be accounted for in the Drug accountability module within 
the IWRS system.  
The investigator, institution or the head of the medical institution (where applicable) is 
delegated by the sponsor to be responsible for IMP accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records). The sponsor will provide 
guidance on the destruction of unused IMP. If destruction is authorised to take place at the 
investigational site, the investigator must ensure that the materials are destroyed in compliance 
with applicable environmental regulations, institutional policy and any special instructions 
provided by the sponsor. All destruction must be adequately documented. Further guidance and 
information for the receipt, preparation, management, disposal and return of the IMP are 
provided in the “Investigational Medicinal Product Handling Manual”. 
6.2 
Study Medications Administered 
At screening, subjects will be allocated a subject number. Following confirmation of eligibility 
for the study, subjects will be allocated to one of the following treatment groups: 
• 
Arm 1: irinotecan liposome injection+oxaliplatin+5-FU/LV 
or 
 
• 
Arm 2: nab-paclitaxel+gemcitabine 
6.2.1 
Irinotecan Liposome Injection+Oxaliplatin+5-FU/LV (Arm 1) 
Prior to the infusions contained in Arm 1 all subjects must be pre-medicated as detailed in 
Section 6.3.1. The order of the infusions to be administered in the clinic is as follows: irinotecan 
liposome injection, followed by oxaliplatin infusion, followed by LV and then 5-FU infusion. 
(Refer to study schedule Table 5). 
Arm 1: Doses and administration of irinotecan liposome injection, oxaliplatin, 5-FU/LV on 
Days 1 and 15 of each 28-day cycle: 
• 
Irinotecan liposome injection will be administered at 50 mg/m2 i.v. over 90 minutes 
(±10 minutes) 
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• 
Oxaliplatin infusion, after completion of irinotecan liposome injection, will be 
administered at 60 mg/m2 i.v. over 120 minutes (±10 minutes). Note that oxaliplatin may 
be omitted due to toxicity (see Section 6.2.5.1 for dose modification to an alternative 
regimen without oxaliplatin for Arm 1 in the case of toxicity). 
• 
LV (l+d racemic form-generic form) infusion will start 30 minutes (+10 minutes) after 
completion of oxaliplatin administration, at 400 mg/m2, i.v. over 30 minutes (±5 minutes) 
• 
5-FU infusion will start within 60 minutes after completion of LV administration, 
at 2400 mg/m2 i.v. over 46-hours (±120 minutes). 
As the infusion of 5-FU is administered over 46 hours the subject will go home with an 
administration pump. The subject will either need to return to the clinic at the end of 
infusion for removal of the pump or, alternatively, if possible, arrangements might be 
made for the pump to be removed at the subject’s home (except on Cycle 1 Day 3). 
6.2.1.1 
Irinotecan Liposome Injection, Dose, Mode of Administration: 
Irinotecan liposome injection is irinotecan in the form of the sucrosofate salt, encapsulated in 
liposomes for i.v. infusion. The liposome is a unilamellar lipid bilayer vesicle, approximately 
110 nm in diameter, which encapsulates an aqueous space containing irinotecan in a gelated or 
precipitated state as the sucrosofate salt. It is supplied in sterile, single-use vials containing 
10 mL of irinotecan liposome injection at a concentration of 4.3 mg/mL free base equivalent 
(FBE).  
Irinotecan liposome injection must be stored refrigerated (2 to 8°C, 36 to 46°F) with protection 
from light and must not be frozen.  
Responsible individuals should inspect vial contents for particulate matter before and after they 
withdraw the drug product from a vial into a syringe. They must contact the sponsor or its 
designee if they notice a problem with the study medication.  
Irinotecan liposome injection must be diluted prior to administration. Because of possible 
microbial contamination during dilution, the diluted solution should be used immediately, but 
the diluted solution may be stored at room temperature (15 to 25°C) for up to 4 hours prior to 
infusion or may be refrigerated (2 to 8°C) for up to 24 hours prior to use. Diluted solution must 
be protected from light prior to infusion. The diluted solution must not be frozen. Further 
instructions are provided in the pharmacy manual. 
6.2.1.2 
Oxaliplatin, Leucovorin, 5-Fluorouracil 
Commercial oxaliplatin, LV and 5-FU are provided by the sponsor. This could be supplied by 
the site where allowed by local regulations, but only when approved by the sponsor. 
Sponsor-sourced commercial oxaliplatin, LV and 5-FU will be labelled in accordance with local 
country requirements. Instructions for storage and handling are provided in the pharmacy 
manual. For commercial treatment supplied locally, all information related to the product 
administered must be reported in source documentation and entered in the eCRF in accordance 
with the requirements stated in the eCRF completion guidelines.  
6.2.2 
Nab-paclitaxel+Gemcitabine (Arm 2) 
Arm 2: Doses and administration of nab-paclitaxel+gemcitabine (established doses as per USPI 
nab-paclitaxel) On Days 1, 8 and 15 of each 28-day cycle: 
• 
Nab-paclitaxel will be administered at 125 mg/m2 i.v. over 35 minutes (±5 minutes) 
• 
Gemcitabine will be administered at 1000 mg/m2 i.v. over 30 minutes (±5 minutes) 
6.2.2.1 
Nab-paclitaxel and Gemcitabine 
Commercial gemcitabine and nab-paclitaxel are provided by the sponsor. This could be 
supplied by the site where allowed by local regulations, but only when approved by the sponsor. 
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Sponsor-sourced commercial gemcitabine and nab-paclitaxel will be labelled in accordance 
with local country requirements. Instructions for storage and handling are provided in the 
pharmacy manual. For commercial treatment supplied locally, all information related to the 
product administered must be entered in the eCRF in accordance with the requirements stated 
in the eCRF completion guidelines. 
6.2.3 
Combination Therapy Study Cycles 
Both regimens are 28-day cycles unless cycle duration is modified by toxicity. 
The toxicity of each dose must be recorded prior to the administration of a subsequent dose and 
graded according to the National Cancer Institute (NCI) CTCAE (Version 5.0). All dose 
modifications for all arms should be based on the worst preceding toxicity. Dose modification 
details are given in Section 6.2.5. 
• 
Arm 1: irinotecan liposome injection+oxaliplatin+5-FU/LV 
Prior to each dosing, subjects must have: 
- 
ANC ≥2000/mm3 
- 
Platelet count ≥100,000/mm3 
- 
Diarrhoea ≤ Grade 1. 
• 
Arm 2: nab-paclitaxel+gemcitabine 
Prior to each cycle, subjects must have: 
- 
ANC ≥1500/mm3 
- 
Platelet count ≥100,000/mm3 
- 
Diarrhoea ≤ Grade 1. 
Dosing may be delayed as detailed in Section 6.2.5, to allow for recovery from toxicity. If the 
subject does not recover this may lead to discontinuation of study treatment (see Section 4.3 for 
details). However, if oxaliplatin is not well tolerated in subjects randomised to Arm 1, 
oxaliplatin may be discontinued and subjects may continue to receive irinotecan liposome 
injection+5-FU/LV at the discretion of the investigator and continue in the study. Toxicity 
requiring discontinuation of any of the drugs in either regimen (apart from oxaliplatin) will 
result in discontinuation from the study treatment (see Section 4.3 and Section 6.2.5). 
6.2.4 
Management of Infusion Reactions  
The guidelines described in this section can be followed in case of infusion reactions to any 
study treatment in either arm given per protocol. Infusion reactions will be defined according 
to the NCI-CTCAE (Version 5.0) definitions of an allergic reaction or anaphylaxis as defined 
below: 
6.2.4.1 
Allergic Reaction 
An allergic reaction is a disorder characterised by an adverse local or general response from 
exposure to an allergen: 
• 
Grade 1: 
Transient flushing or rash, drug fever <38°C (<100.4°F); intervention not 
indicated 
• 
Grade 2: 
Intervention or infusion interruption indicated; responds promptly to 
symptomatic treatment (e.g. antihistamines, NSAIDS, narcotics); prophylactic 
medications indicated for ≤ 24 hrs 
• 
Grade 3:  
Prolonged (e.g. not rapidly responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of symptoms following initial improvement; 
hospitalisation indicated for clinical sequelae (e.g. renal impairment, pulmonary 
infiltrates) 
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• 
Grade 4:  
Life-threatening consequences; urgent intervention indicated. 
6.2.4.2 
Anaphylaxis 
Anaphylaxis is a disorder characterised by an acute inflammatory reaction resulting from the 
release of histamine and histamine-like substances from mast cells, causing hypersensitivity 
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, 
cyanosis and loss of consciousness and may lead to death): 
• 
Grade 1: 
Not applicable 
• 
Grade 2: 
Not applicable 
• 
Grade 3:  
Symptomatic bronchospasm, with or without urticaria; parenteral 
intervention indicated; allergy-related oedema/angioedema; hypotension 
• 
Grade 4:  
Life-threatening consequences; urgent intervention indicated. 
6.2.4.3 
Treatment Guidelines 
Institutional policies or the following treatment guidelines shall be used for the management of 
infusion reactions. 
(1) 
Grade 1: 
• 
Slow infusion rate by 50% 
• 
Monitor subject every 15 minutes for worsening of condition 
• 
Future infusions may be administered at a reduced rate (e.g. over 120 minutes for 
irinotecan liposome injection), at the discretion of the investigator. 
(2) 
Grade 2: 
• 
Stop infusion 
• 
Administer diphenhydramine hydrochloride 50 mg i.v., acetaminophen 650 mg 
orally, and oxygen 
• 
Resume infusion at 50% of the prior rate once infusion reaction has resolved 
• 
Monitor subject every 15 minutes for worsening of condition 
• 
For all subsequent infusions, pre-medicate with diphenhydramine hydrochloride 
50 mg i.v., dexamethasone 10 mg i.v., and acetaminophen 650 mg orally
• 
Future infusions may be administered at a reduced rate (e.g. over 120 minutes for 
irinotecan liposome injection), at the discretion of the investigator. 
(3) 
Grade 3: 
• 
Stop infusion and disconnect infusion tubing from subject 
• 
Administer diphenhydramine hydrochloride 50 mg i.v., dexamethasone 10 mg i.v., 
bronchodilators for bronchospasm, and other medications or oxygen as medically 
necessary 
• 
No further treatment will be permitted. 
(4) 
Grade 4: 
• 
Stop the infusion and disconnect infusion tubing from subject 
• 
Administer epinephrine, bronchodilators or oxygen as indicated for bronchospasm 
• 
Administer diphenhydramine hydrochloride 50 mg i.v., dexamethasone 10 mg i.v. 
and other medications as medically necessary 
• 
Consider hospital admission for observation 
• 
No further treatment will be permitted. 
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For subjects who experience a second Grade 1 infusion reaction, administer dexamethasone 
10 mg i.v. All subsequent infusions should be pre-medicated with diphenhydramine 
hydrochloride 50 mg i.v., dexamethasone 10 mg i.v. and acetaminophen 650 mg orally or as 
per institutional guidelines. 
6.2.5 
Dose Modifications  
In both treatment arms the toxicity of each dose must be recorded prior to the administration of 
a subsequent dose and graded according to the NCI-CTCAE (Version 5.0). All dose reductions 
for all arms should be based on the worst preceding toxicity. 
Prior to D1 and D15 of each new dose of treatment, the dose of drug should be determined by 
re-calculating the subject’s BSA and it must be confirmed that subjects have haematology 
within the limits described in Section 6.2.3. A variation of 5% between the dose calculated by 
the IWRS and the total dose administered is permitted. 
If a subject’s dose is reduced during the study due to toxicity, it should remain reduced for the 
duration of the study; dose re-escalation is not permitted (with exception, see Appendix 3). 
Treatment should be delayed allowing sufficient time for recovery to levels noted above, and 
upon recovery, treatment should be administered according to the guidelines in Appendix 2 for 
Arm 1 or Appendix 3 for Arm 2. The use of transfusions is permitted if within normal 
institutional policies and procedures (see also Section 6.3.3). If the subject had febrile 
neutropenia, the ANC must have resolved to 2000/mm3 in Arm 1 and 1500/mm3 in Arm 2; and 
the subject must have recovered from infection.  
Dose modifications are therefore defined as the following: 
• 
Dose reduction: the new dose should be specified. 
• 
Infusion interruption: the timepoint, reason and timing of interruption of infusion will be 
recorded. 
• 
Dose delay: 
- 
Arm 1: documented as such if delayed dose is given within the per-protocol 
maximum days permitted between doses i.e. 28 days. 
- 
Arms 2: documented as such if delayed dose is given within the per-protocol 
maximum days permitted between doses i.e. 21 days. 
Any dose delays longer than the above must be discussed with the sponsor or delegate. 
• 
Dose omission 
- 
Arm 1: documented as such if delayed dose >28 days i.e. more than the 
per-protocol maximum permitted days between doses. 
- 
Arm 2- documented as such if delayed dose >21 days i.e. more than the 
per-protocol maximum permitted days between doses. 
6.2.5.1 
Dose 
Modifications 
and 
Omissions 
Arm 
1: 
Irinotecan 
Liposome 
Injection+Oxaliplatin+5-FU/LV 
In Arm 1, dosing may be delayed for up to 14 days from when it was scheduled (permitting a 
total of 28 days between the scheduled Day 1 and Day 15 doses) to allow for recovery from 
toxicity related to the study treatment, administrative, or personal reasons. If the time required 
for recovery from toxicity is more than 14 days, the dose is marked as omitted and consideration 
should be given to withdrawal from treatment in the study, unless the subject is demonstrating 
benefit overall, in which case the possibility of remaining on study medication should be 
discussed between investigator and sponsor (or delegate), after review of the associated risks 
and benefits. 
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Dose level reductions required due to toxicity related to irinotecan liposome 
injection+oxaliplatin+5-FU/LV should be made following the guidelines outlined in 
Appendix 2. 
Any subject who has three dose reductions and experiences an AE that would require a fourth 
dose reduction must be discontinued from study treatment. 
If oxaliplatin is not well tolerated in subjects randomised to Arm 1, oxaliplatin may be 
discontinued and subjects may continue to receive irinotecan liposome injection+5-FU/LV at 
the discretion of the investigator and continue in the study. (For discontinuation details please 
see Section 4.3). In the case that oxaliplatin is removed from the regimen, the following doses 
and administration of irinotecan liposome injection, 5-FU/LV will occur on Days 1 and 15 of 
each 28-day cycle: 
• 
Irinotecan liposome injection will be administered at 50 mg/m2 i.v. over 90 minutes 
(±10 minutes) 
• 
LV (l+d racemic form-generic form) infusion will start 30 minutes (+10 minutes) after 
completion of irinotecan liposome injection administration, at 400 mg/m2, i.v. over 
30 minutes (±5 minutes) 
• 
5-FU infusion will start within 60 minutes after completion of LV administration, 
at 2400 mg/m2 i.v. over 46-hours (±120 minutes). 
No dose adjustments for toxicity are required for LV. 
6.2.5.2 
Dose Modifications and Omissions Arm 2: Nab-paclitaxel+Gemcitabine 
Dose level reductions required due to toxicity related to nab-paclitaxel and gemcitabine should 
be made following the guidelines outlined in Appendix 3. 
Recommended dose modifications for neutropenia and thrombocytopenia and adjustments 
related to other toxicities are also provided in Appendix 3. 
In Arm 2 any subject who has two dose reductions and experiences an AE that would require a 
third dose reduction must be discontinued from study treatment (Appendix 3). 
The following rules will be applied if any of the following doses are missed in the 28-day cycle 
for Arm 2: 
• 
CxD1: can be delayed by a maximum of 7 days to accommodate 21 days between the 
previous cycle’s D15 and CxD1. 
• 
CxD8: cannot be delayed and if the subject is not well, this dose is not given, and the 
next dose scheduled for the CxD15 date. 
• 
CxD15:  
- 
in the case that the CxD8 dose was missed, the CxD15 dose can be delayed by a 
further week (leading to 21 days between CxD1 and the rescheduled CxD15 dose)  
- 
in the case that the CxD8 dose was given on schedule, CxD15 may be delayed by 
a maximum of 2 weeks (leading to 21 days between CxD8 and the rescheduled 
CxD15 dose):  
In Arm 2, the maximum delay between a missed scheduled dose and the next one (whichever 
dose is missed) should not be longer than 21 days to allow for recovery from toxicity related to 
the study treatment, and administrative, or personal reasons (see Appendix 3 for dose 
modification guidance). If the time required for recovery from toxicity is more than 21 days, 
consideration should be given to withdrawal from treatment in the study, unless the subject is 
demonstrating benefit overall, in which case the possibility of remaining on study medication 
should be discussed between investigator and sponsor (or delegate), after review of the 
associated risks and benefits. 
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6.2.5.3 
UGT1A1*28 Monitoring 
As part of this study, pharmacogenomic data will be collected on all subjects and assessed 
centrally for determination of the genotype at the UGT1A1 (TA)n repeat polymorphism, 
especially of UGT1A1*28 status. Results will be provided to the sponsor.  
Based on previous experience with non-liposomal irinotecan, individuals who are homozygous 
for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia 
following initiation of irinotecan treatment. According to the prescribing information for 
irinotecan [Camptosar® USPI 2016], in a study of 66 subjects who received single-agent 
non-liposomal irinotecan (350 mg/m2 once every 3-weeks), the incidence of Grade 4 
neutropenia in subjects homozygous for the UGT1A1*28 allele was as high as 50%, and in 
subjects heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%.  
Importantly however, no Grade 4 neutropenia was observed in subjects homozygous for the 
wild-type allele (UGT1A1 6/6 genotype). Additionally, in other studies, a lower prevalence of 
life-threatening neutropenia has been described (for details refer to the prescribing information 
for irinotecan [Camptosar® USPI 2016]. Population PK studies of irinotecan liposome injection 
have not identified a clinically significant relationship between UGT1A1*28 homozygosity and 
increased SN-38 exposure (see IB). In a phase I study (UCSF 8103, as referenced in 
Section 2.1.1.6) no differences in toxicity were seen in cohorts of heterozygous or wild-type 
subjects, and dose limiting toxicities of diarrhoea with or without accompanying dehydration 
or fatigue, were seen in both cohorts. 
All subjects treated in Arm 1, regardless of the results of the UGT1A1*28 genotype, will be 
treated with the same starting dose of irinotecan liposome injection and will follow the same 
dose reduction rules. Regular safety monitoring of subjects will be conducted by the sponsor 
medical monitor(s) (or delegate) and by the IDMC during the study. The safety and any 
available PK of UGT1A1*28 homozygous subjects will be compared to those who are 
non-homozygous for UGT1A1*28 to determine whether any different dosing strategy (such as 
a lower starting dose and/or different dose reduction for irinotecan liposome injection) is 
required for subjects who are homozygous for UGT1A1*28.  
6.3 
Concomitant Medication/Treatment/Therapy 
All concurrent medical conditions and complications of the underlying malignancy will be 
treated at the discretion of the investigator according to acceptable local standards of medical 
care. Subjects should receive analgesics, antiemetics, antibiotics, anti-pyretics, and blood 
products as necessary. 
Careful monitoring of coagulation parameters is imperative, in order to avoid complications of 
any possible drug interactions (see below). All concomitant medications, including transfusions 
of blood products, will be recorded on the appropriate case report form.  
Guidelines for treating certain medical conditions are discussed below; however, institutional 
guidelines for the treatment of these conditions may also be used. The concomitant therapies 
that warrant special attention are discussed below. 
Any prior or concomitant therapy or medication given to a subject within 4 weeks, or within a 
time interval less than at least five half-lives (whichever is shorter) before study medication 
administration or during study medication administration will be recorded on the eCRF. Dose 
and generic name or trade name will be recorded. 
6.3.1 
Pre-Medication 
6.3.1.1 
Arm 1: Irinotecan Liposome Injection+Oxaliplatin+5-FU/LV 
All subjects must be pre-medicated prior to irinotecan liposome injection infusion with standard 
doses of dexamethasone and a 5-HT3 antagonist, or equivalent other anti-emetics (according to 
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standard institutional practices). In situations where differences in standard institutional 
practices and recommendations within the country relevant SmPC occur, standard institutional 
practice will take precedence, excluding prohibited medications as per Section 6.3.2. Atropine 
may be prescribed as per standard of care and/or prophylactically for subjects who experienced 
acute cholinergic symptoms.  
6.3.1.2 
Arm 2: Nab-paclitaxel+Gemcitabine 
Pre-medication administration is not required prior to nab-paclitaxel treatment, as 
hypersensitivity reactions are not expected, although initial antiemetic prophylaxis is 
recommended due to administration of gemcitabine following nab-paclitaxel treatment. 
If a hypersensitivity reaction occurs, the infusion will be stopped and not restarted. If it is in the 
subject’s best interests, at the investigator’s discretion, treatment may continue over subsequent 
cycles using the pre-medication regimen that the institution typically uses for gemcitabine. 
6.3.2 
Prohibited Therapy and Therapy to be Monitored Closely 
The following drugs are noted in the irinotecan liposome injection prescribing information as 
interacting with irinotecan (see Appendix 1, which lists examples of prohibited strong CYP3A, 
CYP2C8, and UGT1A inhibitors or inducers): 
• 
Strong CYP3A4 inducers, e.g. St. John’s Wort, CYP3A4 inducing anticonvulsants 
(phenytoin, phenobarbital, and carbamazepine), rifampin, rifabutin, rifapentine 
• 
CYP3A4 inhibitors, e.g. clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole, troleandomycin, 
erythromycin, diltiazem, verapamil  
• 
Strong UGT1A1 inhibitors, e.g. atazanavir, gemfibrozil, indinavir, ketoconazole. 
Treatment with these agents and any others that interact with irinotecan, oxaliplatin, 5-FU, LV, 
nab-paclitaxel or gemcitabine should be avoided wherever possible. Aprepitant is a moderate 
CYP3A inhibitor and mild inducer of CYP3A4. Fosaprepitant and aprepitant interact with 
irinotecan: caution should be exercised when administering either agent as their use may result 
in increased toxicity (neutropenia and diarrhoea). For the prevention of chemotherapy-induced 
nausea and/or vomiting, selection of an appropriate antiemetic should avoid potential drug-drug 
interactions and employ a multimodal combination with either a 5-HT3 antagonist, 
dexamethasone, olanzapine and a NK-1 antagonist that does not interact with the CYP3A4 
pathway (e.g. rolapitant). Where anti-emetic options are limited to aprepitant and fosaprepitant, 
these should only be used based on investigator judgement considering the risk/benefit to the 
subject. Because 5-FU interacts with warfarin, caution should be exercised if concomitant use 
is necessary. Standard institutional practices should be used for any other drug interactions. 
No live attenuated vaccines should be given to subjects in the study and for 3 months after last 
dose of study therapy (e.g. yellow fever vaccine and polio virus vaccine). If a subject receives 
SARS-CoV-2 vaccinations (COVID-19 vaccinations) during study participation, it is the 
responsibility of the investigator to determine the suitability of the vaccine being given with the 
information provided by the manufacturer. 
The following therapies are not permitted during the study treatment phase (see also Section 6.4 
for lifestyle recommendations): 
(a) 
Other anti-neoplastic therapy, including cytotoxics, targeted agents, endocrine therapy 
or antibodies  
(b) 
Potentially curative radiotherapy; palliative radiotherapy is permitted 
(c) 
Other antiretroviral therapies with overlapping toxicities with the irinotecan liposome 
injection+oxaliplatin+5-FU/LV regimen, including the agent zidovudine, which has an 
overlapping toxicity for increased risk of neutropenia. 
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(d) 
Any other investigational therapy. 
6.3.3 
Permitted Concomitant Medication/Therapy 
Concomitant medications for treatment of febrile neutropenia with G-CSF and diarrhoea are 
permitted during this study, but they must be monitored closely and every effort should be made 
to keep their dose and dose regimen constant throughout the course of the study. 
6.3.3.1 
Granulocyte Colony-Stimulating Factors 
Deaths due to sepsis following severe neutropenia have been reported in patients treated with 
non-liposomal irinotecan and irinotecan liposome injection. In subjects with metastatic 
pancreatic cancer in the NAPOLI-1 study, neutropenic fever/sepsis appeared more frequently 
in the irinotecan liposome injection containing arms (4.8% irinotecan liposome injection 
monotherapy arm, 3.4% irinotecan liposome injection+5-FU/LV arm and 0.7% 5 FU/LV 
control arm). The incidence of Grade 3 or 4 neutropenia was higher among Asian subjects (18 
of 33 (55%)) compared to white subjects (13 of 73 (18%)) (see the IB for further details). 
In the ongoing phase I/II open-label, dose-expansion study of irinotecan liposome injection plus 
5-FU/LV and oxaliplatin in subjects with previously untreated metastatic pancreatic cancer 
(MM 398-07-02-03) Grade 3 or higher treatment-related febrile neutropenia occurred in 12.5% 
of the pooled population treated with 50 mg/m2 irinotecan liposome injection, LV 400 mg/m2, 
5-FU 2400 mg/m2 and 60 mg/m2 oxaliplatin (n=4/32) (see Section 1.2.2.1 and the IB for further 
details). 
For both arms, neutropenic complications should be managed promptly and adequately with 
antibiotic support. Granulocyte-colony stimulating factor (G-CSF) may be used at the 
investigator's discretion for the treatment of neutropenic fever or infections associated with 
neutropenia and for the prevention of febrile neutropenia in subjects with an ANC 
<500 cells/μL. Prophylactic use of G-CSF should be considered if subjects are considered high 
risk in the opinion of the investigator (e.g. age >60, co-morbidities, poor nutritional status, 
previous episode of febrile neutropenia) [Smith 2015, Klastersky 2016, Lyman 2005]. Subjects 
with prolonged a diarrhoeal episode lasting ≥48 hours should be closely monitored for a trend 
of decrease in white blood cells (WBC) and/or neutropenia with high consideration given to 
administer G-CSF to avoid infectious/septic complications. See Section 6.3.3.2 and the detailed 
algorithm of diarrhoea management for chemotherapy-induced diarrhoea provided in Appendix 
5.  
6.3.3.2 
Therapy for Diarrhoea 
Acute diarrhoea and abdominal cramps, developing during or within 24 hours after irinotecan 
liposome injection administration, may occur as part of a cholinergic syndrome. The syndrome 
can be treated with atropine. Prophylactic or therapeutic administration of atropine, according 
to institutional standards, should be considered in subjects experiencing cholinergic symptoms 
during the study.  
Diarrhoea can be debilitating and on rare occasions is potentially life-threatening. 
Anti-diarrhoea management should be initiated at the first episode of poorly formed or loose 
stools or the earliest onset of bowel movements that are more frequent than normal. For both 
arms, diarrhoea should be managed according to institutional guidelines, or according to the 
guidelines developed by an American Society of Clinical Oncology panel and ESMO Clinical 
Practice Guidelines for treating chemotherapy-induced diarrhoea [Benson 2004, Utaris 2015, 
Bossi 2018]. 
For a detailed algorithm of diarrhoea management for chemotherapy-induced diarrhoea see 
Appendix 5. 
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6.4 
Lifestyle Restrictions/Recommendations 
Vacations or holidays of 14 calendar days in length can be accommodated in the schedule. 
Besides restrictions already presented in the exclusion criteria (see Section 4.2) and any related 
to smoking or alcohol consumption, subjects will also be requested to avoid the following from 
48 hours prior to Day 1 and until EoT visit: 
• 
poppy-seeds consumption 
• 
cannabis (including medicinal). 
Subjects are to use contraception throughout the study, as well as after they stop receiving study 
medication, as described in Section 4.3.3. 
Prior to treatment, male subjects will be informed of the possibility of irreversible 
infertility/testicular damage and they will be advised to consider conservation of sperm. 
Subjects in Arm 1 receiving 5-FU will be advised to take measures to minimise exposure to UV 
light for the duration of the study and for one week after the last dose of 5-FU because of the 
associated risk of photosensitivity. 
6.5 
Procedures for Monitoring Subject Compliance 
The investigator will be responsible for monitoring subject compliance. Subjects may be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
subject is not in compliance with the study protocol. 
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7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule in Table 5. 
7.1 
Primary Efficacy Endpoint and Evaluation 
As described in Section 3.2.1, the primary efficacy endpoint is the OS of subjects randomised 
to irinotecan liposome injection+oxaliplatin+5-FU/LV compared to subjects randomised to 
nab-paclitaxel+gemcitabine. 
7.2 
Secondary Efficacy Endpoints and Evaluations 
7.2.1 
Time to Event Endpoints 
Secondary efficacy endpoints are PFS and ORR. These are defined in Section 3.2.2. These 
endpoints will only be evaluated if the primary efficacy endpoint demonstrates superiority for 
irinotecan liposome injection+oxaliplatin+5 FU/LV over nab paclitaxel+gemcitabine. 
Investigator-assessed tumour response will be used in efficacy analysis. 
7.3 
Exploratory Efficacy Endpoints and Evaluations 
The exploratory endpoints TTF, DOR and TTR are described in Sections 3.3.3, 3.3.4 and 3.3.5, 
respectively. These will be summarised as described in the statistical analysis plan (SAP). 
The PRO exploratory endpoints are as follows: 
• 
Assess time to deterioration or worsening of subjects physical functioning, disease 
related symptoms and treatment related symptoms of interest using the European 
Organisation for Research and Treatment of Cancer quality-of-life-core questionnaire 
(EORTC QLQ-C30) and, specific pancreatic cancer module (QLQ-PAN26) 
questionnaire and PRO of Common Terminology Criteria of Adverse Events (CTCAE) 
• 
Assess time to deterioration or worsening on remaining QoL subscales of QLQ-C30 and 
QLQ-PAN26 
• 
Compare % of subjects with stable, improved or worsened QoL scores as assessed by 
QLQ-C30, QLQ-PAN26 and PRO-CTCAE 
• 
Summarise HRQoL score at each visit as assessed by QLQ-C30, QLQ-PAN26, 
PRO-CTCAE and EQ-5D-5L. 
EORTC QLQ-C30 and QLQ-PAN26 questionnaire data will be collected to assess how 
subjects’ functioning, disease-related symptoms and treatment-related symptoms are affected 
by treatment with irinotecan liposome injection+oxaliplatin+5-FU/LV in comparison with 
nab-paclitaxel+gemcitabine.  
The EORTC QLQ-C30 is a generic questionnaire that has been developed and validated to 
assess the QoL of cancer patients. The QLQ-PAN26 is a disease-specific module that 
complements the QLQ-C30 questionnaire to capture concepts that are specific to pancreatic 
cancer (all disease stages) such as jaundice, digestive function, decreased muscle strength. It 
has not yet undergone psychometric testing in a large international group of subjects, but 
pre-testing has already been conducted and it is currently tested in international clinical trials. 
The QoL questionnaires should be completed in a language that is understood by the subject. 
The sponsor (or delegate) is to be consulted should a subject be illiterate or not understanding 
local language for advice. 
Scoring will be performed as described in the EORTC QLQ-C30 scoring manual [EORTC 
QLQ-C30, 2001]. Scores range from 0 to 100. A high score for the global health status/QoL 
representing a high QoL; a high score for the functional scale representing a high/healthy level 
of functioning; but a high score for a symptom scale/item representing a high level of 
symptomatology/problems. 
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A subject perspective on TEAEs will be collected through the PRO-CTCAE and the EQ-5D-5L 
instrument will be used to provide a generic preference-based measure and health utility. 
7.4 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data 
Methods for assessing primary, secondary and exploratory efficacy data, are described in 
Section 3.2.1, Section 3.2.2 and Section 3.3, respectively. 
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PAGE 73
 
8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events  
Adverse events will be monitored from the time that the subject gives informed consent until 
30 days after the last dose of study medication (see Section 3.7 for a definition of the study 
duration) and will be elicited by direct, nonleading questioning. Further details for AE reporting 
can be found in Section 8.1.4 and 8.1.5. 
Reference information for safety of study medication is listed at the beginning of Section 18. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 
be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g. laboratory findings, ECG). In clinical studies an AE can include 
an undesirable medical condition occurring at any time, including run in or washout periods, 
even if no study medication has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until 30 days after last study medication administration (as defined in Section 3.7).  
Natural progression or deterioration of the disease under study will be recorded as part of the 
efficacy evaluation and should not be recorded as an AE/SAE. 
Death due to disease progression will be recorded as part of the efficacy evaluation and will not 
be regarded as an SAE. 
Signs and symptoms should not be reported as AEs/SAEs if they are clearly related to a relapse 
or an expected change or progression of the baseline disease. 
These signs and symptoms should only be reported as AEs/SAEs (depending on the 
investigator’s judgement) if they are: 
• 
Judged by the investigator to be unusually severe or accelerated disease, or 
• 
If the investigator considers the deterioration of disease signs and symptoms to be caused 
directly by the IMP. 
If there is any uncertainty about an AE being due solely to the disease under study, it should be 
reported as an AE/SAE as appropriate. 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
Adverse events will be recorded and graded according to NCI-CTCAE (Version 5.0). In view 
of meta-analyses and for conversion purposes, the following conversion mapping will apply if 
the NCI-CTCAE scale is not available for a given AE: 
• 
NCI-CTCAE Grade 1 corresponds to mild, 
• 
NCI-CTCAE Grade 2 corresponds to moderate, 
• 
NCI-CTCAE Grade 3 corresponds to severe, 
• 
NCI-CTCAE Grade 4 corresponds to life threatening/disabling, 
• 
NCI-CTCAE Grade 5 corresponds to death (related to AE). 
Where:  
• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject 
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• 
Severe: symptoms definitely hazardous to wellbeing or causing significant impairment 
of function or incapacitation. 
• 
Life threatening: any event that places the subject at immediate risk of death from the 
event as it occurred, i.e. it does not include a reaction that, had it occurred in a more 
severe form, might have caused death (also see Section 8.1.5). 
8.1.2.2 
Causality Classification 
The relationship of an AE will be assessed for each drug of the regimen for each arm and will 
be classified according to the following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with each drug of the regimen in the sense 
that it is plausible, conceivable or likely. 
• 
Not related: reports including good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with each drug of the regimen. 
8.1.2.3 
Assessment of Expectedness 
The reference document for each study medication for assessing expectedness of AEs/event in 
this study is listed at the beginning of Section 18. 
8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in study medication schedule of administration (change in 
dosage, delay in administration, study medication discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are SAEs, 
• 
They are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings 
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings judged by the investigator as clinically significant (e.g. ECG changes) 
that result in a change in study medication dosage or administration schedule, or in 
discontinuation of the study medication, or require intervention or diagnostic evaluation to 
assess the risk to the subject, should be recorded as AEs.  
8.1.3 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) for this study include: 
• 
Thrombo-embolic events, NCI-CTCAE Grade 1 to 5  
These events must be collected in the CRF using the AESI reporting option on the AE page of 
the eCRF. If they meet the seriousness criteria, they should also be reported as SAEs (refer to 
Section 8.1.5). 
8.1.4 
Recording and Follow-up of Adverse Events 
At each visit, the subject should be asked a nonleading question such as: “How have you felt 
since the last visit?” 
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All AEs, regardless of treatment group or suspected causal relationship to study medication, 
will be recorded on the AE page(s) of the eCRF. Events involving drug reactions, accidents, 
illnesses with onset during the treatment phase of the study (i.e. from signing consent up to 
30 days after last study medication administration), or exacerbations of pre-existing illnesses 
should be recorded according to the NCI terminology if applicable. Any AEs already recorded 
and designated as ‘continuing’ should be reviewed at each subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
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 (i.e. study medication or other illness). The investigator is required to assess causality and 
record that assessment in the source documentation and the eCRF. Follow-up of the AE, after 
the date of study medication discontinuation, is required if the AE or its sequelae persist. 
Follow-up is required until the event or its sequelae resolve or stabilise at a level acceptable to 
the investigator and the sponsor’s clinical monitor or his/her designated representative. 
8.1.5 
Reporting of Serious Adverse Events 
All SAEs (as defined below), regardless of treatment group or suspected relationship to study 
medication, must be reported immediately (within 24 hours of the investigator or staff becoming 
aware of the event) using the SAE reporting option on the AE page of the eCRF. In case of no 
access to eCRF then a paper SAE form should be completed and emailed to 
. If the immediate report is submitted by telephone or using the paper 
SAE form, then this must be followed by reports using the eCRF. 
An SAE is any AE that: 
(1) 
Results in death 
(2) 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons (see below) 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received the 
study medication 
(6) 
Is an important medical event that may not result in death, be life threatening, or require 
hospitalisation when, based upon appropriate medical judgement, it may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalisation, or the development of drug 
dependency or drug abuse. 
In addition to the above criteria, any suspected or confirmed coronavirus COVID-19 
(SARS-CoV-2) infection should be considered serious and be immediately reported to the 
sponsor. The seriousness criteria should be “other medically significant” if no other seriousness 
criteria are present (e.g. hospitalisation). 
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long-term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
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• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the investigator or treating physician. For 
protocol-specified hospitalisation in clinical studies, prolongation is defined as any 
extension beyond the length of stay described in the protocol. Prolongation in the absence 
of a precipitating, treatment emergent, clinical AE (i.e. not associated with the 
development of a new AE or worsening of a pre-existing condition) may meet the criteria 
for “seriousness” but is not an adverse experience and thus is not subject to immediate 
reporting to the sponsor.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the subject’s 
screening documentation. Hospitalisation for a preplanned or elective treatment/surgical 
procedure should not be reported as an SAE unless there are complications or sequelae 
which meet the criteria for seriousness described above. 
Any SAE must be reported immediately (within 24 hours of the investigator or staff becoming 
aware of the event), using the SAE reporting option on the AE page of the eCRF. In case of no 
access to eCRF then a paper SAE form should be completed and emailed to the email specified 
at the beginning of this protocol, independent of the circumstances or suspected cause, if it 
occurs or comes to the attention of the investigator at any time during the study period. 
Any AE/SAE with a suspected causal relationship to study medication administration occurring 
at any other time after completion of the study must be reported promptly. 
The following information is the minimum that must be provided to the sponsor within 24 hours 
for each SAE: 
• 
study number 
• 
centre number 
• 
subject number 
• 
AE 
• 
investigator's name and contact details. 
The additional information included in the SAE page or form must be provided to the sponsor 
or representative as soon as it is available. The investigator should always provide an 
assessment of causality for each event reported to the sponsor. Upon receipt of the initial report, 
the sponsor will ask for the investigator's causality assessment if it was not provided with the 
initial report. 
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary AE considered as the foremost 
untoward medical occurrence from secondary AEs which occurred as complications. 
8.1.6 
Pregnancy 
Information regarding pregnancies must be collected as an SAE on the AE page of the eCRF 
and reported to the sponsor within 24 hours as described in Section 8.1.5. 
If pregnancy occurs during the study, the outcome of the pregnancy will be collected following 
completion of the study and it may be necessary to discontinue administration of the IMP.  
The sponsor will request further information from the investigator as to the course and outcome 
of the pregnancy using the Standard Pregnancy Outcome Report Form.  
The investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the study. The investigator should counsel the subject, discuss the risks 
of continuing with the pregnancy and the possible effects on the foetus. Monitoring of the 
subject should continue until conclusion of the pregnancy, which may involve follow-up after 
the subject’s involvement in the study has ended. 
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Pregnancies with a conception date within 7 months after a female subject’s last dose of study 
medication must also be reported to the investigator for onward reporting to the sponsor. 
If the investigator becomes aware of a pregnancy occurring in the partner of a male subject 
participating in the study, this should be reported to the sponsor as described above. Pregnancies 
in the partner with a conception date until 6 months after subject’s last dose of study medication 
should be reported after the partner has given written consent and the partner should be 
counselled and followed as described above. Monitoring of the partner should continue until 
conclusion of the pregnancy. 
8.1.7 
Deaths 
For AEs leading to death, NCI CTCAE Grade 5 is the only appropriate grade 
(see Section 8.1.2.1). Deaths that cannot be attributed to an NCI CTCAE term associated with 
Grade 5 or that cannot be reported within an NCI CTCAE category as ‘Other’ have to be 
reported as one of these four AE options: 
• 
death not otherwise specified (NOS) 
• 
multi-organ failure 
• 
sudden death. 
8.1.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the study medication (see 
Section 4.3). 
If the study medication is discontinued due to an SAE, it must be reported immediately to the 
sponsor’s designated representative (see Section 8.1.5). 
In case of suspected or confirmed COVID-19 infection, the administration of study medication 
may be temporarily discontinued depending on the subject clinical presentation. In some cases, 
the investigator may request a subject be retested before the administration of study medication 
is resumed. The decision to restart a subject’s study treatment will be managed on an individual 
subject basis per the sponsor (or delegate). 
In all cases, the investigator must ensure that the subject receives appropriate medical follow-up 
(see Section 8.1.4). 
8.1.9 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for the submission of reports of suspected 
unexpected serious adverse reactions (SUSARs) occurring during the study to the CAs, IECs 
and other investigators concerned by the study medication. Reporting will be in accordance 
with the applicable regulatory requirements. 
8.2 
Clinical Laboratory Tests 
Full details regarding the required processing, labelling, shipment and destruction processes for 
these samples are provided in the laboratory manual. 
Blood samples will be collected at screening, prior to each dosing visit and at the EoT follow-up 
visit (as per Table 5) for the evaluation of haematology and chemistry. As described in 
Section 6.2.3, ANC, WBC and platelets results must be obtained and reviewed prior to each 
dosing.   
The investigator will review the safety laboratory test results, document the review and record 
any clinically relevant changes occurring or observed during the study in the source 
documentation and in the AE section of the eCRF (see Section 8.1.2.4 for abnormal laboratory 
tests that should be recorded as AEs). 
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All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to baseline or to a level deemed acceptable by the 
investigator and the sponsor’s clinical monitor (or his/her designated representative) or until the 
abnormality is explained by an appropriate diagnosis.  
8.2.1 
Haematology 
Haematology samples will be analysed at each site’s local laboratory and results must be 
available and reviewed prior to dosing. 
Blood samples will be collected to assess the following variables: haemoglobin, WBC count 
with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and others), 
platelet count and coagulation (Prothrombin Time with International Normalised Ratio and 
Activated Partial Thromboplastin Time). 
8.2.2 
Blood Biochemistry 
Serum samples for blood biochemistry must be analysed centrally but can also be analysed 
locally in the case of requiring timely results for medical management. Centrally assessed 
biochemistry is required to confirm eligibility. If local laboratory results are required, the local 
laboratory ranges for ULN and lower limits of normal (LLN) should be included in the 
reporting. Central laboratory samples should always be taken, even if local laboratory samples 
have also been taken: 
• 
creatinine, total bilirubin, conjugated bilirubin 
• 
sodium, potassium, calcium, phosphate 
• 
alkaline phosphatase, AST, ALT, gamma glutamyl transferase 
• 
albumin, total protein. 
8.2.3 
UGT1A1*28 Genotyping 
A whole blood sample will be collected and assessed centrally at baseline to test for 
UGT1A1(TA) repeat polymorphism, which includes UGT1A1*28 allele status. The result is 
not needed prior to the initial dose of irinotecan liposome injection. 
8.2.4 
CA19-9 Biomarker  
Blood samples will be collected and assessed centrally throughout the study for the assay of 
CA19-9 biomarker levels. The CA19-9 biomarker levels will be collected for all subjects as per 
Table 5. 
8.2.5 
Pregnancy Test 
A urine or beta human chorionic gonadotrophin (HCG) serum test will be performed locally for 
all female subjects of childbearing potential as per Table 5. Any positive urine pregnancy test 
must be confirmed via serum β-HCG. Exempt female subjects will include those who have 
undergone a bilateral oophorectomy, bilateral salpingectomy or hysterectomy or who are 
menopausal (defined as absence of a menstrual cycle for at least 2 years). Any subject becoming 
pregnant during the study will be withdrawn. All pregnancies that occur during the study are to 
be reported as described in Section 8.1.6. 
8.2.6 
Urinalysis 
Urinalysis (dipstick) will be completed locally and undertaken as per schedule of assessments 
in Table 5. 
8.2.7 
Dihydropyrimidine Dehydrogenase Testing 
Dihydropyrimidine dehydrogenase (DPD) testing, where required by local regulations, will be 
undertaken as per schedule of assessments in Table 5 and as detailed in Appendix 7. Results 
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should be received and reviewed prior to randomisation to ensure patients with low or absent 
DPD activity will not be enrolled in this study. 
8.3 
Physical Examination 
Physical examinations, including neurological examination will be conducted as per schedule 
of assessments in Table 5. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Vital Signs 
Vital signs will include height (at screening only) weight, resting blood pressure, pulse and 
temperature. BSA is calculated within 2 days before D1 and D15 of each cycle before treatment 
administration. 
8.5 
Electrocardiography 
The ECGs will be recorded at the timepoints described in Table 5, including footnotes 
specifying the different requirements for Arm 1 and Arm 2.  
Any clinically significant abnormalities will be recorded as AEs. 
A 12-lead ECG will include a description of the cardiac rate, rhythm, interval durations and an 
overall clinical interpretation. If the ECG is abnormal, clinical significance or non-significance 
should be indicated. Any QTc prolongation that occurs in the setting of diarrhoea induced 
electrolyte imbalance should be treated with appropriate electrolyte repletion. Once the 
underlying abnormality is corrected and the ECG abnormalities have reversed, treatment may 
continue under careful monitoring and with appropriate dose modification for diarrhoea as 
described in Appendices 2 and 3. 
8.6 
Performance Status  
The ECOG performance status will be recorded at the timepoints in Table 5. The ECOG will 
be assessed by the investigator or his/her designee via questioning of the subject about their 
functional capabilities. See Appendix 6 for ECOG. 
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PAGE 80
 
9 
ASSESSMENTS OF PHARMACOKINETICS 
9.1 
Pharmacokinetics 
9.1.1 
Sample Collection 
For subjects in Arm 1, blood samples for the determination of total irinotecan, SN-38, 5-FU 
and oxaliplatin plasma concentrations will be collected at the timepoints indicated in Table 7. 
Additional analytes which may impact the PK of irinotecan liposome injection may also be 
measured from this sample. 
During the study, the nominal sample collection times may be changed, but the total number of 
samples will not increase. The exact dates and times of blood sample collection, study 
medication administration must be recorded in the eCRF. 
Directions for collection, processing and shipping the PK plasma samples can be found in the 
laboratory manual. Full details regarding the destruction processes for these samples are 
documented in the PK Sample Management Plan. 
The number of draws (and consequently the number of aliquots collected) are detailed in Table 
7. 
Irinotecan and SN-38 levels will be measured in a same aliquot. 5-FU and oxaliplatin levels 
will be measured in different aliquots. 
• 
Sample 1: three aliquots will be collected for irinotecan and SN-38, 5-FU, oxaliplatin 
determination 
• 
Sample 2: one aliquot will be collected for irinotecan and SN-38 determination 
• 
Sample 3: two aliquots will be collected for irinotecan and SN-38, oxaliplatin 
determination 
• 
Sample 4: three aliquots will be collected for irinotecan and SN-38, 5-FU, oxaliplatin 
determination 
• 
Sample 5: two aliquots will be collected for irinotecan and SN-38, oxaliplatin 
determination 
• 
Sample 6: two aliquots will be collected for irinotecan and SN-38, oxaliplatin 
determination. 
Table 7 
Summary of Pharmacokinetic Sampling Timepoints  
Sample 
Time-point 
Number of 
Draws 
Window 
1 
Cycle 1 Day 1 (Pre-Dose): prior to irinotecan liposome 
injection infusion 
3 
-24 hours 
2 
Cycle 1 Day 1: at the end of the irinotecan liposome 
injection infusion 
1 
+15 mins 
3 
Cycle 1 Day 1: at the end of the oxaliplatin infusion 
2 
+5 mins 
4 
Cycle 1 Day 3: within 2 hours prior to the completion of the 
5-FU infusion 
3 
- 
5 
Cycle 1 Days 4 to 14 (Optional[a]): anytime between 1 and 
11 days after the end of the 5-FU infusion 
2 
N/A 
6 
Cycle 1 Day 15 (Pre-Dose): prior to irinotecan liposome 
injection infusion 
2 
-24 hours 
5-FU=5-fluorouracil, N/A=not applicable 
a 
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9.1.2 
Analytical Procedures 
Plasma samples will be analysed to determine concentrations of total irinotecan, SN-38, 5-FU 
and oxaliplatin using validated, specific and sensitive liquid chromatography-mass 
spectrometry methods.  
9.1.3 
Use of Samples After Study Completion 
Leftover samples (plasma) may be used, during the course of the study, or after completion of 
the study to develop new laboratory tests (such as sample stability assessment, analytical 
comedication interference or cross-validation of the bioanalytical method or other bioanalytical 
assessments such as additional analytes that may impact the pharmacokinetics of the drug). If 
the subject consents to this, the samples will be stored up to 1 year after the end of the study in 
a bioanalytical contracted research organisation (CRO) contracted by the sponsor. Subjects will 
be informed that they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the storage period. 
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10 
EXPLORATORY BIOMARKERS AND BIOBANKING 
Biobanking sample collection is optional, requiring separate optional informed consent from 
participants (see Section 14.2.1). Samples for biobanking will be collected as follows: 
• 
Archived tumour samples at baseline, if available 
• 
Whole blood for DNA (2.5 mL) 
• 
Whole blood for RNA (2.5 mL) 
• 
Whole blood for plasma (4 mL) 
• 
Stool sample  
• 
Whole blood for circulating free DNA (10 mL). 
An additional 16.5 to 19 mL of blood will be collected from subjects who have signed the 
optional biobanking informed consent. This will be taken prior to treatment dosing, for a total 
of 19 mL at Cycle 1 Day 1 and 16.5 mL at Day 1 of every other cycle (C3D1, C5D1, C7D1 
etc). Whole blood (for DNA, RNA, circulating free DNA and plasma) and stool samples will 
be collected as follows in both Arm 1 and Arm 2: 
• 
At baseline (Cycle 1 Day 1) prior to treatment dosing: whole blood samples (for DNA, 
RNA, circulating free DNA and plasma) and stool sample. 
• 
At Day 1 of every other additional cycle (i.e. C3D1, C5D1, etc) prior to treatment dosing: 
whole blood samples (for RNA, circulating free DNA and plasma) and stool sample. 
Instructions for collection, processing, handling and shipment of the biobanking samples will 
be outlined in the laboratory manual. Full details regarding the destruction processes for these 
samples are documented in the Biobanking Sample Management Plan. 
 
 
 
 
 
 
 
 
 
 
 
The biobanked samples will be stored for up to 15 years from the end of the study to be made 
available for future research towards further understanding of:  
(1) 
treatment response including, but not limited to, the safety profile 
(2) 
drug treatment mode of actions, and  
(3) 
disease understanding. 
Samples will be archived in a central biorepository designated by the sponsor and according to 
local administration regulations and/or the EMA and will not carry personal identification 
(e.g. social security number or name). Analysis of additional biomarkers (including potential 
genetic research) from the biobank samples will be performed outside the scope of the main 
study and reported separately. 
Only people designated by the sponsor will be allowed access to the samples. All information 
collected will be kept strictly confidential and all clinical information will be de-identified. This 
means that no personally identifiable information will be retained with the results of the 
exploratory analyses, so that no individual or collective results will be linked to the individual 
subject whose sample was taken in the study. No individual genetic results will be 
communicated to the investigator or subject unless required by local regulation. 
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PAGE 83
 
The sponsor will comply with all local regulations related to the establishment, management 
and application of a human blood samples biobank. 
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PAGE 84
 
11 
STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in the SAP, which will be dated and completed before first subject being 
randomised. The SAP may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (Version 9.3 
or higher) 
11.1 
Analysis Populations 
The following populations will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent). 
• 
Intention-to-Treat (ITT) population: This population includes all randomised subjects 
who have given their informed consent. A subject is randomised (after informed consent 
has been provided) if there is confirmation of successful allocation of a randomisation 
number through the study treatment allocation system (IWRS). This population is the 
primary population for all efficacy parameters. All analyses using this population will be 
based on the treatment assigned by IWRS.  
• 
Safety population: The safety population is a subset of the ITT population that received 
at least one dose (including a partial dose) of any study medication. This population is 
for safety analyses. All analyses using this population will be based on the treatment 
actually received. 
• 
Per protocol (PP) population: This is a subset of the ITT population. It includes subjects 
who have no major protocol deviations (i.e. that could potentially affect the primary 
efficacy analysis for the subject) as described in the protocol deviations document. 
Subjects will be analysed as randomised.  
• 
PRO population: All subjects of the randomised ITT population that have provided 
baseline and at least one subsequent assessment on each PRO instrument. 
• 
Pharmacokinetics population: All subjects who received at least one irinotecan 
liposome injection and who have at least one plasma concentration and no major protocol 
deviations affecting PK variables. 
11.1.1 
Populations Analysed 
The final analysis based on the primary efficacy endpoint will be performed on the 
ITT population. In addition, PP analysis may be performed as secondary/confirmatory. 
The analyses of safety data will be performed based on the safety population. 
11.1.2 
Reasons for Exclusion from the Analyses 
Any major protocol deviation (see Section 13.1.2 for definition) will be described and its impact 
on inclusion in each analysis population (ITT, PP and safety populations) for any subject will 
be specified. The final list of protocol deviations impacting the safety, ITT and PP populations 
will be reviewed prior to database lock. The list may be updated, up to the point of database 
lock, to include any additional major protocol deviations impacting inclusion in the PP 
population. 
11.2 
Sample Size Determination 
The primary objective of this study is to compare OS in subjects treated with irinotecan 
liposome 
injection+oxaliplatin+5-FU/LV 
to 
OS 
in 
subjects 
treated 
with 
nab-paclitaxel+gemcitabine.  
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Approximately 750 subjects will be randomised in a 1:1 ratio to the two treatment arms. 
Accounting for the planned interim analysis, follow-up until at least 543 OS events are observed 
across the two treatment arms provides at least 90% power to detect a true HR ≤0.75 (modified 
OS: 9 versus 12 months) using a stratified log rank test with overall 1-sided significance level 
of 0.025 (adjusted for interim analysis). The study plans to enrol 750 subjects, with expected 
follow-up time for the final analysis at 15 months from the last subject enrolled to the 543rd 
OS event. For operational purposes, the expected timing of the final analysis triggering event 
will be periodically projected using blinded study data regardless of treatment arm. The sample 
size may be increased if a review of the accumulating OS events suggests that the timing of the 
final analysis will be extended. If blinded projection of the accumulating OS events suggests 
that the number required for the final analysis will not be reached (due to censoring) within 
32 months of study initiation, the sample size may be increased up to 800 subjects or until 
prespecified events are met, whichever comes earlier. The projection to inform the decision to 
potentially increase the number of subjects will be carried out within 3 months prior to expected 
completion of planned enrolment of 750 subjects. 
Assuming enrolment over 16 months increasing to approximately 62 subjects per month and 
lost-to-follow-up rate of 5% across both treatment arms, the timing of the interim analysis is 
expected to be at 24 months after the first subject treated and the timing of the final analysis, 
estimated via simulation, is expected to be at 36.5 months after the first subject treated. 
11.3 
Significance Testing and Estimations 
The evaluation of the primary endpoint OS includes an interim analysis for futility and efficacy, 
and a final analysis with a prospective error-spending plan to control the overall type I error 
rate at a one-sided 0.025 level and overall type II error rate at 0.100 level. The interim analysis 
is planned when at least 272 OS events (i.e. 50% of information time) have been observed in 
the ITT population. If the OS analysis does not indicate futility at interim analysis, the final 
analysis is planned when 543 OS events are observed. 
An alpha and beta spending function according to Hwang-Shi-Decani (HSD) γalpha=-4 and 
γbeta=-1 will be utilised to control type I and type II error for the OS comparison. In the 
computation of the type I error rate, futility analyses are considered non-binding. Since the 
futility and efficacy boundary is dependent on the number of OS events, the actual boundary 
used will be re-calculated, incorporating the spending function as defined, based on the number 
of actual OS events analysed at the time of analysis. P-boundary will be used as the criteria for 
the formal statistical inference. 
The interim analysis specifications per the plan are provided in Table 8.  
Table 8 
Type I (α) and Type II (β) Error Spending for the Planned Analyses  
(α = 0.025) 
 
 
Futility 
Efficacy 
Analysis 
 
D 
Zboundary 
pboundary 
CUM 
β spend 
HRcrit 
Zboundary 
pboundary 
CUM 
α spend 
HRcrit
Interim  
272 
-0.592 
0.277 
0.038 
0.931 
-2.750 
0.003 
0.003 
0.716 
Final 
543 
-1.981 
0.024 
0.100 
0.844 
-1.981 
0.024 
0.025 
0.844 
 
D = # of OS events at analysis. Z-boundary is the critical test statistic value at which futility (< Z) or efficacy (> Z) would 
be concluded. P-boundary is the critical one-sided p-value threshold for the comparison. Cum α-spend and cum β-spend 
are the amount of cumulative type I and type II error spent at each analysis, respectively. HRcrit is the observed hazard 
ratio threshold (> HR for futility, < HR for efficacy).  
 
 
Secondary efficacy endpoints (PFS and ORR) will only be evaluated if the primary efficacy 
endpoint demonstrates superiority for irinotecan liposome injection+oxaliplatin+5-FU/LV over 
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PAGE 86
 
nab-paclitaxel+gemcitabine. Investigator-assessed tumour response will be used in secondary 
efficacy analyses. If the primary endpoint of OS is declared significant at the interim, secondary 
endpoints will be tested at the interim. Otherwise, secondary efficacy endpoints will be tested 
at the final analysis if OS is found to be statistically significant at that analysis. Hypothesis 
testing of secondary endpoints will be conducted in a stagewise hierarchical manner 
incorporating alpha spending for each endpoint using HSD γalpha= -4, similar to that specified 
for the primary efficacy analysis. The nominal level for each comparison will depend on 
whether the analysis is carried out at the interim or at the planned final analysis. 
The first endpoint in the hierarchy of secondary endpoints will be PFS. If OS and PFS are both 
significant, then ORR would be tested. Any parameter which is not formally tested for 
significance (per the hierarchy) will be regarded as descriptive and exploratory. 
11.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s biometry 
department. All planned efficacy and safety analyses will be done using SAS®. 
Categorical variables will be summarised by frequency distributions (number and percentage 
of subjects). Continuous variables may be summarised by a clinically relevant discretisation 
of the variable. 
All CIs for parameters to be estimated will be constructed with a significance level α =0.05 (i.e. 
a 95% CI). Additional exploratory analyses may be conducted as deemed appropriate. 
The interpretation of study results will be the responsibility of a sponsor physician and 
statistician. The sponsor’s  physician and statistician will also be responsible for the appropriate 
conduct of an internal review process for both the final study report and any study related 
material to be authorised by the sponsor for publication. 
11.4.1 
Demographic and Other Baseline Characteristics 
Descriptive summary statistics (n, mean, standard deviation (SD), median, minimum, 
maximum) or frequency counts of demographic and baseline data will be presented by 
treatment group on the ITT population. No formal statistical analysis will be performed on these 
data. 
Subject characteristics will be summarised and compared between study treatment arms. 
This will include a comparison on: 
• 
Subject demographics 
• 
Baseline disease characteristics 
• 
Baseline disease-related symptoms 
• 
Pre-existing conditions 
• 
Prior and concomitant drugs ongoing at baseline. 
Additional subject characteristics may be summarised and compared between Arm 1 and Arm 2 
as deemed appropriate. 
Unless prohibited by local regulation, race and ethnicity will be collected to ensure data 
robustness for safety and efficacy evaluation and to prevent adverse reactions or improve 
benefits in the target population. 
11.4.2 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in each of the ITT and safety 
populations will be tabulated. In addition, the numbers of subjects who were randomised, 
treated, discontinued and completed at each of the study periods will be tabulated by treatment 
group. Primary reasons for discontinuation of study treatment will be tabulated.  
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PAGE 87
 
Figure 3 CONSORT Flow Diagram 
 
 
11.4.3 
Pharmacokinetic Data 
11.4.3.1 Listings and Summary Statistics of Concentrations 
Individual plasma concentrations for total irinotecan, SN-38, 5-FU and oxaliplatin will be listed 
and summarised by timepoint and dose level using descriptive statistics for continuous variables 
(number of available observations, mean, median, SD, minimum, maximum, geometric mean 
and geometric coefficient of variation assuming log-normally distributed data).  
Linear and semilogarithmic plots of individual and mean plasma concentration-time profiles of 
irinotecan and SN-38 as well as spaghetti plots will be reported. 
11.4.3.2 Pharmacokinetic Data Analysis  
Plasma concentrations of total irinotecan and SN-38 will be used to characterise their 
corresponding PK parameters, in co-administration with 5-FU and oxaliplatin, using a nonlinear 
mixed effects approach. If warranted by the data, parameters reported after single dose could 
include, but not be limited to: 
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• 
Maximum observed plasma drug concentration (Cmax) 
• 
Concentration at the end of the dosing interval (Ctrough) 
• 
Time to maximum observed plasma drug concentration (tmax) 
• 
Area Under the plasma concentration̻time curve over the dosing interval (AUCTau) 
If warranted by the data, plasma concentrations for 5-FU and/or oxaliplatin will be used to 
calculate individual PK parameters after single dose. These may include, but not be limited to: 
• 
Total clearance of drug from plasma  
• 
Area Under the plasma concentration̻time curve over the dosing interval (AUCTau) 
A full description of the analysis of the concentration data will be captured separately in a data 
analysis plan, and PK results will be reported in a standalone report. 
11.4.3.3  Pharmacokinetics/Pharmacodynamics Relationship 
Graphical exploration will be performed to investigate any relationship between PK and 
pharmacodynamic endpoints (efficacy, safety). If a trend is shown, PK/PD modelling will be 
performed and this will be described in a separate Data Analysis Plan and reported in a 
standalone report. 
11.4.4 
Efficacy Evaluation 
11.4.4.1 Primary Efficacy Analysis 
The primary endpoint of this study is OS, which is defined as the time from the date of subject 
randomisation to date of death or the date last known alive. For each subject who is not known 
to have died as of the data-inclusion cut-off date for a particular analysis, OS will be censored 
for that analysis at the date of last contact prior to the data cut-off date. 
The OS for each treatment arm will be summarised by median survival time (including 
95% CIs) from Kaplan-Meier estimation. The Kaplan Meier curve for survival will be presented 
for each treatment arm. Stratified analyses based on the randomisation stratification factors 
from the IWRS data will be used in all stratified analyses for treatment comparisons on the ITT 
population. Differences in the OS curves will be tested using a stratified log-rank test. The 
estimated treatment effect for Arm 1 will be summarised by the HR (including 95% CI) from 
stratified Cox regression analysis.  
The following additional sensitivity analyses may be carried out for OS on the ITT population 
and/or PP population to evaluate the robustness of the final analysis results: 
• 
log-rank comparisons of treatments on the PP population 
• 
Wilcoxon comparisons of treatments on the ITT population and PP population 
• 
log-rank test comparisons of treatments with OS censored at the date where any 
post-treatment anti-cancer therapy is first administered on the ITT population 
• 
Cox regression model with stepwise selection (p value to enter <0.25, p-value to remain 
<0.15) of model terms where treatment and the prognostic factors (noted below) are 
candidates for inclusion 
• 
univariate analyses to evaluate potential independent prognostic factors using Cox 
regression. 
Subgroup analyses will also be performed to examine differences in the effects of treatment in 
different segments of the study population. 
Prognostic factors to be examined may include: baseline ECOG, baseline albumin, ethnicity, 
geographic location, disease stage at diagnosis, original tumour location, prior radiotherapy, 
prior surgery, time since last treatment, best response on prior treatment, baseline CA 19-9, 
gender and age. 
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11.4.4.2 Secondary Efficacy Analysis 
The secondary efficacy endpoints (PFS and ORR) will only be evaluated if the primary efficacy 
endpoint demonstrates superiority for irinotecan liposome injection+oxaliplatin+5-FU/LV over 
nab-paclitaxel+gemcitabine. Investigator-assessed tumour response will be used in the 
secondary efficacy analyses. 
The PFS is defined as time from the date of randomisation to the date of death or progression, 
whichever occurred earlier (per RECIST Version 1.1). If neither death nor progression is 
observed, data will be censored on the date of the last evaluable tumour assessment. 
General censoring rules for the analysis of PFS are described below: 
• 
Subjects who receive non-protocol therapy before a PFS event (documented progression 
or death) will be right censored at the date of the last evaluable tumour assessment prior 
to the date of initiation of subsequent therapy/surgery 
• 
Subjects who have not experienced a PFS event (and are not otherwise censored) at the 
time of data cut-off will be right censored on the date of their last evaluable tumour 
assessment post randomisation that is on or prior to the data cut-off. If there is no such 
tumour assessment post randomisation, the subject will be right censored on the date of 
randomisation 
• 
Subjects who miss two or more scheduled tumour assessments followed by a PFS event 
will be right censored on the date of their most-recent tumour assessment prior to the 
missing assessments.  
Detailed censoring rules and sensitivity analyses will be specified in the SAP. 
For each arm, PFS will be estimated by Kaplan-Meier methodology. Treatment arms will be 
compared for PFS using stratified log-rank test and the estimated HR from stratified Cox 
regression analysis will be presented to summarise the effect of Arm 1. Estimates of median 
PFS and HR will be presented with corresponding 95% CIs. In addition, different censoring 
and missing data imputing methods may be used to perform sensitivity analyses on PFS. 
Methodology for the sensitivity analyses will be fully specified in the SAP. 
Analysis of PFS will be performed for ITT and PP populations. 
The ORR is defined as the proportion of subjects with a BOR of confirmed complete response 
or partial response per RECIST Version 1.1. BOR is defined as the best response as recorded 
from randomisation until documented objective disease progression using RECIST Version 1.1. 
To classify BOR as stable disease, there should be a qualifying stable disease assessment at 
least 8 weeks from randomisation.  
The ORR of irinotecan liposome injection+oxaliplatin+5-FU/LV arm will be compared to the 
nab-paclitaxel+gemcitabine arm. Differences in ORR between Arm 1 and Arm 2 will be 
provided with 95% CIs. A Cochran-Mantel-Haenszel test, adjusting by randomisation strata, 
will be used to compare ORR. Analysis of ORR will be performed for ITT and PP populations. 
11.4.4.3 Patient-Reported Outcomes Analysis 
The PRO exploratory endpoints are described in Section 7.3. 
Analyses of quality of life is an exploratory analysis that will be carried out on treated subjects 
who provide baseline and at least one post-baseline assessment (i.e. there will be 
instrument-specific analysis populations). EORTC QLQ-C30, QLQ-PAN26, EQ-5D-5L and 
PRO-CTCAE results will be summarised at each visit by treatment group. More details of the 
PRO analyses will be provided in the SAP. 
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11.4.5 
Safety Evaluation  
The safety endpoints are indicated in Section 3.2.3. 
All safety data will be included in the subject data listings. Analyses and summary tables will 
be based upon the safety population. 
All AEs will be coded according to MedDRA Version 22.0 or later and will be classified by 
MedDRA preferred term and system organ class. Adverse event listings will be presented by 
subject, system organ class and preferred term. 
The incidence of all reported TEAE and SAEs will be tabulated by arm and overall. In addition, 
summary tables will be presented by maximum severity (per NCI-CTCAE) drug relationship 
and TEAEs associated with premature discontinuation of study treatment. All the safety data 
will be described by grade (all grades and Grade 3 and higher). 
A TEAE is defined as any AE that occurs during the active phase of the study (between first 
dose of study medication and 30 days after the end of study treatment) if:  
• 
it was not present prior to receiving the first dose of study medication, or 
• 
it was present prior to receiving the first dose of study medication but the grade increased 
or became serious during the active phase of the study, or 
• 
it was present prior to receiving the first dose of study medication, the grade/seriousness 
is the same but the causality changed to “related” during the active phase of the study. 
All TEAEs will be flagged in the AEs listings. 
Summary statistics (mean, median, SD and range as appropriate) will be presented by treatment 
group and overall for vital signs, blood pressure, heart rate, ECG variables, clinical laboratory 
tests etc. at each assessment, with change from baseline. For laboratory data, abnormal values 
will be flagged in the data listings and a list of clinically significant abnormal values will be 
presented. Shift tables will be presented for the number and percentage of subjects with low, 
normal or high values and normal or abnormal examinations. 
The AEs reported by investigators using the NCI-CTCAE classification (Version 5.0) will be 
coded using MedDRA (Version 22.0 or later).  
Summary incidence tables will be provided by treatment arm, classified by body system, 
preferred term and associated NCI-CTCAE worst grade. In the event of multiple occurrences 
of the same AEs being reported by the same subject, the maximum intensity (Grade 5 >Grade 4 
>Grade 3 >Grade 2 >Grade 1 >missing >not applicable) will be chosen. Dose delays, 
omissions, and infusion interruptions will be listed by cycle. Summaries of events that resulted 
in dose modifications (e.g. delay, reduction) will also be provided. 
Haematological and biochemical toxicities will be recorded and graded according to the 
NCI-CTCAE criteria, where available. The NCI-CTCAE Grade 3 and 4 haematology and 
biochemistry variables by subject and by cycle will be listed.  
11.5 
Subgroup Analyses 
Descriptive statistics for primary and key secondary endpoints may be provided within each 
category of the following variables:  
• 
presence of liver metastases at baseline 
• 
number of metastatic sites 
• 
baseline ECOG performance status (0/1) 
• 
region (North America/East Asia/Rest of the World)  
• 
disease stage at diagnosis 
• 
primary tumour location 
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• 
baseline CA 19-9 
• 
race 
• 
gender 
• 
age (<65 years, ≥65years, >75 years). 
• 
UGT1A1*28 allele status (homozygous/other). 
Other subgroups will be defined in the Statistical Analysis Plan (SAP). 
11.6 
Independent Data Monitoring Board and Interim Analysis 
An IDMC will be established for this study to operate as an independent expert advisory group 
with the responsibility of evaluating cumulative safety and other clinical trial data at regular 
intervals. As such, the primary objective of the IDMC is to monitor the safety of the subjects 
enrolled in the study by reviewing the available clinical data at scheduled time points, to be 
described in the IDMC Charter, as well as on an ad hoc basis, as needed. Items reviewed will 
include (but not limited to) safety events, any available results of PK testing, and UGT1A1*28 
genotype. Attention will be paid to determining whether any study procedure needs to be 
modified for subjects who are homozygous for the UGT1A1*28 allele. 
The same IDMC will evaluate also the efficacy data as well as the safety data at the time of the 
interim analysis. The IDMC will be responsible for reviewing the futility and efficacy results 
in the interim analysis and making appropriate recommendations based on those results. 
The operating procedures of the IDMC will be based on and in compliance with the FDA’s 
“Guidance for Clinical Trial Sponsors [on the] Establishment and Operation of Clinical Trial 
Data Monitoring Committees” (March 2006, OMB Control Number: 0910-0581) and with the 
EMA’s 
“Guideline 
on 
Data 
Monitoring 
Committees” 
(January 
2006, 
EMEA/CHMP/EWP/5872/03 Corr). 
The planned frequency of the IDMC is planned to be as follows and will be agreed with the 
IDMC experts: 
• 
After the 50th randomised subject has been followed for at least 28 days (follow-up time-
frame equivalent of one cycle) 
• 
Every 6 months and additionally timed with the planned interim analysis: 
- 
Interim analysis for futility and efficacy (no less than 50% of the planned final 
number of OS events in ITT population i.e. 272 of 543) 
All the details of IDMC activities will be described in the IDMC charter. 
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IPSEN GROUP 
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12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external Regulatory Authorities and sponsor authorised Quality 
Assurance personnel may carry out inspections and audits. The purpose of an audit is to ensure 
that ethical, regulatory and quality requirements are fulfilled in all studies performed by the 
sponsor. 
Auditors and inspectors must have direct access to study documents and site facilities as 
specified in Section 13.4 and to any other locations used for the purpose of the study in question 
(e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 
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IPSEN GROUP 
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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Protocol Amendments and Protocol Deviations 
13.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favourable opinion by the IEC/IRB, except when necessary to eliminate immediate 
safety concerns to the subjects or when the change involves only logistics or administration.  
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
• 
Non-substantial amendments are those that are not considered ‘substantial’ 
(e.g. administrative changes) and as such only need to be notified to the IECs or 
regulatory authorities for information purposes. 
• 
Substantial amendments are those considered ‘substantial’ to the conduct of the clinical 
study where they are likely to have a significant impact on: 
• 
the safety or physical or mental integrity of the subjects; 
• 
the scientific value of the study; 
• 
the conduct or management of the study; or 
• 
the quality or safety of the study medication used in the study. 
Substantial amendments must be submitted to and approved by the IECs and relevant 
regulatory authorities, according to local regulations, prior to implementing changes. 
• 
Urgent amendments are those that require urgent safety measures to protect the study 
subjects from immediate hazard and as such may be implemented immediately by the 
sponsor with subsequent IECs and regulatory authority notification, forthwith. 
The principal investigator and the sponsor will sign all protocol amendments. 
13.1.2 
Protocol Deviations and Exceptions 
All protocol deviations will be identified and recorded by the sponsor or sponsor’s 
representative. 
A major protocol deviation is any significant divergence from the protocol, i.e. nonadherence 
on the part of the subject, the investigator, or the sponsor to protocol specific 
inclusion/exclusion criteria, primary objective evaluation criteria and/or GCP guidelines. 
Generally, a protocol deviation qualifies as major if: 
(1) 
The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject 
(2) 
The deviation compromises the scientific integrity of the data collected for the study 
(3) 
The deviation is a wilful or knowing breach of human subject protection regulations, 
policies, or procedures on the part of the investigator(s) 
(4) 
The deviation involves a serious or continuing noncompliance with any applicable 
human subject protection regulations, policies, or procedures 
(5) 
The deviation is inconsistent with the sponsor’s research, medical and/or ethical 
principles. 
See also Section 11.1.2 for details on the impact of major protocol deviations on the inclusion 
of subjects in each analysis population. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria to 
allow subjects to enter a study. If investigative centre personnel learn that a subject who did not 
meet protocol eligibility criteria was entered in a study (a protocol violation), they must 
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immediately inform the sponsor. Such subjects will be discontinued from the study, except in 
an exceptional instance following review and written approval by the sponsor and the 
responsible IRB/IEC, according to the applicable SOP. Retention of these subjects in the study 
will be discussed between sponsor and investigator, taking into account subject safety and data 
reliability. The IRB/IEC will be informed if subject safety/protection is ignorantly impacted. 
13.2 
Information to Study Personnel 
To ensure accurate, complete and reliable data, the sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A study initiation visit will be conducted 
prior to screening start to instruct the investigators and study coordinators. This session will 
give instruction on the protocol, the completion of the eCRF and all study procedures. The 
investigator is responsible for giving information about the study to all staff members involved 
in the study or in any element of subject management, both before starting any study procedures 
and during the course of the study (e.g. when new staff become involved). The investigator 
must assure that all study staff members are qualified by education, experience and training to 
perform their specific responsibilities. These study staff members must be listed on the study 
centre log, which includes a clear description of each staff member’s responsibilities. This list 
must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
13.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring these data to verify that the rights and wellbeing of 
subjects are protected, that study data are accurate (complete and verifiable to source data) and 
that the study is conducted in compliance with the protocol, GCP guidelines and regulatory 
requirements. 
Sponsor assigned monitors will conduct regular site and/or remote visits. The investigator will 
allow direct access to all relevant files (for all subjects) and clinical study supplies (dispensing 
and storage areas) for the purpose of verifying entries made in the eCRF and will assist with 
the monitor’s activities, if requested. Adequate time and space for monitoring visits should be 
made available by the investigator. 
The site must complete the eCRFs on an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The central study monitor at the 
sponsor will use functions of the EDC system to address any queries raised while reviewing the 
data entered by the study site personnel in a timely manner. 
Whenever a subject name (or other identifiable details) is revealed on a document required by 
the sponsor (e.g. laboratory print outs) the information must be blacked out permanently by the 
site personnel and the document annotated with the subject number as identification.  
13.4 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP guidelines. This 
includes that the study may be audited at any time by a quality assurance personnel designated 
by the sponsor or inspected by regulatory bodies. The investigator must adhere to ICH GCP 
guidelines in addition to any applicable local regulations. 
If requested, the investigator will provide the sponsor, applicable regulatory agencies and 
applicable EC with direct access to any original source documents. 
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The investigator(s) should demonstrate due diligence in recruitment and screening of potential 
study subjects. The enrolment rate should be sufficient to complete the study as agreed with the 
sponsor. The sponsor should be notified of any projected delays, which may impact the 
completion of the study. 
This clinical trial will be conducted in compliance with all international laws and regulations 
and national laws and regulations of the country(ies) in which the clinical trial is performed, as 
well as any applicable guidelines. 
13.5 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 12). 
13.6 
Data Quality Assurance 
All eCRFs completed by the investigational site will be reviewed (secondary monitoring) for 
completeness, consistency, legibility and protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator by the monitor for 
clarification/correction. The investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 
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14 
ETHICS 
14.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, the 
Declaration of Helsinki and ICH GCP guidelines (Section 1.6). 
For EDC studies the following regulations are adhered to: FDA 21 CFR Part 11, Electronic 
Records, Electronic Signatures and FDA, Guidance for Industry: Computerized Systems Used 
in Clinical Trials. 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating the study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
ICF, any consent form updates, subject emergency study contact cards, subject recruitment 
procedures (e.g. advertisements), any written information to be provided to subjects and a 
statement from the IEC/IRB that they comply with GCP requirements. The IEC/IRB approval 
must identify the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has started, 
amendments should be made only in exceptional circumstances. Changes that do not affect 
subject safety or data integrity are classified as administrative changes and generally do not 
require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
14.2 
Informed Consent for Participation in the Study 
Prior to study entry, the investigator, or (if applicable under local regulatory guidelines) a 
person designated by the investigator, will explain the nature, purpose, benefits and risks of 
participation in the study to each subject, subject’s legally acceptable representative or impartial 
witness. Written informed consent must be obtained prior to the subject entering the study 
(before initiation of any study-related procedure and administration of the study medication). 
Sufficient time will be allowed to discuss any questions raised by the subject. 
As applicable under local regulatory guidelines, the sponsor will provide a sample ICF. The 
final version controlled form must be agreed to by the sponsor and the IEC/IRB and must 
contain all elements included in the sample form, in language readily understood by the subject. 
Each subject’s original consent form, personally signed and dated by the subject or by the 
subject’s legally acceptable representative and by the person who conducted the informed 
consent discussion, will be retained by the investigator. The investigator will supply subjects 
with a copy of their signed ICF. 
The ICF may need to be revised during the study should important new information become 
available that may be relevant to the safety of the subject or as a result of protocol amendments. 
In this instance, approval should always be given by the IEC/IRB. It is the investigator’s 
responsibility to ensure that all subjects subsequently entered into the study and those currently 
in the study are informed of these changes and sign the amended form. This is documented in 
the same way as described above. Subjects who have completed the study should be informed 
of any new information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 
14.2.1 
Optional Informed Consent for Biobanking 
This study has the option for subjects to consent to the collection of samples for biobanking for 
future exploratory analysis and storage for up to 15 years (where local regulations allow). A 
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specific informed consent is required for the collection of these samples and will be explained 
after the subject has given written informed consent for the main study.  
Subjects must receive an explanation that they are completely free to refuse to enter the 
exploratory part of the study and may withdraw from it at any time and for any reason up to 
15 years after the end of the study and will still be allowed to take part in the main study. 
14.3 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study. Financial remuneration will 
cover the cost per included subject, based on the calculated costs of performing the study 
assessments in accordance with the protocol and the specified terms of payment will be 
described in the contract. The contract should describe whether costs for pharmacy, laboratory 
and other protocol required services are being paid directly or indirectly. 
Financial disclosure statements will be completed, as requested by FDA 21 CFR Part 54. 
14.4 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs group (or delegate CRO) will 
ensure all legal regulatory aspects are covered and obtain approval of the appropriate regulatory 
bodies, prior to study initiation in regions where an approval is required. 
The following documents should be submitted to the relevant ethics committee(s) (EC) for 
review and approval to conduct the study (this list may not be exhaustive and is dependent on 
country requirements):  
• 
protocol/amendment(s) approved by the sponsor; 
• 
currently applicable IB or package labelling; 
• 
relevant investigator’s curriculum vitae; 
• 
subject information and informed consent document(s) and form(s); 
• 
subject emergency study contact cards; 
• 
recruitment procedures/materials (advertisements), if any. 
The EC(s) will review all submission documents as required and a written favourable opinion 
for the conduct of the study should be made available to the investigator before initiating the 
study. This document must be dated and clearly identify the version number(s) and date(s) of 
the documents submitted/reviewed and should include a statement from the EC that they 
comply with GCP requirements. 
The study may begin at the investigative site(s) only after receiving this dated and signed 
documentation of the EC approval or favourable opinion. 
During the study, any update to the following documents will be sent to the EC, either for 
information, or for review and approval, depending on how substantial the modifications are: 
(1) IB; (2) reports or listings of SAEs; (3) all protocol amendments and revised informed 
consent(s), if any. 
At the end of the study, the EC will be notified about the study completion. 
14.5 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In eCRFs and other 
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documents or image material submitted to the sponsor, subjects will be identified by an 
identification code and not by their names, initials or date of birth. 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons on 
behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal medical 
information will always be treated as confidential. 
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15 
DATA HANDLING AND RECORD KEEPING 
15.1 
Recording of Study Data 
In compliance with GCP guidelines, the medical records/medical notes, etc., should be clearly 
marked and permit easy identification of a subject’s participation in the specified clinical study. 
The investigator must record all data relating to protocol procedures, study medication 
administration, laboratory data, safety data and efficacy ratings on the eCRFs provided for the 
study. The investigator, by completing the signature log, may formally designate authority to 
complete eCRFs to appropriately qualified staff having certified user access to the eCRF. 
Subjects’ questionnaires will be collected using an electronic patient-reported outcome (ePRO) 
system.  
The investigator (or delegated sub-investigator) must provide an electronic signature 
(e-signature) to each case report book to attest to the accuracy and completeness of all the data. 
If any changes are made to the eCRF after a form has been locked and electronically signed, 
the investigator (or delegated sub-investigator) will be required to perform an additional 
e-signature authorising agreement with any new information or changes to the eCRF. 
All corrections on the eCRF and ePRO system will be automatically tracked and a reason for 
change is always required. In the eCRF, the audit trail function will allow the changes made to 
be viewed on each item entered. 
15.2 
Data Management 
Electronic data capture will be utilised for collecting subject data. Each site is required to have 
a computer and internet connection available for site entry of clinical data. All entries in the 
eCRF will be made under the e-signature of the person performing the action. This electronic 
signature consists of an individual and confidential username and password combination. It is 
declared to be the legally binding equivalent of the handwritten signature. Only sponsor authorised 
users will have access to the eCRF as appropriate to their study responsibilities. Users must have 
successfully undergone software application training prior to entering data into the eCRF. 
Data management will be conducted by a CRO, directed by the sponsor’s Biometry department. 
All data management procedures will be completed in accordance with the contracted CRO SOPs.  
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately 
and suitable queries are raised to resolve any missing or inconsistent data. The investigator will 
receive their data, from the clinical study, in an electronic format (PDF files) which will be an 
exact copy of the eCRF and will include the full audit trail, for archiving purposes and future 
reference. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. It is the central study 
monitor’s responsibility to ensure that all queries are resolved by the relevant parties. 
The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history, surgical procedures and concomitant medication terms 
will be performed by the sponsor’s central coding group and reviewed and approved by the 
sponsor. Concomitant medications will be coded using WHODRUG and AEs/medical history 
terms will be coded using MedDRA (Version 22.0 or later). 
Only data from screened subjects will be reported in the eCRFs and collected in the sponsor’s 
database. 
For screen failure subjects, only the Unique Subject Identifier, the date of informed consent 
signature, the reason why the subject failed screening and the potential AEs which occurred 
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during the screening phase will be reported in the eCRFs and collected in the sponsor’s 
database. 
15.3 
Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 25 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing out the site. The sponsor will inform the investigator, in writing, as to 
when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 
15.4 
Use of Data After Study Completion 
The study data from consenting subjects may be used, after the end of the study, outside the 
strict context of this study for further or complementary analysis, to better understand the study 
disease or related conditions. The data will be retained while related research activities continue 
but no longer than 25 years after study completion or other period as per local requirements. 
Each subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law and will be informed that they are free to 
refuse. The level of disclosure must also be explained to the subject who will be required to 
give consent for their data to be used as described in the informed consent. 
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16 
FINANCING AND INSURANCE 
16.1 
Insurance, Indemnity and Compensation 
The sponsor will provide product liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 
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17 
REPORTING AND PUBLICATION OF RESULTS 
17.1 
Publication Policy 
The sponsor is committed to disclosing information about the clinical trials it sponsors. Results 
will be communicated at scientific meetings and all reasonable efforts must be made to seek 
publication in a peer-reviewed scientific journal. Specific publication concepts, including data 
to be covered, target congress/journal and proposed authors, should be discussed with the 
appropriate Global Publications Manager and incorporated in the relevant publication plan 
before initiation. A dedicated Publications Committee, involving interested members of the 
study Steering Committee as well as the Global Publications Manager, may be established to 
plan specific publications. As a minimum, summary results of this study should be posted on 
the relevant clinical trial registry. When the trial has been conducted by a large multicentre 
group, the principal investigator, the study steering committee (if applicable) and the sponsor’s 
responsible physician should discuss and agree the selection of authors for planned publications 
in advance. They may decide to use a group name and nominate authors on behalf of the study 
group. All contributing investigators will be listed in the acknowledgements together with any 
others who may have contributed but not sufficiently to qualify for authorship. 
Selection of authors for scientific publications will follow the International Committee of 
Medical Journal Editors guidelines  
[http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-
of-authors-and-contributors.html]. In particular, those named as authors, whether employed by 
a sponsor’s affiliate or the sponsor, or external investigators, ‘should have participated 
sufficiently in the work to take public responsibility for the content’. 
Authorship should be based on: 
• 
Substantial contributions to the conception and design, or acquisition of data, or analysis 
and interpretation of data; AND 
• 
Drafting the article or revising it critically for important intellectual content; AND 
• 
Final approval of the version to be published; AND 
• 
Agreement to be accountable for all aspects for the work, thereby ensuring that questions 
related to the accuracy or integrity of any part of the work were appropriately investigated 
and resolved. 
All authors of a publication should meet all four criteria. Each author must agree to their 
inclusion in the list of authors. Use of professional medical writing support may be employed.  
Resolution of scientific differences in the presentation or interpretation of study findings will 
be conducted along principles of honest scientific debate. The sponsor shall be promptly 
notified of any amendments subsequently requested by referees or journal editors. 
The sponsor requests acknowledgement of all individuals/organisations involved in the funding 
or conduct of the study, including statisticians subject to the consent of each individual and 
entity concerned, including acknowledgement of the sponsor. Any medical writing support 
should also be acknowledged. 
The author undertakes to reasonably consider the sponsor's request for delay to the proposed 
publication should the sponsor reasonably deem premature to publish the results obtained at the 
then stage of the study 
All publications arising from this study will be reviewed by relevant functions at the sponsor, 
coordinated by the Global Publications team. Requests and suggestions for changes will be 
discussed with all authors (and medical writer, if applicable). Resolution of scientific 
differences in the presentation or interpretation of study findings will be conducted along 
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principles of honest scientific debate. The sponsor’s review comments must be answered before 
a final version for submission can be approved by the author team. 
If patentability would be adversely affected by publication, this will be delayed until (i) a patent 
application is filed for the content of the publication in accordance with applicable provisions 
of the clinical trial agreement concerned, (ii) the sponsor consents to the publication, or (iii) the 
time period as may be agreed in the contractual arrangements, including clinical trial 
agreements, governing the relationship between the sponsor and authors (or authors’ institution) 
after receipt of the proposed publication by the sponsor, whichever of (i), (ii) or (iii) occurs 
first. 
17.2 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on structure 
and contents of CSRs. A final CSR will be prepared where any subject has signed informed 
consent, regardless of whether the study is completed or prematurely terminated. Where 
appropriate, an abbreviated report may be prepared. The CSR will comply with any applicable 
regulatory requirements, national laws in force and will be in English. 
As indicated in Section 11.2, an analysis will be performed on the final OS data after the last 
subject has completed the treatment period. This analysis will be included in the final study 
report. Should any subjects remain on treatment at the time of the final analysis an addendum 
to the report will be prepared after the last subject completes study treatment. 
Analysis of biobank samples will be performed outside the scope of the main study and reported 
separately. 
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18 
REFERENCES 
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• 
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Reference 
Documents 
as 
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electronic 
medicines 
compendium 
(emc) 
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• 
Oxaliplatin SmPC 
• 
5-FU SmPC 
• 
LV SmPC 
• 
Nab-paclitaxel SmPC 
• 
Gemcitabine SmPC 
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19 
LIST OF APPENDICES 
Appendix 1 Concomitant Use of Enzyme Inducers and Inhibitors ........................ 109 
Appendix 2 Arm 1 (Irinotecan liposome injection+oxaliplatin+5-FU/LV) Dose 
Modifications .......................................................................................................... 111 
Appendix 3 Arm 2 (Nab-paclitaxel+Gemcitabine) Dose Modifications ................ 115 
Appendix 4 Recommended Birth Control Methods for Women of Child Bearing 
Potential (WOCBP) ................................................................................................ 118 
Appendix 5 Recommendations for Management of Chemotherapy Induced 
Diarrhoea ................................................................................................................ 119 
Appendix 6 ECOG Performance Status ................................................................. 121 
Appendix 7 Dihydropyrimidine Dehydrogenase (DPD) Testing Requirements .... 122 
Appendix 8 Temporary Measures and Procedures Related to COVID-19 
Pandemic ................................................................................................................. 123 
Appendix 9 Amendment 1 Summary of Changes (Version 1.0) to 28 
November 2019 Version 2.0 ................................................................................... 128 
Appendix 10 Amendment 2 Summary of Changes Protocol 28 November 2019 
(Version 2.0) to 20 May 2020 (Version 3.0) .......................................................... 136 
Appendix 11 Amendment 3 Summary of Changes Protocol 20 May 2020 
(Version 3.0) to 03 June 2020 (Version 4.0) .......................................................... 166 
Appendix 12 Amendment 4 Summary of Changes Protocol 03 June 2020 
(Version 4.0) to 19 August 2021 (Version 5.0) ...................................................... 168 
 
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Appendix 1 Concomitant Use of Enzyme Inducers and Inhibitors 
The use of strong CYP3A, CYP2C8, and UGT1A inhibitors or inducers are not allowed during 
the study and specific moderate CYP3A inhibitors and mild inducers of CYP3A4 should be 
approached with caution, as detailed below. Specific stopping periods prior to randomisation 
for enzyme inhibitors and inducers are described below. CYP3A/2C* and UGT1A enzyme 
inhibitors and inducers include prescribed medicines, over the counter medicines, 
complementary and alternative medicines, food supplements and food substances. 
Examples of strong inducers and inhibitors 
• 
Strong CYP3A inducers: rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, 
phenobarbital, St. John's wort, avasimibe, lumacaftor, mitotane, avasimibe, apalutamide, 
ivosidenib, enzalutamide. 
• 
Strong CYP3A inhibitors: grapefruit juice, clarithromycin, indinavir, itraconazole, 
ketoconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, 
voriconazole, troleandomycin, telithromycin, danoprevir, boceprevir, tipranavir, 
posaconazole, mibefradil, conivaptan, regorafenib, cobicistat, elvitegravir, mifepristone, 
ceritinib, ribociclib, idelalisib, LCL161, VIEKIRA PAK 
• 
Strong UGT1A inhibitors: atazanavir, gemfibrozil, ketoconazole, indinavir, regorafenib. 
• 
Strong CYP2C8 inhibitors: ketoconazole and other imidazole antifungals, fluoxetine, 
gemfibrozil, ritonavir, saquinavir, indinavir, nelfinavir, clopidogrel 
• 
Strong CYP2C8 inducers: rifampicin, carbamazepine, phenytoin, efavirenz, and 
nevirapine 
Moderate inhibitor and mild inducer 
• 
Moderate CYP3A inhibitor and mild inducer of CYP3A4: aprepitant, fosaprepitant 
• 
Moderate CYP3A inhibitor: netupitant 
See for further examples e.g. http://medicine.iupui.edu/CLINPHARM/ddis/clinical-table 
or  https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm. 
Arm 1: irinotecan liposomal injection+oxaliplatin+5-FU/LV  
Following administration of non-liposomal irinotecan exposure to irinotecan or its active 
metabolite, SN-38, is substantially reduced in subjects concomitantly receiving the CYP3A 
enzyme-inducing anticonvulsants phenytoin and strong CYP3A inducers. CYP3A inducers 
may impact irinotecan liposome injection similarly. Avoid the use of strong CYP3A inducers 
if possible. Substitute for non-enzyme inducing therapies at least 2 weeks prior to initiation of 
liposomal irinotecan therapy. 
Following administration of non-liposomal irinotecan, subjects receiving concomitant 
ketoconazole, a CYP3A and UGT1A inhibitor, have increased exposure to irinotecan and its 
active metabolite SN-38. Concomitant administration of aprepitant and fosaprepitant (moderate 
inhibitors of CYP3A4) with irinotecan should be approached with caution as the combination 
might result in increased toxicity (neutropenia and diarrhoea). Where anti-emetic options are 
limited to aprepitant and fosaprepitant, these should only be used based on investigator 
judgement considering the risk/benefit to the subject. Co-administration of irinotecan liposome 
injection with CYP3A or UGT1A inhibitors may increase systemic exposure to irinotecan or 
SN-38. Avoid the use of strong CYP3A or UGT1A inhibitors if possible. Discontinue strong 
CYP3A inhibitors at least 1 week prior to starting irinotecan liposome injection therapy. (Data 
source: irinotecan liposome injection USPI). 
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Arm 2: nab-paclitaxel+gemcitabine  
The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A. In the absence of formal 
clinical drug interaction studies, caution should be exercised when administering nab-paclitaxel 
concomitantly with CYP2C8 or CYP3A inhibitors or inducers. (Data source: nab-paclitaxel 
USPI). 
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Appendix 2 Arm 1 (Irinotecan liposome injection+oxaliplatin+5-FU/LV) Dose 
Modifications  
Prior to each dosing subjects must have: 
• 
ANC ≥2000/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Diarrhoea ≤ Grade 1. 
Table 9 summarises dose modifications for Arm 1 haematological toxicities, Table 10 
summarises dose modifications for Arm 1 diarrhoea, and Table 11 summarises dose 
modifications for non-haematological toxicities other than diarrhoea, asthenia and Grade 3 
anorexia. 
Table 9 
Arm 1 (Irinotecan liposome injection+oxaliplatin+5-FU/LV) Dose Modifications for 
Haematological Toxicities 
 
Worst Toxicity by CTCAE 
Grade 
Irinotecan 
liposome 
injection 
5-FU 
Oxaliplatin 
LV 
Grade 2 haematotoxicity 
100% of previous dose 
should remain 
at the same 
dose level 
throughout the 
study 
Grade 3- 4 neutropenia 
(ANC <1000/mm3) or febrile 
neutropenia and/or 
thrombocytopenia 
 
1st occurrence: 
Reduce original dose by 20% 
(80% of original dose) 
2nd occurrence:  Reduce original dose by another 15% 
(65% of original dose) 
3rd occurrence: Reduce original dose by another 15% 
(50% of original dose) 
 
Other Grade 3 or 4 
haematologic toxicities not 
specifically listed above 
1st occurrence: 
Reduce original dose by 20% 
(80% of original dose) 
2nd occurrence:  Reduce original dose by another 15% 
(65% of original dose) 
3rd occurrence: Reduce original dose by another 15% 
(50% of original dose) 
 
5-FU=5-fluorouracil, ANC=absolute neutrophil count, CTCAE=Common Terminology Criteria for Adverse Events, 
G-CSF=Granulocyte-colony stimulating factor, LV=leucovorin 
Note: Any toxicity ≥ Grade 2 can justify a dose reduction if medically indicated following above guidance. At the 
discretion of investigator, study discontinuation can occur prior to 3 dose reductions if risk of potential recurrence of 
febrile neutropenia/neutropenia is considered too high. Subjects who require more than 3 dose reductions must 
discontinue study treatment. Primary prophylactic use of G-CSF should be considered if subjects are considered high risk 
in the opinion of the investigator. Secondary prophylactic use of G-CSF after one episode of febrile neutropenia, infection 
associated with neutropenia and neutropenic sepsis should be considered. 
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Table 10 Arm 1 (Irinotecan liposome injection+oxaliplatin+5-FU/LV) Dose Modifications for Diarrhoea 
  
5-FU=5-fluorouracil, LV=leucovorin, Nal-IRI=irinotecan liposome injection,  
Note: Any toxicity ≥ Grade 2 can justify a dose reduction if medically indicated following above guidance. Subjects who 
require more than 3 dose reductions must discontinue study treatment.  Prophylactic or therapeutic administration of atropine 
should be considered in subjects experiencing cholinergic symptoms (acute diarrhoea and abdominal cramps during or within 
24 hours after nal-IRI administration). 
LV should remain at the same dose level throughout the study. 
a 
Grade 1 diarrhoea: <4 stools/day > pretreatment; Grade 2 diarrhoea: 4-6 stools/day > pretreatment. 
b  
Grade 3 diarrhoea: ≥7 stools/day > pretreatment; Grade 4 diarrhoea: life threatening consequences. 
 
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Table 11 Dose Modifications for Non-Haematological Toxicities Other than Diarrhoea, Asthenia and 
Grade 3 Anorexia 
Worst Toxicity 
by CTCAE 
Grade 
Irinotecan 
liposome 
injection 
5-FU 
Oxaliplatin 
LV 
Grade 3 or 4 
nausea and/or 
vomiting despite 
anti-emetic 
therapy[a] 
Optimise anti-emetic therapy AND 
1st occurrence:  Reduce original dose by 20% 
(80% of original dose) 
2nd occurrence:  Reduce original dose by another 15% 
(65% of original dose) 
3rd occurrence: Reduce original dose by another 15% 
(50% of original dose) 
should remain at 
the same dose 
level throughout 
the study 
Grade 2 hand foot 
syndrome 
100% of 
previous 
dose[b] 
1st occurrence: 
Reduce original dose by 
20% 
(80% of original dose) 
2nd occurrence: Reduce 
original dose by another 
15% 
(65% of original dose) 
3rd occurrence: Reduce 
original dose by another 
15% 
(50% of original dose) 
100% of previous 
dose[b] 
Grade 3 or 4 hand 
foot syndrome 
Discontinue study therapy 
Any grade 
neurocerebellar or 
t Grade 2 cardiac 
toxicity 
Discontinue study therapy 
Sensory 
neuropathy 
100% of 
previous 
dose[b] 
100% of previous dose[b] 
Grade 2, persistent: 
Reduce original dose 
by 20% 
(80% of original dose) 
Grade 3, recovers prior 
to next cycle: 
Reduce original dose 
by 35%  
(65% of original dose) 
Grade 3, recurrent: 
Reduce original dose 
by another 15%[c] 
(50% of original dose) 
Grade 3 persistent or 
Grade 4: 
Discontinue therapy[d] 
Grade 3 or 4 
hepatic, renal, 
respiratory or 
other toxicities 
1st occurrence:  Reduce original dose by 20% 
(80% of original dose) 
2nd occurrence:  Reduce original dose by another 15% 
(65% of original dose) 
3rd occurrence: Reduce original dose by another 15% 
(50% of original dose) 
5-FU=5-fluorouracil, LV=leucovorin 
Note: Asthenia and Grade 3 Anorexia do not require dose modification.  Subjects who require more than three dose 
reductions must discontinue study treatment. Any toxicity ≥ Grade 2, except asthenia and alopecia, can justify a dose 
reduction if medically indicated. 
a 
Recommend dose reduction if not resolved to Grade 1 or 2 after a maximum of 5 days of i.v. anti-emetic treatment 
b 
Any toxicity ≥ Grade 2, except asthenia and alopecia, can justify a dose reduction if medically indicated 
c 
At the discretion of the investigator, subjects can discontinue oxaliplatin therapy if Grade 3 persistent sensory 
neuropathy occurs. 
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d  
Subjects who discontinue therapy due to oxaliplatin-related neuropathy may remain on study and continue to receive 
irinotecan liposome injection+5-FU/LV 
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Appendix 3 Arm 2 (Nab-paclitaxel+Gemcitabine) Dose Modifications 
Prior to each cycle, subjects must have: 
• 
ANC ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Diarrhoea ≤ Grade 1. 
Two levels of dose modifications are permitted according to the criteria described below. If a 
toxicity requiring dose modification occurs following the second dose reduction of either study 
medication, further treatment should be discontinued. Any further dose modification requires 
prior sponsor approval. Subjects experiencing study medication-related toxicities that require a 
delay in scheduled nab-paclitaxel or gemcitabine dosing for more than 21 days will be 
discontinued from further treatment in this study.  
When a dose reduction is required, no dose re-escalation will be permitted for the duration of 
study treatment (with the exception that on Day 15, re-escalation with G-CSF support is 
permitted, after a previous dose reduction on Day 8 of the same cycle).  
Dose level reductions required due to toxicity related to nab-paclitaxel and gemcitabine should 
be made following the guidelines outlined in Table 12. 
Table 12 Dose Level Reductions for Nab-paclitaxel and Gemcitabine 
Dose Level 
Nab-paclitaxel (mg/m2)[a] 
Gemcitabine (mg/m2)[a] 
Full dose 
125 
1000 
1st dose reduction 
100 
800 
2nd dose reduction[b] 
75 
600 
If additional dose reductions required 
Discontinue study therapy 
Discontinue study therapy 
a 
Dose reductions may or may not be concomitant. Please refer to Table 13 and Table 14 for specific recommendations 
regarding dose modifications within a cycle for hematologic and non-hematologic toxicities, respectively. 
b  A maximum of 2 dose level reductions are allowed. 
 
Recommended dose modifications for neutropenia and thrombocytopenia are provided in 
Table 13 and adjustments related to other toxicities are provided in Table 14. 
Table 13 Nab-paclitaxel and Gemcitabine Dose Modifications at the Start of Each Cycle or Within a 
Cycle for Neutropenia and/or Thrombocytopenia 
Cycle 
Day 
ANC (cells/mm3) 
 
Platelet count 
(cells/mm3) 
Nab-paclitaxel/Gemcitabine 
Day 1 
<1500 
OR 
< 100,000 
Delay doses until recovery 
Day 8 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 1 dose level 
 
< 500 
OR 
< 50,000 
Withhold therapy [a] 
Day 15: IF day 8 doses were reduced or given without modification: 
 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 1 dose level from Day 8 
 
< 500 
OR 
< 50,000 
Withhold therapy 
Day 15: IF day 8 doses were withheld: 
 
≥ 1000 
OR 
≥ 75,000 
Reduce 1 dose level from Day 1 
 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 2 dose levels from Day 1
 
< 500 
OR 
< 50,000 
Withhold therapy 
ANC = absolute neutrophil count 
Primary prophylactic use of G-CSF should be considered if subjects are considered high risk in the opinion of the 
investigator. Secondary prophylactic use of G-CSF after one episode of febrile neutropenia, infection associated with 
neutropenia and neutropenic sepsis should be considered. 
See Section 6.2.5.2 for the maximum interval of delay allowed between doses. 
a If Day 8 is delayed, this dose should be omitted and the next dose scheduled for Day15. 
 
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Table 14 Nab-paclitaxel and Gemcitabine Dose Modifications for Other Adverse Drug Events 
Adverse Drug Reaction 
Nab-paclitaxel 
Gemcitabine 
Febrile Neutropenia: 
Grade 3 or 4 
Withhold until fever resolves and ANC ≥1500 cells/mm3; resume at next 
lower dose level 
Peripheral Neuropathy:  
Grade 3 or 4 
Withhold until improves ≤ Grade 1; resume at 
next lower dose level 
No dose reduction 
Cutaneous Toxicity: 
Grade 2 or 3 
Reduce to next lower dose level; discontinue treatment if toxicity persists 
Gastrointestinal Toxicity: 
Grade 3 mucositis or diarrhoea 
Withhold until improves to ≤ Grade 1; resume at next lower dose level 
ANC = absolute neutrophil count 
Data source: nab-paclitaxel USPI 
Primary prophylactic use of G-CSF should be considered if subjects are considered high risk in the opinion of the 
investigator. Secondary prophylactic use of G-CSF after one episode of febrile neutropenia, infection associated with 
neutropenia and neutropenic sepsis should be considered. 
Peripheral Neuropathy 
Nab-paclitaxel treatment should be withheld in subjects who experience ≥Grade 3 peripheral 
neuropathy. Gemcitabine administration can continue during this period. Nab-paclitaxel 
treatment may be resumed at the next lower dose level in subsequent cycles after the peripheral 
neuropathy improves to ≤Grade 1. Subjects experiencing peripheral neuropathy that requires a 
delay in scheduled nab-paclitaxel dosing for ≥21 days will discontinue study treatment. The 
time to resolution to Grade ≤1 should be the AE duration used for AE reporting. 
Cutaneous Toxicity 
Subjects who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to the 
next lower dose level for both drugs. If the subject continues to experience these reactions, 
despite dose reduction, treatment should be discontinued. Subjects who develop Grade 4 
cutaneous toxicity should have treatment discontinued. 
Gastrointestinal Toxicity 
If Grade 3 mucositis or diarrhoea occurs, study medication should be withheld until resolution 
to ≤Grade 1, then reinstituted at the next lower dose level of both drugs. Subjects who develop 
Grade 4 mucositis or diarrhoea should have treatment discontinued. 
Pulmonary Embolism 
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular-
weight heparin without interruption of therapy. Moderate to severe pulmonary embolism will 
require permanent discontinuation of treatment. 
Interstitial Pneumonitis 
During study participation, subjects should be carefully monitored for signs and symptoms of 
pneumonitis (i.e. episodes of transient or repeated dyspnoea with unproductive persistent cough 
or fever) and, if observed, immediate clinical evaluation and timely institution of appropriate 
management (emphasising the need for corticosteroids if an infectious process has been ruled 
out as well as appropriate ventilation and oxygen support when required). Study medication 
administration should be permanently discontinued upon making a diagnosis of interstitial 
pneumonitis. 
Hypersensitivity Reactions 
Hypersensitivity reactions are not expected with either nab-paclitaxel or gemcitabine. If they 
do occur, minor symptoms such as flushing, skin reactions, dyspnoea, hypotension, or 
tachycardia may require temporary interruption of the infusion. However, severe reactions, such 
as hypotension requiring treatment, dyspnoea requiring bronchodilators, angioedema, or 
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generalised urticaria require immediate discontinuation of study medication administration and 
aggressive symptomatic therapy. 
Subjects who develop a severe hypersensitivity reaction should not be re-challenged. 
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PAGE 118
 
Appendix 4  Recommended Birth Control Methods for Women of Child Bearing 
Potential (WOCBP) 
Below is a guideline which lists contraceptive methods that can achieve a failure rate of less 
than 1% per year when used consistently and correctly, and are considered as highly effective 
birth control methods, as published by the Clinical Trials Facilitation Group: 
• 
combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation: 
• 
oral 
• 
injectable 
• 
implantablea 
• 
intrauterine device (IUD)a 
• 
intrauterine hormone-releasing system (IUS)a 
• 
bilateral tubal occlusiona 
• 
vasectomised partnera,b 
• 
sexual abstinencec 
a Contraception methods that in the context of this guidance are considered to have low user dependency. 
b Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical 
success. 
c In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject 
 
Note: A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
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Appendix 5 Recommendations for Management of Chemotherapy Induced Diarrhoea
Proposed algorithm for the assessment and management of treatment-induced diarrhoea is 
provided below in Table 15. These guidelines are adapted from those developed by an 
American Society of Clinical Oncology (ASCO) panel and ESMO Clinical Practice Guidelines 
for treating chemotherapy-induced diarrhoea [Benson 2004, Utaris 2015, Bossi 2018]. Also 
Appendix 2, Table 10 for Arm 1 management of dose modifications. 
Anti-diarrhoea management should be initiated at the first episode of poorly formed or loose 
stools or the earliest onset of bowel movements that are more frequent than normal. 
Table 15 Recommendations for Management of Chemotherapy Induced Diarrhoea 
Dietetic 
Dietetic Measures (applicable for all grades of diarrhoea) 
Stop all lactose-containing products 
Drink 8 to 10 large glasses of clear liquids per day 
Eat frequent small meals 
Recommend low-fat diet enriched with bananas, rice, apple sauce and toast i.e. BRAT diet 
Fluid Intake 
Approximately 2L should be maintained 
Ensure appropriate fluid and electrolyte replacement 
Pharmacological Treatment 
First Line Therapy: loperamide 
Clinical Presentation 
Intervention 
If receiving prophylaxis:  
Increase loperamide dose to a maximum of 16 mg/day. Continue until 
diarrhoea free for 12 hours. If no improvement within 48 hours implement 
second-line therapy. 
If new-onset diarrhoea: 
Take loperamide 4 mg with first bout of diarrhoea followed by 2 mg every 
4 hours or after every unformed stool (maximum 16 mg/day). Continue 
until diarrhoea free for 12 hours. If no improvement within 48 hours 
implement second-line therapy. 
With recovery to ≤Grade 1: 
Take loperamide 4 mg one dose with each subsequent cycle of irinotecan 
liposome injection administration. 
Second Line Therapy 
Grade 1 
If persistent diarrhoea on loperamide: 
Add diphenoxylate, hydrochloride plus atropine suffate (Lotomil®) 2.5 mg 
every 6-8 hours. 
Monitor for trend in decreasing WBC and/or neutropenia. 
Recommend G-CSF if decreasing WBC and/or neutropenia to avoid 
infectious/septic complications. See Section 6.3.3. 
Grade 2  
If persistent diarrhoea on loperamide: 
Add octreotide (short acting) 150 μg subcutaneously tid or after initial dose 
of short acting octreotide, if well tolerated, a single dose of octreotide LAR 
20 mg intramuscularly. 
Monitor for trend in decreasing WBC and/or neutropenia. 
Recommend G-CSF if decreasing WBC and/or neutropenia to avoid 
infectious/septic complications. See Section 6.3.3. 
Consider stool cultures to exclude infectious causes (e.g. Clostridium 
difficile) prior to prophylactic antibiotics, especially if diarrhoea is 
persistent beyond 24 hours or if there is a fever or Grade 3 or 4 neutropenia 
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CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 120
 
 
Grade 3/4 
After intensive loperamide therapy:  
Titrate loperamide to keep diarrhoea controlled (<4 stools/day). 
Octreotide (100 to 150 μg subcutaneously bid or 25 to 50 μg/hour 
intravenously if dehydration is severe, with dose escalation up to 500μg 
subcutaneously tid). 
Intravenous fluids as appropriate. 
Consider prophylactic antibiotics, especially if diarrhoea is persistent 
beyond 24 hours or if there is a fever or Grade 3 or 4 neutropenia. 
Stool cultures to exclude infectious causes. 
Monitor for trend in decreasing WBC and/or neutropenia. 
Recommend G-CSF if decreasing WBC and/or neutropenia to avoid 
infectious/septic complications. See Section 6.3.3 
Consider stool cultures to exclude infectious causes (e.g. Clostridium 
difficile) prior to prophylactic antibiotics, especially if diarrhoea is 
persistent beyond 24 hours or if there is a fever or Grade 3 or 4 neutropenia 
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IPSEN GROUP 
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PAGE 121
 
Appendix 6  ECOG Performance Status 
Grade 
ECOG Performance Statusa 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
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 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
a Published by Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group.Am J Clin Oncol. 1982;5:649-655. 
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PAGE 122
 
Appendix 7  Dihydropyrimidine Dehydrogenase (DPD) Testing Requirements 
Requirements for France 
The Haute Autorité de Santé (HAS) (French National Authority for Health) and the Institut 
National du Cancer (INCa) (French National Cancer Institute) recommend testing for DPD 
deficiency by determination of uracil plasma concentration (uracilemia) where 
fluoropyrimidine treatment is planned. 
This test is recommended in the following conditions: 
• 
pre-analytical conditions: use of blood collection tubes without separator gel and with 
anticoagulant, maximum delay between sample and centrifugation 1 hour 30 minutes if 
the sample is stored at ambient temperature, and 4 hours if it is stored at +4°C, 
centrifugation preferably at +4°C then immediate freezing of the resulting plasma, 
transport respecting the cold chain, 
• 
assay technique: by high or ultra-high performance liquid chromatography (several 
possible detection modalities). 
Failure to comply with these conditions must lead to a report of non-compliance brought to 
the attention of the clinician as soon as possible so that a new sample can be sent to the 
laboratory quickly. 
• 
interpretation and expression of the results: 
- 
uracilemia ≥150 ng/ml suggests complete DPD deficiency 
- 
uracilemia ≥16 ng/ml and <150 ng/ml suggests partial DPD deficiency 
• 
interpretation of the results on the basis of these threshold values must take account the 
fact that uracilemia is a continuous variable and that the risk of severe toxicity increases 
therefore theoretically as uracilemia increases. 
Subjects with low or absent DPD activity (complete deficiency i.e. blood uracil level 
≥150 ng/ml and partial deficiency i.e. blood uracil level between ≥16 ng/ml and <150 ng/ml) 
will not be eligible for inclusion in this study. 
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IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 123
 
Appendix 8 Temporary Measures and Procedures Related to COVID-19 Pandemic 
This appendix is intended to provide temporary measures to manage study assessments that 
cannot be done in compliance with the current protocol version approved at your site, because 
of the COVID-19 pandemic. 
The implementation of the below measures must be in line with applicable country regulation 
or national temporary COVID-19 measures guidance and must remain temporary until situation 
resolves, at which point the protocol assessments will return to those specified in the current 
approved protocol effective at that time. The temporary measures may remain in place for 
differing periods of time per country/site. 
The temporary measures specified in the appendix must be reported as deviation related to 
COVID-19 and must still be documented and reported to the ECs/IRB and/or Health 
Authorities, based on the regulatory requirements applicable at your country/site, in addition to 
any deviation to the current protocol. 
Investigators will determine the feasibility of starting or continuing study treatment on a 
subject-by-subject basis, depending on the ability to conduct safety monitoring and providing 
subjects an adequate supply of study treatment, in accordance with local requirements.  
Specific Guidance for Study Visits and Assessments  
Study Schedule  
If the COVID-19 pandemic prevents subjects from coming to the site, subjects can have their 
study visit assessments performed remotely as judged appropriate by the investigator. This must 
be discussed with the sponsor or delegate before being implemented. In such a case, the 
investigator will perform a telemedicine visit and will make every effort, where applicable, to 
contact the subject’s general practitioner or specialist physician to ensure all important medical 
information and safety event(s) occurring since the last visit are collected. Guidance on how to 
collect protocol-planned assessments is provided below. 
The IECs/IRBs will be notified of the changes as applicable locally. Of note, as the adapted 
visit deviates from the regular protocol plan, the changes will be recorded as protocol deviations 
related to COVID-19. 
Screening and Enrolment 
Subjects cannot be screened more than once. However, if a subject tests positive for COVID-19 
during the screening period, this should be escalated to the sponsor (or delegate), in case an 
extension of the screening period is required for the subject to recover. In exceptional 
circumstances, where a subject starts screening procedures, which are then delayed due to 
COVID-19 (for example testing positive for COVID-19), the subject might continue with the 
screening assessment once a negative test is confirmed to confirm all eligibility criteria are met 
prior to randomisation, even if this is outside the normal 28-day screening window, after 
discussion with the sponsor (or delegate).  
Informed Consent (including Re-consent) 
As per guidelines issued by the FDA in the US and in line with guidance in other countries, the 
use of electronic signatures is authorised to obtain the subject’s informed consent. The sponsor 
and IRB need to be notified of the use of electronic informed consent signature and the accepted 
electronic formats need to be clearly documented. This is not meant to replace the important 
discussion between the subject, investigator and site staff. Such a discussion must still occur 
and be part of a screening visit (in-person, by telemedicine, or home health visit). A clearly 
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IPSEN GROUP 
D-US-60010-001 
 
CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 124
 
documented process on how subjects are contacted virtually to explain the study and close 
monitoring needs to be in place. 
Screening visit and assessments (apart from informed consent as described above) must be 
performed on site. 
Dosing Visits (Arm 1 and Arm 2) 
In case of dosing visit delayed due to COVID-19 (temporary closure of the site, subject 
unable to travel etc). 
• 
Dose delay rules should be followed as per last protocol version approved at your site. 
In case of dosing visit delays outside of the protocol, these should be discussed between 
the investigator and the sponsor or delegate 
In case of suspected COVID-19 infection 
• 
The administration of study medication may be temporarily discontinued depending on 
the patient clinical presentation. In some cases, the investigator may request a subject be 
retested before the administration of study treatment is resumed. 
• 
In all cases, the investigator must ensure that the subject receives appropriate medical 
follow-up. It will be in the PI’s medical judgement to assess the benefit and risks of 
restarting study treatment. If a subject has temporarily discontinued study treatment, the 
decision to restart subjects on study treatment will be managed on an individual subject 
basis in discussion with the sponsor (or delegate) and investigator. 
In case of confirmed COVID-19 infection 
• 
Subjects who presents with COVID-19 positive-confirmed infection should be placed on 
immediate study treatment delay as per institutional guidelines [Curigliano 2020]. In 
addition, any suspected or confirmed coronavirus COVID-19 (SARS-CoV-2) infection 
should be considered serious and be immediately reported to the sponsor. 
• 
Since there is lack of data on risk/benefit analysis of the study treatment arms and 
COVID-19 infection, in the absence of a confirmatory negative COVID-19 PCR test in 
an asymptomatic subject, it is in the investigator’s medical judgement to assess the 
benefit and risks of restarting study treatment. The management of subjects following 
this quarantine period and decision to restart subjects on study treatment will be managed 
on an individual subject basis in discussion with the sponsor (or delegate) and 
investigator. 
• 
In addition to the above criteria, any suspected or confirmed coronavirus COVID-19 
(SARS-CoV-2) infection should be considered serious and be immediately reported to 
the sponsor. The seriousness criteria should be “other medically significant” if no other 
seriousness criteria are present (e.g. hospitalisation). 
Physical Examinations and ECOG Performance Status  
Assessment can be done via telemedicine (as per the rules below) and should be done according 
to local practice.  
Quality of Life Assessments  
The subject has access to the ePRO application via their own devices (mobile phone, tablet) via 
an electronic application. Site staff are to ensure this has been set up for a subject and provide 
training where required. If the subject is unable to use the application on their own then the 
information can be collected via a telephone call; the site staff will call the subject, ask the 
questions as per the assessment in exactly the same order and wording (paraphrasing is not 
allowed) and directly enter the data into the eCRF on behalf of the subject. Answers to questions 
must not be noted down first and then entered into the eCRF as this could impact validation of 
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IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL: VERSION 5.0 WITH AMENDMENT #4 – 19 AUGUST 2021 
PAGE 125
 
the ePRO tool. Details of the verification of the patient and the site personnel conducting the 
assessment should be documented. 
Disease Evaluation: CT/MRI Scans  
This study assessment does not always coincide with a dosing day, though it might coincide if 
the subject has had no dosing delays (e.g. due to toxicity). In the case where the assessment 
does not coincide with a dosing visit, to reduce the risk associated with travelling to a study 
site, imaging may be performed at a local imaging facility. The modality to be used for the 
imaging is to be documented and shared with the local imaging facility. The same imaging 
modality must be used to ensure consistency and secure central reading. Also, central reading 
requires that consistent slide thickness (deemed acceptable <5mm) and same methodology 
(with vs without contrast agent) across acquisitions timepoints is met. Please secure scan 
modality slide thickness and methodology used from baseline are shared with local imaging 
facility.  
Documentation of the imaging facility is to be collected by the site and retained. Scanned 
images are to be shared with the site. The site is responsible for submitting scans for Medpace 
Imaging Central Laboratory. The RECIST reading is to be done by the investigator for 
treatment choices. The local facility must be informed about potential queries that may be sent 
from the central reader after image upload by the main site. These queries may need to be 
addressed by the local imaging facility. A clear process should be documented in writing to 
explain how the queries issued from central image QC will be managed between the local 
facility and the site. 
Sample Collection 
Haematology and Biochemistry: To reduce the risk associated with travel to the site if the 
patient comes in the day prior to dosing for haematology sampling, or to reduce the risk 
associated with time the subject spends at the study site, a local laboratory may be used to obtain 
and analyse the haematology samples. Results of haematology samples taken need to be shared 
with the investigational site and assessed prior to dosing as per protocol requirements. 
Documentation of the local laboratory (accreditation and reference ranges) are required to be 
collected and shared with the sponsor. As the subject attends the site for dosing, effort should 
be made to collect biochemistry samples for central laboratory assessment, as well as all other 
central laboratory samples. If this is not possible, local biochemistry samples are to be collected 
as described above. 
Pregnancy Test: Pregnancy testing is required on Day 1 of each cycle. To reduce the risk 
associated with travel to the site, if the subject comes in the day prior to dosing for pregnancy 
testing, or to reduce the risk associated with time the subject spends at the study site, a local 
laboratory, hospital or general medical practice may be used to obtain the pregnancy test. 
Results of the pregnancy test need to be shared with the investigational site and assessed prior 
to dosing as per protocol requirements. 
Arm 1: 5-FU Pump Removal 
To reduce the risk associated with travel to site, pump removal can be performed at home, a 
local hospital or at a general medical practice. In case of a home visit, the patient must agree 
that someone will visit them at home for this pump removal. Agreement between the study site 
and the responsible personnel removing the pump needs to be in place, including documentation 
of how information will be shared, and must be in line with local regulations with regards to 
privacy and confidentiality. Details of the time of pump removal must be shared by the 
responsible personnel with the site. The site staff should call the subject on the day of the pump 
removal to discuss the medications the subject may be taking as well as any AE updates since 
the previous visit. Details of the verification of the identity of the subject and the site personnel 
conducting the assessments (both the pump removal as well as the phone call) must be 
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IPSEN GROUP 
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PAGE 126
 
documented. In case of home removal of the 5-FU pump, PK samples that will not be collected 
will have to be reported as deviation. 
Concomitant Medications and Procedures 
Details can be collected by site staff via telephone call as per the rules relating to use of 
telemedicine below. 
COVID-19 vaccines and or medication shall be reported as concomitant medication. 
AE Reporting 
Of note, as per protocol Section 8.1.5, all COVID-19 cases (suspected or confirmed) should be 
considered as Serious Adverse Events. 
“Other Medically significant” should be selected as seriousness criterium if no other seriousness 
criteria are present (e.g. hospitalisation). 
Details can be collected by site staff via telephone call as per the rules relating to use of 
telemedicine below. 
Note that further information about measures adopted for the COVID-19 situation to cover SAE 
reporting and temporary discontinuations are found in Sections 8.1.5 and 8.1.8, respectively. 
Specific Rules Relating to use of Telemedicine 
The form of telemedicine used (phone call or use of a platform), the legal and privacy protection 
of the subjects as well as details of the verification of the identity of the subject and site 
personnel conducting the assessment should be documented at site level and should be available 
for review by the monitor. 
Source Data Verification 
When remote data monitoring is allowed per local regulations/national guidance and possible 
at site, PI or delegate must: 
• 
document in the source documents verbal consent from their subject for remote 
monitoring of their data by the sponsor during the pandemic 
or 
• 
obtain written consent from their subject for remote monitoring of their data if required 
by local regulations and/or “on site” monitoring of subject data is specified in the local 
ICF. 
Guidance on COVID-19 Vaccine and/or Medication 
Currently available COVID-19 vaccines do not contain live virus; therefore, they are permitted 
during the study period. 
Future approved COVID-19 vaccines and or medication will be assessed by the Sponsor. 
Subjects may receive COVID-19 vaccination if they have no contraindications to any 
component of the specific vaccine. However, they should be counselled by the investigator 
about benefit/risk of getting the vaccination based on their individual health conditions as well 
as with the healthcare physician administrating the vaccination, about the unknown vaccine 
safety profile and effectiveness in immunocompromised populations, as well as the potential 
for insufficient immune responses, and the need to continue to follow all current guidance to 
protect themselves against COVID-19. 
The co-administration of the COVID-19 vaccines with study treatment has not been studied. 
Based on the lack of evidence following is recommended [Desai 2021]: 
• 
Avoiding administration of study treatment within 48 to 72 hours of vaccination to 
minimize confusion and/or inaccurate attribution of adverse event causation. 
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• 
On study treatment: patients can be vaccinated between cycles of intermittent cytotoxic 
chemotherapy 1 to 2 weeks before or 1 to 2 weeks after drug dose, when possible, to 
increase the potential for the immune system to mount a response. 
Investigator discretion is necessary to ascertain benefit/risk taking into consideration subject’s 
clinical condition. COVID-19 vaccines and or medication shall be reported as concomitant 
medication. 
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Ipsen Bioscience 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60010-001 
  
Version 5.0, 20 September 2022 
 
STATISTICAL ANALYSIS PLAN 
Protocol Title: 
An open-label, randomised, multicentre, phase III study of 
irinotecan liposome injection, oxaliplatin, 
5-fluorouracil/leucovorin versus nab-paclitaxel plus 
gemcitabine in subjects who have not previously received 
chemotherapy for metastatic adenocarcinoma of the pancreas 
Protocol Number: 
D-US-60010-001 
Protocol Version/Date: 
Version 5.0/19 August 2021 
Investigational Product: 
Irinotecan liposome injection (IPN60010) 
 
 
Sponsor: 
Ipsen Bioscience 
Ipsen Group 
1 Main St, Cambridge, MA 02142, USA 
 
 
 
SAP Version/Date: 
Version 5.0/20 September 2022 
CONFIDENTIAL 
Persons supplied with this information must understand that it is strictly confidential. Information 
contained herein cannot be disclosed, submitted for publication or used for any purpose other than that 
contemplated herein without the sponsor’s prior written authorisation. 
 


Ipsen Bioscience 
D-US-60010-001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 5.0, 20 September 2022 
Page 2 of 63 
 
 
SIGNATURE PAGE 
Protocol Title: 
An open-label, randomised, multicentre, phase III study of 
irinotecan liposome injection, oxaliplatin, 
5-fluorouracil/leucovorin versus nab-paclitaxel plus gemcitabine 
in subjects who have not previously received chemotherapy for 
metastatic adenocarcinoma of the pancreas 
Protocol Number: 
Version 5.0 
SAP Version/Date: 
Version 5.0/20 September 2022 
 
 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
 
 
Signature 
Date 
 
 
 
 
Medpace 
Medpace 
 
Medpace 
 
Medpace 
 
 
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Ipsen Bioscience 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60010-001 
  
Version 5.0, 20 September 2022 
Page 3 of 63 
 
 
 
 
 
 
 
Ipsen 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Ipsen Bioscience 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60010-001 
  
Version 5.0, 20 September 2022 
Page 4 of 63 
 
VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
16 January 2020 
Original signed version 
2.0 
16 September 2020 
Updates based on protocol version 4.0 
• 
Futility-only interim analysis changes to at 181 
OS events; interim analysis for both futility 
and efficacy at 401 overall survival events; 
total sample size changes to 565 overall 
survival events. 
• 
Other updates to be consistent with protocol 
version 4.0. 
3.0 
06 January 2022 
• 
Futility-only interim analysis at 181 OS event 
is removed. The interim analysis is planned 
when at least 272 OS events. Final analysis is 
planned at least 543 OS events. 
• 
Move study endpoint description and 
derivation language in section 2 to analysis 
section 3 and appendix. 
• 
Adverse events of special interest language is 
modified to use case report option. Standard 
MedDRA Query for adverse events of special 
interest is removed from appendix. 
• 
Duration of response definition is modified to 
include death in addition to tumor progression 
using RECIST 1.1. 
• 
BOR definition is clarified from randomization 
until documented objective disease progression 
using RECIST Version 1.1. 
• 
Estimand language is added in section 3.4. 
• 
Other editorial revisions throughout the 
statistical analysis plan document. 
• 
Other updates to be consistent with protocol 
version 5.0. 
• 
Clarify further subsequent anti-cancer therapy 
includes drug therapy, curative radiotherapy, 
curative surgery 
4.0 
10 August 2022 
• 
Change time to deterioration exploratory 
objective only includes GHS, function 
domains, and disease related symptoms from 
EORTC QLQ-C30 
• 
Change analysis day calculation from using 
first dose of study treatment to randomization. 
• 
Disposition includes subjects who received 
non-planned study treatments and subjects with 
ongoing long-term follow up 
• 
Remove summary of post-treatment 
medications 
• 
Modify prior medication definition 


Ipsen Bioscience 
CONFIDENTIAL 
Statistical Analysis Plan 
D-US-60010-001 
  
Version 5.0, 20 September 2022 
Page 5 of 63 
 
Version 
Version Date 
Description 
• 
Change OS sensitivity analysis Wilcoxon 
analysis to Unstratified log rank 
• 
Add Unstratified log rank to PFS sensitivity 
analysis 
• 
Remove summary and plots for tumor size 
(sum of diameters) 
• 
Add analysis visit windows for PRO data 
• 
Clarify new anti-cancer therapy to subsequent 
anti-cancer therapy (drug therapy, curative 
radiotherapy, curative surgery) including new 
antineoplastic treatment. 
• 
Clarify analysis Intent-to-Treat definition from 
all randomised subjects who have given their 
informed consent to all randomised subjects to 
whom study treatment has been assigned by 
randomization. Subjects will be analyzed 
according to the assigned treatment per 
randomization procedure.  
• 
Clarify Safety Population is a subset of the ITT 
population that received at least one dose 
(including a partial dose) of any component of 
the study medication in the combination 
therapy). Subjects will be analyzed according 
to the actual received treatment 
• 
Tumor assessments performed after or on any 
further subsequent anti-cancer therapy will not 
be used in the assessment of best overall 
response (BOR).   
• 
Clarify TEAEs leading to discontinuation of 
study treatment summary will also include 
related to IMP and related to Irinotecan 
liposome injection 
• 
Sensitivity analysis of OS using Cox 
regression with stepwise selection and 
univariate analysis of OS for prognostic factors 
are removed. 
• 
Change all baseline summaries to use ITT 
population 
• 
Add AE combining rules and modify TEAE 
summaries 
• 
Add lab abnormality tables 
• 
Change analyses of QoL primarily based on 
ITT population. PRO population may be used 
as the sensitivity analyses 
• 
Add results from unstratified log-rank test and 
Cox model into main OS and PFS analyses 
• 
Clarify study exposure analyses 
• 
Update TEAE and death summary 


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Version 
Version Date 
Description 
5.0 
20 September 2022 
• 
Clarification of ECOG baseline definition in 
section 3.1.3 
• 
Update demographic and baseline 
characteristics in section 3.3.4 
• 
Section 3.3.8 add withdrawal of study consent 
with lost to follow-up to last date of exposure 
of study drug calculation 
• 
Remove withdrawal from study ICE from 
Table 1 in section 3.4.1 
• 
PFS censoring rules in section 3.4.2 Table 3 
replace censoring rule of treatment 
discontinuation with withdrawal of study 
consent and/or lost to follow-up 
• 
PFS sensitivity analysis and Table 4 in section 
3.4.2 update following Table 3 change 
• 
clarify ICE1 handling strategy Table 5 in 
section 3.4.2. 
• 
Update number of complete cycle formula in 
section 3.3.8 
• 
Section 3.4.4 remove AJCC prognostic stage 
subgroup 
• 
Modify age subgroup to <65 years, >=65 years 
in sections 3.4.4 and 3.6 
• 
Section 3.6.3 revised ALT/AST abnormal 
categories  
 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION .............................................................................................................................. 11 
2 
STUDY OVERVIEW ......................................................................................................................... 11 
2.1 
Study Objectives ......................................................................................................................... 11 
2.1.1 
Primary Objective ............................................................................................................... 11 
2.1.2 
Secondary Objectives .......................................................................................................... 11 
2.1.3 
Exploratory Objectives ....................................................................................................... 11 
2.2 
Study Design ............................................................................................................................... 12 
2.2.1 
General Design and Study Schema ..................................................................................... 12 
2.2.2 
Randomization and Blinding .............................................................................................. 12 
2.2.3 
Study Treatments ................................................................................................................ 12 
2.2.4 
Sample Size Determination ................................................................................................. 12 
2.2.5 
Significance Testing and Estimations ................................................................................. 14 
2.3 
Study Endpoints .......................................................................................................................... 15 
2.3.1 
Primary Endpoint ................................................................................................................ 15 
2.3.2 
Secondary Endpoints........................................................................................................... 15 
2.3.3 
Exploratory Endpoints ........................................................................................................ 17 
3 
STATISTICAL METHODOLOGY ................................................................................................... 18 
3.1 
General Considerations ............................................................................................................... 18 
3.1.1 
Analysis Day ....................................................................................................................... 18 
3.1.2 
Analysis Visits .................................................................................................................... 18 
3.1.3 
Definition of Baseline ......................................................................................................... 19 
3.1.4 
Summary Statistics .............................................................................................................. 19 
3.1.5 
Study Hypothesis ................................................................................................................ 19 
3.1.6 
Evaluation of Site Effect ..................................................................................................... 19 
3.1.7 
Handling of Missing Data ................................................................................................... 20 
3.1.8 
Handling of Repeated and Unscheduled Measurements ..................................................... 20 
3.2 
Analysis Populations ................................................................................................................... 20 
3.2.1 
Screened Population ............................................................................................................ 20 
3.2.2 
Intent-to-Treat Population ................................................................................................... 20 
3.2.3 
Per-Protocol (PP) Population .............................................................................................. 20 
3.2.4 
Safety Population ................................................................................................................ 21 
3.2.5 
PRO Population .................................................................................................................. 21 
3.2.6 
Pharmacokinetics Population .............................................................................................. 21 
3.3 
Subject Data and Study Conduct ................................................................................................ 21 
3.3.1 
Subject Disposition ............................................................................................................. 21 
3.3.2 
Protocol Deviations ............................................................................................................. 22 
3.3.3 
Analysis Populations ........................................................................................................... 22 
3.3.4 
Demographic and Baseline Characteristics ......................................................................... 22 
3.3.5 
Baseline stratification factors .............................................................................................. 23 
3.3.6 
Medical History................................................................................................................... 23 


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3.3.7 
Prior and concomitant Medications .................................................................................... 24 
3.3.8 
Study Treatment Exposure .................................................................................................. 24 
3.4 
Efficacy Analysis ........................................................................................................................ 26 
3.4.1 
Primary Efficacy Endpoint Analysis ................................................................................... 26 
3.4.2 
Secondary Efficacy Endpoint Analysis ............................................................................... 28 
3.4.3 
Exploratory Efficacy Endpoint Analysis ............................................................................ 32 
3.4.4 
Subgroups ........................................................................................................................... 35 
3.5 
Pharmacokinetic Assessment ...................................................................................................... 36 
3.6 
Safety Analysis ........................................................................................................................... 37 
3.6.1 
Adverse Events ................................................................................................................... 37 
3.6.2 
Death ................................................................................................................................... 39 
3.6.3 
Clinical Laboratory Tests .................................................................................................... 39 
3.6.4 
Pregnancy Test .................................................................................................................... 40 
3.6.5 
Electrocardiograms ............................................................................................................. 40 
3.6.6 
Vital Signs ........................................................................................................................... 41 
3.6.7 
Physical Examinations ........................................................................................................ 41 
3.6.8 
ECOG Performance Status .................................................................................................. 41 
3.6.9 
Other Data ........................................................................................................................... 41 
4 
INDEPENDENT DATA MONITORING BOARD AND INTERIM ANALYSIS ........................... 41 
5 
CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES .................................. 42 
6 
PROGRAMMING SPECIFICATIONS ............................................................................................. 43 
APPENDIX A:  REFERENCES ................................................................................................................. 44 
APPENDIX B:  NCI PRO-CTCAE ITEMS ............................................................................................... 45 
APPENDIX C:  PARTIAL DATE CONVENTIONS ................................................................................ 50 
APPENDIX D:  EORTC QLQ - C30 (V3.0) .............................................................................................. 52 
APPENDIX E:  EORTC QLQ - PAN26 (1999) ......................................................................................... 56 
APPENDIX F:  EQ-5D-5L (PER USER GUIDE V3.0) ............................................................................. 60 
APPENDIX G:  AJCC PROGNOSTIC STAGE GROUPS TABLE (8TH EDITION) ............................... 63 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatase 
ALT 
Aspartate amino transferase 
ANCOVA 
Analysis of Covariance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase  
BMI 
Body mass index 
BOR  
Best overall response 
BSA 
Body surface area 
CA19-9  
Carbohydrate antigen 19.9 
CI  
Confidence interval 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical Study Report 
CT  
Computed tomography 
DOR  
Duration of response 
ECOG  
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EORTC  
European Organisation for Research and Treatment of Cancer 
EQ VAS 
EuroQol Visual Analogue scale 
EQ-5D-5L  
EuroQol 5 dimension health status questionnaire (5 level) 
GHS 
Global health status 
HCG 
Human chorionic gonadotrophin 
HR  
Hazard Ratio 
HRQoL 
Health-related quality of life 
HSD  
Hwang-Shi-Decani 
IA 
Interim analysis 
ICE 
Intercurrent event 
IDMC  
Independent data monitoring committee 
INR 
International normalised ratio 
ITT  
Intention to treat 
IWRS  
Interactive Web Response System 
KM 
Kaplan-Meier 
LLN 
Lower limits of normal 
LOCF 
Last observation carried forward  
LV  
Leucovorin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI-CTC  
National Cancer Institute – Common Toxicity Criteria 
NE 
Not evaluable 
ORR  
Overall response rate 
OS  
Overall survival 
PD 
Progressive disease 


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Abbreviation 
Definition 
PFS  
Progression-free survival 
PK 
Pharmacokinetics 
PP  
Per protocol 
PT 
Preferred term 
PR 
Partial response 
PRO  
Patient Reported Outcome 
QLQ-C30  
Quality-of-life core 30 questionnaire 
QLQ-PAN26  
Quality-of-life questionnaire pancreatic cancer module 
QoL 
Quality of life 
QTcF  
QT interval corrected by Fridericia’s formula 
RECIST  
Response Evaluation Criteria in Solid Tumours 
RS 
Raw score 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SmPC  
Summary of Product Characteristics 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TNM 
Tumor node metastasis 
TTF  
Time to treatment failure 
TTR  
Time to Response 
ULN 
Upper limits of normal 
USPI  
United States package insert 
WHODD 
World Health Organization Drug Dictionary 
 
 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical methods to 
be implemented for the analysis of data from the study with protocol number D-US-60010-001.  The first 
version of the SAP was finalized prior to the first subject randomised.  Any deviations from the SAP after 
database lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of the regimen of irinotecan liposome 
injection + oxaliplatin + 5-fluorouracil (5-FU)/leucovorin (LV) versus nab-paclitaxel + gemcitabine in 
improving overall survival (OS) in subjects who have not previously received chemotherapy for 
metastatic adenocarcinoma of the pancreas. 
2.1.2 Secondary Objectives 
The secondary objectives of this study are as follows: 
• 
To evaluate progression free survival (PFS) according to Response Evaluation Criteria in Solid 
Tumours (RECIST) Version 1.1 guidelines 
• 
To evaluate the overall response rate (ORR) according to RECIST Version 1.1 guidelines 
• 
To evaluate the safety of this regimen in this patient population. 
2.1.3 Exploratory Objectives 
• 
To evaluate time to deterioration of subjects in global health status (GHS),  function domains, and 
disease related symptoms using patient reported outcome (PRO) data collected in the European 
Organisation for Research and Treatment of Cancer quality-of-life-core questionnaire (EORTC 
QLQ-C30). 
• 
To evaluate the pharmacokinetics (PK), and the relationship between PK exposure and efficacy 
and safety, of the regimen of irinotecan liposome injection+oxaliplatin+5-FU/LV (Arm 1)  
• 
To compare time to treatment failure (TTF) between treatment arms 
• 
To compare duration of response (DOR) between treatment arms 
• 
To compare time to response (TTR) between treatment arms 
• 
To describe the possible association between genotypes to include but not be limited to 
UGT1A1*28 allele status, SN-38 concentration (only for subjects treated with irinotecan 
liposome injection+oxaliplatin+5-FU/LV) and safety 
• 
To explore the pharmacodynamic biomarker CA 19-9 for the regimen of irinotecan liposome 
injection+oxaliplatin+5-FU/LV compared with nab-paclitaxel+gemcitabine in this patient 
population. 
• 
To conduct biobanking of samples for future analysis of biomarkers amongst subjects who 
consent to optional biobanking. 


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• 
To collect gene mutation and genomic alteration status associated with pancreatic 
adenocarcinoma of subjects determined prior to screening (if available). 
2.2 Study Design 
2.2.1 General Design and Study Schema 
This is an open-label, randomised, multicentre, phase III study to evaluate the efficacy and safety of the 
irinotecan liposome injection+oxaliplatin+5-FU/LV combination regimen versus 
nab-paclitaxel+gemcitabine in adult subjects with metastatic adenocarcinoma of the pancreas. 
After informed consent is obtained and subjects have been successfully screened, subjects will be 
randomised in a 1:1 ratio to one of the following treatment regimens: 
• 
Arm 1: irinotecan liposome injection+oxaliplatin+5-FU/LV 
• 
Arm 2: nab-paclitaxel+gemcitabine. 
Approximately 750 subjects are planned to be randomised (1:1 approximately 375 subjects per arm).  
The study will be completed once all subjects have discontinued the study treatment and at least 543 OS 
events have occurred in the randomised subjects. 
2.2.2 Randomization and Blinding 
This is an open-label study. 
The sponsor’s randomisation manager or a designee, who is a statistician independent from the study, will 
prepare a list of randomisation numbers. It will be produced in blocks, on a balanced ratio [1:1] and will 
be stratified according to: 
• 
Eastern Cooperative Oncology Group (ECOG) performance status (0/1) 
• 
Region (North America/East Asia/Rest of the World) 
• 
Liver metastases (Yes/No). 
2.2.3 Study Treatments 
Irinotecan liposome injection will be administered in combination with oxaliplatin and 5-FU/LV, as 
follows: 
Arm 1: Doses and administration of irinotecan liposome injection, oxaliplatin, 5-FU/LV, on Days 1 and 
15 of each 28-day cycle. 
The comparator treatment will be administered as follows: 
Arm 2: Doses and administration of nab-paclitaxel and gemcitabine (established doses as per United 
States package insert (USPI) and EU Summary of Product Characteristics (SmPC) nab-paclitaxel), on 
Days 1, 8 and 15 of each 28-day cycle: 
2.2.4 Sample Size Determination 
The primary objective of this study is to compare OS in subjects treated with irinotecan liposome 
injection+oxaliplatin+5-FU/LV to OS in subjects treated with nab-paclitaxel+gemcitabine. 
Approximately 750 subjects will be randomised in a 1:1 ratio to the two treatment arms. Accounting for 
the planned interim analysis, follow-up until at least 543 OS events are observed across the two treatment 


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arms provides at least 90% power to detect a true hazard ratio (HR) of HR≤0.75 (modified OS: 9 versus 
12 months) using a stratified log-rank test with overall 1-sided significance level of 0.025 (adjusted for 
interim analysis). The study plans to enrol 750 subjects. For operational purposes, the expected timing of 
the final analysis triggering event will be periodically projected using blinded study data regardless of 
treatment arm. The sample size may be increased if a review of the accumulating OS events suggests that 
the timing of the final analysis will be extended. 
Assuming enrolment over 16 months increasing to approximately 62 subjects per month and lost-to-
follow-up rate of 5% across both treatment arms, the timing of the interim analysis, estimated via 
simulation, is expected to be at 24 months after the first subject treated and the timing of the final analysis 
is expected to be at 36.5 months after the first subject treated. 
If blinded projection of the accumulating OS events suggests that the number required for the final 
analysis will not be reached (due to censoring) within 32 months of study initiation, the sample size may 
be increased up to 800 subjects or until prespecified events are met, whichever comes earlier. The 
projection to inform the decision to potentially increase the number of subjects will be carried out within 
3 months prior to expected completion of planned enrolment of 750 subjects. 
There are two planned analyses for OS: interim analysis (IA) and final analysis. The IA is planned when 
at least 272 OS events (i.e. 50% information time) have been observed in the Intention to treat (ITT) 
population. If that analysis does not indicate futility or efficacy, then the final analysis is planned at  least 
543 OS events when 100% of the planned number of subjects have been enrolled. The overall type I error 
is controlled at 1-sided significance level of 0.025 (adjusted for interim analysis). 
An alpha and beta spending function according to Hwang-Shi-Decani (HSD) γalpha=-4 and γbeta=-1 will be 
utilised to control type I and type II errors for the OS comparison. In the computation of the type I error 
rate, futility analyses are considered non-binding. Since the futility and efficacy boundary is dependent on 
the number of OS events, the actual boundary used will be re-calculated, incorporating the spending 
function, as defined, based on the number of actual OS events analysed at the time of analysis. P-
boundary will be used as the criteria for the formal statistical inference. 
The interim analysis specifications per the plan are provided in Table 1. 
Table 1 Type I (α) and Type II (β) Error Spending for the Planned Analyses (α = 0.025) 
 
 
Futility 
Efficacy 
Analysis 
 
D 
Zboundary 
pboundary 
CUM 
β spend 
HRcrit 
Zboundary 
pboundary 
CUM 
α spend 
HRcrit 
Interim  
272 
-0.592 
0.277 
0.038 
0.931 
-2.750 
0.003 
0.003 
0.716 
Final 
543 
-1.981 
0.024 
0.100 
0.844 
-1.981 
0.024 
0.025 
0.844 
 
D = # of OS events at analysis. Z-boundary is the critical test statistic value at which futility (< Z) or efficacy (> 
Z) would be concluded. P-boundary is the critical one-sided p-value threshold for the comparison. Cum α-spend 
and cum β-spend are the amount of cumulative type I and type II error spent at each analysis, respectively. HRcrit 
is the observed hazard ratio threshold (> HR for futility, < HR for efficacy).  
 
The Independent data monitoring committee (IDMC) will be responsible for evaluating the interim 
analyses and making a recommendation about early termination due to observed study results from the 
interim analyses. Details are documented in the separate IDMC charter. 


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2.2.5 Significance Testing and Estimations 
Secondary efficacy endpoints (PFS and ORR) will only be evaluated if the primary efficacy endpoint 
demonstrates superiority for irinotecan liposome injection+oxaliplatin+5 FU/LV over nab 
paclitaxel+gemcitabine. If the primary endpoint of OS is declared significant at the interim, secondary 
endpoints will be tested at the interim. Otherwise, secondary efficacy endpoints will be tested at the final 
analysis if OS is found to be statistically significant at that analysis. Hypothesis testing of secondary 
endpoints will be conducted in a stagewise hierarchical manner incorporating alpha spending for each 
endpoint using HSD γalpha= -4, similar to that specified for the primary efficacy analysis. The nominal 
level for each comparison will depend on whether the analysis is carried out at the interim or at the 
planned final analysis. 
The first endpoint in the hierarchy of secondary endpoints will be PFS. If OS and PFS are both 
significant, then ORR would be tested. Any parameter which is not formally tested for significance (per 
the hierarchy) will be regarded as descriptive and exploratory. 
Figure 1 Primary and Secondary Endpoints Analyses Flow Chart 
 
 
The first endpoint in the hierarchy of secondary endpoints will be PFS. If OS and PFS are both 
significant, then ORR would be tested. Figure 1 illustrates the testing strategy of primary and key 
secondary endpoints.  
• 
If OS is significant at the interim analysis, the analysis of secondary endpoints will be performed 
at the interim analysis.  
• 
If OS is not significant at the time of the interim analysis but is significant at the final analysis, 
the analysis of secondary endpoints will be performed at the final analysis only.  
• 
If OS is not significant after either the interim analysis or the final analysis, secondary endpoints 
will not be statistically evaluated. 
Any parameter which is not formally tested for significance (per the hierarchy) will be regarded as 
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Hypothesis testing of key secondary endpoints will be conducted in a stagewise hierarchical manner 
[Glimm 2010] incorporating alpha spending for each endpoint using HSD γalpha= -4, same as that specified 
for the final analysis. The nominal level for each comparison will depend on whether the analysis is 
carried out at the OS interim or at the planned OS final analysis.  
HSD γalpha error spending function =𝛼(1 −𝑒ିఊ௧)/(1 −𝑒ିఊ) with 1 sided α=0.025 and γ=-4. 
The information fraction at each analysis will be calculated based on the actual number of events 
observed at the time of analysis if the actual number of events observed is different from planned for OS. 
The information fraction of OS and PFS will be based on the actual number of events observed at the time 
of analysis and the information fraction of ORR will be based on the number of subjects randomized in 
the study. 
2.3 Study Endpoints 
2.3.1 Primary Endpoint 
The primary efficacy endpoint is the OS of subjects randomised to irinotecan liposome 
injection+oxaliplatin+5-FU/LV compared to subjects randomised to nab-paclitaxel+gemcitabine.  
Survival will be defined, in the standard way for OS evaluation, as time from the date of randomisation to 
the date of death (any cause).  
2.3.2 Secondary Endpoints 
PFS and ORR endpoints will only be evaluated if the primary efficacy endpoint demonstrates superiority 
for irinotecan liposome injection+oxaliplatin+5-FU/LV over nab-paclitaxel+gemcitabine. 
Investigator-assessed tumour response will be used in efficacy analysis. Tumour response will be 
evaluated according to the RECIST Version 1.1 [Eisenhauer 2009]. 
Progression Free Survival  
The PFS is the time from randomisation to the first documented objective disease progression using 
RECIST Version 1.1 or death due to any cause, whichever occurs first.  
PFS will be calculated as follows: 
PFS (months) = (Event or Censoring Date – Date of Randomisation + 1)/30.4375 
Determination of PFS will be per investigator assessment. Subjects will have computed tomography (CT) 
scans (or MRI if the subject is allergic to CT contrast media) performed every 8 weeks that will be 
evaluated by the investigator site using RECIST guidelines Version 1.1. After end of treatment visit, for 
subjects who discontinue the study for reasons other than radiologically confirmed disease progression 
only and have not started any further subsequent anti-cancer treatment will have scan every 2 months, or 
8 weeks. 
Overall Response Rate   
The ORR is defined as the proportion of subjects with a best overall response (BOR) characterised as 
either a complete response or partial response per RECIST Version 1.1.  
Safety Endpoints  
Safety will be monitored through continuous reporting of AEs and serious adverse events (SAEs), 
laboratory abnormalities, incidence of subjects experiencing dose modifications (including infusion 


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interruptions, dose omissions and dose delays) and/or premature discontinuation of study treatment (and 
reason for discontinuation). 
• 
Adverse Events 
Adverse events (AEs) will be monitored from the time that the subject gives informed consent 
until 30 days after the last dose of study medication. All AEs will be coded according to Medical 
Dictionary for Regulatory Activities (MedDRA) Version 22.0 or later and will be classified by 
MedDRA preferred term and system organ class. 
A treatment emergent adverse event (TEAE) is defined as any AE that occurs during the active 
phase of the study (between first dose of study treatment and 30 days after the end of study 
treatment) if: 
o it was not present prior to receiving the first dose of study medication, or  
o it was present prior to receiving the first dose of study medication but the grade increased 
or became serious during the active phase of the study, or 
o it was present prior to receiving the first dose of study medication, the grade/seriousness 
is the same but the causality changed to “related” during the active phase of the study. 
Adverse events of special interest (AESIs) are thrombo-embolic events, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0) Grade 1 to 5. These 
AESI will be collected in the case report form (CRF) using the AESI reporting option on the AE 
page of the eCRF. 
• 
Clinical Safety Laboratory Tests 
Haematology blood samples will be collected to assess the following variables: haemoglobin, 
WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and 
others), platelet count and coagulation (Prothrombin Time with International Normalised Ratio 
(INR) and Activated Partial Thromboplastin Time (aPTT)). 
Serum biochemistry will be analysed centrally but can also be analysed locally (optional) in the 
case of requiring timely results. If local laboratory results are required, the local laboratory ranges 
for upper limit of normal (ULN) and lower limits of normal (LLN) should be included in the 
reporting. Central laboratory samples should always be taken, even if local laboratory samples 
have also been taken: creatinine, total bilirubin, conjugated bilirubin, sodium, potassium, calcium, 
phosphate, alkaline phosphatase (ALP), aspartate amino transferase (AST), aspartate 
aminotransferase (ALT), gamma glutamyl transferase, albumin, and total protein. 
Urinalysis (dipstick) will be undertaken. 
• 
Pregnancy Test 
A urine or beta human chorionic gonadotrophin (HCG) serum test will be performed locally for 
all female subjects of childbearing potential. 
• 
12-lead ECG  
A 12-lead ECG will include a description of the cardiac rate, rhythm, interval durations and an 
overall clinical interpretation. If the ECG is abnormal, clinical significance or non-significance 
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Standard 12-lead ECG parameters include sinus rhythm (yes/no), RR interval, PR interval, QRS 
duration, QT interval, QT interval corrected by Fridericia’s formula (QTcF) interval, and 
interpretation of clinical significance. 
• 
Vital signs 
Vital signs include height (at screening only) weight, resting blood pressure, pulse and 
temperature. 
• 
Physical Examination 
Physical examinations will be conducted as per schedule of assessments. Any clinically 
significant physical examination findings (abnormalities) observed during the study will be 
reported. 
• 
ECOG performance status 
The ECOG performance status will be recorded at the timepoints per schedule of assessments. 
The ECOG will be assessed by the investigator or his/her designee via questioning of the subject 
about their functional capabilities. 
2.3.3 Exploratory Endpoints 
Patient-Reported Outcomes  
The PRO exploratory endpoints are as follows:  
• 
Assess time to deterioration or worsening of subjects GHS, physical functioning, disease related 
symptoms of interest using EORTC-QLQ-C30 in Appendix D 
• 
Summarise Health-related quality of life (HRQoL) score at each visit as assessed by QLQ-C30, 
QLQ-PAN26, PRO-CTCAE and EQ-5D-5L. 
Pharmacokinetics  
The pharmacokinetics (PK), and the relationship between PK exposure and efficacy and safety, of the 
regimen of irinotecan liposome injection+oxaliplatin+5-FU/LV (Arm 1) in this patient population will be 
evaluated.  
Time to Treatment Failure  
The TTF is defined as the time from randomisation to treatment discontinuation for any reason, including 
• 
progressive disease per RECIST, 
• 
progressive disease clinical, 
• 
adverse event, 
• 
death, 
• 
withdrawal by subject, 
• 
protocol deviation, 
• 
physician decision, 
• 
site terminated by sponsor, 
• 
study terminated by sponsor, 
• 
lost to follow-up, 
• 
pregnancy, 
• 
any other reasons collected in the eCRF, or 


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• 
initiation of subsequent anti-cancer therapy (drug therapy, curative radiotherapy, curative 
surgery) including new antineoplastic treatment. 
Duration of Response (DoR) 
DOR is defined as the time of initial response (complete response or partial response) until documented 
objective tumor progression using RECIST Version 1.1 or death. DoR will be computed only for subjects 
who achieved complete response or partial response. For subjects who do not have documented disease 
progression or death, DOR will be censored following the same rules as PFS specified in Table 3. 
Time to Response 
TTR is defined as the time from randomisation to the first documented objective tumor response (CR or 
PR) using RECIST Version 1.1. TTR will be computed only for subjects who achieved complete response 
or partial response.  
Genotyping: UGT1A1 and SN-38 
The possible association between genotypes to include but not limited to UGT1A1*28 and other UGT1A 
genotypes, SN-38 concentration (only for subjects treated with irinotecan liposome 
injection+oxaliplatin+5-FU/LV) and safety will be described. 
Biomarkers CA 19-9  
The biomarker CA 19-9 concentrations will be measured and compared between treatment arms. 
Biobanking  
The exploratory endpoint comprises biobanking of samples for future analysis, among subjects who 
consent. Analysis of biobank samples will be performed outside the scope of the main study and reported 
separately. 
Gene Mutations and Genomic Alterations 
The exploratory endpoint comprises of collection of gene mutation and genomic alteration status 
associated with pancreatic adenocarcinoma of the subjects, determined prior to screening where available. 
Several genes are associated with an increased risk of developing PDAC. Those of key interest include: 
• 
Germline mutations and genomic alterations: BRCA1, BRCA2, PALB2, ATM , CDKN2A, 
MLH1, MSH2, MSH6, TP53 and EPCAM.  
• 
Somatic mutations and genomic alterations: KRAS, TP53, CDKN2A, SMAD4, RNF43, 
ARID1A, TGFβR2, GNAS, RREB1 and PBRM1.  
Analysis will be performed outside the scope of the main study and results reported separately. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of randomization.  The day of the randomization will be 
Day 1, and the day immediately before Day 1 will be Day -1.  There will be no Day 0. 
3.1.2 Analysis Visits 
No study visit windows will be used for analyses.  


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3.1.3 Definition of Baseline  
Baseline for a safety assessment is defined as the last non-missing measurement on or prior to the first 
dose of study treatment. 
Baseline for an efficacy assessment is defined as the last non-missing measurement, including 
unscheduled assessment on or prior to the date of the randomisation. If a subject’s first assessment occurs 
after randomisation but prior to the first dose, this assessment will be used as the baseline. 
For ECOG, baseline is defined as the last observed measurement on or prior to the date of the 
randomization. 
For all PRO assessments, baseline is defined as the last observed measurement on or prior to first drug 
administration at C1D1. 
3.1.4 Summary Statistics 
Categorical variables will be summarised by frequency distributions (number and percentage of subjects). 
Percentages given in these tables will be rounded and, therefore, may not always sum to 100.0%. 
Continuous variables may be summarised by a clinically relevant discretization of the variable. 
All confidence intervals (CIs) for parameters to be estimated will be constructed with a significance level 
α =0.05 (i.e. a 95% CI).  
Time to event distribution (e.g. progression free survival, overall survival, time to response, and duration 
of response) will be estimated using Kaplan Meier methodology. Median survival time along with 95% 
CI will be constructed based on a log-log transformed CI for the survival function S(t). Rates at fixed time 
points will be derived from the Kaplan Meier estimate and corresponding confidence interval will be 
derived based on Greenwood formula for variance derivation and on log-log transformation applied on 
the survival function S(t). 
Minimum and maximum will be reported to the same precision as the collected data, mean and median 
will be reported to one additional decimal place, and standard deviation will be reported to two additional 
decimal places.  Some discretion may be applied. Confidence intervals will be reported to the same 
precision as the summary statistic for the interval (e.g., the confidence interval for a mean will be reported 
to the same precision as the mean). P-values will be reported to 4 decimal places.   
The stratification factors are captured in the interactive web response system (IWRS) and on electronic 
case report forms (eCRFs). The primary efficacy analysis (OS) and key secondary efficacy analyses (PFS 
and ORR) will use the randomization stratification factors from IWRS. Unless otherwise specified, all 
stratified analyses will be based on the stratification factors per eCRF. A cross tabulation of the frequency 
of each level of each stratification factor per IWRS and eCRF will be produced. 
3.1.5 Study Hypothesis 
Irinotecan liposome injection+oxaliplatin+5-FU/LV has superior efficacy over nab-
aclitaxel+gemcitabine, demonstrated by a 3-month improvement in OS, in the treatment of subjects who 
have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas. 
3.1.6 Evaluation of Site Effect 
It is not planned to perform a subgroup analysis on individual centres. Region is a randomsition 
stratification factor and is one of the planned variables to perform subgroup analyses. 


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3.1.7 Handling of Missing Data 
In all listings, missing or incomplete dates should be left as they have been recorded. However, for 
calculation / sorting / assignation based on dates, the following methods will be used:  
1) The most conservative approach will be systematically considered (i.e. if the onset date of an 
AE/concomitant medication is missing / incomplete, it is assumed to have occurred during the 
active phase (i.e. a TEAE for AEs) except if the partial onset date or other data [stop date, …] 
indicates differently).  
2) A missing/incomplete date of medical history or disease diagnosis will be assumed to have 
occurred before any study treatment.  
3) If a partial date and the associated information do not allow to state about the assignation to a 
group / category, all the possible groups / categories will be considered (i.e.: an AE could be 
assigned to several possible doses at event onset according to its partial onset date and stop date. 
Particularly an AE with missing start date will be assigned to each dose received before its end 
date. Similarly a medication with partial start and stop dates could be considered as prior and 
concomitant treatment).  
4) Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2021 after the administration performed on 
31JAN2021, the days since last dose will be “≥2”, similarly the duration of ongoing AEs or 
medication will be“≥xx” according to the start and last visit dates).  
 
Other rules for handling missing data related to endpoints are described in the endpoint definitions 
(Section 2.3) or in the description of analyses (Section 3).  
3.1.8 Handling of Repeated and Unscheduled Measurements 
All repeated and unscheduled measurements will be presented in the listings, where applicable.  
Both scheduled and unscheduled results will be considered in clinical laboratory, ECG and vital sign 
tables.  
3.2 Analysis Populations 
3.2.1 Screened Population 
All subjects screened (i.e. who signed the informed consent). 
3.2.2 Intent-to-Treat Population 
This population includes all randomised subjects to whom study treatment has been assigned by 
randomization. A subject is randomised (after informed consent has been provided) if there is 
confirmation of successful allocation of a randomization number through IWRS. According to ITT 
principle, subjects will be analyzed according to the treatment and strata they have been assigned to 
during the randomization procedure.  
3.2.3 Per-Protocol (PP) Population 
This is a subset of the ITT population. It includes subjects who have no major protocol deviations that 
could potentially affect the primary efficacy analysis for the subject as described in the protocol 
deviations document. 


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3.2.4 Safety Population 
The safety population is a subset of the ITT population that received at least one dose (including a partial 
dose) of any component of the study medication in the combination therapy). Subjects will be analyzed 
according to study treatment actually received. 
3.2.5 PRO Population 
All subjects of the randomised ITT population that have provided baseline and at least one subsequent 
assessment on each PRO instrument. 
3.2.6 Pharmacokinetics Population 
All subjects who received at least one dose and who have at least one plasma concentration and no major 
protocol deviations affecting PK variables. 
PK sampling is performed in Arm 1 (irinotecan liposome injection+oxaliplatin+5-FU/LV) only. 
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
The following subject disposition categories will be summarized by treatment arm and in total using 
screened population: 
• 
Study treatment 
• 
Subjects who were screened 
• 
Subjects who were randomised 
• 
Subjects who were not randomised and reasons 
• 
Subjects who were randomised but not treated 
• 
Subjects who received study treatments 
• 
Subjects who received non-planned study treatments 
• 
Subjects with ongoing study treatments 
• 
Subjects who permanently discontinued from study treatment 
• 
Subjects who permanently discontinued from study treatment due to 
COVID-19 pandemic 
 
Primary reasons for treatment discontinuation 
• 
Long-term follow up 
• 
Subjects who entered long-term follow up 
• 
Subjects with ongoing long-term follow up 
• 
Subjects who discontinued from long-term follow up 
• 
Study  
• 
Subjects who discontinued from study  
• 
Subjects who discontinued from study due to COVID-19 pandemic 


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 
Primary reasons for end of study 
• 
Survival status at data cut-off 
• 
Alive 
• 
Death 
• 
Lost to Follow up 
Subjects who were randomised by country and site, and by treatment arm and overall will also be 
summarized using ITT population. 
Subject disposition, inclusion and exclusion criteria, assessment visits, randomization and withdrawal of 
consent will be listed. 
3.3.2 Protocol Deviations 
Any major and minor protocol deviation will be documented as described in the protocol deviation plan, 
and its impact on inclusion in each analysis population for any subject will be specified. The final list of 
protocol deviations impacting the analysis populations will be reviewed prior to database lock.  
Counts and percentages of subjects with major protocol deviations by deviation category and by COVID-
19 relationship will be summarised using ITT population. Study visits impacted by COVID-19 will be 
summarized and listed. 
Major protocol deviations and subjects excluded from analysis population will be listed using ITT 
population. 
3.3.3 Analysis Populations 
The numbers and percentages of subjects enroled and included in each analysis population will be 
tabulated using ITT population. The reasons for subject exclusions from each of the analysis populations 
will also be tabulated. 
Analysis population will be listed with subject disposition. 
3.3.4 Demographic and Baseline Characteristics 
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum) or frequency 
counts of demographic and baseline data will be presented by treatment group on the ITT population. No 
formal statistical analysis will be performed on these data. 
Demographic characteristics will include 
• 
age (years),  
• 
age category (<65 years, ≥65 years [65-75years, >75+ years]), 
• 
sex (male, female),  
• 
ethnicity (Hispanic or Latino, Not Hispanic or Latino, not reported),  
• 
race (Asian, American Indian or Alaska Native, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, not reported, Other),  
• 
baseline weight (kg),  
• 
baseline height (cm), 
• 
baseline body mass index (BMI) in kg/m2,  
• 
baseline body surface area (BSA) (m2)  
• 
baseline albumin (g/L),  


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• 
baseline CA 19-9 (U/mL), 
• 
baseline CA 19-9 category (<37 U/mL, ≥37 U/mL), 
• 
baseline UGT1A1*28 allele status (homozygous/non-homozygous), 
• 
baseline ECOG performance status (0, 1),  
• 
liver metastases (yes, no) and 
• 
geographic location (North America/East Asia/Rest of the World). 
Note: Some countries may not collect race and/or ethnicity information. Baseline ECOG, liver metastases 
and geographic location are based on eCRF data. 
Baseline disease characteristics will include  
• 
time from initial diagnosis of pancreatic adenocarcinoma until date of randomization (weeks), 
• 
time from diagnosis of metastatic disease at study entry until date of randomization (weeks),  
• 
stage of original diagnosis, 
• 
histological grade, 
• 
American Joint Committee on Cancer (AJCC, 8th edition) prognostic stage (I-III, IV) at study 
entry, 
• 
number of metastatic sites (0, 1, 2, ≥3),  
• 
selected metastatic site (liver, lung) and 
• 
main pancreatic tumor location (head, body, tail, unknown). 
Prior cancer therapy will include  
• 
prior anti-cancer therapy for pancreatic cancer (yes, no), 
• 
prior chemotherapy for pancreatic cancer (yes, no),  
• 
prior radiotherapy for pancreatic cancer (yes, no),  
• 
prior surgical procedures for pancreatic cancer (yes, no), and 
• 
time from last anti-cancer treatment for pancreatic cancer until date of randomization (weeks),  
AJCC prognostic stage group from AJCC 8th edition is derived from TNM staging collected from eCRF 
data (Appendix G). 
Demographic, pancreatic adenocarcinoma history, disease history, and prior cancer therapy data will also 
be listed. 
3.3.5 Baseline stratification factors 
The number (%) of subjects in each stratum based on data obtain from IWRS will be summarized overall 
and by treatment arm for the ITT. Discordances between the stratum records in the IWRS at the time of 
randomization and the actual stratum recorded in the clinical databased through the data collected on the 
eCRF will be cross-tabulated and listed. 
3.3.6 Medical History 
Medical and surgical history and baseline signs and symptoms related to cancer will be coded initially 
using the latest version of MedDRA in use in Ipsen system. 
Listings will present the preferred term and verbatim text.  
Frequency tables of the number and percentage of subjects will be provided for medical and surgical 
history and baseline signs and symptoms related to cancer by system organ class (SOC) and preferred 
term (PT) using ITT population. 


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3.3.7 Prior and concomitant Medications 
Prior, concomitant, and post-treatment medications are defined as following: 
• 
Prior medications will include medications which started prior to the first study treatment 
administration date, but exclude medications captured on Prior Chemotherapy, Hormonal and 
Immunotherapy for Pancreatic Cancer or Other Cancer CRF. 
• 
Concomitant medications will include medications taken any time from the first study treatment 
administration date through 30 days following the last study treatment administration date or until 
the start of a subsequent anti-cancer therapy(drug therapy, curative radiotherapy, curative 
surgery), whichever is earlier. Medications that started prior to the first dose of study treatment 
but continued into treatment are considered concomitant. 
Prior, concomitant medications, and further subsequent anti-cancer therapy will be coded using the latest 
version of World Health Organization Drug Dictionary (WHODD) in use in Ipsen system.  
Frequency tables of the number and percentage of subjects will be provided using ITT population for 
prior medications, concomitant medications, and prior chemotherapy, hormonal and immunotherapy for 
pancreatic cancer separately by therapeutic class and PT for each treatment arm. Listings will be 
presented for the therapeutic class, PT and verbatim text.  
Further subsequent anti-cancer therapy (drug therapy, curative radiotherapy, curative surgery) collected in 
eCRF will be summarized separately. Pre-medications and all further subsequent anti-cancer treatments 
including regimen name, start and stop dates, best response, and reason of discontinuation will be listed. 
Concomitant surgical procedures, and prior and concomitant non-drug therapies will be coded initially 
using the latest version of MedDRA in use in Ipsen system. Frequency tables of the number and 
percentage of subjects will be provided by PT on safety population for concomitant surgical procedures, 
and prior and concomitant non-drug therapies by system organ class and preferred term. Listing will be 
provided. 
Additionally, a listing of prior and concomitant blood transfusions will also be provided. 
3.3.8 Study Treatment Exposure 
The following summaries will be presented using safety population by each study treatment (irinotecan 
liposome injection, oxaliplatin infusion, leucovorin infusion, 5-FU infusion, nab-paclitaxel injection, and 
gemcitabine injection) and treatment arm: 
• 
Last date of exposure to study drug = last dose date of study treatment + planned days to next 
dose. Arm 1 irinotecan liposome injection, oxaliplatin, 5-FU/LV planned days to next dose is 14 
days. Arm 2 nab-paclitaxel+gemcitabine planned days to next dose is 7 days if the last dose 
occurs on Day 1 or Day 8 of a cycle and is 14 days if last dose occurs on Day 15 of a cycle. 
If a patient died or was withdrawal of study consent and/or lost to follow-up before the derived 
last date of exposure, the last date of exposure of study drug is the date of death or the date of last 
contact before withdrawal of study consent and/or lost to follow up respectively. If the derived 
last date of exposure goes beyond the date of cutoff date, it should be truncated to the date of data 
cutoff.  
• 
Duration of exposure to study drug (week) = (last exposure to study drug - first dosing date of 
study drug +1) / 7 (period of dose interruption are not excluded) 


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Duration of exposure to a treatment arm (week) = [The last day of exposure to any study drug of 
a non-zero dose administrated – earliest dosing date of any study drug with a non-zero 
administrated +1]/ 7 (period of dose interruption are not excluded) 
• 
Total number of treatment cycles administered 
• 
Total number of treatment cycles of study treatment administered categorized as follows: 
• 
Cycle 1  
• 
Cycle 2  
• 
Cycle 3  
• 
Cycle 4  
• 
Cycle 5  
• 
Cycle 6  
• 
Cycle 7  
• 
Cycle 8 or more  
• 
The number and percentage of subjects with infusion interruptions/dose adjustments including:  
• 
Dose reductions 
• 
Dose delays 
• 
Drug withdrawals 
• 
Dose omitted 
 
The following summaries will be provided by each study treatment only. 
• 
Cumulative actual dose administered (mg/m2), calculated as  
෍𝑎𝑐𝑡𝑢𝑎𝑙 𝑑𝑜𝑠𝑒 (𝑚𝑔) 𝑎𝑡 𝐷𝑥 𝑓𝑜𝑟 𝑐𝑦𝑐𝑙𝑒 𝑘
𝐵𝑆𝐴 (𝑚ଶ)𝑎𝑡 𝐷𝑥 𝑓𝑜𝑟 𝑐𝑦𝑐𝑙𝑒 𝑘
௞
 
where Dx is the dosing day in each arm. BSA will be calculated using weight and height within a 
dosing day based on Dubois equation. If a subject has missing BSA due to missing weight and/or 
height on a dosing day, the last observation carried forward (LOCF) approach will be used. 
• 
Cumulative planned dose will be calculated in the same manner as cumulative actual dose but 
using planned dose per cycle times number of complete cycles. If a subject has dose skip or 
discontinues the treatment, the planned dose (mg) and BSA (m2) in the missing dosing visits will 
be imputed using LOCF method. 
- 
number of complete cycle = (last dosing date of study drug – first dosing date of 
study drug + 1) / 28 
• 
Overall actual dose intensity (ADI) administered (mg/m2/week), calculated as 
𝐴𝐷𝐼= 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑎𝑐𝑡𝑢𝑎𝑙 𝑑𝑜𝑠𝑒 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 (𝑚𝑔/𝑚ଶ)
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑤𝑒𝑒𝑘)
 
• 
Overall planned dose intensity (PDI) (mg/m2/week), calculated as 
𝑃𝐷𝐼= 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 (𝑚𝑔/𝑚ଶ)
𝑃𝑙𝑎𝑛𝑛𝑒𝑑  𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑤𝑒𝑒𝑘)
 
 
where planned treatment duration = 4 weeks * the number of complete cycles. 


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• 
Overall relative dose intensity (RDI) (%), calculated as  
𝑅𝐷𝐼 (%) = 𝐴𝐷𝐼
𝑃𝐷𝐼 × 100 
• 
Actual dose intensity administered by cycle 
• 
Planned dose intensity administered by cycle 
• 
Relative dose intensity administered by cycle  
All information collected on the eCRF related to for each study treatment including planned dose, actual 
dose, any dose adjustments will be listed.  
3.4 Efficacy Analysis 
The ITT population is the primary population for all demographic, baseline disease characteristics, and 
efficacy parameters. All analyses using this population will be based on the treatment assigned by IWRS.  
In addition, PP analysis may be performed as secondary/confirmatory. Subjects will be analysed as 
randomised. 
3.4.1 
Primary Efficacy Endpoint Analysis 
3.4.1.1 
Overall Survival 
OS will be calculated as follows: 
OS (months) = (Death or Censoring Date – Date of Randomisation + 1)/30.4375 
All death occurring on or before the cut-off date in the ITT will be used in the OS analysis. Subjects who 
do not have a date of death recorded at the time of the final analysis will be censored at the last known 
time that the subject was alive. For each subject who is not known to have died as of the data-inclusion 
cut-off date for a particular analysis, OS will be censored for that analysis at the date of the last known 
time that the subject was alive prior to the data cut-off date. 
Primary Analysis 
The OS for each treatment arm will be summarised by median survival time and its 95% CIs from 
Kaplan-Meier (KM) estimation. Stratified analyses, based on the randomisation stratification factors per 
IWRS, will be used for treatment comparisons on the ITT population. Differences in the OS curves will 
be tested using a stratified and unstratified log-rank test separately. The estimated treatment effect for 
Arm 1 will be summarised by the HR (including 95% CI) from stratified and unstratified Cox regression 
analysis separately. The Kaplan Meier curves of the two treatment arms with HR and 95% CI will be 
presented. KM based OS rates at 3, 6, 9, 12, and 18 months will be estimated and associated two-sided 
95% CIs will be provided.  
KM curve will be plotted by treatment arm on ITT and PP population respectively. 
OS data will be listed by treatment arm and subject. 
Sensitivity Analyses 
The following additional sensitivity analyses may be carried out for OS on the ITT population and/or PP 
population to evaluate the robustness of the primary analysis results: 
• 
log-rank comparisons of treatments on the PP population 


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• 
log-rank test comparisons of treatments with OS censored at the date where any post-treatment 
anti-cancer therapy (drug therapy, curative radiotherapy, curative surgery) is first administered on 
the ITT population 
Primary efficacy endpoint in estimand framework is described in Table 2. 
Table 2 Primary Efficacy Endpoint in Estimand Framework 
Statistical 
category 
Estimand: 
Treatment: Randomized Arm 1 (irinotecan liposome injection+oxaliplatin+5-
FU/LV) or Arm 2 (nab-paclitaxel+gemcitabine). 
Population: Subjects who have not previously received chemotherapy for metastatic 
adenocarcinoma of the pancreas as specified in the inclusion and exclusion criteria 
(Protocol Section 4.1 and Section 4.2), respectively. 
Endpoint (Variable): Overall survival, defined as the time from randomization date 
to the date of death. 
Intercurrent events:  
1. Start of subsequent anti-cancer therapy (drug therapy, curative radiotherapy, 
curative surgery) including new antineoplastic treatment 
2. Permanently discontinuation from study treatment due to any reasons 
Analysis 
set 
Intercurrent event handling strategy 
Population-level summary 
(Analysis): 
Primary 
ITT 
1. Treatment policy strategy: ICE 
1 and 2 will not affect the 
assessment of OS. 
Treatment comparison using a 
stratified log-rank test and HR 
estimated by stratified Cox 
regression model. 
Sensitivity 1 
PP 
As primary 
As primary 
Sensitivity 2 
ITT 
1. Hypothetical strategy: Patients 
with ICE 1 will be censored at 
the date when any post-
treatment anti-cancer therapy 
(drug therapy, curative 
radiotherapy, curative surgery) 
is first administered 
2. Treatment policy strategy: ICE 
2 will not affect the assessment 
of OS. 
As primary 


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3.4.2 Secondary Efficacy Endpoint Analysis 
The secondary efficacy endpoints will be analyzed at the time of the OS analysis (interim or final), only if 
the OS analysis crosses the stopping boundary.  
3.4.2.1 
Progression Free Survival 
PFS will be calculated as follows: 
PFS (months) = (Event or Censoring Date – Date of Randomisation + 1)/30.4375 
Determination of PFS will be per investigator assessment using RECIST guidelines Version 1.1.  
General censoring rules for the analysis of PFS are described in Table 3. 
Table 3 Date of Event or Censoring for PFS 
Situation 
Date of progression or censoring 
Outcome 
Description 
in TLFs 
No evaluable baseline tumour 
assessment  
Date of randomisation 
 
Censored 
Censored on 
Day 1 
No evaluable post-baseline  tumour 
assessment  
Documented disease progression or 
death after missing ≥2 consecutive 
scheduled tumour assessments* of 
baseline or the last non-PD tumour 
assessment 
Date of last evaluable tumour 
assessment prior to the first missed 
assessment 
or  
Date of randomisation 
Censored 
≥2 
consecutive 
missing 
tumour 
assessments  
Documented disease progression 
within 2 consecutive scheduled 
tumour assessments* of baseline or 
the last non-PD tumour assessment 
The Earliest of:  
• 
date of tumour assessment showing 
new lesion (if progression based on 
new lesion) or  
• 
date of tumour assessment of 
target/non-target lesions in which 
progression is documented 
Event 
Progression 
disease 
Death within 2 consecutive scheduled 
tumour assessments of last the non-
PD tumour assessment 
Date of death 
Event 
Death 
Withdrawal of study consent and/or 
lost to follow-up without documented 
disease progression or death 
Date of the last evaluable tumour 
assessment prior to withdrawal of study 
consent and/or lost to follow-up  
or 
Date of randomisation if no post-
baseline tumor assessment 
Censored 
Withdrawal 
of study 
consent 
and/or lost to 
follow up 
Subsequent anti-cancer therapy (drug 
therapy, curative radiotherapy, 
curative surgery including subsequent 
antineoplastic treatment) started 
without disease progression or death 
Date of the last evaluable tumour 
assessment prior to starting subsequent 
anti-cancer therapy (drug therapy, 
curative radiotherapy, curative surgery) 
including new antineoplastic treatment 
or 
Censored 
Subsequent 
anti-cancer 
therapy   


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Situation 
Date of progression or censoring 
Outcome 
Description 
in TLFs 
Date of randomisation if no post-
baseline tumor assessment 
None of the following:  
• 
disease progression or death  
• 
2 consecutive missing scheduled 
tumour assessments 
• 
Withdrawal of study consent 
and/or lost to follow-up 
• 
Subsequent anti-cancer therapy  
Date of the last evaluable tumour 
assessment  
or 
Date of randomisation if no post-
baseline tumor assessment 
Censored 
Censored on 
last tumour 
assessments 
*Two consecutive post-baseline tumor assessments are based on protocol scheduled tumor assessments. The 
window of the tumor assessment is considered. Subjects are expected to have scans every 8 weeks, a subject who 
goes more than 18 weeks (16 weeks + 2 week) without a scan is considered missing 2 consecutive scheduled tumour 
assessments. If patients had subsequent anti-cancer therapy, missing 2 consecutive scheduled tumour assessments 
and withdrawal of study consent or lost to follow-up on same date, censored reason will be assigned in the order of 2 
consecutive scheduled tumour assessments > anti-cancer therapy > withdrawal of study consent or lost to follow-up. 
Main analysis of PFS will be performed on ITT populations using the same approach as primary analysis 
(see Section 3.4.1.1).  
Sensitivity analysis will be repeated on PP population. A sensitivity analysis will be performed by 
applying treatment policy on withdrawal of study consent and/or lost to follow-up without documented 
disease progression or death on ITT population.  
KM curves will be plotted by treatment arm on ITT and PP populations respectively. 
The following information will also be summarized: 
• 
Number and type of events (progression: RECIST 1.1, death), 
• 
Number of subjects censored by type of censoring based on Table 3 
PFS data will also be listed by treatment arm and subject. 
The estimand of PFS is described in Table 4. 


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Table 4 Secondary Efficacy Endpoint (PFS) in Estimand Framework 
Statistical 
category 
Estimand: 
Treatment: Randomized Arm 1 (irinotecan liposome injection+oxaliplatin+5-
FU/LV) or Arm 2 (nab-paclitaxel+gemcitabine). 
Population: Subjects who have not previously received chemotherapy for metastatic 
adenocarcinoma of the pancreas as specified in the inclusion and exclusion criteria 
(Protocol Section 4.1 and Section 4.2), respectively. 
Endpoint (Variable): PFS, defined as the time from randomization date to the date 
of death or disease progression per RECIST v1.1. 
Intercurrent events:  
1. Start of subsequent anti-cancer treatment(drug therapy, curative radiotherapy, 
curative surgery) including new antineoplastic treatment 
2. Withdrawal of study consent and/or lost to follow-up without documented disease 
progression or death 
3. Two and more consecutively missing scheduled tumor assessments 
Analysis 
set 
Intercurrent event handling strategy 
Population-level summary 
(Analysis): 
Secondary 
ITT 
Hypothetical strategy: Patients with ICE 
1, 2 and 3 will be censored at last 
evaluable tumour assessment prior to 
starting subsequent  anti-cancer therapy 
(drug therapy, curative radiotherapy, 
curative surgery) including new 
antineoplastic treatment, withdrawal of 
study consent and/or lost to follow-up or 
the first missed tumour assessment, 
respectively 
Treatment comparison using a 
stratified log-rank test and HR 
estimated by stratified Cox 
regression model. 
Sensitivity 1 
PP 
As secondary 
As secondary 
Sensitivity 2 
ITT 
1. Hypothetical strategy: Patients with 
ICE 1 and 3 will be censored at last 
evaluable tumour assessment prior to 
starting subsequent anti-cancer therapy 
(drug therapy, curative radiotherapy, 
curative surgery) including 
antineoplastic treatment or the first 
missed tumour assessment, respectively 
2. Treatment policy:  
ICE 2 will not affect the analysis of PFS 
(i.e. tumor assessment or death after ICE 
2 will be used in the analysis) 
As secondary 


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3.4.2.2 
Overall Response Rate  
The ORR is defined as the proportion of subjects with a best overall response (BOR) characterised as 
either a complete response or partial response per RECIST Version 1.1. ORR will be calculated based on 
the intent to treatment population as assessed by investigator. Subjects with only non-measurable disease 
at baseline will be part of the analysis and will be included in the numerator only if a CR was observed. 
Tumor assessments performed before the start of any further subsequent anti-cancer therapy will be 
considered in the assessment of BOR.   
BOR is defined as the best response as recorded from randomization until documented objective disease 
progression using RECIST Version 1.1. BOR is derived from all time point responses observed while on 
study treatment and during the follow up period (but before the initiation of subsequent anti-cancer 
therapy [drug therapy, curative radiotherapy, curative surgery]). Each subject’s BOR will be categorized 
as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or not 
evaluable (NE).  To classify BOR as SD, there should be a qualifying SD assessment at least 8 weeks 
after randomisation. Subjects without baseline or post-baseline tumor assessments will be treated as NE 
for BOR. 
The ORR will be summarized by treatment arm and the associated 95% CI will be estimated using the 
Clopper Pearson method on ITT populations. The ORR of Arm 1 will be compared to Arm 2 using a 
Cochran-Mantel-Haenszel test adjusting by randomisation stratification factors per IWRS and odds ratio 
(and its 95% CI) will be estimated using Mantel-Haenszel method. Sensitivity analysis will be repeated 
for PP populations. 
The number and percent of subjects with their best overall response will be summarised by treatment arm. 
The estimand of ORR is described in Table 5. 
Table 5 Secondary Efficacy Endpoint (ORR) in Estimand Framework 
Statistical 
category 
Estimand: 
Treatment: Randomized Arm 1 (irinotecan liposome injection+oxaliplatin+5-
FU/LV) or Arm 2 (nab-paclitaxel+gemcitabine). 
Population: Subjects who have not previously received chemotherapy for metastatic 
adenocarcinoma of the pancreas as specified in the inclusion and exclusion criteria 
(Protocol Section 4.1 and Section 4.2), respectively. 
Endpoint (Variable): ORR, defined as the proportion of subjects with a BOR 
characterised as either a CR or PR per RECIST v1.1 
Intercurrent events:  
1. Start of subsequent anti-cancer therapy (drug therapy, curative radiotherapy, 
curative surgery) including new antineoplastic treatment 
2. Permanently discontinuation from study treatment without documented disease 
progression 
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
Secondary 
ITT 
1. Hypothetical strategy: 
Response assessments prior to 
ICE1 will be used. 
Treatment comparison and odds ratio 
estimated using a Cochran-Mantel-
Haenszel test 


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Statistical 
category 
Estimand: 
Treatment: Randomized Arm 1 (irinotecan liposome injection+oxaliplatin+5-
FU/LV) or Arm 2 (nab-paclitaxel+gemcitabine). 
Population: Subjects who have not previously received chemotherapy for metastatic 
adenocarcinoma of the pancreas as specified in the inclusion and exclusion criteria 
(Protocol Section 4.1 and Section 4.2), respectively. 
Endpoint (Variable): ORR, defined as the proportion of subjects with a BOR 
characterised as either a CR or PR per RECIST v1.1 
Intercurrent events:  
1. Start of subsequent anti-cancer therapy (drug therapy, curative radiotherapy, 
curative surgery) including new antineoplastic treatment 
2. Permanently discontinuation from study treatment without documented disease 
progression 
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
2. Treatment policy strategy: 
ICE 2 will not affect the 
assessment of ORR. 
Sensitivity 
PP 
As secondary 
As secondary 
Tumor assessment 
Tumor assessment for target, non-target and new lesions, and overall response will be listed. 
3.4.3 Exploratory Efficacy Endpoint Analysis 
3.4.3.1 
Patient-Reported Outcomes Analysis 
Analyses of quality of life is an exploratory analysis that will be carried out primarily on ITT. Analyses of 
QoL based on the PRO population may be used as the sensitivity analyses.  
The instrument descriptions and scoring algorithms of EORTC QLQ-C30, QLQ-PAN26, EQ-5D-5L and 
PRO-CTCAE are detailed in Appendix B, D, E, and F respectively.  
For all PRO assessments, baseline is defined as the last observed measurement prior to first drug 
administration at C1D1. Post-baseline value is defined as a measurement taken after the first 
administration of study drug. Change from baseline is defined as post-baseline value minus baseline value 
and will be calculated for each post-baseline assessment. Questionnaires EORTC QLQ-C30, QLQ-
PAN26, EQ-5D-5L are planned to be collected at CXD1. PRO-CTCAE is planned to be collected at 
CXD1 and CXD15.  
The principle for scoring is the same for all domains. Outcome scores are computed by standardizing the 
average of the items (i.e., a raw score) comprising the domain. A linear transformation of the raw score is 
computed such that scores range from 0 to 100. Details are provided in Appendix. Depending on the 
domain, a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of 
symptoms. More specifically, a high score for a functional domain represents a high/healthy level of 
functioning and a high score for the GHS represents a high level of QoL, but a high score for a symptom 
domain/item represents a high level of symptomatology/problems. Note that the global health status 
domain is based on only the two specific HRQoL items and not the entire questionnaire. If ≥50% of the 
items of a domain are present for a timepoint then the score will be calculated using the average of all 


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items answered, otherwise the score will be set to missing. For single measures, if the item is missing the 
domain score is set to missing. 
Change from baseline defined as post-baseline value minus baseline value will be calculated for each 
assessment. At each post-baseline assessment, the change in symptoms, functioning, or GHS from 
baseline will be calculated for each domain and each item.  
Analysis Visit Window 
For summaries of PRO data, assessments will be assigned to calculated visit windows (4 weeks per cycle, 
details in Study Protocol Table 5). The time windows will be exhaustive so that data recorded at any 
timepoint have the potential to be summarized. Inclusion within the visit window will be based on the 
actual date and not the intended date of the visit. The window for the visits following baseline will be 
constructed in such a way that the upper limit of the interval falls half-way between the two visits.  If 
there is more than one value per patient within an assessment window then the closest to the planned 
study day value should be summarised, or the earlier in the event the values are equidistant from the 
planned study day. The value at a given timepoint will be missing if no assessment was reported within 
the specified assessment window around the planned study day. 
All PRO instruments will be listed separately by treatment arm and subject. 
Descriptive summary 
EORTC QLQ-C30, QLQ-PAN26, and PRO-CTCAE results will be summarised at each visit by treatment 
arm using the number of subjects with non-missing data (n), mean, standard deviation, median, minimum 
and maximum. Change from baseline will be summarized using the same statistics. Change from baseline 
scores at each visit will be compared using an analysis of covariance (ANCOVA) model with treatment as 
a fixed effect and baseline as a covariate adjusting by randomisation stratification factors per IWRS. Least 
square mean, standard error and 95% CI of treatment difference will be presented.  
EQ VAS and EQ-5D index value will be summarized and analyzed using the same method as above. 
Standard EQ-5D-5L value set from US will be applied to generate index value. EQ-5D-5L descriptive 
system will also be summarized by presenting the frequency and proportion of each level for each 
dimension by visit and by treatment arm. 
The mean with standard error of above PRO scores over time will be plotted by visit and treatment arm. 
Time to deterioration (TTD) 
TTD will be defined as the duration of time from the date of randomization to the date of the first 
deterioration in PRO scores of at least one threshold unit as compared to the baseline 
score.  
For subjects who experienced a firs deterioration, TTD will be computed as follows and then converted to 
months:  
Time to deterioration on EORTC QLQ-C30 outcomes is calculated as follows: 
TTD = (First Deterioration Date– Date of Randomisation + 1)/30.4375 
where first deterioration date refers to the first time that the subject’s domain/item score hit a threshold of 
10 points or more worsening from their baseline score with no later improvement above this threshold 
observed during the course of the study. [Bonnetain, 2010] 
Subjects who do not experience deterioration prior to the end of follow up or data cutoff date will be 
censored at the date of last available PRO assessment. Patients with no baseline assessment, and patients 
with no post-baseline assessments or with scores at baseline that are close to “floor” (GHS, Function scale 


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<20, Symptom scale >80) will be censored at the date of randomization. Death or disease progression will 
not be considered events. 
Number and percent of subjects with deterioration and censored will be summarized by treatment arm. 
Time to deterioration will be estimated by KM methodology. Treatment arms will be compared using 
stratified log rank test and the estimated HR from stratified Cox regression analysis will be presented to 
summarise the effect of Arm 1. Estimates of median time to deterioration and HR will be presented with 
corresponding 95% CIs. KM based rates of being alive without deterioration at 3, 6, 9, 12, and 18 months 
will be estimated and associated two-sided 95% CIs will be provided. The KM curves of the two 
treatment arms with HR will be plotted. 
Stable, improved or worsened scores 
Number and percent of subjects with improved (>=10% improvement vs baseline and remaining 
improved over baseline for >= 4 weeks ± 2 weeks), worsened (either died or had scores that worsened by 
10% vs baseline), or stable (did not meet criteria for improved or worsened) QoL scores as assessed by 
QLQ-C30 will be summarized by visit and treatment arm. Differences in percentages between Arm 1 and 
Arm 2 will be provided with 95% CIs. The two treatment arms will be compared using a Cochran-
Mantel-Haenszel test, adjusting by randomisation stratification factors per IWRS. 
Notes:  
• 
For those with multiple records on the same assessment date, the first one by time point and 
sequence number will be selected as scheduled assessment. All assessments will be included in 
the time-to-event analysis. 
• 
For subjects who receive a subsequent anti-cancer therapy (drug therapy, curative radiotherapy, 
curative surgery), only PRO measurements before the initiation of subsequent therapy will be 
included in the analyses. 
3.4.3.2 
Other Exploratory Efficacy Endpoint Analysis 
Time to Treatment Failure  
TTF will be calculated as follows: 
TTF (months) = (Event or Censoring Date – Date of Randomisation + 1)/30.4375 
Subjects who do not have a treatment failure will be censored on the date of last contact. 
The number and proportion of subjects of treatment failure in each treatment arm will be summarised. 
TTF will be estimated by KM methodology. Treatment arms will be compared using stratified log rank 
test and the estimated HR from stratified Cox regression analysis will be presented to summarise the 
effect of Arm 1. Estimates of median TTF and HR will be presented with corresponding 95% CIs. 
Duration of Response 
DOR will be calculated as follows: 
DOR (months) = (Progression/Death/Censoring Date – Response Start Date + 1) / 30.4375 
Subjects who do not have documented disease progression or death will be censored following the same 
rules as PFS specified in Table 3 
For each treatment arm, the number of subjects with and without subsequent disease progression or death 
will be summarized. DOR will be analyzed using the same approach as TTF. 


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Time to Response 
TTR will be computed only for subjects who achieved complete response or partial response.  
TTR will be calculated as follows: 
TTR (months) = (First response Start Date – Date of Randomisation + 1)/30.4375 
TTR of each treatment arm will be summarized descriptively. 
Genotyping: UGT1A1  
The number and percentage of subjects in each UGT1A1*28 allele status (homozygous/other) and other 
UGT1A genotypes (if known) will be summarised. Analyses by UGT1A1*28 allele status 
(homozygous/other) are described in Sections 3.4.4, 3.5, and 3.6.1. UGT1A1 data will also be listed in 
subject-level data listing. 
Biomarkers CA 19-9  
The biomarker CA 19-9 concentration will be summarised descriptively by treatment arm. CA 19-9 data 
will also be listed in subject-level data listing. 
Biobanking  
The exploratory endpoint comprises biobanking of samples for future analysis, among subjects who 
consent. Analysis of biobank samples will be performed outside the scope of the main study and reported 
separately. 
3.4.4 Subgroups 
Subgroup analyses will be performed to explore the consistency of the treatment effect for subgroups. 
Descriptive statistics of primary and key secondary endpoints (OS, PFS and ORR) will be provided 
within each category of the following variables: 
• 
presence of liver metastases at baseline (yes, no) 
• 
number of metastatic sites (0, 1, 2, ≥3) 
• 
baseline ECOG performance status (0/1) 
• 
region (North America/East Asia/Rest of the World) 
• 
main pancreatic tumour location (head, other) 
• 
baseline CA 19-9 (<37 U/mL, ≥37 U/mL) 
• 
race (Asian, American Indian or Alaska Native, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, not reported, Other) 
• 
sex (male, female) 
• 
age (<65 years, >=65 years) 
• 
UGT1A1*28 allele status (homozygous/non-homozygous).  
If a level of a factor consists of fewer than 5% of randomized subjects, analysis within that level will be 
omitted. 
Analyses will be done within subgroup. Estimated HRs and CIs for OS and PFS and odds ratios and CIs 
for ORR within subgroup analyses will be presented as a forest plot. 


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Other subgroup analyses may be performed as deemed appropriate. If any safety analyses identify 
important imbalances between arms, subgroup analyses of these endpoints (OS, PFS and ORR) may be 
performed. 
3.5 Pharmacokinetic Assessment 
Listings, Figures and Summary Statistics of Concentrations  
PK assessments will be performed for Arm 1 only. Individual plasma concentrations for total irinotecan, 
SN-38, 5-FU, and oxaliplatin will be listed and summarised by timepoint and dose level using descriptive 
statistics for continuous variables (number of available observations, mean, median, SD, minimum, 
maximum, geometric mean and geometric coefficient of variation assuming log-normally distributed 
data) on PK population. When applicable, the descriptive statistics should be displayed by visit/time 
point, only if at least 2/3 (two thirds) of the data are above the limit of quantification (LoQ). Otherwise, 
only minimum and maximum will be reported. As a standard rule, PK concentration should be displayed 
with the same precision as the LoQ. In descriptive statistics, calculations derived from PK concentrations 
(mean, min, max, median, SD, etc) should follow the same rule whereas coefficient of variation (CV%) 
will only be displayed with one decimal digit only.  
Linear and semilogarithmic plots of individual and mean plasma concentration-time profiles of total 
irinotecan, SN-38 and oxaliplatin as well as spaghetti plots will be reported. 
A full description of the bioanalytical methods used and bioanalysis results obtained of the plasma 
concentrations will be described in a separate standalone bioanalytical report. 
Pharmacokinetic Data Analysis 
Pharmacokinetics of total irinotecan and SN-38 will be quantified from the concentrations from plasma 
samples using nonlinear mixed effect modeling (NONMEM). The initial PK analysis will use the 
empirical Bayesian estimation; however, additional covariate analyses will be performed to evaluate 
alternative baseline factors specific to PDAC. The resulting PK estimates will be used to evaluate the 
association between PK and pharmacodynamics (efficacy and safety endpoints). 
Oxaliplatin and/or 5-FU concentrations might be used for further PK characterisation if more 
investigations are required. 
A full description of the pharmacokinetic analysis of the concentration data will be captured separately in 
a data analysis plan, and PK results will be reported in a standalone report. 
Pharmacokinetics/Pharmacodynamics Relationship 
Graphical exploration will be performed to investigate any relationship between PK and 
pharmacodynamic endpoints (efficacy, safety). If a trend is shown, PK/PD modelling will be performed 
and this will be described in a separate Data Analysis Plan and reported in a standalone report. 
Genotyping: UGT1A1 and Pharmacokinetics 
The impact of UGT1A1*28 allele status on pharmacokinetic profile of subjects treated with irinotecan 
liposome injection+oxaliplatin+5-FU/LV will be evaluated. 
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3.6 Safety Analysis 
All safety data will be included in the subject data listings. Analyses and summary tables will be based 
upon the safety population. 
3.6.1 Adverse Events 
1. An overall summary table of all adverse events will be presented, which will summarize the number 
and percentages of subjects and number of events of the following categories: 
• 
AEs, 
• 
TEAEs, 
• 
NCI CTCAE grade 3/4/5 TEAEs, 
• 
Serious TEAEs, 
• 
Serious TEAEs due to COVID-19 
• 
TEAEs leading to discontinuation of any Investigational Medicinal Product (IMP), 
• 
TEAEs leading to discontinuation of Irinotecan liposome injection, 
• 
TEAEs leading to dose reduction of any IMP, 
• 
TEAEs leading to dose reduction of Irinotecan liposome injection, 
• 
TEAEs leading to dose interruption of any IMP, 
• 
TEAEs leading to dose interruption of Irinotecan liposome injection, and 
• 
TEAEs leading to death. 
All the above events (except for regular AEs) related to any IMP or Irinotecan liposome injection will be 
summarized respectively. TEAEs leading to death due to COVID-19 will be summarized. 
2. The number, percentage of subjects and frequency of the following TEAEs will be summarized by 
SOC, PT, CTCAE grade (Any Grade, Grade 3-4) and by treatment arm and overall. 
• 
TEAEs 
o Related to any IMP 
o Related to Irinotecan liposome injection 
• 
Serious TEAEs 
o Related to any IMP 
o Related to Irinotecan liposome injection 
• 
TEAEs leading to discontinuation of any IMP 
o Related to any IMP 
o Related to Irinotecan liposome injection 
• 
TEAEs leading to discontinuation of Irinotecan liposome injection 
o Related to Irinotecan liposome injection 


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• 
TEAEs leading to dose reduction of any IMP 
• 
TEAEs leading to dose reduction of Irinotecan liposome injection 
• 
TEAEs leading to dose interruption of any IMP 
• 
TEAEs leading to dose interruption of Irinotecan liposome injection 
• 
TEAEs leading to death 
o Related to any IMP 
o Related to Irinotecan liposome injection 
• 
Treatment-emergent AESIs 
3. The number, percentage of subjects and frequency of the following TEAEs will be summarized by 
SOC, PT, UGT1A1*28 Allele Status (homozygous/other), and by treatment arm and overall. 
• 
TEAEs 
o Related to Irinotecan liposome injection 
• 
NCI CTCAE grade 3/4/5 TEAEs related to Irinotecan liposome injection 
• 
Serious TEAEs related to Irinotecan liposome injection 
• 
TEAEs leading to discontinuation of study treatment related to Irinotecan liposome injection 
• 
TEAEs leading to death 
o Related to any IMP 
o Related to Irinotecan liposome injection 
4. The number, percentage of subjects and frequency of the following TEAEs will be summarized by 
SOC, preferred term (PT), age (<65 years, >=65 years), race, gender and by treatment arm and 
overall.  
• 
TEAEs 
• 
TEAEs leading to death 
Overall summary of TEAEs will also be present by age, race, gender and by treatment arm and 
overall. 
5. Listings of following AEs will be presented by subject, SOC and PT. All TEAEs will be flagged in 
the listings. 
• 
AEs 
• 
NCI CTCAE grade 3/4/5 TEAEs 
• 
SAEs 
• 
SAEs due to COVID-19 
• 
AEs leading to discontinuation of any IMP 
• 
AEs leading to discontinuation of Irinotecan liposome injection, Oxaliplatin, Leucovorin, 5-FU, 
Nab-paclitaxel or Gemcitabine respectively 


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• 
AEs leading to dose reduction of Irinotecan liposome injection, Oxaliplatin, Leucovorin, 5-FU, 
Nab-paclitaxel or Gemcitabine respectively 
• 
AEs leading to dose interruption of Irinotecan liposome injection, Oxaliplatin, Leucovorin, 5-FU, 
Nab-paclitaxel or Gemcitabine respectively 
• 
AEs leading to death 
• 
AESIs 
All COVID-19 cases (suspected or confirmed) should be considered as SAEs. AE due to COVID-19 is 
derived per COVID-19 SMQ list. 
3.6.2 Death 
The number, percentage of subjects who died (any death, TEAE, treatment related TEAE), and primary 
reason for death (any death) will be summarized by treatment arm.  
All deaths on study will be listed along with the primary reason for death. For those deaths attributed to 
TEAE, the tables and listings will be presented per Section 3.6.1.  
3.6.3 Clinical Laboratory Tests 
Hematological and biochemistry toxicities when available will be recorded and graded according to the 
NCI-CTC criteria, version 5.0.  
Descriptive statistics will be provided for selected clinical laboratory test results (haematology and 
chemistry) and changes from baseline for the minimum post-baseline value, maximum post-baseline 
value, and last post-baseline value. 
Directional shifts in laboratory toxicity grades (comparing baseline grade with worst post-baseline grade) 
will be analyzed using standard shift tables, presenting number and proportion of subjects and their 
maximum grade shift for selected laboratory parameters (ALT, AST, total bilirubin, ALP, creatinine, 
hemoglobin, absolute neutrophils, platelet counts, white blood cell counts, aPTT, and INR). Individual 
line plots over time will also be presented for these selected laboratory parameters. 
The number and percentage of subjects with the following potentially clinically significant abnormal liver 
function tests at any post-Baseline visits will be summarized: 
• 
ALT ≥3xULN to <5xULN, ≥5xULN to <10xULN, ≥10xULN to <20xULN, and ≥20xULN 
• 
AST ≥3xULN to <5xULN, ≥5xULN to <10xULN, ≥10xULN to <20xULN, and ≥20xULN 
• 
Total bilirubin ≥2xULN 
• 
ALT or AST ≥3×ULN with total bilirubin ≥2×ULN without elevation of ALP (< 2xULN) 
• 
ALT or AST ≥3xULN, total bilirubin ≥2xULN, and ALP ≥2xULN 
The same summary will also be repeated by presence of liver metastases at baseline (yes, no). 
Number of subjects for selected laboratory parameters with a difference ≥ 5% for CTCAE grade 1-4 
toxicity or ≥ 2% for grade 3-4 toxicity between treatment groups will be summarized. 
Chemistry 
• 
Albumin Decrease 
• 
Calcium Decrease 


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• 
Phosphate Decrease 
• 
Potassium Decrease 
• 
Sodium Decrease 
• 
Alanine Aminotransferase Increase 
• 
Alkaline Phosphatase Increase 
• 
Aspartate Aminotransferase Increase 
• 
Bilirubin Increase 
• 
Calcium Increase 
• 
Creatinine Increase 
• 
Potassium Increase 
Hematology 
• 
Hemoglobin Decrease 
• 
Lymphocyte Count Decrease 
• 
Neutrophil Count Decrease 
• 
Platelet Count Decrease 
• 
Leukocytes Count decrease 
Standard International (SI) units will be used in the descriptive summary tables. 
• 
When both central and local results from the same sampling date are available or only central is 
available but local is missing, central results will be used. 
• 
When central is missing but local results from the same sampling date is available, local results 
will be used.  
• 
For those with multiple results from central lab on the same sampling date, the first one by time 
point will be used. 
Listings of hematological and biochemistry will list both central and local lab results in Standard 
International units and local units and sort by test, date and time. Local lab will be flagged. Additionally, 
listings of urinalysis (dipstick) and dihydropyrimidine dehydrogenase (DPD) deficiency testing will be 
provided. 
3.6.4 Pregnancy Test 
Urine or serum pregnancy test will be listed. 
3.6.5 Electrocardiograms 
Number and percentage of subjects with QTcF intervals in the categories below will be provided. 
• 
Post-baseline absolute QTcF interval >450 msec, 
• 
Post-baseline absolute QTcF interval >480 msec, 
• 
Post-baseline absolute QTcF interval >500 msec. 
• 
Change from baseline QTcF interval increase >30 msec, 


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• 
Change from baseline QTcF interval increase >60 msec. 
For continuous ECG parameters (heart rate, RR interval, PR interval, QRS duration, QT interval, QTcF 
interval), summary statistics will be presented for baseline and changes from baseline for the minimum 
post-baseline value, maximum post-baseline value and last post-baseline value. 
For interpretation of clinical significance (normal / abnormal, not clinically significant / abnormal, 
clinically significant / not evaluable), a frequency table will be presented at baseline and the worst post-
baseline assessment. 
ECG data will be listed at each assessment. 
3.6.6 Vital Signs 
Summary statistics will be presented for baseline and changes from baseline for the minimum post-
baseline value, maximum post-baseline value and last post-baseline value. 
Vital signs will be listed at each assessment. 
3.6.7 Physical Examinations 
For interpretation of clinical significance (normal / abnormal, not clinically significant / abnormal, 
clinically significant / not evaluable), a frequency table will be presented at baseline and post-baseline 
assessment. 
3.6.8 ECOG Performance Status 
The frequency and percentage of subjects with each performance status score will be displayed by visit. A 
shift table presenting the shift from baseline to worst post-baseline score will also be presented. ECOG 
data will also be listed in subject-level data listing. 
3.6.9 Other Data 
Hospitalization data will be listed. 
4 INDEPENDENT DATA MONITORING BOARD AND INTERIM 
ANALYSIS 
An IDMC will be established for this study to operate as an independent expert advisory group with the 
responsibility of evaluating cumulative safety and other clinical trial data at regular intervals. As such, the 
primary objective of the IDMC is to monitor the safety of the subjects enroled in the study by reviewing 
the available clinical data at scheduled time points as well as on an ad hoc basis, as needed. Items 
reviewed will include (but not limited to) safety events, any available results of PK testing, and 
UGT1A1*28 allele status (homozygous/other). Attention will be paid to determining whether any study 
procedure needs to be modified for subjects who are homozygous for the UGT1A1*28 allele.  
The same IDMC will evaluate also the efficacy data as well as the safety data at the time of the interim 
analysis. The IDMC will be responsible for reviewing the futility and efficacy results in the interim 
analysis and making appropriate recommendations based on those results. 
The planned frequency of the IDMC is planned to be as follows and will be agreed with the IDMC 
experts: 
After the 50th randomised subject has been followed for at least 28 days (follow-up timeframe equivalent 
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• 
Every 6 months and additionally timed with each planned interim analysis: 
- 
Interim analysis for futility and efficacy (no less than 50% of the planned final 
number of OS events in ITT population i.e. 272 of 543) 
At the time of interim analysis, analyses provided to the IDMC will include: 
• 
the boundary values for significance, 
• 
for OS and PFS,  
− the p-value from a stratified log rank test comparing the two treatment arms, stratified by 
the randomisation stratification factors, 
− an estimate of the HR between the two arms based on a Cox proportional hazards model, 
stratified by the randomisation stratification factors, and 
− median survival time and its 95% CIs KM analysis by treatment arm.  
− Number and type of events and Number of subjects censored by type of censoring by 
treatment arm 
• 
for ORR,  
− the p-value from a Cochran-Mantel-Haenszel test comparing the two treatment arms, 
adjusting by randomisation stratification factors, and 
− proportion of ORR and associated 95% CI will be estimated using the Clopper Pearson 
method by treatment arm 
− Number and percent of subjects with their best overall response by treatment arm 
Details are documented in the separate IDMC charter. 
In order to maintain the scientific integrity of this trial, access to by treatment arm study data will be 
strictly controlled prior to the interim and final analyses. During this time, analyses using actual treatment 
codes will be performed only at the interim analysis points and IDMC data review specified in the 
protocol/SAP. For those safety and efficacy analyses assigned to the IDMC, only the designed 
independent statistical team, will perform the by treatment arm analyses.  
Data sets will be created for the purpose of aggregate data review by the sponsor in which treatment 
assignment is scrambled so that personnel involved in the day-to-day conduct of the trial and 
development and validation of analysis programs will be blinded to subject treatment assignment. 
5 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL 
ANALYSES 
The following updates in the SAP not in protocol version 5 dated 19 August 2021. 
• 
Change time to deterioration exploratory objective only includes GHS, function domains, and 
disease related symptoms from EORTC QLQ-C30Change analysis day calculation from using 
first dose of study treatment to randomization 
• 
Disposition includes subjects who received non-planned study treatments and subjects with 
ongoing long-term follow up 
• 
Change OS sensitivity analysis Wilcoxon analysis to Unstratified log rank 
• 
Clarify new anti-cancer therapy to subsequent anti-cancer therapy (drug therapy, curative 
radiotherapy, curative surgery) including new antineoplastic treatment. 
• 
Clarify analysis Intent-to-Treat definition from all randomised subjects who have given their 
informed consent to all randomised subjects to whom study treatment has been assigned by 


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randomization. Subjects will be analyzed according to the assigned treatment per randomization 
procedure.  
• 
Clarify Safety Population is a subset of the ITT population that received at least one dose 
(including a partial dose) of any component of the study medication in the combination therapy). 
Subjects will be analyzed according to the actual received treatment 
• 
Remove sensitivity analysis of OS using Cox regression with stepwise selection and univariate 
analysis of OS for prognostic factors 
• 
Change analyses of QoL primarily based on ITT population. PRO population may be used as the 
sensitivity analyses 
6 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.3 or higher.  All available data will be presented in 
subject data listings which will be sorted by subject and visit date as applicable.  Detailed Programming 
Specifications will be provided in a separate document. 
 


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APPENDIX A:  REFERENCES 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0. November 27, 2017. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference
_5x7.pdf 
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur. J. Cancer 2009;45(2):228–47. 
EORTC QLQ-C30 Manual, (third edition), Brussels, 2001. 
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential trials. Stat 
Med 2010;29(2):219-28. 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error probability 
spending functions. Stat Med 1990;9:1439-45. 
Bonnetain F, Dahan L, Maillard E, et al. Time until definitive quality of life score deterioration as a 
means of longitudinal analysis for treatment trials in patients with metastatic pancreatic adenocarcinoma. 
Eur J Cancer. 2010;46:2753-2762.


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APPENDIX B:  NCI PRO-CTCAE ITEMS 
PRO-CTCAE (version 1.0) is PRO measure of the frequency, severity and/or interference of symptoms 
experienced by patients participating in cancer clinical trials. A subset of items relevant to this study are 
selected. 
The full instrument can be found at https://healthcaredelivery.cancer.gov/pro-ctcae/instrument-pro.html . 
 
 
 


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APPENDIX D:  EORTC QLQ - C30 (V3.0) 
 


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The EORTC QLQ-C30 (version 3) is a generic questionnaire that has been developed and validated to 
assess the QoL of cancer patients. 
The PRO measure contains 30 items that measure health-related quality of life in patients with cancer. It 
includes a total of 30 items and is composed of scales that evaluate physical (five items), emotional (four 
items), role (two items), cognitive (two items), and social (two items) functioning, as well as global health 


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status (two items). There are also three symptom scales measuring nausea and vomiting (two items), 
fatigue (three items), and pain (two items), and six single items assessing financial impact and various 
physical symptoms, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. 
The items are based on 4-point (1 and 4 indicating ‘not at all’ and ‘very much’, respectively) and 7-point 
Likert scales (1 and 7 indicating ‘very poor’ and ‘excellent’, respectively). 
The minimally significant mean change is 5 to 10 points on a scale of 0 to 100. 
A high scale score represents a higher response level. Thus a high score for a functional scale represents a 
high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, 
but a high score for a symptom scale / item represents a high level of symptomatology / problems. 
All scoring information specific to the QLQ-C30 is presented in Table 6. 
The principle for scoring these domains is the same in all cases: 
1. Estimate the average of the items that contribute to the domain; this is the raw score. 
2. Use a linear transformation to standardize the raw score, so that scores range from 0 to 100; a higher 
score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.  
The technical details are provided below. 
If items I1, I2, ... In are included in a domain, the procedure is as follows: 
Calculate the raw score (RS) as follows: RS=( I1+I2+ ... +In)/n 
Apply the linear transformation as follows: 
Functional scales: S = 1 – ((RS −1)/range)×100 
Symptom scales / items: S = (RS −1)/range×100 
Global health status/QoL: S = (RS −1)/range×100 
where Range is the difference between the maximum possible value of RS and the minimum possible value. 
The EORTC-QLQ-C30 has been designed so that all items in any domain take the same range of values. 
Therefore, the range of RS equals the range of the item values (see Table 6). 
If at least half the components of a domain are present, then the domain score will be calculated using the 
average of all items answered as the raw score; otherwise the score will be set to missing. For single 
measures, it the item is missing the domain score is set to missing.  
 
 


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Table 6 QLQ-C30 Scales and Scoring Details 
 
Number of 
items 
Item 
range* 
Item 
numbers 
Minimum 
Not Missing 
Global health status/QoL 
 
 
 
 
  Global health status/QoL 
2 
6 
29, 30 
1 
 
 
 
 
 
Functional scales 
 
 
 
 
  Physical functioning 
5 
3 
1-5 
3 
  Role functioning 
2 
3 
6, 7 
1 
  Emotional functioning 
4 
3 
21-24 
2 
  Cognitive functioning 
2 
3 
20, 25 
1 
  Social functioning 
2 
3 
26, 27 
1 
 
 
 
 
 
Symptom scales / items 
 
 
 
 
  Fatigue 
3 
3 
10, 12, 18 
2 
  Nausea and vomiting 
2 
3 
14, 15 
1 
  Pain 
2 
3 
9, 19 
1 
  Dyspnea 
1 
3 
8 
NA 
  Insomnia 
1 
3 
11 
NA 
  Appetite loss 
1 
3 
13 
NA 
  Constipation 
1 
3 
16 
NA 
  Diarrhoea 
1 
3 
17 
NA 
  Financial difficulties 
1 
3 
28 
NA 
* Item range is the difference between the possible maximum and the minimum response to individual items; most 
items take values from 1 to 4, giving range = 3. 
 
 
 


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APPENDIX E:  EORTC QLQ - PAN26 (1999) 
 


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The QLQ-PAN26 is a disease-specific module that complements the QLQ-C30 questionnaire to capture 
concepts that are specific to pancreatic cancer (all disease stages).  
The EORTC QLQ-PAN26 uses 26 items to quantify pain, dietary changes, jaundice, altered bowel habit, 
emotional problems related to pancreatic cancer, and other symptoms including cachexia, indigestion, 
flatulence, dry mouth, and taste changes. The items are based on 4-piont Likert scale, 1 and 4 indicating 
‘not at all’ and ‘very much’, respectively. The questionnaire consists of symptom scales such as 
pancreatic pain symptom scale (four items 31, 33, 34, 35), upper gastrointestinal symptom scale (two 
items 36, 37), jaundice scale (two items 44, 45), body image scale (two items 48, 49), altered bowel habit 


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scale (two items 46, 47), health satisfaction scale (two items 53, 54), sexuality scale (two items 55, 56) 
and 10 single items. 
The scoring approach for the QLQ-PAN26 is identical in principle to that for the symptom scales / single 
items of the QLQ-C30. All scoring information specific to the QLQ-PAN26 is presented in Table 7. 
Interpretation: 
All of the scales and single item measures range in score from 0 to 100. A high score for the symptom 
scales and/or single items represents a high level of symptomatology or problems, whereas a high score 
for the functional scales represents a high level of functioning. 
Principle for scoring 
1) Raw score 
For each multi-item scale, calculate the average of the corresponding items. 
Raw Score = 𝑅𝑆={(𝐼1+ 𝐼2+ … +𝐼𝑛) 𝑛} 
For each single-item measure, the score of the concerning item corresponds to the raw score. 
Take into account that the scoring of questions 55 and 56 must be reversed prior to statistical analysis. 
2) Linear Transformation 
To obtain the Score S, standardize the raw score to a 0 – 100 range following the transformation: 
Functional scales: S = 1 – ((RS −1)/range)×100 
Symptom scales / items: S = (RS −1)/range×100 
The same missing data handling rule as QLQ-C30 will be implemented. 


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Table 7 QLQ-PAN26 Scales and Scoring Details 
 
Number of 
items 
Item 
range* 
Item 
numbers 
Minimum 
Not Missing 
Symptom scales / items 
 
 
 
 
  Pancreatic pain 
4 
3 
31, 33 - 35 
1 
  Bloating 
1 
3 
32 
1 
  Digestive symptoms 
2 
3 
36, 37 
1 
  Taste 
1 
3 
38 
NA 
  Indigestion 
1 
3 
39 
NA 
  Flatulence 
1 
3 
40 
NA 
  Weight loss 
1 
3 
41 
NA 
  Weakness arms and legs 
1 
3 
42 
NA 
  Dry mouth 
1 
3 
43 
NA 
  Hepatic symptoms 
2 
3 
44, 45 
1 
  Altered bowel habit 
2 
3 
46, 47 
1 
  Body image 
2 
3 
48, 49 
1 
  Troubled with side-effects 
1 
3 
50 
NA 
  Future Worries 
1 
3 
51 
NA 
  Planning of activities 
1 
3 
52 
NA 
 
 
 
 
 
Functional scales 
 
 
 
 
  Satisfaction with health care 
2 
3 
53, 54 
1 
  Sexuality 
2 
3 
55, 56 
1 
* Item range is the difference between the possible maximum and the minimum response to individual items; most 
items take values from 1 to 4, giving range = 3. 
 
 


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APPENDIX F:  EQ-5D-5L (PER USER GUIDE V3.0) 
 


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EuroQol/EQ-5D is a standardized, reliable and validated instrument to measure quality of life. It consists 
of the EQ-5D descriptive system and the EQ Visual Analogue scale (EQ VAS).  
The EQ-5D 5 level version (EQ-5D-5L) descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 
level 1 (no problems), level 2 (slight problems), level 3 (moderate problems), level 4 (severe problems), 
and level 5 (extreme problems).  


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A total of 3125 health states are possible. Each state is referred to in terms of a 5-digit code. For example, 
state 11111 indicates no problem on any of the 5 dimensions, while state 12345 indicates no problems 
with mobility, slight problems with self-care, moderate problems with doing usual activities, severe pain 
or discomfort and extreme anxiety or depression. There should be only one response for each dimension 
and missing values will be coded as 9. If 2 levels are selected for a dimension, the dimension will be 
treated as missing. 
The health state can be summarized to be a single number (5-digit code), or represented by a single 
summary number (index value), which reflects how good or bad a health state is according to the 
preferences of the general population of a country/region.  
An EQ-5D summary index is derived by applying a formula that attaches values (weights) to each of the 
levels in each dimension. The index is calculated by deducting the appropriate weights from 1, the value 
for full health (i.e. state 11111). The collection of index values (weights) for all possible EQ-5D health 
states is called a value set. Most EQ-5D value sets have been obtained from a standardized valuation 
exercise, in which a representative sample of the general population in a country/region is asked to place a 
value on EQ-5D health states. 
The EQ VAS records the subject’s self-rated health state on a 100-point vertical, visual analogue scale (0 
= worst imaginable health state; 100 = best imaginable health state). 
 
 


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APPENDIX G:  AJCC PROGNOSTIC STAGE GROUPS TABLE (8TH 
EDITION)