Clinical trial NCT02551991
Conditions: Pancreatic Cancer
Keywords: Pancreatic cancer MM-398 Metastatic pancreatic cancer First line pancreatic cancer treatment
Sponsor: Ipsen
Start date: 2015-10-19; Completion date: 2021-02-15
Enrollment: 56 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, phase 2 non-comparative study to assess the safety, tolerability, and preliminary efficacy of nal-IRI in combination with other anticancer therapies in patients not previously treated for metastatic pancreatic adenocarcinoma. This study will assess the following regimen:

• nal-IRI + 5-fluorouracil (5-FU)/leucovorin (LV) + oxaliplatin

The study will be conducted in two parts:

Part 1, consisting of an initial dose exploration (Part 1A) followed by dose expansion (Part 1B) of the irinotecan liposome injection +5-FU/LV + oxaliplatin regimen and Part 2, consisting of a comparison of irinotecan liposome injection-containing regimen versus nab-paclitaxel plus gemcitabine. The comparative Part 2 was removed in a protocol amendment, dated 11 April 2018 (Version 6.0), before it was initiated, as this comparative part of the study is being undertaken as a stand-alone phase III study D-US-60010-001. This CSR only pertains to the single-arm dose exploration and dose expansion Part 1 results and no further reference is made to the comparative Part 2.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: nal-IRI intervention 2: 5 fluorouracil intervention 3: Leucovorin intervention 4: Oxaliplatin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
 
 
 
MM-398-07-02-03: A Randomized, Open-label Phase 
2 Study of Nanoliposomal Irinotecan (nal-IRI)-
containing Regimens versus nab-paclitaxel plus 
Gemcitabine in Patients with Previously Untreated, 
Metastatic Pancreatic Adenocarcinoma 
 
IPSEN BIOSCIENCE, Inc. 
 
 
 
 
 
 
Version 7.0: 27 September 2019 
IND Number: 102799 
EudraCT #: 2015-003086-28 
ClinicalTrials.gov Identifier: NCT02551991 
 
 
 
 
Sponsor:  
IPSEN BIOSCIENCE, Inc. 
650 East Kendall Street,  
Cambridge MA 02142 
USA 
 
Confidentiality Statement 
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 authorization. 


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Table of Contents 
SUMMARY OF CHANGES ................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................. 8 
STUDY SYNOPSIS ................................................................................................................ 10 
1 
INTRODUCTION ........................................................................................................ 20 
1.1 
Pancreatic Cancer ......................................................................................................... 20 
1.1.1 
Pancreatic Cancer Treatment ..................................................................... 20 
1.2 
Nal-IRI (MM-398) ......................................................................................................... 21 
1.2.1 
Nal-IRI Pre-Clinical Experience ................................................................ 21 
1.2.2 
Nal-IRI Clinical Experience ....................................................................... 22 
1.3 
Study Rationale ............................................................................................................. 28 
1.3.1 
Rationale for Nal-IRI + 5-FU/LV + Oxaliplatin ....................................... 29 
1.3.2 
Clinical Data in UGT1A1*28 Homozygous Patients................................. 30 
2 
STUDY OBJECTIVES ................................................................................................. 32 
2.1 
Primary Objectives ....................................................................................................... 32 
2.2 
Secondary Objectives ................................................................................................... 32 
2.3 
Exploratory Objectives ................................................................................................. 32 
3 
STUDY DESIGN ........................................................................................................... 32 
3.1 
Study Design Overview ................................................................................................ 32 
3.2 
Safety Assessment ......................................................................................................... 34 
3.2.1 
Overview ...................................................................................................... 34 
3.2.2 
DLT Definition (Nal-IRI + 5-FU/LV + Oxaliplatin) ................................. 35 
4 
ENROLLMENT AND TREATMENT ....................................................................... 35 
4.1 
Dose levels ...................................................................................................................... 36 
4.1.1 
Decision Process for Cohort Progression .................................................. 37 
4.1.2 
Decision Criteria for Cohort Progression .................................................. 37 
4.2 
Patient Replacement ..................................................................................................... 37 
5 
PATIENT SELECTION AND DISCONTINUATION ............................................. 37 
5.1 
Inclusion Criteria .......................................................................................................... 37 
5.2 
Exclusion Criteria ......................................................................................................... 38 
5.3 
Patient Discontinuation ................................................................................................ 39 
5.3.1 
Discontinuation of Study Treatment .......................................................... 39 
5.3.2 
Withdrawal from the Study ......................................................................... 40 
5.3.3 
Procedures following Study Drug Discontinuation or Study Withdrawal
 ...................................................................................................................... 40 
6 
STUDY TREATMENT ................................................................................................ 41 
6.1 
Investigational Product ................................................................................................ 41 
6.1.1 
Description of Nal-IRI (MM-398) .............................................................. 41 
6.2 
Additional Anticancer Therapies ................................................................................ 43 
6.2.1 
Description of Combination Therapies ...................................................... 43 
6.2.2 
Storage and Handling of Combination Therapies..................................... 43 
6.2.3 
Packaging and Labeling of Combination Therapies ................................. 43 


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6.2.4 
Potential Toxicities of Combination Therapies ......................................... 43 
6.3 
Combination Regimen Dosage and Administration .................................................. 44 
6.3.1 
Nal-IRI + 5-FU/LV + Oxaliplatin .............................................................. 44 
6.3.2 
Doses and Administration of Nal-IRI ........................................................ 44 
6.3.3 
Doses and Administration of 5-FU and Leucovorin ................................. 45 
6.3.4 
Doses and Administration of Oxaliplatin ................................................... 45 
6.4 
Management of Infusion Reactions ............................................................................. 45 
6.5 
Dose Modifications ........................................................................................................ 46 
6.5.1 
Nal-IRI Dose Modifications for UGT1A1*28 Positive Patients ............... 49 
6.5.2 
Other Toxicities Requiring Special Attention ............................................ 50 
6.5.3 
Rules for Dose Omissions and Modified Schedules .................................. 50 
6.6 
Drug Accountability ..................................................................................................... 50 
6.7 
Concomitant Therapy ................................................................................................... 51 
6.7.1 
Granulocyte Colony Stimulating Factors .................................................. 51 
6.7.2 
Therapy for Diarrhea .................................................................................. 51 
6.8 
Prohibited Therapy ....................................................................................................... 52 
7 
STUDY PROCEDURES .............................................................................................. 52 
7.1 
Protocol Visits ............................................................................................................... 52 
7.1.1 
Screening Visit ............................................................................................ 52 
7.1.2 
On-Study Visits ............................................................................................ 52 
7.1.3 
End of Treatment Visit ................................................................................ 53 
7.1.4 
Long-term Follow-up .................................................................................. 53 
7.2 
Clinical Procedures ....................................................................................................... 53 
7.2.1 
Medical History ........................................................................................... 53 
7.2.2 
Vital Signs ................................................................................................... 53 
7.2.3 
Performance Status ..................................................................................... 53 
7.2.4 
Electrocardiogram (ECG)........................................................................... 53 
7.2.5 
Adverse Event and Hospitalization Assessment ......................................... 53 
7.2.6 
Disease Evaluation ...................................................................................... 54 
7.3 
Laboratory Procedures ................................................................................................ 54 
7.3.1 
Complete Blood Count ................................................................................ 54 
7.3.2 
Serum Chemistry ......................................................................................... 54 
7.3.3 
CA19-9 ......................................................................................................... 54 
7.3.4 
UGT1A1*28 ................................................................................................. 54 
7.3.5 
Biomarker Samples ..................................................................................... 54 
7.3.6 
Urine or Serum Pregnancy Test ................................................................. 55 
7.3.7 
Pharmacokinetic Assessments .................................................................... 55 
8 
SCHEDULE OF ASSESSMENTS .............................................................................. 56 
9 
ADVERSE EVENT REPORTING ............................................................................. 58 
9.1 
Definitions ...................................................................................................................... 58 
9.1.1 
Adverse Event .............................................................................................. 58 


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9.1.2 
Unexpected Adverse Event .......................................................................... 58 
9.1.3 
Serious Adverse Event ................................................................................ 58 
9.2 
Documenting Adverse Events ...................................................................................... 58 
9.3 
Reporting Serious Adverse Events .............................................................................. 59 
9.4 
Determining the Severity and Relatedness of Adverse Events ................................. 60 
9.4.1 
Grading the Severity of an Adverse Event ................................................. 60 
9.4.2 
Relatedness to Study Drug .......................................................................... 60 
9.4.3 
Reporting and Follow-Up of Pregnancy .................................................... 60 
10 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ................................... 60 
10.1 Case Report Forms ....................................................................................................... 60 
10.2 Data Quality Assurance ................................................................................................ 60 
10.3 Statistical Analysis ........................................................................................................ 61 
10.4 Study Populations ......................................................................................................... 61 
10.5 Disposition and Baseline Characteristics .................................................................... 61 
10.6 Efficacy Analysis ........................................................................................................... 61 
10.7 Safety Analysis .............................................................................................................. 62 
10.8 Biomarker Analysis ...................................................................................................... 62 
10.9 Pharmacokinetics Analysis .......................................................................................... 62 
10.10 Sample Size Justification .............................................................................................. 62 
11 
EXTENSION PHASE ................................................................................................... 63 
12 
STUDY ADMINISTRATION ..................................................................................... 63 
12.1 Pre-Study Documentation ............................................................................................ 63 
12.2 Source Documents ......................................................................................................... 64 
12.3 Trial Ethics .................................................................................................................... 64 
12.4 Patient Informed Consent ............................................................................................ 64 
12.5 Investigational Review Board/Ethics Committee Approval ..................................... 65 
12.6 Monitoring ..................................................................................................................... 65 
12.7 Confidentiality ............................................................................................................... 65 
12.7.1 
Samples for Central Lab Testing ................................................................ 66 
12.7.2 
Confidentiality of Biomarker Samples ....................................................... 66 
12.8 Protocol Amendments .................................................................................................. 66 
12.9 Publication ..................................................................................................................... 66 
12.10 Records Retention ......................................................................................................... 67 
12.11 Study Termination ........................................................................................................ 67 
13 
REFERENCES .............................................................................................................. 68 
14 
INVESTIGATOR AND SPONSOR SIGNATURE PAGE ....................................... 72 
APPENDICES ........................................................................................................................ 73 
Appendix 1: 
Recommended Birth Control Methods for Women of Child Bearing 
Potential (WOCBP) ...................................................................................................... 73 
Appendix 2: 
Proposed Algorithm for Diarrhea Management ..................................... 74 
Appendix 3: 
Karnofsky Performance Status ................................................................ 75 
Appendix 4: 
ECOG Performance Status ....................................................................... 76 


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Appendix 5: Summary of Changes 28 December 2016 (Version 3.1) to 29 September 
2017 (Version 5.0) ......................................................................................................... 77 
Appendix 6: Summary of Changes: 03 April 2017 (version 4.0) to 29 September 2017 
(version 5.0) ................................................................................................................... 90 
Appendix 7: Summary of Changes: 29 September 2017 (version 5.0) to 11 April 2018 
(version 6.0) ................................................................................................................. 103 
Appendix 8: Summary of Changes: 11 April 2018 (version 6.0) to 27 September 2019 
(version 7.0) ................................................................................................................. 166 


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List of Tables 
Table 1: 
Summary of Completed Studies with Nal-IRI .................................................. 23 
Table 2: 
Summary of Open Studies with Nal-IRI ........................................................... 24 
Table 3: 
Summary Statistics of nal-IRI PK Parameters across Multiple PK Studies . 26 
Table 4: 
Summary of Grade 3 or Higher Adverse Events in NAPOLI-1 Study .......... 28 
Table 5: 
Dose Escalation Table (Nal-IRI + 5-FU/LV + Oxaliplatin) ............................. 36 
Table 6: 
Dose Modifications for Hematologic Toxicities(a,b,c,d) ....................................... 48 
Table 7: 
Dose Modifications for Diarrhea(a,b) .................................................................. 48 
Table 8: 
Dose Modifications for Non-Hematological Toxicities Other than Diarrhea, 
Asthenia and Grade 3 Anorexiaa,b,e ................................................................... 49 
Table 9: 
Recommendations for Management of Chemotherapy Induced Diarrhea ... 52 
Table 10: Summary of PK Timepoints ............................................................................... 55 
Table 11: Probability to Escalate as a Function of Toxicity Rate .................................... 63 
Table 12: Probability probabilities of outcomes for DCR16 ............................................. 63 
 
List of Figures 
Figure 1: Tissue Distribution of nal-IRI in an HT-29 Xenograft Study. ........................ 22 
Figure 2: Mean Plasma Concentrations of Total Irinotecan and SN-38 Following the 
Administration of Either MM-398 (120mg/m2) or Camptosar® (300mg/m2) 
in Study PEP0206 ................................................................................................ 25 
Figure 3: Clinical Evidence for Local Activation and Accumulation of SN-38 in 
Tumor Tissue ....................................................................................................... 27 
Figure 4: Efficacy of Nal-IRI in a 5-FU Insensitive Pancreatic Cancer Model 
(BxPC-3) ............................................................................................................... 30 
Figure 5: Overview of Study Design ................................................................................... 33 
 
 
 


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SUMMARY OF CHANGES 
The current version of the protocol (Version 7.0) was released on 27 September 2019. This 
protocol version includes all amendments, with summaries of changes from Version 3.1 
included in the following appendices. The main purpose of this amendment is to amend details 
of the extension part of the study (see Appendix 8). 
• 
Appendix 5: Summary of Changes 28 December 2016 (Version 3.1) to 29 September 
2017 (Version 5.0) 
• 
Appendix 6: Summary of Changes: 03 April 2017 (Version 4.0) to 29 September 2017 
(Version 5.0). 
• 
Appendix 7: Summary of Changes 29 September 2017 (Version 5.0) to 11 April 2018 
(Version 6.0) 
• 
Appendix 8: Summary of Changes 11 April 2018 (Version 6.0) to 27 September 2019 
(Version 7.0) 
 
The changes for all these amendments were substantial. 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
5-FU 
5-Fluorouracil 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
ASCO 
American Society of Clinical Oncology 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CA19-9 
Carbohydrate antigen 19-9 
CBC 
Complete blood count 
Cmax 
Maximum concentration 
CR 
Complete response 
CRF 
Case report forms 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EPR 
Enhanced permeability and retention 
EU 
European Union 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factors 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on harmonization 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
Kg 
KPS 
Kilogram 
Karnofsky Performance Status 
L 
Liter 
LDH 
Lactate dehydrogenase 
LV 
Leucovorin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 


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Abbreviation 
Definition 
MUGA 
Multiple gated acquisition scan 
nal-IRI 
Nanoliposomal irinotecan; MM-398 
NCI 
National Cancer Institute 
ng 
Nanogram 
nm 
Nanometer 
OS 
Overall survival 
PD 
Progressive disease 
PK 
Pharmacokinetic 
PFS 
Progression free survival 
PR 
Partial response 
PS 
Performance Status 
QTcF 
QT interval, Fridericia correction 
RBC 
Red blood cell 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
t1/2 
Half-life 
TOP-1 
Topoisomerase-1 
TAM 
Tumor associated macrophages 
UDP 
Uridine diphosphate  
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
Vss 
Volume at steady state 
WBC 
White blood count 
 
 


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STUDY SYNOPSIS 
Sponsor Ipsen Bioscience, Inc 
Protocol Title 
A randomized, open-label, Phase 2 study of nanoliposomal irinotecan (nal-IRI)-
containing regimens versus nab-paclitaxel plus gemcitabine in patients with 
previously untreated, metastatic pancreatic adenocarcinoma 
Protocol 
Number MM-398-07-02-03 
Phase of 
Development Phase 2 
Trial 
Location: International; multiple sites 
Rationale 
Nal-IRI (also known as MM-398) is a nanoliposomal formulation designed to 
deliver irinotecan to the tumor microenvironment for local drug activation. In a 
randomized phase 3 study, patients with metastatic pancreatic cancer who had 
progressed following gemcitabine-based therapy (the NAPOLI-1 study), nal-IRI 
in combination with 5-FU/LV demonstrated significant clinical activity, 
increasing OS and progression free survival (PFS) relative to 5-FU/LV. The goal 
of this current study is to assess the safety, tolerability and preliminary efficacy 
of nal-IRI in combination with 5-FU/LV and oxaliplatin in patients not 
previously treated for metastatic pancreatic adenocarcinoma to select a regimen 
for further development. 
Primary 
Objective 
The study primary objectives are: 
x 
To evaluate the safety and tolerability of nal-IRI + 5-FU/LV + oxaliplatin  
x 
To characterize dose-limiting toxicities (DLTs) associated with nal-IRI + 
5-FU/LV + oxaliplatin and determine the recommended dose of the 
triplet combination for future development  
Secondary 
Objectives 
x 
To characterize the pharmacokinetics (PK) of nal-IRI in combination 
with 5-FU + oxaliplatin 
x 
To evaluate efficacy signals with nal-IRI in combination with 5-FU/LV + 
oxaliplatin using overall response rate (ORR) [CR + PR, per RECIST 
v1.1], disease control rate (DCR) [CR + PR + SD, per RECIST v1.1], 
duration of response, PFS, and OS 
Exploratory 
Objectives 
x 
To evaluate the relationship between plasma PK of nal-IRI (total 
irinotecan, SN-38) in combination with 5-FU and oxaliplatin, and safety 
and efficacy endpoints in first-line metastatic pancreatic cancer 
x 
To evaluate blood samples and archived tumor tissue for potential 
biomarkers that may correlate with nal-IRI in combination with 5-FU/LV 
and oxaliplatin, PK, toxicity, and/or response 
Study Design 
This is an open-label, Phase 2 study to assess the safety, tolerability, and 
preliminary efficacy of nal-IRI in combination with 5- FU/LV and oxaliplatin in 
patients not previously treated for metastatic pancreatic adenocarcinoma.  
 
The study will be conducted, as illustrated in the schematic below, with an initial 
dose exploration (Part 1A) followed by dose expansion (Part 1B) of the nal-IRI + 
5-FU/LV + oxaliplatin regimen.  
 


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In Part 1A, safety and tolerability will be evaluated across a range of oxaliplatin 
and nal-IRI dose permutations, as summarized in the table below. Oxaliplatin 
will be administered at intended dose levels of 60 mg/m2 - 85 mg/m2 IV over 120 
minutes (±10 minutes), on Days 1 and 15 of each 28-day cycle. Nal-IRI will be 
administered at a dose range of 60 mg/m2 – 80 mg/m2 IV over 90 minutes (±10 
minutes), on Days 1 and 15 of each cycle. 5-FU and leucovorin will be 
administered at fixed dose levels (2400 and 400 mg/m2 respectively) for all dose 
level cohorts. 
 
Dose Level* 
Dose 
Day 
Oxaliplatin 
(mg/m2) 
5-FU/LV 
(mg/m2) 
Nal-IRI 
(mg/m2)a 
1 
1, 15 
60 
2400/400 
80 
-1 
1, 15 
60 
2400/400 
60 
2 
-2A 
-2B 
1, 15 
85 
2400/400 
60 
-3 
1, 15 
70 
2400/400 
65 
a Nal-IRI the dose is calculated in salt base. 
Note: Dose level specifics and dose de-escalation plans are presented in 
protocol Section 4.1.  
 
The original plan in the study was to evaluate dose levels as described in the table 
above. Dose level cohorts 1, -1 and -2B have been evaluated. Dose levels 1 and -
2B were considered to be not tolerable. Dose level -1 (oxaliplatin 60 mg/m2 + 
nal-IRI 60 mg/m2) was determined to be safe and tolerable. Following the 
completion of the three predefined dose level cohorts, a new dose level -3 
(oxaliplatin 70 mg/m2 + nal-IRI 65 mg/m2) was introduced following a protocol 
amendment (protocol Version 5.0) to evaluate its safety and tolerability. Dose 
levels 2 and -2A were considered not to be evaluated in the study. Prior to this 
Version 5.0, the enrollment of dose level cohorts 1, -1 and -2B had been 
completed. 
 
Patients will be enrolled in cohorts following a 3 + 3 dose escalation design in 
Part 1A, in order to select the dose level of the combination of oxaliplatin and 
nal-IRI to be used in Part 1B (dose expansion). Dose limiting toxicities (DLTs) 
will be assessed during the safety evaluation period (i.e. 28 days in Cycle 1; or 14 
days after the 2nd dose of study treatment if there is a treatment delay according 
to Section 6.5). 
 
Safety evaluations are to be conducted regularly by the DLT committee to review 
all SAEs, AEs and DLTs for each patient to determine the safety and tolerability 
in each Cohort. The DLT Committee is comprised of the Investigators, the 
Medical Monitor, and the Sponsor. 
 
CCI


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In the absence of DLT, a minimum of 3 patients will be treated within each dose 
level cohort for a minimum of one cycle of therapy. Additional patients will be 
recruited into a cohort according to the DLT provisions outlined below, or if 
non-DLT toxicity is identified as requiring further evaluation by the DLT 
Committee. 
 
In each dose level cohort, if there are no DLTs within the safety evaluation 
period, then additional dose level cohorts will be initiated following agreement 
by the DLT Committee. If one DLT occurs within the first 3 patients in a given 
dose level cohort, then the cohort will be expanded to a minimum of 6 patients. If 
2 or more patients have DLTs within a given dose level cohort, that cohort will 
be considered to have not met the safety and tolerability criteria of the 
combination, and the cohort will stop. 
 
As DLT within any cohort is potentially determined by a complex interaction 
between the respective dose levels of oxaliplatin and nal-IRI, the sequence of 
cohorts examined (dose levels -1 to -3) contains both dose escalation and dose 
de-escalation strategies for each individual drug, in order to control the total 
combined dose level within any given cohort. This means that for each individual 
drug, the dose level may decrease, increase or remain the same between 
successive cohorts. 
 
At the completion of the safety evaluation period (as defined in Section 3.2.2) for 
the last patient enrolled for dose level cohorts -1 to -3 (Part 1A) detailed in Table 
5, all available data (DLT, SAE, and grade 3-4 adverse events, any available 
pharmacokinetic, pharmacogenomic, pharmacodynamic results and any initial 
efficacy data) are reviewed by the DLT Committee. A dose level will be selected 
for expansion (Part 1B as described below). The expansion cohort is intended to 
enroll 24 additional patients (total of 30 patients for the selected dose level) to 
obtain additional safety and efficacy data. 
x 
If the dose level cohort -3 (oxaliplatin 70 mg/m2 + nal-IRI 65 mg/m2) is 
considered to meet the safety and tolerability criteria, this dose will be 
selected for expansion. 
x 
If the dose level cohort -3 is not considered to meet the defined safety 
and tolerability criteria, the dose level cohort -1 (oxaliplatin 60 mg/m2 + 
nal-IRI 60 mg/m2) will be selected for expansion.  
 
No DLT assessment will be conducted for the expansion cohort.  
 
Final determination of an appropriate combination regimen for potential future 
development will be made after all patients in the Part 1A (dose escalation) and 
Part 1B (expansion cohort) have completed two scheduled assessments 
(approximately 16 weeks of therapy; unless withdrawn at an earlier time point 
due to disease progression or drug-related toxicity) and will take into account all 
available data from the expansion cohort and also all available updated data for 
patients still receiving ongoing therapy in the other dose level cohorts. Data will 
include DLT, SAE, and grade 3-4 adverse events along with any available 
pharmacokinetic, pharmacogenomic, pharmacodynamic results and any initial 
efficacy data. 
 
Dose Limiting Toxicity  
The following adverse events will be considered as DLTs if they occur during the 
safety evaluation period and are deemed related to the study treatment regimen: 
x 
Grade 4 neutropenia or thrombocytopenia that does not resolve within 
7 days despite optimal therapy (withholding study drug and 


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administering concomitant medication, e.g. G-CSF administration for 
neutropenia) 
x 
Grade 4 neutropenia complicated by fever ≥ 38.5 °C (i.e. febrile 
neutropenia) and/or Grade 3 neutropenia with infection 
x 
Any study regimen related adverse event that leads to a delay of the next 
scheduled study treatment dose for more than 14 days  
x 
Any grade 4 non-hematologic toxicity with the specific exclusion of:  
o Fatigue/asthenia < 2 weeks in duration 
o Increases in alkaline phosphatase levels 
o Nausea and vomiting ≤ 3 days duration (only considered dose 
limiting if they last > 72 hours after treatment with an optimal 
anti-emetic regimen) 
o Diarrhea ≤3 days duration (only considered dose limiting if 
diarrhea lasts > 72 hours after treatment with an optimal anti-
diarrheal regimen) 
  
Any adverse event that is related to disease progression will not be considered a 
DLT.  
 
To be DLT evaluable, a patient should have received both doses of study 
medication at Cycle 1. A delay of up to 14 additional days (a total of 28 days) is 
permitted between the scheduled Day 1 and Day 15 administrations due to non-
DLT drug related toxicity.  
 
For Part 1A (dose level cohorts -1 to -3), any patient requiring a dose delay of 
>14 days during the safety evaluation period due to non-drug related reasons will 
be replaced for DLT evaluation purposes. Any patient not receiving both doses of 
study drug during the safety evaluation period, for reasons other than dose 
limiting toxicity, will be replaced for DLT evaluation purposes.  
 
For Part 1B (the expansion period) patients withdrawing from treatment with 
study medication will not be replaced. 
 
All patients will continue to be monitored for safety beyond Cycle 1, in order to 
determine if multiple cycles of treatment are tolerable.  
 
If a patient within a given cohort experiences a DLT in Part 1A, they may 
continue in the study at a lower dose level of oxaliplatin and/or nal-IRI, (as 
determined by the DLT Committee, in accordance with Section 6.5) upon 
resolution of the relevant toxicity. Other patients in the same cohort who do not 
experience a DLT will continue with unmodified dose levels of oxaliplatin and/or 
irinotecan (unless a dose modification is judged to be necessary by the DLT 
Committee on safety grounds). 
 
In Part 1A and Part 1B, patients within any given cohort will remain on the dose 
levels of oxaliplatin and nal-IRI they were originally allocated to. Dose escalation 
within a cohort will not be permitted, although dose modifications for toxicity 
will occur in accordance with Section 6.5. 
Translational Research 
Translational research components will include collection of blood samples and 
archived tumor (during screening, if available) to look for potential biomarkers. 
Analyses may include cytokine levels (e.g. MCSF1, and IL-6), growth factors 
(e.g. IGF1 and EGFR family receptors and ligands), or enzyme levels (e.g. 
MMP9).   


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Number of 
Patients 
Approximately 54 patients will be enrolled in the study.  
Inclusion 
Criteria 
Inclusion Criteria: 
To be eligible for inclusion into the study patients must meet the following 
inclusion criteria: 
a) Histologically or cytologically confirmed adenocarcinoma of the pancreas 
that has not been previously treated in the metastatic setting: unresectable, 
locally advanced or metastatic disease is allowed, diagnosed within 6 weeks 
prior to Screening 
b) At least one tumor lesion measurable by CT or MRI scan (according to 
RECIST v1.1 criteria)  
c) ECOG performance status of 0 or 1 at Screening, and within 72 hours prior 
to first dose if first dose occurs more than 72 hours post screening. Two 
observers will be required to assess ECOG. If different, the lowest 
assessment will be used for the eligibility evaluation at each assessment 
(criterion applicable only for Part 1A) 
d) Adequate biological parameters as evidenced by all of the following blood 
counts: 
x 
Absolute neutrophil count (ANC) > 1,500 cells/μl without the use of 
hematopoietic growth factors within last 7 days prior to Screening 
x 
Platelet count > 100,000 cells/μl 
x 
Hemoglobin > 9 g/dL; transfusion is allowed, provided interval is ≥ 7 
days prior to Screening 
e) Adequate hepatic function as evidenced by: 
x 
Serum total bilirubin ≤ ULN (biliary drainage is allowed for biliary 
obstruction), and 
x 
AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver metastases 
are present) 
f) Adequate renal function as evidenced by serum creatinine ≤ 1.5 x ULN, and 
calculated clearance ≥60 mL/min/1.73 m2 for patients with serum creatinine 
levels above or below the institutional normal value. Actual body weight 
should be used for calculating creatinine clearance using the Cockcroft-Gault 
Equation (CreatClear = Sex * ((140 - Age) / (SerumCreat)) * (Weight / 72); 
for patients with body mass index (BMI) >30 kg/m2, lean body weight should 
be used instead 
g) ECG without any clinically significant findings (e.g. QTc ≤450 ms for males 
and ≤470 ms for females and no known arrhythmias) 
h) Recovered from the effects of any prior surgery or radiotherapy  
i) ≥ 18 years of age  
j) Inclusion criteria removed (protocol Version 5.0)  
k) Able to understand and provide an informed consent 
l) Patient has a Karnofsky performance status (KPS) ≥ 70 at Screening, and 
within 72 hours prior to date of first dose if first dose occurs more than 72 
hours after screening. Two observers will be required to assess KPS. If 
discrepant, the one with the lowest assessment will be considered true 
(criterion applicable only for Part 1B, added in protocol Version 6.0) 
Exclusion 
Criteria 
Patients must meet all the inclusion criteria listed above and none of the 
following exclusion criteria: 
a) Prior treatment of pancreatic cancer in the metastatic setting (or locally 
advanced setting) with surgery, radiotherapy, chemotherapy or 
investigational therapy (Note: palliative radiotherapy is permitted; placement 
of biliary stent is allowed) 
b) Prior treatment of pancreatic adenocarcinoma with chemotherapy in the 
adjuvant setting, except those where at least 12 months have elapsed since 


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completion of the last dose and no persistent treatment-related toxicities are 
present 
c) Uncontrolled CNS metastases (Note: Patients who require steroids should be 
on a stable or decreasing dose to be eligible) 
d) Clinically significant gastrointestinal disorder including hepatic disorders, 
bleeding, inflammation, occlusion, diarrhea > grade 1, malabsorption 
syndrome, ulcerative colitis, inflammatory bowel disease, or partial bowel 
obstruction 
e) History of any second malignancy in the last 3 years; patients with prior 
history of in-situ cancer or basal or squamous cell skin cancer are eligible. 
Patients with a history of other malignancies are eligible if they have been 
continuously disease free for at least 3 years. 
f) Known hypersensitivity to any of the components of nal-IRI, other liposomal 
products, or any components of 5-FU, leucovorin or oxaliplatin 
g) Exclusion Criteria removed (protocol Version 6.0) 
h) Concurrent illnesses that would be a relative contraindication to trial 
participation such as active cardiac or liver disease, including:  
x 
Severe arterial thromboembolic events (myocardial infarction, 
unstable angina pectoris, stroke) less than 6 months before inclusion 
x 
NYHA Class III or IV congestive heart failure, ventricular 
arrhythmias or uncontrolled blood pressure  
x 
Known historical or active infection with HIV, hepatitis B, or 
hepatitis C 
i) 
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, 
patients with tumor fever may be enrolled), which in the investigator’s 
opinion might compromise the patient’s participation in the trial or affect the 
study outcome 
j) 
Use of strong CYP3A4 inhibitors or inducers, or strong UGT1A1 inhibitors 
(patients are ineligible if unable to discontinue the use of strong CYP3A4 or 
UGT1A1 inhibitors at least 1 week or strong CYP3A4 inducers at least 2 
weeks prior to receiving first dose of irinotecan liposome injection), or 
presence of any other contraindications for irinotecan1 
k) Presence of any contraindications for nal-IRI, 5-FU, leucovorin, or 
oxaliplatin. 
l) 
Exclusion Criteria removed (protocol Version 6.0) 
m) Any other medical or social condition deemed by the Investigator to be likely 
to interfere with a patient’s ability to sign informed consent, cooperate and 
participate in the study, or interfere with the interpretation of the results 
n) Pregnant or breast feeding; females of child-bearing potential must test 
negative for pregnancy within 7 days prior to the first dose based on a urine 
or serum pregnancy test. Both male and female patients of reproductive 
potential must agree to use a highly effective method of birth control, during 
the study and for 6 months following the last dose of study drug2. 
o) Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma 
p) Documented serum albumin <3 g/dL at Screening, and within 72 hours prior 
to first dose if first dose occurs more than 72 hours post screening (both labs 
at screening and prior to first dose may be confirmed locally) 
q) Patients 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 
r) Previous treatment with irinotecan-based, nab-paclitaxel-based or 
gemcitabine-based resulting in disease progression (added in protocol 
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1 See Section 6.8 for examples of strong CYP3A4 or UGT1A1 inhibitors or CYP3A4 
inducers. 
2 For a description of highly effective contraceptive measures, please see 
Appendix 1. 
Length of 
Study 
All patients in the study will be treated until disease progression, unacceptable 
drug related toxicity, or physician or patient’s choice.  
 
A follow up clinic visit is required approximately 30 days after last dose of study 
treatment to complete the final safety assessments. Subsequently, patients will be 
followed for survival once every 2 months via telephone, email, or clinic visit 
until death, lost to follow-up, withdrawal of consent, or study closure, whichever 
occurs first. 
 
Following fulfilment of analysis requirements for the primary and/or secondary 
endpoints, the sponsor may elect to transition patients that are still receiving 
treatment or are being followed for OS to an extension phase of the study. 
Investigational 
Product:  
Nal-IRI (irinotecan liposome injection; also known as MM-398) is irinotecan in 
the form of the sucrosofate salt, encapsulated in liposomes for intravenous 
infusion. It will be supplied in sterile, single-use vials containing 10 mL of nal-
IRI at a concentration of 5 mg/mL. Nal-IRI must be stored refrigerated at 2 to 
8°C, with protection from light. 
Additional 
Anti-cancer 
Therapies: 
Patients will be treated with one or more of the following approved therapies: 
x 
5-FU/LV  
x 
oxaliplatin  
Please reference the respective package inserts for additional information. 
Dosing 
Regimen: 
The regimen below will be tested in 28-day cycles, unless cycle duration is 
modified by toxicity in accordance with Section 6.5.3.  
 
nal-IRI + 5-FU/LV + oxaliplatin 
x 
Oxaliplatin will be administered at dose levels as indicated in Table 5 (60 
mg/m2 - 85 mg/m2), IV over 120 minutes (±10 minutes), on Days 1 and 
15 of each 28-day cycle.  
x 
Nal-IRI will be administered over a dose range 60 mg/m2 – 80 mg/m2 IV 
over 90 minutes (±10 minutes), on Days 1 and 15 of each 28-day cycle. 
x 
5-FU will be administered 2400 mg/m2 IV over 46-hours (±60 minutes), 
on Days 1 and 15 of each 28-day cycle with leucovorin (l + d racemic 
form) 400 mg/m2, IV over 30 minutes (±5 minutes), on Days 1 and 15 of 
each 28-day cycle. 
 
If oxaliplatin is not well tolerated, oxaliplatin may be discontinued and patients 
may continue to receive nal-IRI + 5-FU/LV at the discretion of the Investigator. 
Toxicity requiring discontinuation of nal-IRI will result in discontinuation from 
all study treatments.   


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Criteria for 
Evaluation: 
Safety evaluation: 
Assessments for safety will include all treated patients and will be based on 
adverse events, laboratory data, and study treatment related dose-limiting 
toxicities.  
 
Pharmacokinetic evaluation: 
Plasma samples will be analyzed for the concentration of nal-IRI (irinotecan) and 
its metabolite (SN-38) in order to derive PK parameters of nal-IRI when given in 
combination with other anticancer therapies. PK parameters of the combination 
therapies (5-FU and oxaliplatin) will also be determined, where warranted by the 
data, to evaluate any drug interactions with nal-IRI. 
 
Efficacy evaluation: 
Preliminary efficacy will be analyzed descriptively. Efficacy parameters 
summarized will include DCR at 16 weeks, duration of response, ORR, PFS and 
OS. 
 
Translational / Exploratory  
Archived tumor tissue (if available) and blood samples will be collected and 
analyzed for biomarkers. Samples will be used to explore potential markers of 
sensitivity and resistance to irinotecan, which may include, but are not limited to, 
the following: Topoisomerase-1, growth factor pathways (IGF1 and EGFR 
family receptors and ligands), and factors involved in CPT-11 conversion to SN-
38. 
Statistical 
Analyses: 
The safety population will include all patients receiving at least one dose of any 
study drug.  
 
Categorical variables will be summarized by frequency distributions (number and 
percentages of patients) and continuous variables will be summarized by 
descriptive statistics (mean, standard deviation, median, minimum, maximum).  
 
Tumor evaluation will be measured according to RECIST v1.1. For each patient, 
PFS time will be determined as the time from the first study drug to the first 
documented radiographical progression of disease (PD), per investigator using 
RECIST v1.1, or death from any cause, whichever comes first. If the progression 
or death occurs at a time point that is greater than 16 weeks after the non-PD last 
tumor assessment, then progression-free survival time will be censored at the 
time of the last non-PD tumor assessment. 
 
Efficacy Analysis 
PFS will be analyzed using Kaplan-Meier method and descriptively summarized 
at 3 months interval for each dose level cohort. Median PFS time and 
corresponding 95% confidence limits will be presented.  
 
Best Overall Response (BOR) is defined as the best response as recorded from 
the start of study drug until disease progression. Patients without a post-baseline 
tumor assessment will be considered to be non-evaluable for BOR. To classify 
BOR as stable disease (SD), there should be a qualifying SD assessment at least 6 
weeks from the first dose of study drug. Overall Response Rate (ORR) is defined 
as the proportion of patients with a BOR characterized as either a Complete 
Response (CR) or Partial Response (PR) relative to the total number of evaluable 
patients. Only patients with measurable disease at baseline will be included in the 
analysis of overall response. The estimates of overall response rate and its 
corresponding 95% CI will be calculated for each dose level cohort.  
 


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A patient will be classified as having achieved disease control at 16 weeks if the 
patient has not progressed at the Week 16 assessment, i.e. has no PD up to and 
including the Week 16 assessment with documented non-PD (SD, PR, or CR) 
assessment. Patients who die, discontinue tumor assessments, or start new anti-
cancer treatment prior to Week 16 will be considered as not having achieved 
DCR at Week 16. The disease control rate at 16 weeks (DCR16) for a treatment 
group/cohort will be estimated by the number of patients who achieve disease 
control at 16 weeks divided by the number of patients treated. 
 
Overall Survival (OS) is the time from the date of first study drug to the date of 
death from any cause. Patients who are alive or lost to follow-up at the time of 
the analysis will be censored at the last known alive date. Similar to PFS, OS will 
be analyzed using Kaplan-Meier method and descriptively summarized for each 
dose level cohort.  
 
Safety Analyses 
Safety analyses (adverse events and laboratory analyses) will be performed using 
the safety population.  Adverse events will be reported by the MedDRA Version 
17.1 or higher. Toxicity will be graded according to the NCI CTCAE Version 
4.03. 
Safety analysis of patients will include a summary of dose-limiting toxicity 
events. 
 
The period for treatment-emergent adverse events and safety findings will be 
from the time of first study drug administration to 30 days after the date of last 
study drug administration. If an adverse event begins on the date of first study 
drug administration with no time recorded, the event will be considered as 
treatment-emergent. 
 
Tabular summaries will be presented for all adverse events, pre-treatment adverse 
events, treatment-emergent adverse events (TEAE), serious adverse events, 
adverse events leading to study drug discontinuation, TEAE-related to study drug 
and TEAE Grade 3/4. Adverse events will be summarized by System Organ 
Class and preferred term.  All adverse event data will be listed by patient. 
 
Laboratory data will be presented by cycle. Abnormal laboratory values will be 
assessed using all available data and toxicity grading will be assigned according 
to NCI CTCAE toxicity scale, where criteria are available to do so. Laboratory, 
vital signs, and ECG data will be summarized according to parameter type. 
 
Pharmacokinetic Analyses 
Plasma concentrations of total irinotecan, SN-38, oxaliplatin and 5-FU in the 
combination therapies will be used to characterize corresponding PK parameters 
using a nonlinear mixed effects approach. Individual PK parameters will be 
estimated if warranted by the data. Graphical exploration will be performed to 
investigate any relationship between PK and pharmacodynamic endpoints. If a 
trend is shown, PK/PD modelling will be performed and reported separately. 
 


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Sample Size 
Justification: 
 
 
The total number of patients enrolled in the study will depend on the number of 
patients examined within each dose level cohort, as determined by the DLT 
Committee. Progression to the next dose level cohort will depend on the 
background toxicity rate (i.e., probability of DLT at a given dose level). When 1 
of 3 patients develops a DLT and the cohort is expanded to a minimum of 6 
patients, the proposed plan for dose escalation provides a 91% probability that 
dose escalation will proceed at doses associated with DLT probability of <10%. 
The table below shows the probability of escalation from cohort to cohort with 
various toxicity rates. 
Background 
Toxicity 
Rate 
1% 
5% 
10% 
20% 
30% 
40% 
50% 
Probability 
of Dose 
Escalation 
0.999 
0.973 
0.906 
0.709 
0.494 0.309 0.172 
A selected dose level cohort will be expanded to include 30 patients in total. An 
estimate of the DCR at Week 16 will be tabulated and summarized. The 
following table displays the probabilities of outcomes for DCR16 with n=30 as a 
function of the true DCR16: 
  
 
True 
DCR16 
Probability 
observed DCR16 
≥ 50% 
Probability 
observed DCR16 
≥ 55% 
Probability 
observed DCR16 
≥ 60% 
45% 
0.36 
0.14 
0.07 
50% 
0.57 
0.29 
0.18 
55% 
0.77 
0.50 
0.36 
60% 
0.90 
0.71 
0.58 
65% 
0.97 
0.87 
0.78 
70% 
0.99 
0.96 
0.92 
 
 
 


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1 
INTRODUCTION 
1.1 
Pancreatic Cancer 
Pancreatic cancer is chemotherapy-resistant, with an extremely poor prognosis. It is the fourth 
leading cause of cancer death in the United States; the 5-year survival rate is 6% [3]. The 
incidence of pancreatic cancer has increased during the past several decades and in 2014, an 
estimated 46,420 patients were diagnosed with pancreatic cancer and 39,590 died [3]. 
Pancreatic cancer is projected to surpass liver, breast, prostate, and colorectal cancers to become 
the second-leading cause of cancer-related death by 2030 [4].These statistics reflect the dire 
nature of the disease and lack of effective therapies. The location of the tumor results in few 
early symptoms and is often diagnosed at a late stage as a result. The absence of effective 
screening tools, and a limited understanding of risk factors, means that patients have advanced 
or metastatic disease at the time of diagnosis. 
1.1.1 
Pancreatic Cancer Treatment 
Gemcitabine monotherapy was the major first-line metastatic pancreatic cancer treatment 
proven to prolong overall survival. Attempts to improve on gemcitabine single agent activity 
by combining it with other available chemotherapies have been largely unsuccessful [5],[6],[7]. 
During the last 5 years, two combination chemotherapy regimens emerged as new standards of 
care for first-line treatment of metastatic pancreatic cancer:  
• 
5-fluorouracil (5-FU)/leucovorin (LV) + irinotecan + oxaliplatin (FOLFIRINOX), and 
• 
nab-paclitaxel + gemcitabine,  
These demonstrate median overall survivals (OS) of 11.1 months and 8.5 months, respectively 
in separate Phase 3 studies [1], [2].  
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 [7], [8].  
Nal-IRI, a liposomal formulation of irinotecan, has recently been studied in a randomized, 
Phase 3, international study (NAPOLI-1), in which the combination of nal-IRI 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 [9].  
The goal of the present study is to assess the safety, tolerability and preliminary efficacy of nal-
IRI, in combination with 5-FU/LV and oxaliplatin in patients not previously treated for 
metastatic pancreatic adenocarcinoma. Descriptions of the approved anticancer therapies to be 
used in combination regimens on this study are briefly described below.  
1.1.1.1 
Description of 5-FU 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 DNA. It also 
interferes with 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 leucovorin. Leucovorin can potentiate the cytotoxic effects of 
fluorinated pyrimidines (i.e., fluorouracil 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. 


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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 package insert for more details [10]). 
1.2 
Nal-IRI (MM-398) 
Nal-IRI is irinotecan (also known as CPT-11) encapsulated in a nanoliposome drug delivery 
system (nanoliposomal irinotecan; nal-IRI). The active ingredient of the nal-IRI injection, 
irinotecan, is a member of the topoisomerase I inhibitor class of drugs and is a semi-synthetic 
and water soluble analog 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 [11], 
[12], [13]. Irinotecan is a pro-drug that is converted by nonspecific carboxylesterases into a 
100-1000 fold more active metabolite, SN-38 [14]. 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 [15], [16]. 
Drug carrier technologies represent a rational strategy to improve the pharmacokinetics and 
biodistribution of irinotecan while protecting it from premature metabolism. Nal-IRI employs 
a novel intraliposomal drug stabilization 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 tumor 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 pharmacokinetics, high intravascular drug retention in 
the liposomes, and enhanced permeability and retention (EPR) effect may potentially result in 
site-specific drug delivery to solid tumors. Stromal targeting results from the subsequent depot 
effect, where liposomes accumulating in tumor associated macrophages (TAMs) release the 
active drug and convert it 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 neighboring cancer cells within the tumor. 
1.2.1 
Nal-IRI Pre-Clinical Experience 
Nal-IRI has been shown in pre-clinical settings to have a broad spectrum of activity in a wide 
range of solid tumors 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-tumor activity against resistant or difficult to 
treat cancer models [17], [18], [19]. Nal-IRI has also shown potent antitumor activity, including 
durable tumor regressions, and was markedly superior to the equivalent dose of free drug in a 
bioluminescent-based orthotopic xenograft pancreatic model [20]. 
1.2.1.1 
Nal-IRI Pre-Clinical Pharmacokinetics 
The pharmacokinetic (PK) properties of nal-IRI were evaluated in an HT-29 colon cancer 
subcutaneous xenograft model, as reported by Kalra et al [19]. Both irinotecan and SN-38 were 
cleared very rapidly (within 8 hours) from the plasma following non-liposomal irinotecan 
administration; however, nal-IRI clearance was demonstrated to be considerably slower and 
remained in circulation for over 50 hours. SN-38 plasma exposure was also greater though Cmax 
levels were reduced following nal-IRI administration, suggesting the advantage of the 


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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 nal-IRI administration), yet 
there were relatively higher levels of prolonged accumulation in the tumor 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 tumoral 
accumulation when non-liposomal irinotecan is administered. In contrast, these data suggest 
that accumulation of nal-IRI in the tumor and subsequent liposome breakdown and local 
conversion of irinotecan to SN-38 is responsible for the enhanced tumor exposure of SN-38 
when nal-IRI is administered. These preclinical data demonstrating longer retention time in 
tumor lesions with nal-IRI administration compared to non-liposomal irinotecan administration 
formed the basis for clinical development. 
Figure 1: Tissue Distribution of nal-IRI in an HT-29 Xenograft Study.   
 
Levels of SN-38 in various tissues following a single nal-IRI (20 mg/kg) dose are shown. Prolonged 
accumulation of SN-38 (~168 h) seen in tumor compared to other organs (~48 h). 
1.2.2 
Nal-IRI Clinical Experience 
Nal-IRI has been studied in patients with solid tumors, including cervical cancer, gastric cancer, 
pancreatic cancer, and colorectal cancer.  Disease areas currently being studied include glioma 
(intravenous and convection-enhanced local delivery), breast cancer and several pediatric solid 
tumors, including Ewing's sarcoma, rhabdomyosarcoma, neuroblastoma, and osteosarcoma. 
Clinical studies of nal-IRI have been completed, with over 400 patients across multiple tumor 
types exposed to various dosing regimens, with additional studies actively recruiting patients 
across multiple tumor types (see Table 1 and Table 2). 
 


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Table 1: Summary of Completed Studies with Nal-IRI 
Study 
PEP0201 
PEP0202 
PEP0203 
PEP0206 
PEP0208 
NAPOLI-1 
Tumor Type 
Solid tumors 
Cervical  
Solid Tumors 
Gastric 
Pancreas 
Pancreas 
Phase 
1 
1 
1 
2 
2 
3 
Study design 
Open label, dose escalation 
Open label, dose 
escalation 
Open label, dose 
escalation 
Open label, 3 arm 
study comparing nal-
IRI, docetaxel and 
irinotecan (44 
patients/arm) 
Open label, single 
arm 
Randomized comparison 
of nal-IRI and nal-IRI+ 
5-FU/LV vs a common 
control of 5-FU/LV 
Number of 
Patients treated 
with nal-IRI 
11 
6 
16 
44  
40 
151 (monotherapy) 
117 (combination) 
Dosing 
Frequency 
Q3W 
Q3W 
Q3W 
Q3W 
Q3W 
Q3W (monotherapy) 
Q2W (combination) 
Dose Level 
(mg/m2) 
60 (n = 1) 
120 (n = 6) 
180 (n = 4) 
60 (n = 3) 
80 (n = 3) 
60 (n = 3) 
80 (n = 6) 
100 (n = 5) 
120 (n = 2) 
120 
120 
120 (monotherapy) 
80 (combination) 
Combination 
No 
Cisplatin 
5FU/LV 
No 
No 
5FU/LV 
Combination 
dose 
--- 
60 mg 
2000/500 mg/m2 
--- 
--- 
2000/200 mg/m2 
Key result 
MTD identified as 120 mg/m2 
Study terminated 
due to protocol 
violation 
MTD identified as 
80 mg/m2 
Similar safety profile 
across irinotecan and 
nal-IRI arms; 6 
responses in nal-IRI 
arm met primary 
endpoint 
Median survival of 
5.2 months 
Combination arm 
achieved median OS 6.1 
months, 1.9-month 
improvement over 
control arm   
(HR=0.57; p-
value=0.0009) 
Date: 28 December 2016 


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Table 2: Summary of Open Studies with Nal-IRI 
Study 
UCSF 8603 
PIST-CRC-01 
PEPCOL 
UCSF 13-12025 
SPOC 2012-001 
DOUBLIRI C13-4 
MM-398-01-01-02 
Tumor Type 
Glioma 
Colorectal 
Colorectal 
Glioma 
Pediatric Solid 
Tumors 
Colorectal 
Breast 
Phase 
1 
1 
2 
1 
1 
1 
1 
Study 
Design 
Open label, dose 
escalation 
Open label, dose 
escalation 
Comparison 
of MM-398 
+ 5FU/LV + 
avastin 
versus 
FOLFIRI + 
avastin 
Open label, dose 
escalation using 
convection-
enhanced delivery 
for direct tumoral 
injection 
Open label, dose 
escalation 
Open label, dose 
escalation. MM-398 
+ irinotecan  
Monotherapy with 
MM-398 evaluating 
Ferumoxytol MRI 
imaging feasibility 
Dosing 
Frequency 
Q3W 
Q2W 
Q2W 
Single dose 
Q3W 
Q2W 
Q2W 
Dose Level 
(mg/m2) 
HTZa 
60 (n = 3) 
90 (n = 5) 
WTb 
120 (n = 6) 
180 (n = 4) 
240 (n = 3) 
80 (n = 6) 
90 (n = 6) 
100 (n = 6) 
80 
 
Dose 
20 mg 
40 mg 
60 mg 
80 mg 
Tumor 
Volume 
1-4 cm3 
1-4 cm3 
2-5 cm3 
2-6 cm3 
60 (n = 1) 
90 
120 
150 
180 
210 
MM-398  
60 (n = 3-6)  
80 (n = 3-6) 
 
80 
Combination 
No 
No 
5FU/LV 
No 
Cyclophosphamide 
Irinotecan  
No 
Combination 
Dose 
--- 
--- 
2400/400 
mg/m2 
(5FU/LV) 
5 mg/kg 
(avastin) 
--- 
250 mg/m2 
90 or 120 
mg/m2 
(Irinotecan) 
 
--- 
Current 
Status 
MTD identified for 
HTZ; escalation 
ongoing for WT 
Enrollment 
completed in 
final cohort 
Enrollment 
Completed 
Enrollment 
ongoing 
Enrollment ongoing 
Enrollment 
completed. No MTD 
reached 
Enrollment ongoing 
a Heterozygous for UGT1A1*28 
b Wildtype for UGT1A1*28 
Date: 28 December 2016 
 
 


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1.2.2.1 
Nal-IRI PK in Humans 
The pharmacokinetic profile of single agent nal-IRI has been investigated in several studies, in 
which plasma levels of total irinotecan, SN-38 and encapsulated irinotecan were measured. In 
a single phase II clinical study (study PEP0206), direct comparison of the pharmacokinetics of 
irinotecan and SN-38 in patients administered nal-IRI or conventional (i.e. free) irinotecan 
(Camptosar®) was evaluated. Compared to the administration of conventional irinotecan 300 
mg/m2 q3w, administration of nal-IRI 120 mg/m2 q3w resulted in higher exposure of total 
irinotecan (Cmax: 13.4 fold, AUC0-∞: 46.2 fold, t1/2: 2.0 fold), and higher SN-38 t1/2 (3 fold) and 
marginally higher AUC0-∞ (1.4 fold), however, SN-38 Cmax was reduced by 5.3 fold (Figure 2). 
In other PK studies of single agent nal-IRI, similar findings were observed when compared to 
standard doses of conventional irinotecan. Based on population pharmacokinetic analysis, no 
significant association was observed between the PK parameters of total irinotecan and SN-38 
following nal-IRI monotherapy and when co-administered with 5-FU/LV. This result is 
consistent with the lack of drug interaction noted between irinotecan and 5-FU (Camptosar® 
US label). A summary table of PK parameters from 95 patients who received 60-180 mg/m2 
nal-IRI is found below (see Table 3). Please reference the Investigator Brochure for nal-IRI for 
additional information on pharmacokinetics. 
Figure 2: Mean Plasma Concentrations of Total Irinotecan and SN-38 Following the Administration of 
Either MM-398 (120mg/m2) or Camptosar® (300mg/m2) in Study PEP0206 
 
Gastric cancer patients received either nal-IRI (MM-398) at a dose of 120 mg/m2 (blue line) or non-liposomal 
irinotecan (Camptosar®) at a dose of 300 mg/m2 (red line) every 3 weeks. Total irinotecan (top) and its active 
metabolite, SN-38 (bottom) were measured during Cycle 1. Error bars indicate 95% confidence interval. Dotted 
lines indicate lower limit of quantification (LLOQ); total irinotecan measurements consist of two LLOQ values 
because of two different irinotecan assay was used to measure low and high range of concentrations. The 
concentrations less than LLOQ values were set to the corresponding LLOQ. 
 
 


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Table 3: Summary Statistics of nal-IRI PK Parameters across Multiple PK Studies 
PK 
Parameters 
Dose, 
mg/m2 
Analytes 
Total Irinotecan 
SN-38 
N 
Median 
%IQR 
N 
Median 
%IQR 
Cmax 
[μg/ml or 
ng/ml]‡ 
60 
4 
28.8 
86 
4 
3.8 
226 
80 
25 
38.0 
36 
25 
4.7 
89 
90 
6 
53.6 
37 
6 
7.5 
89 
100 
11 
41.9 
25 
11 
6.2 
79 
120 
45 
59.4 
41 
45 
7.2 
57 
180 
4 
102.4 
32 
4 
11.8 
89 
t1/2 [h] 
60 
4 
22.0 
87 
3† 
145.1 
233 
80 
23† 
26.8 
110 
13† 
49.3 
103 
90 
6 
14.8 
97 
6 
35.7 
53 
100 
11 
21.6 
192 
10† 
62.3 
37 
120 
45 
15.6 
198 
40† 
57.4 
67 
180 
4 
22.8 
86 
4 
50.2 
122 
AUC0-∞ 
[h∙μg/ml or 
h∙ng/ml]‡ 
60 
4 
352 
489 
3† 
813 
249 
80 
23† 
1030 
169 
13† 
587 
69 
90 
6 
1481 
112 
6 
506 
102 
100 
11 
919 
256 
10† 
453 
99 
120 
45 
1258 
192 
40† 
574 
64 
180 
4 
2076 
90 
4 
1069 
183 
Vd [L/m2] 
60 
4 
3.0 
87 
NA 
NA 
NA 
80 
23† 
2.2 
55 
NA 
NA 
NA 
90 
6 
1.5 
40 
NA 
NA 
NA 
100 
11 
2.2 
24 
NA 
NA 
NA 
120 
45 
1.9 
52 
NA 
NA 
NA 
180 
4 
2.1 
30 
NA 
NA 
NA 
† t1/2 and AUC0-∞ were not calculated for a subset of patients due to insufficient number of samples in the 
terminal phase. NA= not available.  
‡ Cmax are in μg/ml for total irinotecan and ng/ml for SN-38; AUC are in h μg/ml for total irinotecan and h 
ng/ml for SN-38. 
 
The above PK results obtained from patients treated with either nal-IRI or non-liposomal 
irinotecan confirmed the pre-clinical observation that nal-IRI extended plasma PK of both CPT-
11 and SN-38 compared to treatment with non-liposomal irinotecan. Further, a Phase I clinical 
study of nal-IRI monotherapy (protocol nal-IRI-01-01-02; NCT# 01770353) investigated tumor 
levels of both CPT-11 and SN-38 following treatment with nal-IRI using post-treatment 
biopsies. Based on model predictions, SN-38 levels in tumor were expected to be higher than 
in plasma, suggesting local conversion of CPT-11 to SN-38 in the tumor microenvironment 
with nal-IRI (Figure 3A). Predictions were confirmed by measuring levels of CPT-11 and SN-
38 in tumor biopsy samples collected from patients 72 hours post-dose, demonstrating 5-fold 
higher levels of SN-38 in the tumor than the plasma (Figure 3B-C). Collectively the evidence 
suggests that the prolonged systemic exposure to CPT-11 and SN-38 leads to prolonged levels 
of SN-38 in tumor tissue, which in turn leads to prolonged DNA damage to tumor cells, 
suggesting an advantage of nal-IRI compared to conventional irinotecan. 


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Figure 3: Clinical Evidence for Local Activation and Accumulation of SN-38 in Tumor Tissue 
 
 
A)  
The mechanistic tumor PK model of nal-IRI predicted higher SN-38 levels in tumor compared to 
plasma. The range of actual data, collected from a Phase I study of patients (n=12) with advanced solid tumors, 
is indicated by the gray (tumor) or green (plasma) vertical bars. 
B)  
CPT-11 levels 
C)  
SN-38 levels, as measured from patient tumor (black) and plasma (green) samples collected 72h post-
nal-IRI infusion. 
1.2.2.2 
Nal-IRI Safety in Humans 
It has been shown in animal and human PK studies that once irinotecan is released from the 
nal-IRI liposomes, the conversion of irinotecan to SN-38 is similar to that of the unencapsulated 
irinotecan. The safety of nal-IRI, therefore, may be indirectly compared with the safety of 
irinotecan, primarily based on a qualitative comparison of adverse reactions, as reported in the 
Camptosar US label for irinotecan [21]. The comparison is qualitative, as both irinotecan and 
nal-IRI have been used in different doses and schedules as monotherapy and combination 
therapy with other chemotherapeutic agents; therefore, quantitative comparisons are difficult. 
The most common adverse reactions of irinotecan and nal-IRI 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, diarrhea, constipation, 
anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, 
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, diarrhea, constipation, anorexia, neutropenia, 
leukopenia (including lymphocytopenia), anemia, asthenia, fever, body weight decreasing, and 
alopecia (Camptosar US label).   
With respect to irinotecan liposome, nal-IRI, when used in combination with 5-FU and 
leucovorin, the most common adverse reactions (≥20 %) observed in clinical trials considered 
to be related to are: diarrhea, nausea, vomiting, decreased appetite, neutropenia, fatigue, 
anemia, stomatitis and pyrexia. The overall safety profile of nal-IRI is presented in detail in the 
related Investigator Brochure. Additionally, Table 4 summarizes ≥ Grade 3 safety data from the 
NAPOLI-1 trial comparing nal-IRI + 5-FU/LV (at a dose of 80 mg/m2 given on an every 2 week 
schedule), or nal-IRI monotherapy (at a dose of 120 mg/m2 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 patients who had received prior gemcitabine therapy. 
A 
B 
C 


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Table 4: Summary of Grade 3 or Higher Adverse Events in NAPOLI-1 Study  
 
Nal-IRI + 
5-FU/LV 
(N=117) 
Nal-IRI 
(N=147) 
5-FU/LV 
(N=134) 
GRADE ≥3 NON-HEMATOLOGIC AEs IN >5% PATIENTS, %a  
Fatigue 
14 
6 
4 
Diarrhea 
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 HEMATOLOGIC AES BASED ON LABORATORY VALUES, %a, b 
Neutrophil count decreased    
20 
16 
2 
Hemoglobin decreased 
6 
7 
5 
Platelet count decreased 
2 
1 
0 
a Per CTCAE Version 4 
b Includes only patients who had at least one post-baseline assessment 
 
1.2.2.3 
Nal-IRI Clinical Efficacy in Pancreatic Cancer 
Clinical efficacy of nal-IRI has been demonstrated in gemcitabine-refractory metastatic 
pancreatic cancer patients: in a randomized, Phase 3, international study (NAPOLI-1), nal-IRI 
was given as a monotherapy, or in combination with 5-FU/LV, compared to the control arm of 
5-FU/LV alone. The majority of patients enrolled in this study had received prior chemotherapy 
in the metastatic setting (others received gemcitabine as neoadjuvant or adjuvant therapy). 
Approximately 1/2 of patients were categorized as second-line, and approximately 1/3 of 
patients were post-second line in the metastatic setting. The nal-IRI + 5-FU/LV combination 
significantly prolonged OS compared to 5-FU/LV treatment alone. The median OS for the nal-
IRI + 5-FU/LV combination arm was 6.1 months compared to 4.2 months for the 5-FU/LV 
alone control arm with a stratified hazard ratio (HR) of 0.57 (95% CI: 0.41-0.80; p = 0.0009). 
The nal-IRI 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 nal-IRI alone. 
Further, in patients who received ≥80% of the protocol defined treatment during the first 6 
weeks of treatment (the per protocol analysis), the nal-IRI + 5-FU/LV combination arm 
achieved a median OS of 8.9 months vs. 5.2 months for the control arm (HR 0.47 [95% CI 0.29-
0.77]; p = 0.0018). The overall response rate in the nal-IRI + 5-FU/LV combination arm was 
16% vs. 1% on the control arm (p <0.001) [22]. The results from this study are very promising 
and provide motivation for testing nal-IRI in pancreatic cancer patients not previously treated 
with gemcitabine. 
1.3 
 Study Rationale 
As mentioned previously, metastatic pancreatic cancer patients have a very poor prognosis and 
low median survival rates (< 1 year), necessitating the need for new treatment options. nal-IRI 
is a novel agent which has demonstrated efficacy in the Phase 3 NAPOLI-1 trial, in patients 
with metastatic pancreatic cancer who had progressed following gemcitabine-based therapy. 
This study will examine the safety, tolerability, and preliminary efficacy of nal-IRI in 
combination with 5-FU/LV and oxaliplatin in patients not previously treated for metastatic 
pancreatic adenocarcinoma.  


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1.3.1 
Rationale for Nal-IRI + 5-FU/LV + Oxaliplatin 
The combination 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 3 trial conducted in France of 342 patients showing mOS of 11.1 months vs. 6.8 
months for the gemcitabine alone control arm (HR 0.57; 95% confidence interval [CI], 0.45 to 
0.73; P<0.001) [1]. The FOLFIRINOX regimen has been recommended by the NCCN as a 
preferred option for first-line metastatic disease since 2011 [23]. However, there are some 
concerns about the toxicity associated with FOLFIRINOX, as the reported incidence of grade 
3 or 4 toxicity was significantly greater in the FOLFIRINOX group than in the gemcitabine 
control group, specifically neutropenia (46% vs. 21%), febrile neutropenia (5% vs. 1%), 
thrombocytopenia (9% vs. 4%), diarrhea (13% vs. 2%), and sensory neuropathy (9% vs. 0%) 
[1]. Concerns over toxicity have motivated attempts to modify the original FOLFIRINOX 
regimen, usually by omitting the 5-FU bolus component or reducing the dose of irinotecan, 
although it is currently unclear whether these modified approaches retain comparable efficacy 
[24]. 
In the current study, a modified FOLFIRINOX regimen will evaluate nal-IRI instead of 
conventional irinotecan, in order to improve the safety, tolerability, and ultimately efficacy of 
the original FOLFIRINOX regimen. With nal-IRI 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 2 study in colorectal cancer, data suggest that nal-IRI + 5-FU/LV may have 
less toxicity than FOLFIRI [25]. Therefore, toxicity of the nal-IRI-containing triplet regimen is 
not expected to be greater than that seen with FOLFIRINOX  
By adding oxaliplatin to nal-IRI and 5-FU the potential to increase DNA damage and potentiate 
efficacy exists. Further, due to the nal-IRI prolonged PK properties and sustained tumor 
exposure, it is thought that using nal-IRI instead of conventional irinotecan would improve 
upon the efficacy of FOLFIRINOX. In order to test this hypothesis pre-clinically, the 
FOLFIRINOX regimen was tested against the nal-IRI + 5-FU/LV + oxaliplatin regimen in a 
pancreatic tumor xenograft mouse model (Figure 4). Results show that nal-IRI performed 
better than conventional irinotecan at equivalent exposure doses (5 mg/kg nal-IRI vs. 25 mg/kg 
free IRI) in the BxPC-3 pancreatic cancer model either alone (Figure 4A), or in combination 
with oxaliplatin and/or 5-FU (Figure 4B) 
Cancer cells were implanted subcutaneously in mice; when tumors were well established and 
had reached mean volumes of ~300 mm3, IV treatment with non-liposomal irinotecan (IRI), 
nal-IRI, 5-FU, oxaliplatin (Ox) or control was initiated. Doses are indicated above for each 
treatment, and were given weekly x4 weeks, at time points indicated by dashed lines on graphs. 


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Figure 4: 
Efficacy of Nal-IRI in a 5-FU Insensitive Pancreatic Cancer Model 
(BxPC-3) 
 
A) 
Single agent results of the individual treatments are shown, demonstrating nal-IRI significant 
inhibits tumor growth compared to free IRI. 
B) 
Doublet or triplet regimens containing either IRI or nal-IRI in combination with oxaliplatin 
and/or 5-FU demonstrate that the nal-IRI-containing doublet and triplet inhibit tumor growth 
significantly better than the IRI-containing regimens. 
In the mouse model tested, the addition of oxaliplatin to the doublet combinations of FOLFIRI 
or nal-IRI+5-FU/LV causes a slight increase in tumor growth inhibition (Figure 4B: compare 
light green to pink for FOLFIRI vs. FOLFIRINOX; compare dark green to red for nal-IRI+5-
FU/LV vs. nal-IRI+5-FU/LV+Ox). However, comparison of FOLFIRI versus the nal-IRI+5-
FU/LV doublet (light green vs. dark green), and FOLFIRINOX vs. the nal-IRI+5-FU/LV+Ox 
triplet (pink vs. red), demonstrates significantly more tumor growth inhibition with the nal-
IRI-containing regimens. Further, the nal-IRI-containing doublet regimen performed better than 
the FOLFIRINOX triplet (dark green vs. pink), owing to the improved efficacy of nal-IRI 
compared to conventional irinotecan.  
In humans, the standard dose regimen of FOLFIRINOX which demonstrated efficacy is 
85 mg/m2 oxaliplatin, 180 mg/m2 irinotecan, and fluorouracil at a dose of 400 mg/m2 
administered by IV bolus followed by a continuous infusion of 2400 mg/m2. 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 [26] [8]. In the current study, 
a modified triplet regimen is proposed, whereby no bolus of 5-FU will be administered. The 
doses of oxaliplatin and nal-IRI determined from the combination regimens will be combined 
with the standard continuous infusion dose of 5-FU (excluding the bolus)/LV. Based on current 
clinical experience with nal-IRI in pancreatic cancer and the pre-clinical considerations outlined 
above, it is considered that the combination of nal-IRI and oxaliplatin with infusional 5-FU 
represents a novel therapeutic approach with the possibility of providing superior efficacy and 
tolerability over established FOLFIRINOX regimens. 
1.3.2 
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. 
UGT1A1*28 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 Camptosar® (nonliposomal irinotecan). Multiple studies have evaluated the 
 
 
p = 0.0499 
p = 0.0207 
p = 0.0003 
A 
B 


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association between UGT1A1*28 7/7 homozygosity, SN-38 concentration and safety in 
patients treated with Camptosar® and suggest 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 15-75 mg/m2 daily for 5 days for 2 consecutive weeks (41-159% vs. 10-40%, 
respectively) [27] [28]. In a study of 66 patients who received single-agent non-liposomal 
irinotecan (350 mg/m2 every 3 weeks), the incidence of Grade 4 neutropenia in patients 
heterozygous (UGT1A1*28 6/7) and homozygous (7/7) for the UGT1A1*28 was 12.5% and 
up to 50% respectively (Camptosar® USPI). In a subsequent study, association between 
UGT1A1*28 homozygosity and hematological toxicity was observed only in patients treated 
with >150 mg/m2 non-liposomal irinotecan. By contrast, at lower dose of non-liposomal 
irinotecan (100-125 mg/m2 every week) similar hematological toxicities were observed for both 
homozygous and non-homozygous patients [29]. 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 
[30]. 
 
In patients treated with irinotecan liposome injection, the association between UGT1A1*28 
homozygosity, SN-38, and hematologic toxicity is primarily obtained from study NAPOLI-1, 
where UGT1A1*28 homozygous patients were treated at reduced dose (50 vs 70 mg/m2 every 
2 weeks in combination with 5-FU/LV, or 70 vs. 100 mg/m2 every 3 weeks monotherapy). The 
evaluation of the association between SN-38 concentration and UGT1A1*28 homozygosity 
was performed only for Caucasians, because homozygosity was rare in Asians (2/129; 1.5%). 
Based on the population PK and exposure-response analysis, similar un-encapsulated SN-38 
Cmax values were observed for homozygous and non-homozygous Caucasian patients if both 
are dosed at 70 mg/m2 (1.99 [95% CI 1.81-2.18, n=12] and 1.76 [95% CI 1.69-1.84, n=141] 
ng/mL; p=0.66; both of these values are approximately half of the expected SN-38 Cmax from a 
120 mg/m2 dose of non-liposomal irinotecan). Consequently, the predicted grade 3 or higher 
neutropenia was also similar if treated at 70 mg/m2 monotherapy (8.7% vs. 7.4%, respectively), 
or if treated at 90 mg/m2 monotherapy (15% vs. 13%, respectively). Additionally, in a phase I 
study (UCSF 8603), no differences in toxicity were seen in cohorts of UGT1A1*28 6/7 (n=18) 
or 6/6 (n=16) patients, 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 hematological toxicity appear to depend on the incoming load of SN-
38 to be metabolized 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 patients 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) [31]. 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). 
 


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Despite the lack of associations between UGT1A1*28 homozygosity, safety, and PK, the 
irinotecan liposome injection US package insert 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 regardless of UGT1A1*28 
genotype. UGT1A1*28 genotype will be collected on all patients as a safety biomarker to 
further analyze the association between UGT1A1*228 homozygosity, SN-38 concentration and 
toxicity. Irinotecan liposome injection dose reduction will follow the same dose reduction rules 
for all patients regardless of UGT1A1*28 genotype. Patients with UGT1A1*28 homozygosity 
will be closely monitored for safety in comparison to the safety in patients with UGT1A1*28 
non-homozygous status by the medical monitors of the sponsor and by the DLT committee. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objectives  
• 
To evaluate the safety and tolerability of nal-IRI + 5FU/LV + oxaliplatin  
• 
To characterize DLTs associated with nal-IRI + 5FU/LV + oxaliplatin and determine the 
recommended dose of the triplet combination for future development  
2.2 
Secondary Objectives 
• 
To characterize the PK of nal-IRI in combination with 5-FU and oxaliplatin 
• 
To evaluate efficacy signals with nal-IRI in combination with 5-FU/LV + oxaliplatin 
using overall response rate (ORR) [CR + PR, per RECIST v1.1], disease control rate 
(DCR) [CR + PR + SD, per RECIST v1.1], duration of response, PFS, and OS 
2.3 
Exploratory Objectives 
• 
To evaluate the relationship between plasma PK of nal-IRI (total irinotecan, SN-38), in 
combination with 5-FU and oxaliplatin, and safety and efficacy endpoints in first-line 
metastatic pancreatic cancer 
• 
To evaluate blood samples and archived tumor tissue for potential biomarkers that may 
correlate with nal-IRI in combination with 5-FU/LV and oxaliplatin, PK, toxicity, and/or 
response  
3 
STUDY DESIGN 
3.1 
Study Design Overview 
This is an open-label, phase 2 study to assess the safety, tolerability, and preliminary efficacy 
of nal-IRI in combination with 5-FU/LV and oxaliplatin in patients not previously treated for 
metastatic pancreatic adenocarcinoma.  
The study will be conducted, as illustrated in the schematic below, with an initial dose 
exploration (Part 1A) followed by dose expansion (Part 1B) of the nal-IRI + 5-FU/LV + 
oxaliplatin regimen.  


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Figure 5: 
Overview of Study Design 
 
 
In Part 1A safety and tolerability will be evaluated across a range of oxaliplatin and nal-IRI 
dose permutations, as summarized in Table 5. Oxaliplatin will be administered at intended dose 
levels of 60 mg/m2 - 85 mg/m2 IV over 120 minutes (±10 minutes), on Days 1 and 15 of each 
28-day cycle. Nal-IRI will be administered at a dose range of 60 mg/m2 – 80 mg/m2 IV over 90 
minutes (±10 minutes), on Days 1 and 15 of each cycle. 5-FU and leucovorin will be 
administered at fixed dose levels (2400 and 400 mg/m2 respectively) for all dose level cohorts. 
 
Part 1A will enroll cohorts of patients following a 3 + 3 dose escalation design, in order to select 
the dose level of the combination of oxaliplatin and nal-IRI to be used in Part 1B (dose 
expansion). Dose limiting toxicities, as defined in Section 3.2.2, will be assessed during the 
safety evaluation period (i.e. 28 days in Cycle 1; or 14 days after the 2nd dose of study treatment 
if there is a treatment delay according to Section 6.5).  
 
Safety evaluations are to be conducted regularly by the DLT committee to review all SAEs, 
AEs and DLTs for each patient to determine the safety and tolerability in each Cohort. The 
DLT Committee is comprised of the Investigators, the Medical Monitor, and the Sponsor. 
 
In the absence of DLT, a minimum of 3 patients will be treated within each dose level cohort 
for a minimum of one cycle of therapy. Additional patients will be recruited into a cohort 
according to the DLT provisions outlined in Section 3.2.2, or if non-DLT toxicity is identified 
as requiring further evaluation by the DLT Committee. 
 
In each dose level cohort, if there are no DLTs within the safety evaluation period, then 
additional dose level cohorts will be initiated following agreement by the DLT Committee. If 
one DLT occurs within the first 3 patients in a given dose level cohort, then the cohort will be 
expanded to a minimum of 6 patients. If 2 or more patients have DLTs within a given dose level 
cohort, that cohort will be considered to have not met the safety and tolerability criteria of the 
combination, and the cohort will stop.  
 
As DLT within any cohort is potentially determined by a complex interaction between the 
respective dose levels of oxaliplatin and nal-IRI, the sequence of cohorts examined (dose 
levels -1 to -3) contains both dose escalation and dose de-escalation strategies for each 
individual drug, in order to control the total combined dose level within any given cohort. This 
means that for each individual drug, the dose level may decrease, increase or remain the same 
between successive cohorts. 
 


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The protocol Version 5.0 introduced a new dose level cohort in Part 1A (dose level -3: 
oxaliplatin 70 mg/m2 + nal-IRI 65 mg/m2) to evaluate its safety and tolerability, following the 
completion of the dose level cohorts 1, -1 and -2B.  
 
At the completion of the safety evaluation period (as defined in Section 3.2.2) for the last patient 
enrolled for dose level cohorts -1 to -3 (Part 1A) detailed in Table 5, all available data (DLT, 
SAE, and grade 3-4 adverse events, any available pharmacokinetic, pharmacogenomic, 
pharmacodynamic results and any initial efficacy data) are reviewed by the DLT Committee. 
A dose level will be selected for expansion (for Part 1B as described below). The expansion 
cohort is intended to enroll 24 additional patients (total of 30 patients for the selected dose level) 
to obtain additional safety and efficacy data: 
• 
If the dose level cohort -3 (oxaliplatin 70 mg/m2 + nal-IRI 65 mg/m2) is considered to 
meet the safety and tolerability criteria, this dose will be selected for expansion. 
• 
If the dose level cohort -3 is not considered to be safe and tolerable, the dose level cohort 
-1 (oxaliplatin 60 mg/m2 + nal-IRI 60 mg/m2) will be selected for expansion.  
 
No DLT assessment will be conducted for the expansion cohort. 
 
Final determination of an appropriate combination regimen for potential future development 
will be made after all patients in the Part 1A (dose escalation) and Part 1B (expansion cohort) 
have completed two scheduled assessments (approximately 16 weeks of therapy; unless 
withdrawn at an earlier time point due to disease progression or drug-related toxicity) and will 
take into account all available data from the expansion cohort and also all available updated 
data for patients still receiving ongoing therapy in the other dose level cohorts. Data will include 
DLT, SAE, and grade 3-4 adverse events along with any available pharmacokinetic, 
pharmacogenomic, pharmacodynamic results and any initial efficacy data. 
 
Efficacy analysis will be performed when Week 16 DCR classifications can be made for all 
patients. This should occur when all patients have either achieved disease control at 16 weeks 
(i.e. have no PD up to and including the Week 16 assessment with documented non-PD [SD, 
PR, or CR] assessment) or have discontinued from treatment (refer to Section 5.3 for study 
treatment discontinuation criteria). Further details on DCR analyses are presented in 
Section 10.6. 
Translational Research: 
Translational research components will include collection of blood samples and archived tumor 
(during screening, if available) to look for potential biomarkers. Analyses may include cytokine 
levels (e.g. MCSF1, and IL-6), growth factors (e.g. IGF1 and EGFR family receptors and 
ligands), or enzyme levels (e.g. MMP9).  
3.2 
Safety Assessment 
3.2.1 
Overview 
Since the individual therapies included in the proposed combination have been studied in 
previous clinical trials, it is important that the safety assessment takes into account the expected 
safety profile of the standard dose regimen (e.g. FOLFIRINOX). The following adverse events 
are common (≥ 40%) with oxaliplatin treatment in combination with 5-FU/LV and are to be 
expected with the nal-IRI-containing combination regimen: peripheral sensory neuropathy, 
neutropenia, thrombocytopenia, anemia, nausea, increases in transaminases and alkaline 
phosphatase, diarrhea, fatigue, emesis, and stomatitis. Additional adverse events may be 


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anticipated, as described in the package insert for oxaliplatin [10], including allergic and 
anaphylactic reactions. In a Phase 3 study of the FOLFIRINOX combination, the most common 
(> 5%) Grade 3-4 adverse events were: neutropenia, fatigue, vomiting, diarrhea, 
thrombocytopenia, sensory neuropathy, anemia, elevated alanine aminotransferase (ALT) 
level, thromboembolism, and febrile neutropenia [1]. 
3.2.2 
DLT Definition (Nal-IRI + 5-FU/LV + Oxaliplatin) 
For nal-IRI administered in combination with 5-FU/LV and oxaliplatin, the following adverse 
events will be considered as dose limiting toxicities (DLTs) if they occur during the safety 
evaluation period (i.e. 28 days of Cycle 1; or 14 days after the 2nd dose of study treatment if 
there is a treatment delay according to Section 6.5) and are deemed related to the study treatment 
regimen.  
• 
Grade 4 neutropenia or thrombocytopenia that does not resolve within 7 days despite 
optimal therapy (withholding study drug and administering concomitant medication, e.g. 
G-CSF administration for neutropenia) 
• 
Grade 4 neutropenia complicated by fever ≥ 38.5 °C (i.e. febrile neutropenia) and/or 
Grade 3 neutropenia with infection 
• 
Any study regimen related adverse event that leads to a delay of the next scheduled study 
treatment dose for more than 14 days  
• 
Any grade 4 non-hematologic toxicity with the specific exclusion of:  
- 
Fatigue/asthenia < 2 weeks in duration 
- 
Increases in alkaline phosphatase levels 
- 
Nausea and vomiting ≤3 days duration (only considered dose limiting if they last 
> 72 hours after treatment with an optimal anti-emetic regimen) 
- 
Diarrhea ≤3 days duration (only considered dose limiting if diarrhea lasts 
> 72 hours after treatment with an optimal anti-diarrheal regimen) 
 
Any adverse event that is related to disease progression will not be considered a DLT.  
 
To be DLT evaluable, a patient should have received both doses of study medication at Cycle 
1. A delay of up to 14 additional days (a total of 28 days) is permitted between the scheduled 
Day 1 and Day 15 administrations due to non-DLT drug related toxicity. Please see Section 4.2 
for the guidance of patient replacement (dose level cohorts -1 to -3). 
The final determination of DLTs will be made following discussion by the DLT Committee.  
All patients will continue to be monitored for safety beyond Cycle 1, in order to determine if 
multiple cycles of treatment are tolerable.  
 
If any patient within a given cohort experiences a DLT in Part 1A, they may continue in the 
study at a lower dose level of oxaliplatin and/or nal-IRI, (as determined by the DLT Committee 
in accordance with Section 6.5) upon resolution of the relevant toxicity. Other patients in the 
same cohort who do not experience a DLT will continue with unmodified dose levels of 
oxaliplatin and/or irinotecan (unless a dose modification is judged to be necessary by the DLT 
Committee on safety grounds). 
4 
ENROLLMENT AND TREATMENT 
Approximately 54 patients will be enrolled in the study. All patients will be treated until disease 
progression (as determined by RECIST v1.1 criteria evaluated every 8 weeks from first dose of 


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study drug), unacceptable drug related toxicity, or physician or patient’s choice (see 
Section 5.3). 
It is expected that multiple sites will participate in this trial.  Enrollment will be based on the 
availability of patients at each site and the availability of slots in each cohort. Slots must be 
confirmed by the Sponsor, or designee, prior to consenting patients to the study. A reasonable 
attempt will be made to equally distribute patients between sites. Enrollment can proceed to the 
next cohort after the safety data from the safety evaluation period in the previous cohort have 
been evaluated in accordance with Sections 4.1.1 and 4.1.2.  
4.1 
Dose levels 
In each dose level cohort, if there are no DLTs within the safety evaluation period, then 
additional dose level cohorts will be initiated following agreement by the DLT Committee. If 
one DLT occurs within the first 3 patients in a given dose level cohort, then the cohort will be 
expanded to a minimum of 6 patients. If 2 or more patients have DLTs within a given dose level 
cohort, that cohort will be considered to have not met the safety and tolerability criteria of the 
combination, and the cohort will stop.  
As DLT within any cohort is potentially determined by a complex interaction between the 
respective dose levels of oxaliplatin and nal-IRI, the sequence of cohorts examined (dose 
levels -1 to -3) contains both dose escalation and dose de-escalation strategies for each 
individual drug, in order to control the total combined dose level within any given cohort. This 
means that for each individual drug, the dose level may decrease, increase or remain the same 
between successive cohorts. 
Planned dose evaluation is outlined in Table 5; additional details on dose administration are 
described in Section 6. 
Any decisions by the DLT Committee to enroll additional dose level cohorts must be made 
according to the established decision process for cohort progression, as described in 
Section 4.1.1. 
Table 5: Dose Escalation Table (Nal-IRI + 5-FU/LV + Oxaliplatin) 
Evaluation Status 
Dose 
Level 
Oxaliplatin 
5-FU/LV 
Nal-IRI 
 
 
Dose 
(mg/m2
) 
Dose 
Daya 
Dose 
(mg/m2) 
Dose 
Daya 
Dose 
(mg/m2)b 
Dose 
Daya 
Evaluation complete 
1 
60 
1, 15 
2400/400 
1, 15 
80 
1, 15 
Evaluation complete 
-1 
60 
1, 15 
2400/400 
1, 15 
60 
1, 15 
Not to be evaluated 
Not to be evaluated 
Evaluation complete 
-2B 
85 
1, 15 
2400/400 
1, 15 
60 
1, 15 
New dose level to 
be evaluated 
-3 
70 
1, 15 
2400/400 
1, 15 
65 
1, 15 
a Day indicated is part of a 28-day cycle 
b Nal-IRI the dose is calculated in salt base. 
  Note: The dose of nal-IRI and 5-FU/LV in Dose Level 1 and 2 above is the same dose and 
schedule that was previously used in the NAPOLI-1 Phase 3 study. 
 
The original plan in the study was to evaluate dose levels as described in the Table 5. Dose 
level cohorts 1, -1 and -2B have been evaluated. Dose levels 1 and -2B were considered to be 
not tolerable. Dose level -1 (oxaliplatin 60 mg/m2 + nal-IRI 60 mg/m2) was determined to be 
safe and tolerable. Following the completion of the three predefined dose level cohorts, a new 
dose level -3 (oxaliplatin 70 mg/m2 + nal-IRI 65 mg/m2) was introduced following a protocol 
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amendment (protocol Version 5.0) to evaluate its safety and tolerability. Dose levels 2 and -2A 
were considered not to be evaluated in the study. Prior to this Version 5.0, the enrollment of 
dose level cohorts 1, -1 and 2B had been completed. 
4.1.1 
Decision Process for Cohort Progression 
Decisions to progress to the next dose level cohort will be made by mutual agreement of the 
DLT Committee (in accordance with the criteria described below (Section 4.1.2)). Regularly 
scheduled teleconferences of the DLT Committee will serve as a forum for ongoing review of 
safety and other relevant data. Decisions to progress to the next dose level cohort must be agreed 
by the majority of the DLT Committee members, and will be documented along with a summary 
of the information supporting the decision.  
4.1.2 
Decision Criteria for Cohort Progression 
The safety assessment period for purposes of DLT evaluation and dose level cohort progression 
decisions will be one cycle of treatment (i.e. 28 days of Cycle 1; or 14 days after the 2nd dose 
of study treatment if there is a treatment delay according to Section 6.5). Progression to the next 
dose level cohort will only occur after all available safety and other relevant data have been 
evaluated for the current dose level cohort (once the last patient enrolled in the cohort completes 
the safety evaluation period). Potential data which may be reviewed by the DLT Committee for 
the purposes of dose level assessment include DLT, SAE, and grade 3-4 adverse events, any 
available pharmacokinetic, pharmacogenomic, pharmacodynamic results and any initial 
efficacy data. 
In addition, any drug-related toxicities of Grade 3 or higher occurring after Cycle 1 of each 
cohort will be assessed by the DLT Committee on an ongoing basis for their potential 
relationship to cumulative toxicity of one or more study agents and will be considered as 
appropriate in decisions to progress to subsequent dose level cohorts.  
4.2 
Patient Replacement 
For Part 1A (dose level cohorts -1 to -3), any patient requiring a dose delay of >14 days during 
the safety evaluation period due to non-drug related reasons will be replaced for DLT evaluation 
purposes. Any patient not receiving both doses of study drug during the safety evaluation 
period, for reasons other than dose limiting toxicity, will be replaced for DLT evaluation 
purposes.  
For Part 1B (the expansion period), patients withdrawing from treatment with study medication 
will not be replaced. 
5 
PATIENT SELECTION AND DISCONTINUATION 
5.1 
Inclusion Criteria 
In order for inclusion into the study, patients must have/be:  
(a) 
Histologically or cytologically confirmed adenocarcinoma of the pancreas that has not 
been previously treated in the metastatic setting: unresectable, locally advanced or 
metastatic disease is allowed, diagnosed within 6 weeks prior to Screening 
(b) 
At least one tumor lesion measurable by CT or MRI scan (according to RECIST v1.1 
criteria) 
(c) 
ECOG performance status of 0 or 1 at Screening, and within 72 hours prior to first dose 
if first dose occurs more than 72 hours post screening. Two observers will be required to 
assess ECOG. If different, the lowest assessment will be used for the eligibility 
evaluation at each assessment (criterion applicable only for Part 1A) 


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(d) 
Adequate biological parameters as evidenced by all of the following blood counts: 
• 
Absolute neutrophil count (ANC) > 1,500 cells/μl without the use of 
hematopoietic growth factors within last 7 days prior to Screening 
• 
Platelet count > 100,000 cells/μl 
• 
Hemoglobin > 9 g/dL; transfusion is allowed, provided interval is ≥ 7 days prior 
to Screening 
(e) 
Adequate hepatic function as evidenced by: 
• 
Serum total bilirubin ≤ ULN (biliary drainage is allowed for biliary obstruction), 
and 
• 
AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver metastases are 
present) 
(f) 
Adequate renal function as evidenced by serum creatinine ≤ 1.5 x ULN, and calculated 
clearance ≥60 mL/min/1.73 m2 for patients with serum creatinine levels above or below 
the institutional normal value. Actual body weight should be used for calculating 
creatinine clearance using the Cockcroft-Gault Equation (CreatClear = Sex * ((140 - 
Age) / (SerumCreat)) * (Weight / 72); for patients with body mass index (BMI) >30 
kg/m2, lean body weight should be used instead. 
(g) 
ECG without any clinically significant findings (e.g. QTc ≤450 ms for males and ≤470 
ms for females and no known arrhythmias)  
(h) 
Recovered from the effects of any prior surgery or radiotherapy   
(i) 
≥ 18 years of age  
(j) 
Inclusion criteria removed (protocol Version 5.0) 
(k) 
Able to understand and provide an informed consent 
(l) 
Patient has a Karnofsky performance status (KPS) ≥ 70 at Screening, and within 72 hours 
prior to date of first dose if first dose occurs more than 72 hours after screening. Two 
observers will be required to assess KPS. If discrepant, the one with the lowest 
assessment will be considered true (criterion applicable only for Part 1B, added in 
protocol Version 6.0) 
 
5.2 
Exclusion Criteria 
Patients must meet all the inclusion criteria listed above and none of the following exclusion 
criteria: 
(a) 
Prior treatment of pancreatic cancer in the metastatic setting (or locally advanced setting) 
with surgery, radiotherapy, chemotherapy or investigational therapy (Note: palliative 
radiotherapy is permitted; placement of biliary stent is allowed) 
(b) 
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 (modified in protocol Version 6.0) 
(c) 
Uncontrolled CNS metastases (Note: Patients who require steroids should be on a stable 
or decreasing dose to be eligible)  
(d) 
Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, 
inflammation, occlusion, diarrhea > grade 1, malabsorption syndrome, ulcerative colitis, 
inflammatory bowel disease, or partial bowel obstruction   
(e) 
History of any second malignancy in the last 3 years; patients with prior history of in-
situ cancer or basal or squamous cell skin cancer are eligible.  Patients with a history of 


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other malignancies are eligible if they have been continuously disease free for at least 
3 years. 
(f) 
Known hypersensitivity to any of the components of nal-IRI, other liposomal products, 
or any components of 5-FU, leucovorin or oxaliplatin 
(g) 
Exclusion Criteria removed (protocol Version 6.0) 
(h) 
Concurrent illnesses that would be a relative contraindication to trial participation such 
as active cardiac or liver disease, including:  
• 
Severe arterial thromboembolic events (myocardial infarction, unstable angina 
pectoris, stroke) less than 6 months before inclusion 
• 
NYHA Class III or IV congestive heart failure, ventricular arrhythmias or 
uncontrolled blood pressure  
• 
Known historical or active infection with HIV, hepatitis B, or hepatitis C 
(i) 
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, patients with tumor fever 
may be enrolled), which in the investigator’s opinion might compromise the patient’s 
participation in the trial or affect the study outcome 
(j) 
Use of strong CYP3A4 inhibitors or inducers, or strong UGT1A1 inhibitors (patients are 
ineligible if unable to discontinue the use of strong CYP3A4 or UGT1A1 inhibitors at 
least 1 week or strong CYP3A4 inducers at least 2 weeks prior to receiving first dose of 
irinotecan liposome injection), or presence of any other contraindications for irinotecan1 
(k) 
Presence of any contraindications for nal-IRI, 5-FU, leucovorin, or oxaliplatin 
(l) 
Exclusion Criteria removed (protocol Version 6.0) 
(m) 
Any other medical or social condition deemed by the Investigator to be likely to interfere 
with a patient’s ability to sign informed consent, cooperate and participate in the study, 
or interfere with the interpretation of the results 
(n) 
Pregnant or breast feeding; females of child-bearing potential must test negative for 
pregnancy within 7 days prior to the first dose based on a urine or serum pregnancy test. 
Both male and female patients of reproductive potential must agree to use a highly 
effective method of birth control, during the study and for 6 months following the last 
dose of study drug.2 
(o) 
Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma 
(p) 
Documented serum albumin <3 g/dL at Screening, and within 72 hours prior to first dose 
if first dose occurs more than 72 hours post screening (both labs at screening and prior 
to first dose may be confirmed locally) 
(q) 
Patients 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  
(r) 
Previous treatment with irinotecan-based, nab-paclitaxel-based or gemcitabine-based 
resulting in disease progression (added in protocol Version 6.0) 
 
1 See Section 6.8 for examples of strong CYP3A4 or UGT1A1 inhibitors or CYP3A4 inducers. 
2 For a description of highly effective contraceptive measures, please see Appendix 1. 
5.3 
Patient Discontinuation 
5.3.1 
Discontinuation of Study Treatment 
It is intended that patients will be treated until radiologically determined progressive disease 
per RECIST v1.1 or unacceptable study drug related toxicity. However, a patient may 


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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 v1.1 
• 
Clinical deterioration sufficient to prevent further radiological assessment 
• 
A study drug related adverse event, prior to disease progression, which: 
- 
in the opinion of the Investigator, precludes further treatment with all study drugs 
- 
requires treatment with one or more study drugs to be withheld for more than 14 
days, unless in the opinion of the investigator the patient is receiving benefit 
overall from the study treatment 
- 
would result in a fourth dose reduction in any single study drug (in a patient having 
already experienced 3 previous dose reductions) 
- 
requires discontinuation of nal-IRI  
• 
Development of an intercurrent medical condition or need for concomitant therapy that 
precludes further treatment with all study drugs 
• 
Withdrawal of consent for further treatment 
• 
Pregnancy 
A patient who discontinues study medication and has not withdrawn from the study must 
continue with all ongoing protocol requirements, as detailed in Section 5.3.3. 
5.3.2 
Withdrawal from the Study 
A patient may withdraw, or be withdrawn, from the study at any time. Reasons for withdrawal 
from the study include, but are not limited to the following: 
• 
Significant noncompliance with the protocol, per Investigator’s assessment 
• 
The Investigator removes the patient from the trial in the best interests of the patient 
• 
Use of prohibited concomitant medications 
• 
Patient is lost to follow up 
• 
Withdrawal of consent for further participation in the study 
• 
Death 
• 
Study termination by the Sponsor 
5.3.3 
Procedures following Study Drug Discontinuation or Study Withdrawal 
Following study drug discontinuation all procedures and evaluations required at the 30-day 
(End of Treatment) follow up visit should be completed. All patients who discontinue study 
medication as a result of an adverse event must be followed until resolution or stabilization of 
the adverse event. Patients who discontinue study drug 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 v1.1 has 
been documented. Overall survival follow-up contacts should continue every 2 months from 
the 30-day follow-up visit until death or study closure, whichever comes first. If a patient does 
not return to the clinic for follow-up visits, attempts should be made to contact the patient via 
phone, email, or mail. At least 3 documented attempts, including one via certified mail, should 
be made to contact the patient before declaring a patient lost to follow-up. If the patient is 
considered lost to follow-up, the date of death may be captured from public records.  
If a patient withdraws from the study at any point, a complete final evaluation at the time of 
the patient’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 patient 
whether they still consent to be followed up for survival status only (including where 


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appropriate through publicly available records) and any such consent to ongoing survival 
follow up must be documented in both the source hospital records and the eCRF. 
6 
STUDY TREATMENT 
6.1 
Investigational Product 
6.1.1 
Description of Nal-IRI (MM-398) 
Nal-IRI (irinotecan liposome injection, also known MM-398) is irinotecan in the form of the 
sucrosofate salt, encapsulated in liposomes for intravenous infusion. It will be supplied in 
sterile, single-use vials containing 10 mL of nal-IRI at a concentration of 5 mg/mL. nal-IRI 
must be stored refrigerated at 2 to 8°C, with protection from light (do not freeze). The 
appearance of nal-IRI is white to slightly yellow opaque liquid. 
6.1.1.1 
Storage and Handling of Nal-IRI (MM-398) 
Nal-IRI must be stored refrigerated at 2 to 8 °C, with protection from light. Nal-IRI 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 drug.  
Nal-IRI must be diluted prior to administration. The diluted solution is physically and 
chemically stable for 4 hours at room temperature (15 – 25 °C), but it is preferred to be stored 
at refrigerated temperatures (2 – 8 °C). The diluted solution must not be frozen, and must be 
protected from light until infusion. Because of possible microbial contamination during 
dilution, the diluted solution should be administered within 24 hours of preparation if 
refrigerated (2 – 8 °C), and within 4 hours if kept at room temperature (15 – 25 °C). 
6.1.1.2 
Packaging and Labeling of Nal-IRI (MM-398) 
Nal-IRI will be packaged in a multi-vial cardboard carton. The individual vials, as well as the 
outside of the cardboard carton, will be labeled in accordance with local regulatory 
requirements. 
6.1.1.3 
Administration of Nal-IRI (MM-398) 
See combination regimen administration instructions below in Section 6.3.2.  
6.1.1.4 
Potential Toxicity of Nal-IRI (MM-398) 
Data from previous nal-IRI studies does not show any unexpected toxicity when compared to 
the active ingredient, irinotecan, which has been studied extensively. The warnings and 
precautions for the use of irinotecan and the recommended treatment procedures for managing 
those toxicities are provided below. Certain known adverse reactions of irinotecan have not 
been observed with nal-IRI to date. This could be due to the limited cumulative patient exposure 
to date of nal-IRI, or the use of appropriate premedication and early recognition and treatment 
of expected adverse events. The adverse reactions not observed include anaphylaxis or 
anaphylactoid reaction, interstitial lung disease-like pulmonary toxicity and acute pancreatitis. 
There is insufficient evidence to know whether these known adverse reactions of irinotecan are 
also associated with nal-IRI.  
Diarrhea 
Irinotecan can induce both early and late forms of diarrhea that appear to be mediated by 
different mechanisms. Early diarrhea (occurring during or shortly after infusion of irinotecan) 
is cholinergic in nature. It is usually transient and only infrequently severe. It may be 
accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, 
flushing, and intestinal hyper-peristalsis that can cause abdominal cramping. For patients who 


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experienced early cholinergic symptoms during the previous cycle of nal-IRI, prophylactic 
administration of atropine will be given at the discretion of the investigator. 
Late diarrhea (generally occurring more than 24 hours after administration of irinotecan) can 
be life threatening since it may be prolonged and may lead to dehydration, electrolyte 
imbalance, or sepsis. Late diarrhea should be treated promptly with loperamide, and octreotide 
should be considered if diarrhea persists after loperamide, as described in Section 6.7.2 
(Therapy for Diarrhea). Loss of fluids and electrolytes associated with persistent or severe 
diarrhea can result in life threatening dehydration, renal insufficiency, and electrolyte 
imbalances, and may contribute to cardiovascular morbidity. The risk of infectious 
complications is increased, which can lead to sepsis in patients with chemotherapy-induced 
neutropenia. Patients with diarrhea should be carefully monitored, given fluid and electrolyte 
replacement if they become dehydrated, and given antibiotic support if they develop ileus, 
fever, or severe neutropenia. 
Neutropenia 
Deaths due to sepsis following severe neutropenia have been reported in patients treated with 
irinotecan and nal-IRI. In patients with metastatic pancreatic cancer in the NAPOLI-1 study 
receiving irinotecan liposome injection/5-FU/LV, the incidence of grade 3 or 4 neutropenia was 
higher among Asian patients (18 of 33 [55%]) compared to White patients (13 of 73 [18%]). 
Neutropenic complications should be managed promptly with antibiotic support. Granulocyte-
colony stimulating factor (G-CSF) may be used to manage neutropenia at the investigator’s 
discretion. Prophylactic use of Granulocyte-colony stimulating factor (G-CSF) will be 
permitted if patients are considered high risk in the opinion of the investigator as specified in 
Section 6.7.1. 
Hypersensitivity 
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been 
observed with irinotecan, however, have not been observed with nal-IRI to date. This could be 
due to the limited cumulative patient exposure to date of nal-IRI, or the use of appropriate 
premedication and early recognition and treatment of expected adverse events. There is 
insufficient evidence to know whether these known adverse reactions of irinotecan are also 
associated with nal-IRI. Suspected drugs should be withheld immediately and aggressive 
therapy should be given if hypersensitivity reactions occur. 
Colitis/Ileus 
Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been observed.  
Patients experiencing ileus should receive prompt antibiotic support.  
Thromboembolism 
Thromboembolic events have been observed in patients receiving irinotecan-containing 
regimens; the specific cause of these events has not been determined.  
Pregnancy 
The pregnancy category of irinotecan is D. Women of childbearing potential should be advised 
to avoid becoming pregnant while receiving treatment with irinotecan. If a pregnancy is 
reported, treatment should be discontinued. The patient should be withdrawn from the study, 
and the pregnancy should be followed until the outcome becomes known. 
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.  


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Patients at Particular Risk 
In clinical trials of the weekly schedule of irinotecan, it has been noted that patients with 
modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) have had a 
significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those 
with bilirubin levels that were less than 1.0 mg/dL (50.0% [19/38] versus 17.7% [47/226]; 
p < 0.001).  Patients with abnormal glucuronidation of bilirubin, such as those with Gilbert's 
syndrome, may also be at greater risk of myelosuppression when receiving therapy with 
irinotecan.  
Acute Infusion Associated Reactions 
Acute infusion-associated reactions characterized by flushing, shortness of breath, facial 
swelling, headache, chills, back pain, tightness of chest or throat, and hypotension have been 
reported in a small number of patients treated with liposome drugs. In most patients, these 
reactions generally resolve within 24 hours after the infusion is terminated. In some patients, 
the reaction resolves by slowing the rate of infusion. Most patients who experienced acute 
infusion reactions to liposome drugs are able to tolerate further infusions without complications. 
See Section 6.4 for guidelines on the management of infusion reactions. 
Other Potential Toxicities 
Nal-IRI, the liposomal formulation of irinotecan is different from irinotecan in unencapsulated 
formulation, so there is a potential for toxicities other than those caused by irinotecan. All 
patients should be monitored closely for signs and symptoms indicative of drug toxicity, 
particularly during the initial administration of treatment. 
6.2 
Additional Anticancer Therapies 
Patients will be treated with one or more of the following approved therapies: 
• 
5-FU/LV 
• 
oxaliplatin 
6.2.1 
Description of Combination Therapies  
A description of each anticancer therapy to be used in combination with nal-IRI is described in 
Section 1.1.1. Please also refer to the package inserts [10], [32], or Summary of Product 
Characteristics (SmPC) for sites located in the European Union (EU), for more details. 
6.2.2 
Storage and Handling of Combination Therapies 
Refer to the country specific package inserts or SmPC for details on storage and handling for 
5-FU and leucovorin and oxaliplatin.  
6.2.3 
Packaging and Labeling of Combination Therapies 
Sites participating in this protocol will source their own combination therapy 
supplies. However, for sites where this is not possible due to country legal or regulatory 
restrictions, Ipsen will provide commercially available 5-FU, leucovorin and oxaliplatin as 
required by their enrolled patients for their specific treatment regimen.   
Ipsen sourced combination therapy supplies will be labeled in accordance with local regulatory 
requirements, and site accountability for all Ipsen sourced clinical trial material is required and 
will be monitored by the sponsor or its representatives. 
6.2.4 
Potential Toxicities of Combination Therapies 
6.2.4.1 
Potential Toxicities with 5-FU  
Stomatitis and esophago-pharyngitis (which may lead to sloughing and ulceration), diarrhea, 
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 


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seen (see US package insert or SmPC). Common adverse events (≥20 %) that were observed 
with nal-IRI in combination with 5-FU/LV in clinical trials considered to be related were: 
diarrhea, nausea, vomiting, decreased appetite, neutropenia, fatigue, anemia, stomatitis and 
pyrexia. 
6.2.4.2 
Potential Toxicities with Oxaliplatin  
The following adverse events are relatively common (≥ 40%) with oxaliplatin treatment in 
combination with 5-FU/LV and are to be expected with the nal-IRI-containing regimen: 
peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increases in 
transaminases and alkaline phosphatase, diarrhea, fatigue, emesis, and stomatitis. In a phase 3 
study of the FOLFIRINOX regimen (5-FU/LV + irinotecan + oxaliplatin), the most common 
(> 5%) Grade 3-4 adverse events were: neutropenia, fatigue, vomiting, diarrhea, 
thrombocytopenia, sensory neuropathy, anemia, elevated alanine aminotransferase (ALT) 
level, thromboembolism, and febrile neutropenia [1]. Grade 3/4 hypersensitivity reactions, 
including anaphylactic reactions, have been observed in 2-3% of colon cancer patients receiving 
oxaliplatin; see package insert for more information. See Section 6.4 for guidelines on the 
management of infusion reactions. Additional adverse events may be anticipated, as described 
in the package insert or SmPC for oxaliplatin [10]. 
6.3 
Combination Regimen Dosage and Administration  
6.3.1 
Nal-IRI + 5-FU/LV + Oxaliplatin  
The order of the infusions to be administered in the clinic will be as follows: nal-IRI will be 
administered first, followed by oxaliplatin, then LV, followed by 5-FU. 
Patients will receive the oxaliplatin infusion 2 hours after the completion of the nal-IRI infusion 
and will receive leucovorin 30 min after oxaliplatin.   
6.3.1.1 
Premedication 
All patients must be premedicated prior to nal-IRI infusion, 5-FU/LV infusion, and oxaliplatin 
infusion with standard doses of dexamethasone and a 5-HT3 antagonist, or equivalent other 
anti-emetics according to standard institutional practices for irinotecan, 5-FU, and oxaliplatin 
administration, or the Summary of Product Characteristics (SmPC) for sites located in the 
European Union (EU). In situations where differences in standard institutional practices and 
recommendations within the country relevant SmPC occur, standard institutional practice will 
take precedence. Atropine may be prescribed prophylactically for patients who experienced 
acute cholinergic symptoms in the previous cycles. 
6.3.2 
Doses and Administration of Nal-IRI  
Nal-IRI will be administered at doses of 60 mg/m2 to 80 mg/m2 (as outlined in Section 4.1). 
Nal-IRI will be administered as an IV infusion over 90 minutes (±10 minutes), on Days 1 and 
15 of each 28-day cycle. The first cycle Day 1 is a fixed day; subsequent doses should be 
administered on the first day of each cycle +/- 2 days. 
Prior to administration, the appropriate dose of nal-IRI must be diluted in 5% Dextrose Injection 
(D5W) or 0.9% Sodium Chloride Injection to a final volume of 500 mL. Care should be taken 
not to use any diluents other than D5W or 0.9% sodium chloride. 
The actual dose of nal-IRI to be administered will be determined by calculating the patient’s 
body surface area at the beginning of each cycle. A +/- 5% variance in the calculated total dose 
will be allowed for ease of dose administration. Since nal-IRI vials are single-use vials, site 
staff must not store any unused portion of a vial for future use and they must discard unused 
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6.3.3 
Doses and Administration of 5-FU and Leucovorin  
• 
Leucovorin will be administered at a dose of 400 mg/m2 of the l + d racemic form, or l 
form 200 mg/m2, as an IV infusion over 30 minutes (±5 minutes), on Days 1 and 15 of 
each 28-day cycle 
• 
5-FU will be administered at a dose of 2400 mg/m2 as an IV infusion over 46-hours 
(±60 minutes), on Days 1 and 15 of each 28-day cycle  
Leucovorin should be reconstituted per the instructions on the package insert, SmPC or standard 
institutional guidelines for reconstitution of leucovorin.  
Leucovorin should be administered prior to the 5-FU infusion. Actual dose of 5-FU and 
leucovorin to be administered will be determined by calculating the patient’s body surface area 
prior to each cycle. A +/- 5% variance in the calculated total dose will be allowed for ease of 
dose administration. 
6.3.4 
Doses and Administration of Oxaliplatin  
Oxaliplatin will be administered at varying dose levels as indicated in Table 5 (from 60 mg/m2 
- 85 mg/m2), IV over 120 minutes (±10 minutes), on Days 1 and 15 of each 28-day cycle 
Oxaliplatin should be prepared according to the instructions on the package insert, SmPC or 
per standard institutional guidelines for preparation and administration of oxaliplatin. In 
situations where differences in standard institutional practices and recommendations within the 
country relevant SmPC occur, standard institutional practice will take precedence. 
Oxaliplatin should be administered following nal-IRI infusion; the first 3 patients in Dose 
Level 1 will begin the oxaliplatin infusion two hours after the completion of the nal-IRI infusion 
(see Section 6.3.1). Actual dose of oxaliplatin to be administered will be determined by 
calculating the patient’s body surface area prior to each cycle.  A +/- 5% variance in the 
calculated total dose will be allowed for ease of dose administration.   
6.4 
Management of Infusion Reactions  
The guidelines described in this section can be followed in case of infusion reactions to any 
study treatment given per protocol (e.g. nal-IRI, oxaliplatin). Infusion reactions will be defined 
according to the National Cancer Institute CTCAE (Version 4.03) definitions of an allergic 
reaction or anaphylaxis as defined below: 
Allergic reaction (i.e., a disorder characterized 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; hospitalization indicated for clinical sequelae (e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4:  
Life-threatening consequences; urgent intervention indicated 
Anaphylaxis (i.e., a disorder characterized 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): 


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Grade 1: 
Not applicable 
Grade 2: 
Not applicable 
Grade 3:  
Symptomatic bronchospasm, with or without urticaria; parenteral 
intervention indicated; allergy-related edema/angioedema; hypotension 
Grade 4:  
Life-threatening consequences; urgent intervention indicated 
Institutional policies or the following treatment guidelines shall be used for the management of 
infusion reactions. 
Grade 1 
• 
Slow infusion rate by 50% 
• 
Monitor patient every 15 minutes for worsening of condition 
• 
Future infusions may be administered at a reduced rate (e.g. over 120 minutes for nal-
IRI), at the discretion of the Investigator 
Grade 2 
• 
Stop infusion 
• 
Administer diphenhydramine hydrochloride 50 mg IV, acetaminophen 650 mg orally, 
and oxygen 
• 
Resume infusion at 50% of the prior rate once infusion reaction has resolved 
• 
Monitor patient every 15 minutes for worsening of condition 
• 
For all subsequent infusions, pre-medicate with diphenhydramine hydrochloride 50 mg 
IV, dexamethasone 10 mg IV, and acetaminophen 650 mg orally. 
• 
Future infusions may be administered at a reduced rate (e.g. over 120 minutes for nal-
IRI), at the discretion of the Investigator 
Grade 3 
• 
Stop infusion and disconnect infusion tubing from patient 
• 
Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV, 
bronchodilators for bronchospasm, and other medications or oxygen as medically 
necessary 
• 
No further treatment will be permitted 
Grade 4 
• 
Stop the infusion and disconnect infusion tubing from patient 
• 
Administer epinephrine, bronchodilators or oxygen as indicated for bronchospasm 
• 
Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 mg IV and 
other medications as medically necessary 
• 
Consider hospital admission for observation 
• 
No further treatment will be permitted 
For patients who experience a second grade 1 infusion reaction, administer dexamethasone 
10 mg IV. All subsequent infusions should be premedicated with diphenhydramine 
hydrochloride 50 mg IV, dexamethasone 10 mg IV, and acetaminophen 650 mg orally or as per 
institutional guidelines.  
6.5 
Dose Modifications  
The toxicity of each cycle must be recorded prior to the administration of a subsequent cycle 
and graded according to the NCI CTCAE (Version 4.03). All dose reductions for all arms 
should be based on the worst preceding toxicity. 


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Dosing may be held 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. If the time required for recovery from toxicity is more than 14 days, 
consideration should be given to discontinuing the patient from further treatment, unless the 
patient 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. If oxaliplatin is not well tolerated, oxaliplatin may be discontinued 
and patients may continue to receive nal-IRI + 5-FU/LV at the discretion of the Investigator. 
Toxicity requiring discontinuation of nal-IRI will result in discontinuation from all study 
treatments.  
If a patient’s dose is reduced during the study due to toxicity, it should remain reduced for the 
duration of the study; dose re-escalation to an earlier dose is not permitted. Any patient who 
has 3 dose reductions and experiences an adverse event that would require a fourth dose 
reduction must be discontinued from study treatment.  
Prior to each dosing, patients must have: 
• 
ANC t 1500/mm3 
• 
WBC t 3500/mm3 
• 
Platelet count t 100,000/mm3 
• 
Diarrhea ≤ Grade 1 
Treatment should be delayed to allow sufficient time for recovery to levels noted above, and 
upon recovery, treatment should be administered according to the guidelines in the tables 
below. The use of transfusions and/or growth factor support is permitted if within normal 
institutional policies and procedures. If the patient had febrile neutropenia, the ANC must have 
resolved to t 1500/mm3 and the patient must have recovered from infection. For Grade 3 or 4 
non-hematological toxicities, treatment should be delayed until they resolve to Grade 1 or 
baseline. Guidelines for dose adjustments of each individual treatment within the regimen are 
found in the tables below for hematologic toxicities (Table 6), and for non-hematological 
toxicities (Table 8), and were based on published dose modifications for the established 
FOLFIRINOX regimen [1]. In case a patient experiences an infusion reaction, either 
institutional guidelines or the guidelines provided for infusion reaction management (see 
Section 6.4) should be followed.  
For all tables below, patient should be withdrawn from study treatment if more than 3 dose 
reductions are required. No dose adjustments for toxicity are required for leucovorin. 
Leucovorin must be given immediately prior to each 5-FU dose; hence, if 5-FU dose is held, 
leucovorin dose should be held as well. 
Toxicity that requires discontinuation from oxaliplatin only (e.g. neuropathy) will result in the 
option, at the discretion of the Investigator to continue on study treatment with nal-IRI + 5-
FU/LV only for all future dosing. Toxicity requiring discontinuation of nal-IRI will result in 
discontinuation from all study treatment.  
 


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Table 6: Dose Modifications for Hematologic Toxicities(a,b,c,d) 
Worst Toxicity by CTCAE Grade 
Nal-IRI 
5-FU 
Oxaliplatin 
Grade 2 hematotoxicity 
100% of previous dose 
Grade 3- 4 neutropeniae (ANC ≤ 
1000/mm3) or febrile neutropenia 
and/or thrombocytopenia 
1st occurrence: Reduce dose by 20% (80% of original dose) 
2nd occurrence: Reduce dose by another 15% (65% of original 
dose) 
3rd occurrence: Reduce dose by another 15% (50% of original 
dose) 
Other Grade 3 or 4 hematologic 
toxicities not specifically listed 
above 
1st occurrence:  Reduce dose by 20% (80% of original dose) 
2nd occurrence: Reduce dose by another 15% (65% of original 
dose) 
3rd occurrence: Reduce dose by another 15% (50% of original 
dose) 
a Any toxicity ≥ Grade 2 can justify a dose reduction if medically indicated following above guidance 
b 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. 
c Patients who require more than 3 dose reductions must discontinue study treatment. 
d Prophylactic use of Granulocyte-colony stimulating factor (G-CSF) will be permitted if patients are 
considered high risk in the opinion of the investigator 
e Consider the use of G-CSF for patients who experience ≥ Grade 3 neutropenia or febrile neutropenia 
 
 
Table 7: Dose Modifications for Diarrhea(a,b) 
 
 
a Any toxicity ≥Grade 2 can justify a dose reduction if medically indicated following above guidance 
b Patients who require more than 3 dose reductions must discontinue study treatment 
c Grade 1 diarrhea: 2-3 stools/day >pretreatment; Grade 2 diarrhea: 4-6 stools/day >pretreatment 
d Grade 3 diarrhea: >9 stools/day >pretreatment; Grade 4 diarrhea: life threatening consequences 
e Prophylactic or therapeutic administration of atropine should be considered in patients experiencing 
cholinergic symptoms (acute diarrhea.  and abdominal cramps during or within 24 hours after nal-IRI 
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Table 8: Dose Modifications for Non-Hematological Toxicities Other than Diarrhea, 
Asthenia and Grade 3 Anorexiaa,b,e 
Worst Toxicity by 
CTCAE Grade 
Nal-IRI 
5-FU 
Oxaliplatin 
Grade 3 or 4 nausea 
and/or vomiting despite 
anti-emetic therapy 
Optimize anti-emetic therapy AND 
1st occurrence:  Reduce dose by 20% (80% of original dose) 
2nd occurrence:  Reduce dose by another 15% (65% of original dose) 
3rd occurrence: Reduce dose by another 15% (50% of original dose) 
Grade 2 hand foot 
syndrome 
100% of previous doseb 
1st occurrence:  
Reduce dose by 20% 
(80% of original dose) 
2nd occurrence:   
Reduce dose by another 
15%  
(65% of original dose) 
3rd occurrence: 
Reduce dose by another 
15% 
(50% of original dose) 
100% of previous 
doseb 
Grade 3 or 4 hand foot 
syndrome 
100% of previous doseb 
Discontinue therapy 
100% of previous 
doseb 
Any grade 
neurocerebellar or t 
Grade 2 cardiac toxicity 
100% of previous doseb 
Discontinue therapy 
100% of previous 
doseb 
Sensory neuropathy 
100% of previous doseb 
100% of previous doseb 
Grade 2, persistent: 
Reduce dose by 20% 
(80% of original dose) 
Grade 3, recovers prior 
to next cycle: 
Reduce dose by 35% 
(65% of original dose) 
Grade 3, recurrent: 
Reduce dose by 15%d 
(50% of original dose) 
Grade 3 persistent or 
Grade 4: 
Discontinue therapyc 
 
Grade 3 or 4 hepatic, 
renal, respiratory or other 
toxicities 
1st occurrence:  Reduce dose by 20% (80% of original dose) 
2nd occurrence:  Reduce dose by another 15% (65% of original dose) 
3rd occurrence: Reduce dose by another 15% (50% of original dose) 
a Asthenia and Grade 3 Anorexia do not require dose modification 
b Any toxicity ≥ Grade 2, except asthenia and alopecia, can justify a dose reduction if medically indicated  
c Patients who discontinue therapy due to oxaliplatin-related neuropathy may remain on study and continue to 
receive nal-IRI + 5-FU/LV  
d At the discretion of the investigator, patients can discontinue oxaliplatin therapy if Grade 3 persistent 
sensory neuropathy occurs. 
e Patients who require more than 3 dose reductions must discontinue study treatment  
 
6.5.1 
Nal-IRI Dose Modifications for UGT1A1*28 Positive Patients 
As part of this study, pharmacogenomic data will be collected on all patients for 
determination of UGT1A1*28 status. 
Based on previous experience with 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 [25], 


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in a study of 66 patients who received single-agent irinotecan (350 mg/m2 once every-3-
weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 
allele was as high as 50%, and in patients heterozygous for this allele (UGT1A1 6/7 
genotype) the incidence was 12.5%.  
Importantly however, no grade 4 neutropenia was observed in patients homozygous for the 
wild-type (WT) 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 [25]). Population PK studies of nal-IRI have not 
identified a relationship between UGT1A1*28 homozygosity and increased SN-38 exposure 
(see Investigator Brochure). In a Phase I study (UCSF 8603, as referenced in Table 2 above) 
no differences in toxicity were seen in cohorts of heterozygous or WT patients, and DLTs of 
diarrhea with or without accompanying dehydration or fatigue, were seen in both cohorts. 
Because of these discrepancies in the severity of previously documented toxicity arising from 
UGT1A1*28 homozygosity, and because the prevalence of UGT1A1*28 homozygosity is 
relatively low, testing results will not be required prior to the first dose of nal-IRI on this 
study and the starting dose for all patients will be as described in Table 5. 
The protocol does not contain formal recommendations on nal-IRI dose modifications as a 
consequence of homozygosity. All patients should receive the full starting dose of nal-IRI. 
The UGT1A1*28 status of each patient will subsequently be made available to individual 
investigators. 
6.5.2 
Other Toxicities Requiring Special Attention 
QTc prolongation that occurs in the setting of diarrhea 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 diarrhea as described above. 
6.5.3 
Rules for Dose Omissions and Modified Schedules 
The following guidance should be followed when all study drugs are held/missed: 
The maximum delay between the date of a scheduled but missed dose and the planned next 
dose should be up to 14 days.  
6.6 
Drug Accountability 
The Investigator and investigational site staff are responsible for maintaining an accurate 
inventory and accounting of all study drugs provided by the Sponsor. A record of all vials of 
study drug received and administered will be maintained on an investigational drug inventory 
form provided by the Sponsor. The following information will be recorded: 
• 
Date and quantity of study drug received 
• 
Date and quantity of study drug dispensed from the pharmacy per patient 
• 
Date and quantity of study drug administered to each patient (the start and stop date/time 
of infusion of drug should be recorded for each patient at each dose) 
• 
Date and quantity of study drug destroyed (if prepared and dispensed, but not 
administered for any reason, the study drug may not be returned to inventory) 
• 
Date and quantity of study drug returned to sponsor 
Each shipment of study drug will contain an invoice describing the amount of drug shipped to 
the investigational site. The information on the invoice will be verified against the actual 
amount of drug received, after which the Investigator or the Investigator’s designee will place 
the invoice in the Investigator’s file. 


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During monitoring, the Sponsor’s monitor will reconcile the information on the investigational 
drug inventory form with the actual amount of study drug remaining at each site. At the 
conclusion of the study, the monitor will perform accountability on all unused vials of study 
drug. Once accountability is complete, destruction may be performed at the site, or if the site 
does not have a destruction process, the monitor may ship the supplies back to the sponsor. In 
case of destruction at the site, the method should be documented in the site files. Following use, 
empty vials of study drug may be destroyed according to local regulatory and environmental 
requirements. A record of any such destruction will be placed in the Investigator’s file. 
6.7 
Concomitant 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.  Patients should receive analgesics, antiemetics, antibiotics, anti-pyretics, and blood 
products as necessary. Although warfarin-type anticoagulant therapies are permitted, careful 
monitoring of coagulation parameters is imperative, in order to avoid complications of any 
possible drug interactions (see also Section 6.8). 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. 
6.7.1 
Granulocyte Colony Stimulating Factors 
Deaths due to sepsis following severe neutropenia have been reported in patients treated with 
irinotecan and nal-IRI. In patients with metastatic pancreatic cancer in the NAPOLI-1 study 
receiving irinotecan liposome injection/5-FU/LV, the incidence of grade 3 or 4 neutropenia was 
higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. 
Neutropenic complications should be managed promptly with antibiotic support. G-CSF may 
be used to manage neutropenia at the investigator’s discretion. Prophylactic use of G-CSF will 
be permitted if patients are considered high risk in the opinion of the investigator [33] [34] [35]. 
6.7.2 
Therapy for Diarrhea 
Acute diarrhea and abdominal cramps, developing during or within 24 hours after nal-IRI 
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 patients experiencing cholinergic symptoms during the 
study.  
Diarrhea can be debilitating and on rare occasions is potentially life-threatening. Diarrhea 
should be managed according to institutional guidelines, or according to the guidelines 
developed by an ASCO panel for treating chemotherapy-induced diarrhea, abstracted in Table 
14 below [36]. For a detailed algorithm of diarrhea management for chemotherapy-induced 
diarrhea, see Appendix 2. 


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Table 9: Recommendations for Management of Chemotherapy Induced Diarrhea 
Clinical Presentation 
Intervention 
Diarrhea, any grade 
Oral loperamide (2 mg every 2 hours for irinotecan induced 
diarrhea; 2 mg every 4 hours for 5-FU induced diarrhea): 
continue until diarrhea-free for t 12 hours 
Oral electrolyte replacement 
Diarrhea persists on loperamide 
for > 24 hours 
Oral fluoroquinolone x 7 days 
Diarrhea persists on loperamide 
for > 48 hours 
Stop loperamide; hospitalize patient; administer IV fluids 
ANC < 500 cells/PL, regardless 
of fever or diarrhea  
Oral fluoroquinolone (continue until resolution of 
neutropenia) 
Fever with persistent diarrhea, 
even in the absence of 
neutropenia 
Oral fluoroquinolone (continue until resolution of fever and 
diarrhea) 
 
6.8 
Prohibited Therapy 
The following drugs are noted in the irinotecan prescribing information as interacting with 
irinotecan: 
• 
Strong CYP3A4 inducers, e.g., St. John’s Wort, CYP3A4 inducing anticonvulsants 
(phenytoin, phenobarbital, and carbamazepine), rifampin, rifabutin, rifapentine 
• 
Strong CYP3A4 inhibitors, e.g., clarithromycin, indinavir, itraconazole, ketoconazole, 
lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole 
• 
Weak to moderate CYP3A4 inhibitors, e.g., troleandomycin, erythromycin, diltiazem, 
verapamil 
• 
Strong UGT1A1 inhibitors, e.g., atazanavir, gemfibrozil, indinavir, ketoconazole 
Treatment with these agents and any others that interact with irinotecan, 5-FU, or oxaliplatin 
should be avoided wherever possible. Because 5-FU interacts with warfarin, caution should be 
exercised if concomitant use is necessary. No live attenuated vaccines should be given to 
patients of the study (e.g., yellow fever vaccine and polio virus vaccine). Refer to the country 
specific package inserts of 5-FU, leucovorin, or oxaliplatin for any other drug interactions. 
The following therapies are not permitted during the study treatment phase: 
(a) 
Other anti-neoplastic therapy, including cytotoxics, targeted agents, endocrine therapy 
or antibodies  
(b) 
Potentially curative radiotherapy; palliative radiotherapy is permitted 
(c) 
Any other investigational therapy  
7 
STUDY PROCEDURES 
7.1 
Protocol Visits 
7.1.1 
Screening Visit 
The screening phase will begin once the patient signs the informed consent form. All procedures 
for screening and baseline are outlined in Section 8. For further descriptions of the clinical and 
laboratory assessments required, please refer to Sections 7.2 and 7.3 respectively. 
7.1.2 
On-Study Visits 
Patients who are confirmed to meet all inclusion and exclusion criteria will be enrolled in the 
study and receive the first dose (Cycle 1 Day 1). All study procedures and assessments are 


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outlined in Sections 7.2, 7.3 and 8. During the treatment period, a window of ±2 days will apply 
to all visits, unless otherwise stated. 
7.1.3 
End of Treatment Visit 
All patients must complete an End of Treatment (EoT) assessment at the time the Investigator 
removes the patient from treatment. This assessment should occur approximately 30 days 
(± 14 days) after the last dose of study treatment. All procedures and assessments are outlined 
in Section 8. 
7.1.4 
Long-term Follow-up 
After the End of Treatment visit, patients should continue to be followed for survival status 
once every 8 weeks (± 7 days) via telephone, email, clinic visit, or medical record review until 
death, lost to follow-up, 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 patients who are discontinued for reasons 
other than progressive disease per RECIST v1.1, disease evaluations (including imaging 
studies) should continue into the follow-up period, as described in Section 7.2.6 below. 
If a patient does not respond to the overall survival follow-up contacts, at least 3 documented 
attempts, including one via certified mail, should be made to contact the patient before declaring 
a patient lost to follow-up. If the patient does not respond to these requests, the date of death 
may be captured from public records.  
7.2 
Clinical Procedures 
7.2.1 
Medical History 
A medical history will include all pertinent prior medical conditions, surgeries or other medical 
procedures.   
7.2.2 
Vital Signs 
Vital signs will include height (at screening only), weight, resting blood pressure, pulse, 
respiratory rate and temperature. 
7.2.3 
Performance Status 
The Eastern Cooperative Oncology Group (ECOG) Performance Status will be obtained at 
Screening, and within 72 hours prior to first dose if first dose occurs more than 72 hours post 
screening, by the Investigator or his/her designee via questioning of the patient about their 
functional capabilities. Additionally, Karnofsky Performance Status (KPS) will be recorded at 
Screening, and within 72 hours prior to first dose if first dose occurs more than 72 hours post 
screening. See Appendix 3 for KPS and Appendix 4 for ECOG scales.  
7.2.4 
Electrocardiogram (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 
should be indicated (see Section 6.5.2 for QTc in relation to diarrhea). 
7.2.5 
Adverse Event and Hospitalization Assessment 
Investigators should complete all routine and standard of care assessments to evaluate for 
toxicity and symptoms of drug-induced adverse events. This may include, but is not limited to, 
verbal reports from the patient and/or caregiver, physical examination and laboratory findings. 
The period for treatment-emergent adverse events and safety findings will be from the time of 
first study drug administration to 30 days after the date of last study drug administration. For 
detailed information on adverse event reporting, see Section 9. In addition, information on 


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patient hospitalizations and/or hospital visits should also be collected, whether or not associated 
with an adverse event. 
Patients who continue infusion of 5-FU in home settings for the extended durations during the 
study, should keep a record of date/time of infusion start and stop and report any adverse events 
to the site. The Investigator or medically qualified person should call the patients who are 
discharged home for extended infusions to record the start and stop date/time for infusion and 
to assess adverse events reported by the patient (see Section 6.2.4.1). 
7.2.6 
Disease Evaluation 
Tumor response will be evaluated according to the Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 [37], to establish disease progression by CT or MRI. 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 v1.1 guidelines. Follow up measurements and overall response 
should also be in accordance with these guidelines. 
Tumor assessments should be completed until it has been determined that the patient has 
progressive disease (in accordance with RECIST v1.1). For patients who do not have 
documented disease progression per RECIST v. 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. Continued imaging follow-up on schedule is 
recommended to reduce potential bias in the evaluations of the impacts of the experimental 
treatments on disease [38]. 
7.3 
Laboratory Procedures 
Laboratory assessments required for screening and enrolment eligibility can be performed 
locally for evaluating patient eligibility and enrolment only.   
7.3.1 
Complete Blood Count 
A complete blood count (locally assessed) will include a white blood count (WBC) and 
differential, hemoglobin, hematocrit and platelet count. 
7.3.2 
Serum Chemistry 
Serum chemistry will be assessed centrally, and will include electrolytes (sodium, potassium, 
chloride and bicarbonate), BUN, serum creatinine, glucose, direct and total bilirubin, AST, 
ALT, alkaline phosphatase, lactate dehydrogenase (LDH), uric acid, total protein, albumin, 
calcium, magnesium and phosphate. Chemistry may also be assessed locally, and local lab 
results may be used for enrollment and treatment decisions, if central lab results are not 
available. 
7.3.3 
CA19-9 
CA19-9 biomarker levels will be measured centrally for all patients. 
7.3.4 
UGT1A1*28 
A whole blood sample will be collected and assessed centrally at baseline to test for 
UGT1A1*28 allele status. The result is not needed prior to the initial dose of nal-IRI. 
7.3.5 
Biomarker Samples 
Archived tissue samples, whole blood, serum and plasma will be collected to potentially 
identify factors that may correlate with tumor response, sensitivity or resistance to nal-IRI, and 
nal-IRI PK. Examples of potential analyses include cytokine levels (e.g. MCSF1, and IL-6), 
growth factors (e.g. IGF1 and EGFR family receptors and ligands), enzyme levels (e.g. MMP9).  


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7.3.6 
Urine or Serum Pregnancy Test 
A urine or serum pregnancy test will be obtained for all females of childbearing potential at 
screening, at the start of each cycle during study treatment, and at the EoT visit. Exempt female 
patients will include those who have undergone a bilateral oophorectomy or hysterectomy or 
who are menopausal (defined as absence of a menstrual cycle for at least 12 consecutive 
months). 
7.3.7 
Pharmacokinetic Assessments 
Since the combination of nal-IRI and oxaliplatin has not yet been tested in the clinic, plasma 
samples will be collected to determine the levels of nal-IRI and SN-38, as well as 5-FU and 
oxaliplatin, in patients. Additional analytes which may impact the pharmacokinetics of nal-IRI 
may also be measured from this sample. Directions for processing and shipping the PK plasma 
samples can be found in the study manual. The PK time points outlined in Table 10 below will 
be drawn during Cycle 1 only. PK samples will be collected during the study. 
Table 10: Summary of PK Timepoints  
Sample 
Time-point 
Window 
Number of 
Drawsa 
1 
Prior to nal-IRI infusion on Day 1 (pre-dose) 
-24 hours 
3 
2 
At the end of the nal-IRI infusion 
+30 mins 
1 
3 
At the end of the oxaliplatin infusion 
+ 5 mins 
2 
4 
Within 2 hours prior to the completion of the 5-FU 
infusion  
- 
3 
5 
+168 hours/7 days after the completion of the nal-IRI 
infusion 
±24 hours 
2 
6 
Prior to nal-IRI infusion on Day 15 (pre-dose) 
-24 hours 
2 
7 
End of Treatment visit (30 days post-last dose) 
± 14 days 
2 
a The number of draws corresponds to the number of analytes that will be measured; for example, sample #3 
at the end of the oxaliplatin infusion will be used to measure nal-IRI and oxaliplatin. 
 


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8 
SCHEDULE OF ASSESSMENTS 
Procedure 
Screening 
Phase 
Treatment Phase 
Follow Up Phase 
-28d 
Cycle 119 
Additional Cycles19 
Every 8w 
after 1st dose 
End of Treatment 
Visit18 
Every 2 months from 
EoT Follow-up visit 
D1 
D3 
D8 
D15 
D1 
D8 
D15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
 
 
 
 
 
Demographics 
X1 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
 
ECOG PS 
XX2, 23 
X 
 
 
 
X 
 
 
 
X 
 
KPS PS 
XX2, 24 
 
 
 
 
 
 
 
 
 
 
CBC4 
X2 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Serum chemistry4 
X2, 25 
X 
 
X 
X 
X 
 
X 
 
X 
 
CA19-9 
X2 
 
 
 
 
 
 
 
X17 
X20 
 
UGT1A1*28 
X2, 5 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X2 
X 
 
 
 
X 
 
 
 
X 
 
ECG6 
X1,7 
 
 
 
 
 
 
 
 
X 
 
Archived slides8 
X 
 
 
 
 
 
 
 
 
 
 
Plasma for PK 
 
X9 
X10 
X11 
X12 
 
 
 
 
X26 
 
Biomarker analysis12, 13 
 
X13 
 
 
 
X 
 
 
 
X 
 
Concomitant meds and 
procedures 
X1 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Dosing14 
 
X 
 
 
X 
X 
 
X 
 
 
 
AE / Hospitalization 
assessment & reporting 
X15 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Disease evaluation16 
X1 
 
 
 
 
 
 
 
X17 
X18 
X21 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
X22 
1 Procedures to be completed within 28 days of 1st dose of study drug 
2 Procedures to be completed within 7 days of 1st dose of study drug 
3 HRQL questionnaires must be completed before study treatment administration 
4 After screening, samples should be obtained within 2 days from scheduled date of collection 
5 Result not required prior to enrollment in the study or prior to receiving the initial dose of nal-IRI 
6 To be repeated as clinically indicated during the study 
7 Two independent readings at least 1 minute apart 


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8 Collection of archived tumor block or paraffin embedded slides is required, if available 
9 Samples collected at the following timepoints: pre-dose (within 24 hours prior to nal-IRI infusion); at the end of the nal-IRI infusion (+30 mins) and at the end of the 
oxaliplatin infusion (+5 mins).  
10 Sample collected within 2 hours prior to the completion of the 5-FU infusion.  
11 Sample collected +168 hours/7 days after the completion of the nal-IRI infusion (±24 hours).  
12 Sample collected just prior to dosing with nal-IRI (within 24 hours). 
13 Blood will be collected for biomarker analyses: plasma samples will be collected at all timepoints; additionally, whole blood and serum samples will be collected on Cycle 
1 Day 1 only. 
14 Study drug administration should occur ±2 days from scheduled date of administration 
15 Adverse events that occur during screening should be documented as pre-existing conditions; only SAEs that are felt by the Investigator to be directly related to a study 
procedure should be reported during screening. 
16 Disease evaluation according to RECIST v. 1.1 (see Section 7.2.6) 
17 Disease evaluations and CA19-9 should be done every 8 weeks (± 7 days) after 1st dose  
18 Unless completed in the prior 8 weeks 
19 All cycles are 28-day cycles, unless modified due to toxicity 
20 The End of Treatment (EoT) Follow-Up visit should occur 30 days (± 14 days) after last dose  
21 For patients who discontinue the study for reasons other than radiologically confirmed disease progression only (e.g. patients who are removed due to adverse events), 
imaging studies should be continued until documented progression of disease per RECIST v1.1 (see Section 7.2.6). 
22 Follow-up contacts should be made every 8 weeks (± 7 days) until death or study completion; data collected should include overall survival status as well as subsequent 
treatment information. 
23 ECOG to be performed at Screening, and within 72 hours prior to first dose if first dose occurs more than 72 hours post screening. ECOG assessment requires 
determination by two independent assessors. In the case of a discrepancy between the 2 assessments, the one with a lower score will be selected at each assessment. 
24 KPS to be performed at Screening, and within 72 hours prior to first dose if first dose occurs more than 72 hours post screening. KPS assessment requires determination 
by two independent assessors. In the case of a discrepancy between the 2 assessments, the one with a lower score will be selected at each assessment. 
25 Serum albumin needs to be collected at Screening, and within 72 hours prior to first dose if first dose occurs more than 72 hours post screening to confirm exclusion criteria 
‘p’ (both labs at screening and prior to first dose may be confirmed locally) (Section 5.2). 
26 Sample to be collected within 5 minutes after ECG recording 


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9 
ADVERSE EVENT REPORTING 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign, including abnormal laboratory findings, symptoms, or diseases temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. Worsening of a medical condition for which the efficacy of the study drug 
is being evaluated will not be considered an adverse event.  
9.1.2 
Unexpected Adverse Event 
An unexpected adverse event is one for which the nature or severity of the event is not consistent 
with the applicable product information, e.g., the Investigator’s Brochure, or the package insert 
or SmPC for approved therapies (see also Section 6.2.4). 
9.1.3 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (an event in which the patient was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed above.  Examples of such events are intensive 
treatment in an emergency room for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency or 
drug abuse. 
The term “severe” is often used to describe the intensity (severity) of an event; the event itself 
may be of relatively minor medical significance (such as a severe headache). This is not the 
same as “serious”, which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning. 
9.2 
Documenting Adverse Events 
SAE reporting will begin on the date the patient provides informed consent to participate in the 
study, however only those SAEs occurring prior to study drug administration, that the 
Investigator believes to be related to a protocol procedure, should be reported according to 
Section 9.3 below. All AEs that occur during the screening phase should be documented as pre-
existing conditions. Treatment-emergent adverse event reporting will begin as of the 
administration of study drugs. The Investigator should elicit information regarding the 
occurrence of adverse events through open-ended questioning of the patient, physical 
examination, and review of laboratory results. 
All adverse events, whether serious or not, will be recorded in the source documents and the 
adverse event page of the case report form (except as noted below). All new events, as well as 
those that worsen in intensity or frequency relative to baseline, must be recorded throughout 


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the study, until the End of Treatment follow-up visit. Adverse events should be followed 
through resolution, where possible. However, new adverse events felt by the Investigator to be 
related to the study treatment, must be reported any time the Investigator becomes aware of 
such an event, even if this occurrence is more than 30 days after the last dose of study drug.  
Laboratory or vital signs abnormalities are to be recorded as Adverse Events only if they are 
clinically significant: symptomatic, requiring corrective treatment, leading to discontinuation 
and/or fulfilling a seriousness criterion. 
Information to be reported in the description of each adverse event includes: 
• 
A medical diagnosis of the event (if a medical diagnosis cannot be determined, a 
description of each sign or symptom characterizing the event should be recorded)  
• 
The date of onset of the event  
• 
The date of resolution of the event  
• 
A determination of whether the event is serious or not 
• 
Action taken: none; change in the study drug administration (e.g., temporary interruption 
in dosing); drug treatment required; non-drug treatment required; hospitalization or 
prolongation of hospitalization required (complete serious adverse event page); 
diagnostic procedure performed; patient discontinued from the study (complete Final 
Visit section of the case report form) 
• 
Outcome:  resolved without sequelae; resolved with sequelae; event resolving; event 
ongoing; patient died (notify the Sponsor immediately, and complete the Serious Adverse 
Event page and the Final Visit section of the case report form) 
9.3 
Reporting Serious Adverse Events 
All fatal or life-threatening adverse events must be reported to the medical monitor immediately 
by telephone, e-mail, or fax. Within 24 hours of knowledge of the event, the Serious Adverse 
Event Form must be faxed to the appropriate contact whether full information regarding the 
event is known or not. Additional follow-up by the Investigator will be required if complete 
information is not known. Source documentation of all examinations, diagnostic procedures, 
etc., which were completed with respect to the event should be included with the SAE form. 
Care should be taken to ensure that the patient’s identity is protected and the patient’s identifiers 
(as assigned at the time of study enrollment) are properly mentioned on any copy of source 
document provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
In case of accidental or intentional overdose of any of the study drugs, even if asymptomatic or 
not fulfilling a seriousness criterion, the overdose is to be reported to the Sponsor immediately 
(within 1 working day) using the AE and SAE forms. Overdose will be defined as ≥133% of 
planned dose. 
All other serious adverse events must be reported to the appropriate contact within 24 hours of 
becoming aware of the event by phone, e-mail or fax. The Serious Adverse Event Form must 
also be faxed to the appropriate contact within 24 hours of the event whether full information 
regarding the event is known or not.  Additional follow-up by the Investigator will be required 
if complete information is not known. 
The medical monitor shall be contacted as deemed necessary by the site.  Current contact 
information shall be maintained at the site within the regulatory binder. 
All SAEs will be evaluated by the medical monitor. If meeting the requirements for expedited 
reporting, the Sponsor will report the adverse event to all regulatory authorities with jurisdiction 
over ongoing trials with the study drug and to all other Investigators involved in clinical trials 
with the study drug.  The Investigator is responsible for reporting all SAEs to the appropriate 
Institutional Review Board (IRB) or Ethics Committee (EC), as per local regulations. 


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9.4 
Determining the Severity and Relatedness of Adverse Events 
9.4.1 
Grading the Severity of an Adverse Event 
Each adverse event will be graded according to the NCI CTCAE Version 4.03, which may be 
found at http://ctep.cancer.gov/reporting/ctc.html.  For events not listed in the CTCAE, severity 
will be designated as mild, moderate, severe or life threatening or fatal which correspond to 
Grades 1, 2, 3, 4 and 5, respectively on the NCI CTCAE, with the following definitions: 
• 
Mild: an event not resulting in disability or incapacity and which resolves without 
intervention;  
• 
Moderate: an event not resulting in disability or incapacity but which requires 
intervention;  
• 
Severe: an event resulting in temporary disability or incapacity and which requires 
intervention;  
• 
Life-threatening: an event in which the patient was at risk of death at the time of the 
event 
• 
Fatal: an event that results in the death of the patient 
9.4.2 
Relatedness to Study Drug 
• 
The Investigator must attempt to determine if there exists reasonable possibility that an 
adverse event is related to the use of the study drug.  This relationship should be described 
as related or non-related.   
9.4.3 
Reporting and Follow-Up of Pregnancy 
Patients who become pregnant while on study must immediately discontinue study treatment, 
and the pregnancy must be immediately reported to the medical monitor. Pregnancies occurring 
up to 90 days after the completion of the study medication must also be reported to the Sponsor.   
The Investigator should inform the patient of the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion of the 
pregnancy. 
In the event of a pregnancy occurring in the partner of a male patient participating in the study, 
the pregnant partner should be requested to report the pregnancy to the Sponsor. The partner 
should also be informed of the risks of continuing with the pregnancy, the possible effects on 
the fetus, and be followed until conclusion of the pregnancy. 
10 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
10.1 
Case Report Forms 
All data for the patients recruited for the trial will be entered onto electronic case report forms 
(eCRFs) via an Electronic Data Capture (EDC) system provided by the Sponsor. Only 
authorized staff may enter data onto the eCRFs. If an entry error is made, the corrections to the 
eCRFs will be made according to eCRF guidelines by an authorized member of the site staff. 
10.2 
Data Quality Assurance 
Electronic CRFs will be checked for correctness against source document data by the Sponsor’s 
monitor. If any entries into the eCRF are incorrect or incomplete, the monitor will ask the 
Investigator or the study site staff to make appropriate corrections, and the corrected eCRF will 
again be reviewed for completeness and consistency. Any discrepancies will be noted in the 
CRF system by means of electronic data queries. Authorized site staff will be asked to respond 
to all electronic queries according to the eCRF guidelines. Additional computer programs that 
identify selected protocol violations, out-of-range data and other data errors may be used to 
help monitor the study. 


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10.3 
Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the Sponsor. The SAP may modify the analysis outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment. 
Categorical variables will be summarized by frequency distributions (number and percentage 
of patients) and continuous variables will be summarized by descriptive statistics (mean, 
standard deviation, median, minimum, and maximum). Testing will be conducted using a one-
sided 0.10 significance level unless stated otherwise. 
10.4 
Study Populations 
Patient populations defined for this study are described below: 
• 
Safety (SAF) population: The safety population includes patients receiving at least one 
dose of any study drug  
• 
PK Population: The PK population will include all nal-IRI treated patients who received 
at least 1 dose and who have at least 1 plasma concentration and no major protocol 
deviations affecting PK variables. 
10.5 
Disposition and Baseline Characteristics 
Study populations (safety, PK) will be summarized and displayed as frequencies. Disposition 
of patients will be summarized including patients screened, treated, and discontinued. Reasons 
for discontinuation will be tabulated. Demographic and baseline characteristics will be 
summarized. Medical history and prior medications will be tabulated. 
10.6 
Efficacy Analysis 
Efficacy analyses will be performed on Safety population. 
Tumor evaluation will be measured according to RECIST v1.1. For each patient, progression 
free survival time will be determined as the time from the date of first study drug to the first 
documented radiographical progression of disease (PD), per investigator using RECIST 1.1, or 
death from any cause, whichever comes first. If the progression or death occurs at a time point 
that is greater than 16 weeks after the non-PD last tumor assessment, then progression-free 
survival time will be censored at the time of the last non-PD tumor assessment. Details on 
censoring rules will be provided in the study statistical analysis plan. 
Efficacy Analysis 
PFS will be analyzed using Kaplan-Meier method and descriptively summarized at 3 months 
interval for each dose level cohort. Median PFS time and corresponding 95% confidence limits 
will be presented. 
Best Overall Response (BOR) is defined as the best response as recorded from the start of study 
drug until disease progression. Patients without a post-baseline tumor assessment will be 
considered to be non-evaluable for BOR. To classify BOR as stable disease (SD), there should 
be a qualifying SD assessment at least 6 weeks from the first dose of study drug. Overall 
Response Rate (ORR) is defined as the proportion of patients with a BOR characterized as 
either a Complete Response (CR) or Partial Response (PR) relative to the total number of 
evaluable patients. Only patients with measurable disease at baseline will be included in the 
analysis of the objective response. The estimates of overall response rate and its corresponding 
95% CI will be calculated for each dose level cohort. 
A patient will be classified as having achieved disease control at 16 weeks if the patient has not 
progressed at the Week 16 assessment, i.e. has no PD up to and including the Week 16 


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assessment with documented non-PD (SD, PR, or CR) assessment. Patients who die, 
discontinue tumor assessments, or start new anti-cancer treatment prior to Week 16 will be 
considered as not having achieved DCR at Week 16. The disease control rate at 16 weeks 
(DCR16) for a treatment group/cohort will be estimated by the number of patients who achieve 
disease control at 16 weeks divided by the number of patients treated. 
Overall Survival (OS) is the time from the date of first study drug to the date of death from any 
cause. Patients who are alive or lost to follow-up at the time of the analysis will be censored at 
the last known alive date. Similar to PFS, OS will be analyzed using Kaplan-Meier method and 
descriptively summarized for each dose level cohort.  
10.7 
Safety Analysis 
Safety analyses (adverse events and laboratory analyses) will be performed using the safety 
population. Adverse events will be reported by the MedDRA Version 17.1 or higher. Toxicity 
will be graded according to the NCI CTCAE Version 4.03. 
Safety analysis of patients will include a summary of dose-limiting toxicity events. 
The period for treatment-emergent adverse events and safety findings will be from the time of 
first study drug administration to 30 days after the date of last study drug administration. If an 
adverse event begins on the date of first study drug administration with no time recorded, the 
event will be considered as treatment-emergent. 
Tabular summaries will be presented for all adverse events, pre-treatment adverse events, 
treatment-emergent adverse events (TEAE), serious adverse events, adverse events leading to 
study drug discontinuation, TEAE-related to study drug and TEAE Grade 3/4. Adverse events 
will be summarized by System Organ Class and preferred term. All adverse event data will be 
listed by patient. 
Laboratory data will be presented by cycle. Abnormal laboratory values will be assessed using 
all available data and toxicity grading will be assigned according to NCI CTCAE toxicity scale, 
where criteria are available to do so. Maximum and minimum decrease/increase in continuous 
laboratory data will be reported. Frequency and percent of abnormal laboratory values (L/ULN, 
2*L/ULN) will be assessed. Shift to most severe toxicity grade will be summarized.  
Vital signs and ECG will be tabulated for the change from baseline by time point.  Additional 
analyses may be performed as described in detail within the SAP. 
10.8 
Biomarker Analysis 
Analyses will be performed to assess the associations between potential biomarkers (from 
plasma, serum, and archived tissue) and efficacy parameters (ORR, percent change in target 
lesion size, and PFS or as appropriate). Graphical displays will be performed when appropriate. 
10.9 
Pharmacokinetics Analysis 
Plasma concentrations of total irinotecan, SN-38, and oxaliplatin and 5-FU in the combination 
therapies will be used to characterize corresponding PK parameters using a nonlinear mixed 
effects approach. Individual PK parameters will be estimated if warranted by the data. 
Graphical exploration will be performed to investigate any relationship between PK and 
pharmacodynamic endpoints. If a trend is shown, PK/PD modelling will be performed and 
reported separately. 
10.10 
Sample Size Justification 
The total number of patients enrolled in the study will depend on the number of patients 
examined within each dose level cohort, as determined by the DLT Committee. Progression to 
the next dose level cohort will depend on the background toxicity rate (i.e., probability of DLT 
at a given dose). When 1 of 3 patients develops a DLT and the cohort is expanded to a minimum 


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of 6 patients, the proposed plan for dose escalation provides a 91% probability that dose 
escalation will proceed at doses associated with DLT probability of <10%. The table below 
shows the probability of escalation from cohort to cohort with various toxicity rates. 
Table 11: Probability to Escalate as a Function of Toxicity Rate 
Background Toxicity Rate 
1% 
5% 
10% 
20% 
30% 
40% 
50% 
Probability of Dose 
Escalation 
0.999 
0.973 
0.906 
0.709 
0.494 
0.309 
0.172 
 
A selected dose level cohort will be expanded to include 30 patients in total. An estimate of the 
DCR at Week 16 will be tabulated and summarized. Table 12 displays the probabilities of 
outcomes for DCR16 with n=30 as a function of the true DCR16: 
Table 12: Probability probabilities of outcomes for DCR16 
 
True 
DCR16 
Probability 
observed DCR16 
≥ 50% 
Probability 
observed DCR16 
≥ 55% 
Probability 
observed DCR16 
≥ 60% 
45% 
0.36 
0.14 
0.07 
50% 
0.57 
0.29 
0.18 
55% 
0.77 
0.50 
0.36 
60% 
0.90 
0.71 
0.58 
65% 
0.97 
0.87 
0.78 
70% 
0.99 
0.96 
0.92 
 
11 
EXTENSION PHASE 
Following fulfillment of analysis requirements for the primary and/or secondary endpoints, the 
Sponsor may elect to transition patients that are still receiving treatment or are being followed 
for OS to an extension phase of the study.  
Patients will continue to be followed for OS every 4 months. 
Patients still receiving treatment will continue to receive this until disease progression, death, 
unacceptable study medication related toxicity or withdrawal of consent (see Section 5.3 for 
other discontinuation criteria). 
For patients receiving treatment in the extension phase of the study only OS and 
treatment-related SAEs will be collected in the eCRF. In the event that an SAE occurs, 
additional information (such as local laboratory results, concomitant medications, and 
procedures) may be requested by the Sponsor in order to evaluate the reported SAE, though this 
additional information does not need to be captured in the eCRF. Investigators may perform 
standard procedures and tests needed to treat and evaluate patients; however, the results of these 
assessments will not be routinely reported. The extension phase of the study will be completed 
once all patients have died, withdraw consent, or lost to follow-up after two attempts on OS 
follow-up. 
12 
STUDY ADMINISTRATION 
12.1 
Pre-Study Documentation 
Prior to initiating the trial, the Investigator will provide to the Sponsor or designee the following 
documents: 
• 
A signed FDA Form 1572 
• 
A current (i.e. updated no more than 24 months prior) curriculum vitae for the Principal 
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• 
A copy of the current medical license for the Investigator  
• 
A letter from the IRB/EC stipulating approval of the protocol, the informed consent 
document and any other material provided to potential trial participants with information 
about the trial (e.g., advertisements) 
• 
A copy of the IRB/EC-approved informed consent document 
• 
A signed Investigator Protocol Agreement 
• 
A completed financial disclosure form for the Investigator 
Additional documents that may be requested include: 
• 
A current (i.e. updated no more than 24 months prior) curriculum vitae for each 
sub-Investigator listed on the FDA Form 1572 
• 
A copy of the current medical license for each sub-Investigator 
• 
A completed financial disclosure form for all sub-Investigators 
• 
A current laboratory certification for the reference laboratory and curriculum vitae of the 
laboratory director 
• 
A list of current laboratory normal values for the reference laboratory  
• 
The current IRB/EC membership list for the reviewing IRB/EC, or, where appropriate, 
the multiple project assurance number from the Federal Wide Assurance program 
(www.ohrp.osophs.dhhs.gov) 
12.2 
Source Documents 
The Investigator will maintain records separate from the eCRFs in the forms of clinic charts, 
medical records, original laboratory, radiology and pathology reports, pharmacy records, etc. 
The Investigator will document in the clinic chart or medical record the date on which the 
patient signed informed consent prior to the patient’s participation in the trial. Source 
documents must completely reflect the nature and extent of the patient’s medical care, and must 
be available for source document verification against entries in the case report forms when the 
Sponsor’s monitor visits the investigational site. Source documents regarding procedures such 
as scans and laboratory evaluations performed as part of the standard of care prior to enrollment 
in the study can be used to fulfill certain screening and baseline assessments. All information 
obtained from source documents will be kept in strict confidentiality. Source data sent as 
supporting documentation for serious adverse events will be de-identified to preserve 
confidentiality. 
12.3 
Trial Ethics 
The study will be performed according to the principles of the Declaration of Helsinki 
(http://www.wma.net/e/policy/b3.htm), the International Conference on Harmonization 
Guidance on Good Clinical Practice and the requirements of the US FDA and/or local 
regulatory authorities regarding the conduct of human clinical trials. 
12.4 
Patient Informed Consent 
No study related procedures will be performed until a patient or a patient’s legal representative 
has given written informed consent. The Sponsor will provide to the Investigator a sample 
informed consent document that includes all the requirements for informed consent according 
the ICH GCP, U.S. FDA guidelines (21 CFR 50) and/or local regulatory or other country 
specific guidelines. However, it is up to the Investigator to provide a final informed consent 
that may include additional elements required by the Investigator’s institution, and that has been 
IRB or EC approved. The informed consent document must clearly describe the potential risks 
and benefits of the trial, and each prospective participant must be given adequate time to discuss 
the trial with the Investigator or site staff and to decide whether or not to participate. Each 


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patient who agrees to participate in the trial and who signs the informed consent will be given 
a copy of the signed, dated and witnessed document (the witness signature is only required for 
cases that fit the criteria for needing a witnessed signature). The provision of informed consent 
will be documented in the medical record. 
12.5 
Investigational Review Board/Ethics Committee Approval 
The trial will not be initiated until there is approval of the protocol, informed consent document 
and any other material used to inform the patient about the nature of the trial by the local/central 
IRB or EC. The IRB/EC should be duly constituted according to local regulatory or other 
country specific requirements. Approval must be in the form of a letter signed by the 
Chairperson or the Chairperson’s designee, must be on official stationary and must include the 
protocol by name and/or by designated number. If an Investigator is a member of the IRB/EC, 
then the approval letter must stipulate that the Investigator did not participate in the final vote, 
although the Investigator may participate in the discussion of the trial. The Investigator will 
also inform the IRB/EC of any SAEs that the Sponsor reports to regulatory authorities, will 
report on the progress of the trial at least yearly (or more frequently if required by local 
regulation or guidance) and will provide to the IRB/EC a final summary of the results of the 
trial at the conclusion of the trial. 
12.6 
Monitoring   
A clinical monitor will make regularly scheduled trips to the investigational site to review the 
progress of the trial. The actual frequency of monitoring trips will depend on the enrollment 
rate and performance at each site. The Investigator will allow the Sponsor or designee access 
to all pertinent medical records, as required by federal or other country specific regulations, in 
order to allow for the verification of data gathered in the CRFs and for the review of the data 
collection process. Monitoring visits will be conducted according to a study monitoring plan, 
and will include review of various aspects of the trial including, but not limited to: screening 
and enrollment logs; compliance with the protocol and with the principles of Good Clinical 
Practice; completion of case report forms; source data verification; study drug accountability 
and storage; facilities and staff. 
During scheduled monitoring visits, the Investigator and the investigational site staff must be 
available to meet with the study monitor in order to discuss the progress of the trial, make 
necessary corrections to case report form entries, respond to data clarification requests and 
respond to any other trial-related inquiries of the monitor. 
In addition to the above, representatives of the FDA and/or local regulatory agencies may 
review the conduct or results of the study at the investigational site. The Investigator must 
promptly inform the Sponsor of any audit requests by health authorities, and will provide the 
Sponsor with the results of any such audits and with copies of any regulatory documents related 
to such audits. 
In accordance with HIPAA and locally applicable privacy regulations, a patient’s authorization 
to use personally identifiable health information may be required for each patient before 
commencement of research activities. This authorization document must clearly specify what 
parties will have access to a patient’s personal health information, for what purpose and for 
what duration. 
12.7 
Confidentiality 
It is the responsibility of the Investigator to ensure that the confidentiality of all patients 
participating in the trial and all of their medical information is maintained. Case report forms 
and other documents submitted to the Sponsor must never contain the name of a trial patient. 
All patients in the trial will be identified by a unique identifier which will be used on all CRF’s 
and any other material submitted to the Sponsor. All case report forms and any identifying 


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information must be kept in a secure location with access limited to the study staff directly 
participating in the trial. 
12.7.1 
Samples for Central Lab Testing 
Samples collected for standard laboratory tests, including biochemistry, UGT1A1 and CA 19-
9 testing will be destroyed within 60 days of receipt of confirmed test results. Certain samples 
may be retained for a longer period, if necessary, to comply with applicable laws, regulations, 
or laboratory certification standards. 
12.7.2 
Confidentiality of Biomarker Samples 
Blood samples collected as part of the biomarker analysis will be identified only by a number 
assigned to the patient at the study site; this number will be used in lieu of the patient’s name 
in order to protect the patient’s identity. The samples will be stored at a facility designated by 
the Sponsor. Other than the patient’s unique identifying number, no additional patient 
information that could potentially disclose the patient’s identity will be stored with these 
samples. Samples will be kept until they are used completely for the specified biomarker 
analyses, or, in the event there is remaining tissue or blood sample available, such specimens 
will be stored for a maximum of 5 years after approval of the final study report for the clinical 
trial; at that time, any remaining samples will be destroyed. Patients may withdraw consent 
from the study at any time. However, data already collected will not be removed from the study 
dataset. 
The results from these exploratory analyses may not necessarily be shared with the Investigators 
or the participating patients. 
12.8 
Protocol Amendments 
The protocol will only be amended with the consent of the Sponsor and the IRB/EC. Changes 
to the protocol must be in the form of a written amendment; changes other than those of a simple 
administrative nature (e.g., a new telephone number for a medical monitor) must be submitted 
by the Investigator to their IRB/EC and such amendments will only be implemented after 
approval of the requisite IRB/EC. All amendments will also be submitted to the FDA and local 
regulatory authorities by the Sponsor. 
Protocol changes to eliminate an immediate hazard to a trial patient may be implemented by 
the Investigator immediately. The Investigator must then immediately inform the Sponsor and 
local IRB or EC; the Sponsor will immediately notify local regulatory authorities. 
12.9 
Publication 
The sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including medical writers or statisticians subject to the consent 
of each individual and entity concerned, including acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings by the 
investigators involved in the study. For multicentre studies, a plan for scientific publication and 
presentation of the results may be agreed and implemented by the study investigators or a 
Steering Committee. The sponsor requires that reasonable opportunity be given to review the 
content and conclusions of any abstract, presentation, or paper before the material is submitted 
for publication or communicated. This condition also applies to any amendments that are 
subsequently requested by referees or journal editors. The sponsor will undertake to comment 
on the draft documents within the time period agreed in the contractual arrangements, including 
clinical trial agreements, governing the relationship between the sponsor and authors (or the 
author’s institution). Requested amendments will be incorporated by the author, provided they 
do not alter the scientific value of the material. 


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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. 
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. 
12.10 
Records Retention 
The Investigator will retain the records of the clinical trial (including, but not necessarily limited 
to, CRFs, source documents, informed consent forms, drug accountability records, IRB/EC 
correspondence, Sponsor correspondence, etc.) for 2 years following the date that the last 
marketing application for the study drug is approved, or if no marketing application is filed, or 
if such an application is not approved, for 2 years after the formal discontinuation of clinical 
development of the study drug. The Sponsor or designee will notify Investigators when 
retention of study records is no longer required. Study records must be stored in a safe and 
secure location permitting timely retrieval, if necessary. 
Study records must be retained as per the GCP guidelines and local regulatory requirements, 
including, but not limited to, case report forms, signed informed consents, correspondence with 
the IRB/EC, study drug dispensing and inventory records, source documents (clinic charts, 
medical records, laboratory results, radiographic reports) and screening/enrollment logs. 
Should the Investigator relocate or retire the responsibility for maintaining the study records 
may be transferred to another Investigator. The Sponsor must be notified of the identity of the 
individual assuming responsibility for maintaining the study records and the location of their 
storage. If no other individual at the site is willing to assume this responsibility, the Sponsor 
will assume responsibility for maintaining the study records.  
12.11 
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 enrollment 
• 
Safety concerns 
• 
Drug supply or manufacturing issues 
• 
The Sponsor’s decision to modify or discontinue the development nal-IRI 
• 
A request to discontinue the study by the FDA and/or local regulatory authorities. 
The Sponsor will promptly inform all Investigators and the FDA and/or local 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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patients with metastatic colorectal cancer. J Clin Oncol. 2006 Jul 1; 24(19):3061-8. 
[31] Roy AC, Park SR, Cunningham D, Kang YK, Chao Y, Chen LT, Rees C, Lim HY, 
Tabernero J, Ramos FJ, Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A 
randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-
line therapy in patients with locally advanced or metastatic gastric or gastro-
oesophageal junction adenocarcinoma. Ann Oncol. 2013 Jun; 24(6):1567-73. 
[32] “ADRUCIL (fluorouracil injection, USP) package insert,” Teva Parenter. Med. Inc., 
pp. 1–7, 2012. 
[33] T.J. Smith, K. Bohlke, G.H. Lymann, K.R. Carson, J. Crawford, S.J. Cross, 
J.M. Goldberg, J.L. Khatcheressian, N.B. Leighl, C.L. Perkins, G. Somlo, J.L Wade, 
A.J. Wozniak, American Society of Clinical oncology, “Recommendations for the 
use of WBC growth factors: American Society of Clinical Oncology Clinical Practice 
Guideline Update,” J Clin Oncol. Vol. 33, no. 28, pp. 3199-3212, Oct. 2015. 
[34] M.S. Aapro, J Bohlius, D.A. Cameron, L.D. Lago, J.P. Donnelly, N. Kearney, G.H. 
Lyman, R. Pettengell, V.C.Tjan-Heijnen, J. Walewski, D.C. Weber, C. Zielinski and 
European Organisation for Research and Treatment of Cancer “2010 update of 
EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the 
incidence of chemotherapy-induced febrile neutropenia in adult patients with 
lymphoproliferative disorders and solid tumours,” Eur J Cancer, vol. 47, no. 1, pp. 
8-32, Jan. 2011. 
[35] J. Crawford, C. Caserta J, F. Roila; ESMA Guidelines Working Group, 
“Haematopoietic growth factors: ESMO Clinical Practice Guidelines. Ann Oncol, 
vol. 21 (Suppl 5), pp. v248-v251, May. 2010. 
[36] A. B. Benson, J. A Ajani, R. B. Catalano, C. Engelking, S. M. Kornblau, J. a 
Martenson, R. McCallum, E. P. Mitchell, T. M. O’Dorisio, E. E. Vokes, and S. 
Wadler, “Recommended guidelines for the treatment of cancer treatment-induced 
diarrhea.,” J. Clin. Oncol., vol. 22, no. 14, pp. 2918–26, Jul. 2004. 
[37] E. A. Eisenhauer, P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, and J. Verweij, “New response evaluation criteria in solid 


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tumours: revised RECIST guideline (version 1.1).,” Eur. J. Cancer, vol. 45, no. 2, pp. 
228–47, Jan. 2009. 
[38] T. R. Fleming, M. D. Rothmann, and H. L. Lu, “Issues in using progression-free 
survival when evaluating oncology products,” J. Clin. Oncol., vol. 27, no. 17, pp. 
2874–2880, 2009. 
[39] “Recommendations related to contraception and pregnancy testing in clinical trials,” 
Clinical 
Trials 
Facilitation 
Group, 
2014. 
[Online]. 
Available: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.  
 


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14 
INVESTIGATOR AND SPONSOR SIGNATURE PAGE 
I have read this protocol and agree that it contains all necessary details for carrying out the study 
as described. I will conduct this study as outlined herein, including all statements regarding 
confidentiality. I will make a reasonable effort to complete the study within the time designated. 
I will provide copies of the protocol and access to all information furnished by the sponsor to 
study personnel under my supervision. I will discuss this material with them to ensure that they 
are fully informed about the drug and the study. I understand that the study may be terminated 
or enrollment suspended at any time by the sponsor, with or without cause, or by me if it 
becomes necessary to protect the best interests of the patients in the study.  
I agree to conduct this study in full accordance with all applicable regulations and Good Clinical 
Practice. 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
 
 
Print Name of Investigator 
 
 
 
 
 
 
 
 
 
 
On behalf of the Sponsor 
 
Oncology 
Ipsen Bioinnovation 
 
 
Date 
PPD


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APPENDICES 
Appendix 1: 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 [39]: 
• 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulationa: 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulationa: 
- 
oral 
- 
injectable 
- 
implantableb 
• 
intrauterine device (IUD)b 
• 
intrauterine hormone-releasing system (IUS)b 
• 
bilateral tubal occlusionb 
• 
vasectomized partnerb,c 
• 
sexual abstinenced 
a Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. For hormonal contraception methods, caution should be taken to possible interaction 
with a non-biologic investigational medicinal product (IMP). Interaction leading to reduced efficacy of the 
hormonal contraception method can occur due to increased metabolism (i.e. enzyme induction). 
b Contraception methods that in the context of this guidance are considered to have low user dependency. 
c Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the 
surgical success. 
d 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 patient 
 
Note: A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilization 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 post-menopausal 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 2: Proposed Algorithm for Diarrhea Management 
 
Proposed algorithm for the assessment and management of treatment-induced diarrhea. 
Note: For radiation-induced cases and select patients with CID, consider intensive outpatient management, 
unless the patient has sepsis, fever, or neutropenia. CTC, Common Toxicity Criteria; NCI, National Cancer 
Institute; RT, radiotherapy; SC, subcutaneous; tid, three times per day; IV, intravenous; CBC, complete blood 
count; CID, chemotherapy-induced diarrhea [36]. 
 
 


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Appendix 3: Karnofsky Performance Status 
Karnofsky Status  
Karnofsky Grade 
Normal, no complaints  
100 
Able to carry on normal activities. Minor signs or 
symptoms of disease  
90 
Normal activity with effort  
80 
Care for self. Unable to carry on normal activity 
or to do active work  
70 
Requires occasional assistance, but able to care 
for most of his needs  
60 
Requires considerable assistance and frequent 
medical care  
50 
Disabled. Requires special care and assistance  
40 
Severly disabled. Hospitalisation indicated 
though death non imminent  
30 
Very sick. Hospitalisation necessary. Active 
supportive treatment necessary  
20 
Moribund  
10 
Dead  
0 
 
 


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Appendix 4: 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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Appendix 5: Summary of Changes 28 December 2016 (Version 3.1) to 29 September 2017 (Version 5.0) 
 
STUDY NUMBER: 
MM-398-07-02-03 
PROTOCOL TITLE: 
A RANDOMIZED, OPEN-LABEL PHASE 2 STUDY OF NANOLIPOSOMAL IRINOTECAN (NAL-IRI)-
CONTAINING REGIMENS VERSUS NAB-PACLITAXEL PLUS GEMCITABINE IN PATIENTS WITH 
PREVIOUSLY UNTREATED, METASTATIC PANCREATIC ADENOCARCINOMA 
AMENDED PROTOCOL 
VERSION NUMBER & DATE 
Version 5.0, 29 September 2017 
 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: Minor formatting, typos and rephrasing of text to enhance clarity have not been recorded. 
 
Version Date 
28 DECEMBER 2016 (VERSION 3.1) 
29 SEPTEMBER 2017 (VERSION 5.0) 
Page  
Section 
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IS 
Throughout 
Header 
Title page 
Signature 
page 
The study Sponsor is Merrimack Pharmaceuticals. 
The study Sponsor is Ipsen Bioscience. 
The protocol header, confidentiality statement and protocol 
signatory were updated to reflect this change.  
These changes were incorporated in Version 4.0 (dated 03 April 
2017) of the protocol, which is now superseded by Version 5.0. 
Throughout  
Synopsis 
3.1, 3.2.1, 
3.2.2, 4.2, 
4.2.1, 
4.2.2, 4.3, 
10.6 
& 
Figure 1 
The study is divided into two parts: Part 1 and 2. 
 
 
Part 1 referred to as the ‘safety run in period’ consisting of 
the dose escalation phase enrolling small cohorts of 
patients.  
 
 
Part 2 refers to the randomised open label comparative 
three arm phase (Arm 1, Arm 2 and Arm 3). 
The study is divided into two parts: Part 1 and 2 (the use of Arm 1 
was reserved for use in the context of Part 2 only). 
 
Part 1 of the study is split into two phases: Part 1A (dose 
escalation phase enrolling small cohorts of patients 
progressively) and Part 1B (dose expansion intended to enroll 24 
additional patients). 
 
Part 2 refers to the randomised open label comparative three arm 
phase (Arm 1, Arm 2 and Arm 3). 
Throughout 
Synopsis 
3.1, 3.2, 
 
As DLT within any cohort is potentially determined by a complex 
interaction between the respective dose levels of each drug 


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3.2.3, 4.2, 
4.3  
& 
Table 6 
 
 
 
 
 
 
 
Part 1 includes dose levels -1, 1, 2, -2A and -2B to be 
evaluated based on the defined escalation and 
de-escalation process (in which the dose for one of the 
three drugs (nal-IRI) will be increased while the other two 
drugs will maintain a constant dose) and the safety and 
tolerability of each dose level cohort. 
 
administered as part of a combination therapy, the sequence of 
dose level cohorts examined (-1 to -3) contains both dose 
escalation and dose de-escalation strategies for each individual 
drug, in order to control the total combined dose level within any 
given cohort. This means that for each individual drug, the dose 
level may decrease, increase or remain the same between 
successive cohorts. 
A new dose level cohort -3 (oxaliplatin 70 mg/m2 + nal-IRI 
65 mg/m2) is introduced for evaluation in Part 1A following the 
completion of three dose level cohorts (1, -1 and -2B). Dose 
level -1 (oxaliplatin 60 mg/m2 + nal-IRI 60 mg/m2) was 
determined to be safe and tolerable, while dose levels 1 and -2B 
were considered to be not tolerable. Dose levels 2 and -2A will 
not be evaluated. If the dose level -3 is found to be safe and 
tolerable, the cohort will be expanded to include an additional 24 
subjects. If the dose level -3 is not found to be safe and tolerable, 
the dose level cohort -1 (oxaliplatin 60 mg/m2 + nal-IRI 
60 mg/m2) will be expanded to include additional 24 subjects. 
Final determination of the Part 2 dose for Arm 1 will be made 
after all patients in the Part 1A (dose escalation) and Part 1B 
(expansion cohort) have completed two scheduled assessments. 
 
 
8 
& 
35  
Synopsis 
& 
2.1.2 
 
2.1.2 
Secondary Objective 
Part 1: 
x To characterize the pharmacokinetics (PK) of nal-IRI 
in combination with 5-FU and oxaliplatin 
 
Another secondary objective was added for the Part 1 evaluation. 
2.1.2 
Secondary Objective  
Part 1: 
x To characterize the pharmacokinetics of nal-IRI in 
combination with 5-FU + oxaliplatin 
x To evaluate efficacy signals with nal-IRI in combination with 
5-FU/LV + oxaliplatin using overall response rate (ORR) [CR 
+ PR, per RECIST v1.1], disease control rate (DCR) [CR + 


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PR + SD, per RECIST v1.1], duration of response, PFS, and 
OS 
11-12 
& 
39  
Synopsis 
& 
3.2.2 
 
 
 
3.2.2 
DLT Definition for Arm 1 (Nal-IRI + 5-FU/LV 
+ Oxaliplatin) 
x Inability to begin subsequent treatment course within 
14 days of the scheduled date, due to drug-related 
toxicity  
 
The DLT criteria (bullet 3) was modified to avoid multiple 
replacements and assess the safety/tolerability in a timely and 
accurate fashion.  
3.2.2 
DLT Definition for Part 1 (Nal-IRI + 5-FU/LV + 
Oxaliplatin) 
x Any study regimen related adverse event that leads to a delay 
of the next scheduled study treatment dose for more than 14 
days  
All patients will continue to be monitored for safety beyond 
Cycle 1, in order to determine if multiple cycles of treatment are 
tolerable.  
If any patient within a given cohort experiences a DLT in Part 1A, 
they may continue in the study at a lower dose level of oxaliplatin 
and/or nal-IRI, (as determined by the DLT Committee in 
accordance with Section 6.5) upon resolution of the relevant 
toxicity. Other patients in the same cohort who do not experience 
a DLT will continue with unmodified dose levels of oxaliplatin 
and/or irinotecan (unless a dose modification is judged to be 
necessary by the DLT Committee on safety grounds. 
13  
&  
40 
Synopsis & 
4 
4 
Enrollment and Treatment 
Approximately 6-18 patients will be enrolled in Part 1. An 
additional 150 patients (50 patients per arm) will be enrolled 
during Part 2. The total enrollment for the study will be 
approximately 156-168 patients.  
Patients will be treated until disease progression (as 
determined by RECIST v1.1 criteria evaluated every 8 
weeks from first dose of study drug), toxicity, or physician 
or patient’s choice (see Section 5.3). 
4 
Enrollment and Treatment 
Approximately 54 patients will be enrolled in Part 1. An additional 
150 patients (50 patients per arm) will be enrolled during Part 2. 
Therefore, the total enrollment for the study will be approximately 
204 patients. All patients will be treated until disease progression 
(as determined by RECIST v1.1 criteria evaluated every 8 weeks 
from first dose of study drug), unacceptable drug related toxicity, 
or physician or patient’s choice (see Section 5.3). 
13-14  
Synopsis 
 
 
Inclusion criteria a), b), c) and d) were modified based on the 
learnings of three completed dose level cohorts and inclusion 


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& 
42-43 
& 
5.1 
 
 
5.1 
Inclusion Criteria 
a)  Pathologically confirmed adenocarcinoma of the 
pancreas that has not been previously treated in the 
metastatic setting:  
b)  Measurable or non-measurable disease as defined by 
RECIST v1.1 
 
c)  ECOG performance status of 0 or 1 
 
 
d)  Adequate biological parameters as evidenced by the 
following blood counts: 
x ANC > 1,500 cells/μl without the use of hematopoietic 
growth factors, 
x Platelet count > 100,000 cells/μl, and 
x Hemoglobin > 9 g/dL 
 
j)  Agreeable to submit unstained archived tumor tissue for 
analysis, if available 
criteria j) was removed (no changes were made to other inclusion 
criteria). 
5.1 
Inclusion Criteria 
a)  Histologically or cytologically confirmed adenocarcinoma of 
the pancreas that has not been previously treated in the metastatic 
setting:  
b)  At least one tumor lesion measurable by CT or MRI scan 
(according to RECIST v1.1 criteria)  
c)  ECOG performance status of 0 or 1 at both Screening and 
within 72 hours prior to randomization. Two observers will be 
required to assess ECOG. If different, the lowest assessment will 
be used for the eligibility evaluation at each assessment 
d)  Adequate biological parameters as evidenced by all of the 
following blood counts: 
x ANC > 1,500 cells/μl without the use of hematopoietic 
growth factors within last 7 days prior to Screening 
x Platelet count > 100,000 cells/μl 
x Hemoglobin > 9 g/dL; transfusion is allowed, provided 
interval is ≥ 7 days prior to Screening 
14-15  
& 
43-44 
Synopsis &  
5.2 
 
 
 
 
5.2 
Exclusion Criteria 
a)  Prior treatment of pancreatic cancer in the metastatic 
setting with surgery, radiotherapy, chemotherapy or 
investigational therapy (note: placement of biliary stent is 
allowed) 
b)  Prior treatment of pancreatic cancer with cytotoxic 
doses of chemotherapy (patients receiving prior treatment 
Existing exclusion criteria a), b) and k) were modified and new 
exclusion criteria o), p) and q) were added based on the 
completion of previous 3 dose level cohorts (no changes were 
made to other exclusion criteria). 
5.2 
Exclusion Criteria 
a)  Prior treatment of pancreatic cancer in the metastatic setting 
(or locally advanced setting, Part 1 only) with surgery, 
radiotherapy, chemotherapy or investigational therapy (note: 
placement of biliary stent is allowed) 
b)  Prior treatment of pancreatic cancer with cytotoxic doses of 
systemic anti-tumor therapy (patients receiving prior treatment 


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with chemotherapy as a radiation sensitizer are eligible if 
≥ 6 months has elapsed from completion of therapy) 
k)  Presence of any contraindications for 5-FU, leucovorin, 
or oxaliplatin 
 
with chemotherapy as a radiation sensitizer are eligible if 
≥ 6 months has elapsed from completion of therapy) 
k)  Presence of any contraindications for 5-FU, leucovorin, 
oxaliplatin, gemcitabine or nab-paclitaxel 
o)  Neuroendocrine (carcinoid, islet cell) or acinar pancreatic 
carcinoma 
p)  Documented serum albumin <3 g/dL at Screening Visit and 
within 72 hours prior to enrollment/ randomization (both labs at 
screening and prior to enrollment/randomization may be 
confirmed locally) 
q)  Patients 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  
44-45 
5.3 
 
 
5.3 
Patient Discontinuation 
A patient may withdraw from the study at any time and for 
any reason. It is intended that patients will be treated until 
Investigator-determined progressive disease per RECIST 
v1.1 or unacceptable toxicity. Some possible reasons for 
early discontinuation of study treatment include, but are 
not limited to the following: 
x Progressive neoplastic disease per RECIST v1.1 
x The patient experiences an adverse event which: 
o in the opinion of the Investigator, precludes further 
participation in the trial 
o requires treatment to be withheld for more than 14 
days, unless in the opinion of the investigator the 
patient is receiving benefit from the study treatment 
o requires more than 2 dose reductions 
x Clinical and/or symptomatic deterioration 
Section 5.3 (Patient Discontinuation) was divided into Sections 
5.3.1, 5.3.2 and 5.3.3. 
5.3 
Patient Discontinuation 
5.3.1 
Discontinuation of Study Treatment  
It is intended that patients will be treated until radiologically 
determined progressive disease per RECIST v1.1 or unacceptable 
study drug related toxicity. However, a patient may discontinue 
study treatment at any other time. Reasons for discontinuation of 
study treatment include, but are not limited to the following: 
x Radiologically determined progressive disease, per RECIST 
v1.1 
x Clinical deterioration sufficient to prevent further radiological 
assessment 
x A study drug related adverse event, prior to disease 
progression, which: 
o 
in the opinion of the Investigator, precludes further 
treatment with all study drugs 
o 
requires treatment with one or more study drugs to be 
withheld for more than 14 days, unless in the opinion of 


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x Development of an intercurrent medical condition or 
need for concomitant treatment that precludes further 
participation in the trial 
x Significant noncompliance with the protocol per PI 
assessment 
x Withdrawal of consent  
x The Investigator removes the patient from the trial in 
the best interests of the patient 
x Study termination by the Sponsor 
x Use of prohibited concomitant medications 
x Patient is lost to follow up 
If a patient withdraws from the trial, a complete final 
evaluation at the time of the patient’s withdrawal should 
be made with an explanation of the reason for withdrawal. 
Following treatment discontinuation for other reasons 
above, all procedures and evaluations required at the 30 
day follow up visit should be completed. All patients who 
discontinue the trial as a result of an adverse event must be 
followed until resolution or stabilization of the adverse 
event. Overall survival follow-up contacts should continue 
every 2 months from the 30-day follow-up visit until death 
or study closure, whichever comes first. If a patient does 
not return to the clinic for follow-up visits, attempts should 
be made to contact the patient via phone, email, or mail. 
At least 3 documented attempts, including one via certified 
mail, should be made to contact the patient before 
declaring a patient lost to follow-up. If the patient is 
considered lost to follow-up, the date of death may be 
captured from public records. 
the investigator the patient is receiving benefit overall 
from the study treatment 
o 
would result in a third dose reduction in any single 
study drug (in a patient having already experienced 2 
previous dose reductions) 
o 
requires discontinuation of nal-IRI (Arm I only) 
x Development of an intercurrent medical condition or need for 
concomitant therapy that precludes further treatment with all 
study drugs 
x Withdrawal of consent for further treatment 
x Pregnancy 
A patient who discontinues study medication has not withdrawn 
from the study and must continue with all ongoing protocol 
requirements, as detailed in Section 5.3.3. 
 
5.3.2 
Withdrawal from the Study) 
A patient may withdraw, or be withdrawn, from the study at any 
time. Reasons for withdrawal from the study include, but are not 
limited to the following: 
x Significant noncompliance with the protocol, per 
Investigator’s assessment 
x The Investigator removes the patient from the trial in the best 
interests of the patient 
x Use of prohibited concomitant medications 
x Patient is lost to follow up 
x Withdrawal of consent for further participation in the study 
x Death 
x Study termination by the Sponsor  


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5.3.3 
Procedures following Study Drug Discontinuation or 
Study Withdrawal 
Following study drug discontinuation all procedures and 
evaluations required at the 30-day (End of Treatment) follow up 
visit should be completed. All patients who discontinue study 
medication as a result of an adverse event must be followed until 
resolution or stabilization of the adverse event. Patients who 
discontinue study drug 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 v1.1 has been 
documented. Overall survival follow-up contacts should continue 
every 2 months from the 30-day follow-up visit until death or 
study closure, whichever comes first. If a patient does not return 
to the clinic for follow-up visits, attempts should be made to 
contact the patient via phone, email, or mail. At least 3 
documented attempts, including one via certified mail, should be 
made to contact the patient before declaring a patient lost to 
follow-up. If the patient is considered lost to follow-up, the date 
of death may be captured from public records.  
If a patient withdraws from the study at any point, a complete 
final evaluation at the time of the patient’s withdrawal should be 
made with an explanation of the reason for withdrawal. At the 
time of withdrawal from the study, it should be clarified with the 
patient whether they still consent to be followed up for survival 
status only (including where appropriate through publicly 
available records) and any such consent to ongoing survival 
follow up must be documented in both the source hospital records 
and the eCRF. 
48 
6.2.3 
6.2.3 
Packaging and Labelling of Combination 
Therapies 
6.2.3 
Packaging and Labelling of Combination Therapies 
Sites participating in this protocol will source their own 
combination therapy supplies. However, for sites where this is not 


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Commercially available 5-FU and leucovorin (l + d 
racemic form, or the levo-leucovorin l form), oxaliplatin, 
nab-Paclitaxel, and gemcitabine will be provided to 
enrolled patients in accordance with the specific treatment 
regimen in the respective arms. All patients who are 
enrolled to Arms 1 and 2 will be provided with 5-FU, 
leucovorin, and oxaliplatin, if applicable. All patients who 
are enrolled to Arm 3 will be provided with nab-Paclitaxel 
and gemcitabine, if applicable. 
 
possible due to country legal or regulatory restrictions, Ipsen will 
provide commercially available 5-FU and leucovorin, oxaliplatin, 
nab-paclitaxel and gemcitabine as required by their enrolled 
patients for their specific treatment regimen. 
Ipsen sourced combination therapy supplies will be labeled in 
accordance with local regulatory requirements, and site 
accountability for all Ipsen sourced clinical trial material is 
required. 
Throughout 
 
Synopsis, 
3.1, 
3.2.2 
6.5.2 
7.3.4 
8 
 
 
 
 
 
 
 
 
Patients will be tested for UGT1A1*28 status during 
screening, however the result of the test is not required 
prior to the initial dose of nal-IRI. For Part 1 patients 
receiving 80 mg/m2 of nal-IRI: depending on the overall 
safety profile seen after the first dose, the dose may be 
reduced to 60 mg/m2 after discussion between the PI, 
Sponsor and Medical Monitor. Any Part 1 patients who 
receive a reduced dose during Cycle 1 due to UGT1A1*28 
homozygosity will not be evaluable for the cohort and will 
be replaced.  
For Part 2, UGT1A1*28 7/7 homozygous and non-
homozygous genotype patients should receive the full 
starting dose of nal-IRI; All Arm 1 subjects should start at 
Patients will be tested for UGT1A1*28 status during screening as 
a safety biomarker to further analyze the association between 
UGT1A1*28 homozygosity, SN-38 concentration and toxicity. 
However, the protocol does not contain formal recommendations 
on nal-IRI dose modifications as a consequence of homozygosity. 
The results of testing are not required prior to the first dose of 
nal-IRI but will be made available for review in Part 1 and the 
starting dose for all patients in Part 1 will be as per the dosing 
table (regardless of UGT1A1*28). 
As part of this study, pharmacogenomic data will be collected on 
all patients for determination of UGT1A1*28 status. 
Importantly however, no grade 4 neutropenia was observed in 
patients homozygous for the wild-type (WT) 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 [25]). Population PK 
studies of nal-IRI have not identified a relationship between 
UGT1A1*28 homozygosity and increased SN-38 exposure (see 
Investigator Brochure). In a Phase I study (UCSF 8603, as 
referenced in Table 2 above) no differences in toxicity were seen 
in cohorts of heterozygous or WT patients, and DLTs of diarrhea 


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60 mg/m2, while all Arm 2 patients will begin dosing at 80 
mg/m2. Follow the tables above for guidance on dose 
modification due to toxicity.  
with or without accompanying dehydration or fatigue, were seen 
in both cohorts. 
Because of these discrepancies in the severity of previously 
documented toxicity arising from UGT1A1*28 homozygosity, 
and because the prevalence of UGT1A1*28 homozygosity is 
relatively low, testing results will not be required prior to the first 
dose of nal-IRI on this study and the starting dose for all patients 
in Part 1 will be as described in Table 5. 
The protocol does not contain formal recommendations on nal-
IRI dose modifications as a consequence of homozygosity. All 
patients should receive the full starting dose of nal-IRI. All Arm 1 
patients should start at the dose level identified from Part 1, while 
all Arm 2 patients will begin dosing at 80 mg/m2. The 
UGT1A1*28 status of each patient will subsequently be made 
available to individual investigators. 
59 
6.5.5 
6.5.5 
Rules for Dose Omissions and Modified 
Schedules 
The following guidance should be followed when all study 
drugs in any arm are held/missed: 
x If Day 1 doses are held/missed: the doses intended for 
Day 1 of a cycle should be delayed, such that the start 
of that cycle will not begin until the doses are actually 
administered to the patient 
x If Day 8 doses are held/missed (applies to Arm 3 only): 
the cycle will continue per protocol and those doses 
will be considered missed. 
x If Day 15 doses are held/missed:  
o 
Arms 1 and 2 only: if toxicity recovers within 7 
days, the day 15 doses may be delayed and 
subsequently given 1 week late. The next cycle 
would then continue 14 days following the 
administration of the delayed Day 15 dose. 
6.5.5 
Rules for Dose Omissions and Modified Schedules 
The following guidance should be followed when all study drugs 
in any arm are held/missed: 
For both Part 1 and Part 2, the maximum delay between the date 
of a scheduled but missed dose and the planned next dose should 
be up to 14 days.  
In Part 2, Arm 3,  
x If Day 1 doses are held/missed: the doses intended for Day 1 
of a cycle should be delayed, such that the start of that cycle 
will not begin until the doses are actually administered to the 
patient 
x If Day 8 doses are held/missed: the cycle will continue per 
protocol and those doses will be considered missed. 
x If Day 15 doses are held/missed: the dose will be considered 
missed and dosing will continue with Day 1 of the next cycle 
when toxicity recovers.  
 


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However, if the toxicity recovers between 7-14 
days after scheduled Day 15 dose (i.e. dose is 
delayed for 2 weeks), that dose will be considered 
missed and Day 1 of the next cycle should occur 
as originally scheduled. 
o 
Arm 3 only: the dose will be considered missed 
and dosing will continue with Day 1 of the next 
cycle when toxicity recovers (e.g. if toxicity 
recovers within 7 days, that week will be 
considered the rest week, and the next cycle can 
begin 1 week after the previously scheduled Day 
15 dose; alternatively, if the toxicity recovers 
between 7-14 days from the scheduled Day 15 
dose, the Day 1 dose of the next cycle should 
occur as originally scheduled).  
63,  
67-69 
90 
 
7.2.3,  
8 & 
Appendix 3 
Only ECOG performance status to be recorded at 
Screening and within 72 hours of 
enrollment/randomization 
In additional to the ECOG performance status, KPS was also to 
be recorded at Screening and within 72 hours of 
enrollment/randomization. 
 
An additional Appendix 3 was added for evaluating the KPS. 
81-82 
12.9 
 
 
As the Study is being conducted at multiple sites, the 
Sponsor agrees that, consistent with scientific standards, 
first presentation or publication of the results of the Study 
shall be made only as part of a publication of the results 
obtained by all sites performing the Protocol. However, if 
no multicenter publication report has been submitted for 
publication in a peer reviewed journal within twelve (12) 
months of the completion of this Study at all sites, the 
Investigator shall have the right to publish or present 
independently the results of this patient to the review 
Publication policy was updated as per Ipsen Bioscience 
standards: 
The sponsor encourages acknowledgement of all 
individuals/organisations involved in the funding or conduct of 
the study, including medical writers or statisticians subject to the 
consent of each individual and entity concerned, including 
acknowledgement of the sponsor. 
The results of this study may be published or communicated to 
scientific meetings by the investigators involved in the study. For 
multicentre studies, a plan for scientific publication and 
presentation of the results may be agreed and implemented by the 
study investigators or a Steering Committee. The sponsor requires 


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procedure set forth herein. The Investigator shall provide 
the Sponsor with a copy of any such presentation or 
publication derived from the Study for review and 
comment at least forty-five (45) days in advance of any 
presentation or submission for publication. In addition, if 
requested by the Sponsor, any presentation or submission 
for publication shall be delayed for a limited time, not to 
exceed ninety (90) days, to allow for filing of a patent 
application or such other measures as the Sponsor deems 
appropriate to establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the Sponsor 
and/or its employees in advertising or promotional 
material or publication without the prior written consent of 
the Sponsor. The Sponsor shall not use the name(s) of the 
Investigator and/or the Collaborators in advertising or 
promotional material or publication without having 
received his/her and/or their prior written consent(s). 
The Sponsor or its designee has the right at any time to 
publish the results of the Study. 
that reasonable opportunity be given to review the content and 
conclusions of any abstract, presentation, or paper before the 
material is submitted for publication or communicated. This 
condition also applies to any amendments that are subsequently 
requested by referees or journal editors. The sponsor will 
undertake to comment on the draft documents within the time 
period agreed in the contractual arrangements, including clinical 
trial agreements, governing the relationship between the sponsor 
and authors (or the author’s institution). Requested amendments 
will be incorporated by the author, provided they do not alter the 
scientific value of the material. 
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. 
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. 
84-85 
13 
 
Five new references were added to the reference list. 
[28] 
R.W. Marsh, M.S. Talamonti, M.H. Katz and J.M. 
Herman, “Pancreatic cancer and FOLFIRINOX: a new era and 
new questions,” Cancer Med., vol. 4, no. 6, pp. 853–863, Jun 
2015. 
 


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[29] 
B. Chibaudel, F. Maindrault-Goebel, J.B. Bachet, C. 
Louvet, A. Zhalil, O. Dupuis, P. Hammel, M-L. Garcia, M. 
Bennamoun, D. Brusquant, C. Tournigand, T. André, C. Arbaud, 
A.K. Larsen, Y-W. Wang, C.G. Yeh, F. Bonnetain and A de 
Gramont, “PEPCOL: a GERCOR randomized phase II study of 
nanoliposomal irinotecan PEP02 (MM-398) or irinotecan with 
leucovorin/5-fluorouracil as second-line therapy in metastatic 
colorectal cancer,” Cancer Med. vol. 5, no. 4, pp. 676-683, Apr. 
2016. 
 
[32] 
T.J. Smith, K. Bohlke, G.H. Lymann, K.R. Carson, J. 
Crawford, S.J. Cross, J.M. Goldberg, J.L. Khatcheressian, N.B. 
Leighl, C.L. Perkins, G. Somlo, J.L Wade, A.J. Wozniak, 
American Society of Clinical oncology, “Recommendations for 
the use of WBC growth factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update,” J Clin Oncol. Vol. 
33, no. 28, pp. 3199-3212, Oct. 2015. 
 
[33] 
M.S. Aapro, J Bohlius, D.A. Cameron, L.D. Lago, J.P. 
Donnelly, N. Kearney, G.H. Lyman, R. Pettengell, V.C.Tjan-
Heijnen, J. Walewski, D.C. Weber, C. Zielinski and European 
Organisation for Research and Treatment of Cancer “2010 update 
of EORTC guidelines for the use of granulocyte-colony 
stimulating factor to reduce the incidence of chemotherapy-
induced febrile neutropenia in adult patients with 
lymphoproliferative disorders and solid tumours,” Eur J Cancer, 
vol. 47, no. 1, pp. 8 32, Jan. 2011. 
 
[34] 
J. Crawford, C. Caserta J, F. Roila; ESMA Guidelines 
Working Group, “Haematopoietic growth factors: ESMO Clinical 
Practice Guidelines. Ann Oncol, vol. 21 (Suppl 5), pp. v248-
v251, May. 2010. 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
MM-398-07-02-03 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Version 5.0, 29 September 2017 
 
SUBSTANTIAL  
 
NON-
SUBSTANTIAL  
 
 
OBJECTIVE(S) OF PROTOCOL 
AMENDMENT 
 
 
1. To optimize the NAPOX regime (irinotecan liposome injection + 5-FU/LV + oxaliplatin) in 
patients with metastatic pancreatic adenocarcinoma by assessing an additional dose for the 
combination regimen (Part 1A)  
2. To expand the study sample size (Part 1B), once the dose is selected from Part 1A, to further 
evaluate the safety and efficacy signals and update the study design accordingly 
3. To adjust the inclusion and exclusion criteria based on learnings from the three completed dose 
level cohorts 
4. To reflect the change in study Sponsor. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM 
UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
REPORTING & 
ANALYSIS PLAN (RAP) 
UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 
 
 
 


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Appendix 6: Summary of Changes: 03 April 2017 (version 4.0) to 29 September 2017 (version 5.0) 
 
STUDY NUMBER: 
MM-398-07-02-03 
PROTOCOL TITLE: 
A RANDOMIZED, OPEN-LABEL PHASE 2 STUDY OF NANOLIPOSOMAL IRINOTECAN (NAL-
IRI)-CONTAINING REGIMENS VERSUS NAB-PACLITAXEL PLUS GEMCITABINE IN 
PATIENTS WITH PREVIOUSLY UNTREATED, METASTATIC PANCREATIC 
ADENOCARCINOMA 
AMENDED PROTOCOL 
VERSION NUMBER & DATE 
Version 5.0, 29 September 2017 
 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: Minor formatting, typos and rephrasing of text to enhance clarity have not been recorded. 
 
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Through
out  
Synopsis 
3.1, 3.2.1, 
3.2.2, 4.2, 
4.2.1, 
4.2.2, 4.3, 
10.6 
& 
Figure 1 
The study is divided into two parts: Part 1 and 2. 
 
 
Part 1 referred to as the ‘safety run in period’ consisting 
of the dose escalation phase enrolling small cohorts of 
patients.  
 
 
Part 2 refers to the randomised open label comparative 
three arm phase (Arm 1, Arm 2 and Arm 3). 
The study is divided into two parts: Part 1 and 2 (the use of 
Arm 1 was reserved for use in the context of Part 2 only). 
 
Part 1 of the study is split into two phases: Part 1A (dose 
escalation phase enrolling small cohorts of patients 
progressively) and Part 1B (dose expansion intended to enroll 
24 additional patients). 
 
Part 2 refers to the randomised open label comparative three 
arm phase (Arm 1, Arm 2 and Arm 3). 
Through
out 
Synopsis 
3.1, 3.2, 
3.2.3, 4.2, 
4.3  
& 
 
 
 
 
As DLT within any cohort is potentially determined by a 
complex interaction between the respective dose levels of each 
drug administered as part of a combination therapy, the 
sequence of dose level cohorts examined (-1 to -3) contains 
both dose escalation and dose de-escalation strategies for each 
individual drug, in order to control the total combined dose 


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Table 6 
 
 
 
 
Part 1 includes dose levels -1, 1, 2, -2A and -2B to be 
evaluated based on the defined escalation and 
de-escalation process (in which the dose for one of the 
three drugs (nal-IRI) will be increased while the other 
two drugs will maintain a constant dose) and the safety 
and tolerability of each dose level cohort. 
 
level within any given cohort. This means that for each 
individual drug, the dose level may decrease, increase or 
remain the same between successive cohorts. 
A new dose level cohort -3 (oxaliplatin 70 mg/m2 + nal-IRI 
65 mg/m2) is introduced for evaluation in Part 1A following the 
completion of three dose level cohorts (1, -1 and -2B). Dose 
level -1 (oxaliplatin 60 mg/m2 + nal-IRI 60 mg/m2) was 
determined to be safe and tolerable, while dose levels 1 and -
2B were considered to be not tolerable. Dose levels 2 and -2A 
will not be evaluated. If the dose level -3 is found to be safe 
and tolerable, the cohort will be expanded to include an 
additional 24 subjects. If the dose level -3 is not found to be 
safe and tolerable, the dose level cohort -1 (oxaliplatin 60 
mg/m2 + nal-IRI 60 mg/m2) will be expanded to include 
additional 24 subjects. 
Final determination of the Part 2 dose for Arm 1 will be made 
after all patients in the Part 1A (dose escalation) and Part 1B 
(expansion cohort) have completed two scheduled assessments. 
8 
& 
35  
Synopsis 
& 
2.1.2 
 
2.1.2 
Secondary Objective 
Part 1: 
x To characterize the pharmacokinetics (PK) of nal-IRI 
in combination with 5-FU and oxaliplatin 
 
Another secondary objective was added for the Part 1 
evaluation. 
2.1.2 
Secondary Objective  
Part 1: 
x To characterize the pharmacokinetics of nal-IRI in 
combination with 5-FU + oxaliplatin 
x To evaluate efficacy signals with nal-IRI in combination 
with 5-FU/LV + oxaliplatin using overall response rate 
(ORR) [CR + PR, per RECIST v1.1], disease control rate 
(DCR) [CR + PR + SD, per RECIST v1.1], duration of 
response, PFS, and OS 


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11-12 
& 
39  
Synopsis 
& 
3.2.2 
 
 
 
3.2.2 
DLT Definition for Arm 1 (Nal-IRI + 5-FU/LV 
+ Oxaliplatin) 
x Inability to begin subsequent treatment course within 
14 days of the scheduled date, due to drug-related 
toxicity  
 
The DLT criteria (bullet 3) was modified to avoid multiple 
replacements and assess the safety/tolerability in a timely and 
accurate fashion.  
3.2.2 
DLT Definition for Part 1 (Nal-IRI + 5-FU/LV + 
Oxaliplatin) 
x Any study regimen related adverse event that leads to a 
delay of the next scheduled study treatment dose for more 
than 14 days  
All patients will continue to be monitored for safety beyond 
Cycle 1, in order to determine if multiple cycles of treatment are 
tolerable.  
If any patient within a given cohort experiences a DLT in Part 
1A, they may continue in the study at a lower dose level of 
oxaliplatin and/or nal-IRI, (as determined by the DLT 
Committee in accordance with Section 6.5) upon resolution of 
the relevant toxicity. Other patients in the same cohort who do 
not experience a DLT will continue with unmodified dose levels 
of oxaliplatin and/or irinotecan (unless a dose modification is 
judged to be necessary by the DLT Committee on safety 
grounds. 
13  
&  
40 
Synopsis 
& 
4 
4 
Enrollment and Treatment 
Approximately 6-18 patients will be enrolled in Part 1. An 
additional 150 patients (50 patients per arm) will be 
enrolled during Part 2. The total enrollment for the study 
will be approximately 156-168 patients.  
Patients will be treated until disease progression (as 
determined by RECIST v1.1 criteria evaluated every 8 
weeks from first dose of study drug), toxicity, or 
physician or patient’s choice (see Section 5.3). 
4 
Enrollment and Treatment 
Approximately 54 patients will be enrolled in Part 1. An 
additional 150 patients (50 patients per arm) will be enrolled 
during Part 2. Therefore, the total enrollment for the study will 
be approximately 204 patients. All patients will be treated until 
disease progression (as determined by RECIST v1.1 criteria 
evaluated every 8 weeks from first dose of study drug), 
unacceptable drug related toxicity, or physician or patient’s 
choice (see Section 5.3). 
13-14  
& 
Synopsis 
& 
 
 
 
Inclusion criteria a), b), c) and d) were modified based on the 
learnings of three completed dose level cohorts and inclusion 


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42-43 
5.1 
 
5.1 
Inclusion Criteria 
a)  Pathologically confirmed adenocarcinoma of the 
pancreas that has not been previously treated in the 
metastatic setting:  
b)  Measurable or non-measurable disease as defined by 
RECIST v1.1 
 
c)  ECOG performance status of 0 or 1 
 
 
d)  Adequate biological parameters as evidenced by the 
following blood counts: 
x ANC > 1,500 cells/μl without the use of 
hematopoietic growth factors, 
x Platelet count > 100,000 cells/μl, and 
x Hemoglobin > 9 g/dL 
 
j)  Agreeable to submit unstained archived tumor tissue 
for analysis, if available 
criteria j) was removed (no changes were made to other 
inclusion criteria). 
5.1 
Inclusion Criteria 
a)  Histologically or cytologically confirmed adenocarcinoma 
of the pancreas that has not been previously treated in the 
metastatic setting:  
b)  At least one tumor lesion measurable by CT or MRI scan 
(according to RECIST v1.1 criteria)  
c)  ECOG performance status of 0 or 1 at both Screening and 
within 72 hours prior to randomization. Two observers will be 
required to assess ECOG. If different, the lowest assessment 
will be used for the eligibility evaluation at each assessment 
d)  Adequate biological parameters as evidenced by all of the 
following blood counts: 
x ANC > 1,500 cells/μl without the use of hematopoietic 
growth factors within last 7 days prior to Screening 
x Platelet count > 100,000 cells/μl 
x Hemoglobin > 9 g/dL; transfusion is allowed, provided 
interval is ≥ 7 days prior to Screening 
14-15  
& 
43-44 
Synopsis 
&  
5.2 
 
 
 
 
5.2 
Exclusion Criteria 
a)  Prior treatment of pancreatic cancer in the metastatic 
setting with surgery, radiotherapy, chemotherapy or 
investigational therapy (note: placement of biliary stent 
is allowed) 
b)  Prior treatment of pancreatic cancer with cytotoxic 
doses of chemotherapy (patients receiving prior 
treatment with chemotherapy as a radiation sensitizer are 
Existing exclusion criteria a), b) and k) were modified and new 
exclusion criteria o), p) and q) were added based on the 
completion of previous 3 dose level cohorts (no changes were 
made to other exclusion criteria). 
5.2 
Exclusion Criteria 
a)  Prior treatment of pancreatic cancer in the metastatic setting 
(or locally advanced setting, Part 1 only) with surgery, 
radiotherapy, chemotherapy or investigational therapy (note: 
placement of biliary stent is allowed) 
b)  Prior treatment of pancreatic cancer with cytotoxic doses of 
systemic anti-tumor therapy (patients receiving prior treatment 


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eligible if ≥ 6 months has elapsed from completion of 
therapy) 
k)  Presence of any contraindications for 5-FU, 
leucovorin, or oxaliplatin 
 
with chemotherapy as a radiation sensitizer are eligible if 
≥ 6 months has elapsed from completion of therapy) 
k)  Presence of any contraindications for 5-FU, leucovorin, 
oxaliplatin, gemcitabine or nab-paclitaxel 
o)  Neuroendocrine (carcinoid, islet cell) or acinar pancreatic 
carcinoma 
p)  Documented serum albumin <3 g/dL at Screening Visit and 
within 72 hours prior to enrollment/ randomization (both labs 
at screening and prior to enrollment/randomization may be 
confirmed locally) 
q)  Patients 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  
44-45 
5.3 
 
 
5.3 
Patient Discontinuation 
A patient may withdraw from the study at any time and 
for any reason. It is intended that patients will be treated 
until Investigator-determined progressive disease per 
RECIST v1.1 or unacceptable toxicity. Some possible 
reasons for early discontinuation of study treatment 
include, but are not limited to the following: 
x Progressive neoplastic disease per RECIST v1.1 
x The patient experiences an adverse event which: 
o in the opinion of the Investigator, precludes 
further participation in the trial 
o requires treatment to be withheld for more than 
14 days, unless in the opinion of the investigator 
the patient is receiving benefit from the study 
treatment 
o requires more than 2 dose reductions 
x Clinical and/or symptomatic deterioration 
Section 5.3 (Patient Discontinuation) was divided into Sections 
5.3.1, 5.3.2 and 5.3.3. 
5.3 
Patient Discontinuation 
5.3.1 
Discontinuation of Study Treatment  
It is intended that patients will be treated until radiologically 
determined progressive disease per RECIST v1.1 or 
unacceptable study drug related toxicity. However, a patient 
may discontinue study treatment at any other time. Reasons for 
discontinuation of study treatment include, but are not limited 
to the following: 
x Radiologically determined progressive disease, per 
RECIST v1.1 
x Clinical deterioration sufficient to prevent further 
radiological assessment 
x A study drug related adverse event, prior to disease 
progression, which: 
o 
in the opinion of the Investigator, precludes further 
treatment with all study drugs 
o 
requires treatment with one or more study drugs to be 
withheld for more than 14 days, unless in the opinion 


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x Development of an intercurrent medical condition or 
need for concomitant treatment that precludes further 
participation in the trial 
x Significant noncompliance with the protocol per PI 
assessment 
x Withdrawal of consent  
x The Investigator removes the patient from the trial in 
the best interests of the patient 
x Study termination by the Sponsor 
x Use of prohibited concomitant medications 
x Patient is lost to follow up 
If a patient withdraws from the trial, a complete final 
evaluation at the time of the patient’s withdrawal should 
be made with an explanation of the reason for 
withdrawal. Following treatment discontinuation for 
other reasons above, all procedures and evaluations 
required at the 30 day follow up visit should be 
completed. All patients who discontinue the trial as a 
result of an adverse event must be followed until 
resolution or stabilization of the adverse event. Overall 
survival follow-up contacts should continue every 2 
months from the 30-day follow-up visit until death or 
study closure, whichever comes first. If a patient does 
not return to the clinic for follow-up visits, attempts 
should be made to contact the patient via phone, email, 
or mail. At least 3 documented attempts, including one 
via certified mail, should be made to contact the patient 
before declaring a patient lost to follow-up. If the patient 
is considered lost to follow-up, the date of death may be 
captured from public records. 
of the investigator the patient is receiving benefit 
overall from the study treatment 
o 
would result in a third dose reduction in any single 
study drug (in a patient having already experienced 2 
previous dose reductions) 
o 
requires discontinuation of nal-IRI (Arm I only) 
x Development of an intercurrent medical condition or need 
for concomitant therapy that precludes further treatment 
with all study drugs 
x Withdrawal of consent for further treatment 
x Pregnancy 
A patient who discontinues study medication has not 
withdrawn from the study and must continue with all ongoing 
protocol requirements, as detailed in Section 5.3.3. 
 
5.3.2 
Withdrawal from the Study) 
A patient may withdraw, or be withdrawn, from the study at 
any time. Reasons for withdrawal from the study include, but 
are not limited to the following: 
x Significant noncompliance with the protocol, per 
Investigator’s assessment 
x The Investigator removes the patient from the trial in the 
best interests of the patient 
x Use of prohibited concomitant medications 
x Patient is lost to follow up 
x Withdrawal of consent for further participation in the study 
x Death 
x Study termination by the Sponsor  


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5.3.3 
Procedures following Study Drug Discontinuation or 
Study Withdrawal 
Following study drug discontinuation all procedures and 
evaluations required at the 30-day (End of Treatment) follow 
up visit should be completed. All patients who discontinue 
study medication as a result of an adverse event must be 
followed until resolution or stabilization of the adverse event. 
Patients who discontinue study drug 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 v1.1 has been documented. Overall survival follow-up 
contacts should continue every 2 months from the 30-day 
follow-up visit until death or study closure, whichever comes 
first. If a patient does not return to the clinic for follow-up 
visits, attempts should be made to contact the patient via 
phone, email, or mail. At least 3 documented attempts, 
including one via certified mail, should be made to contact the 
patient before declaring a patient lost to follow-up. If the 
patient is considered lost to follow-up, the date of death may be 
captured from public records.  
If a patient withdraws from the study at any point, a complete 
final evaluation at the time of the patient’s withdrawal should 
be made with an explanation of the reason for withdrawal. At 
the time of withdrawal from the study, it should be clarified 
with the patient whether they still consent to be followed up for 
survival status only (including where appropriate through 
publicly available records) and any such consent to ongoing 
survival follow up must be documented in both the source 
hospital records and the eCRF. 
48 
6.2.3 
6.2.3 
Packaging and Labelling of Combination 
Therapies 
6.2.3 
Packaging and Labelling of Combination Therapies 


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Commercially available 5-FU and leucovorin (l + d 
racemic form, or the levo-leucovorin l form), oxaliplatin, 
nab-Paclitaxel, and gemcitabine will be provided to 
enrolled patients in accordance with the specific 
treatment regimen in the respective arms. All patients 
who are enrolled to Arms 1 and 2 will be provided with 
5-FU, leucovorin, and oxaliplatin, if applicable. All 
patients who are enrolled to Arm 3 will be provided with 
nab-Paclitaxel and gemcitabine, if applicable. 
 
Sites participating in this protocol will source their own 
combination therapy supplies. However, for sites where this is 
not possible due to country legal or regulatory restrictions, 
Ipsen will provide commercially available 5-FU and 
leucovorin, oxaliplatin, nab-paclitaxel and gemcitabine as 
required by their enrolled patients for their specific treatment 
regimen. 
Ipsen sourced combination therapy supplies will be labeled in 
accordance with local regulatory requirements, and site 
accountability for all Ipsen sourced clinical trial material is 
required. 
Through
out 
 
Synopsis, 
3.1, 
3.2.2 
6.5.2 
7.3.4 
8 
 
 
 
 
 
 
 
 
Patients will be tested for UGT1A1*28 status during 
screening, however the result of the test is not required 
prior to the initial dose of nal-IRI. For Part 1 patients 
receiving 80 mg/m2 of nal-IRI: depending on the overall 
safety profile seen after the first dose, the dose may be 
reduced to 60 mg/m2 after discussion between the PI, 
Sponsor and Medical Monitor. Any Part 1 patients who 
receive a reduced dose during Cycle 1 due to 
UGT1A1*28 homozygosity will not be evaluable for the 
cohort and will be replaced.  
For Part 2, UGT1A1*28 7/7 homozygous and non-
homozygous genotype patients should receive the full 
Patients will be tested for UGT1A1*28 status during screening 
as a safety biomarker to further analyze the association 
between UGT1A1*28 homozygosity, SN-38 concentration and 
toxicity. However, the protocol does not contain formal 
recommendations on nal-IRI dose modifications as a 
consequence of homozygosity. The results of testing are not 
required prior to the first dose of nal-IRI but will be made 
available for review in Part 1 and the starting dose for all 
patients in Part 1 will be as per the dosing table (regardless of 
UGT1A1*28). 
As part of this study, pharmacogenomic data will be collected 
on all patients for determination of UGT1A1*28 status. 
Importantly however, no grade 4 neutropenia was observed in 
patients homozygous for the wild-type (WT) 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 
[25]). Population PK studies of nal-IRI have not identified a 
relationship between UGT1A1*28 homozygosity and increased 
SN-38 exposure (see Investigator Brochure). In a Phase I study 
(UCSF 8603, as referenced in Table 2 above) no differences in 
toxicity were seen in cohorts of heterozygous or WT patients, 


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starting dose of nal-IRI; All Arm 1 subjects should start 
at 60 mg/m2, while all Arm 2 patients will begin dosing 
at 80 mg/m2. Follow the tables above for guidance on 
dose modification due to toxicity.  
and DLTs of diarrhea with or without accompanying 
dehydration or fatigue, were seen in both cohorts. 
Because of these discrepancies in the severity of previously 
documented toxicity arising from UGT1A1*28 homozygosity, 
and because the prevalence of UGT1A1*28 homozygosity is 
relatively low, testing results will not be required prior to the 
first dose of nal-IRI on this study and the starting dose for all 
patients in Part 1 will be as described in Table 5. 
The protocol does not contain formal recommendations on nal-
IRI dose modifications as a consequence of homozygosity. All 
patients should receive the full starting dose of nal-IRI. All 
Arm 1 patients should start at the dose level identified from 
Part 1, while all Arm 2 patients will begin dosing at 80 mg/m2. 
The UGT1A1*28 status of each patient will subsequently be 
made available to individual investigators. 
59 
6.5.5 
6.5.5 
Rules for Dose Omissions and Modified 
Schedules 
The following guidance should be followed when all 
study drugs in any arm are held/missed: 
x If Day 1 doses are held/missed: the doses intended 
for Day 1 of a cycle should be delayed, such that the 
start of that cycle will not begin until the doses are 
actually administered to the patient 
x If Day 8 doses are held/missed (applies to Arm 3 
only): the cycle will continue per protocol and those 
doses will be considered missed. 
x If Day 15 doses are held/missed:  
o 
Arms 1 and 2 only: if toxicity recovers within 
7 days, the day 15 doses may be delayed and 
subsequently given 1 week late. The next cycle 
would then continue 14 days following the 
administration of the delayed Day 15 dose. 
6.5.5 
Rules for Dose Omissions and Modified Schedules 
The following guidance should be followed when all study 
drugs in any arm are held/missed: 
For both Part 1 and Part 2, the maximum delay between the 
date of a scheduled but missed dose and the planned next dose 
should be up to 14 days.  
In Part 2, Arm 3,  
x If Day 1 doses are held/missed: the doses intended for Day 
1 of a cycle should be delayed, such that the start of that 
cycle will not begin until the doses are actually 
administered to the patient 
x If Day 8 doses are held/missed: the cycle will continue per 
protocol and those doses will be considered missed. 
x If Day 15 doses are held/missed: the dose will be 
considered missed and dosing will continue with Day 1 of 
the next cycle when toxicity recovers.  
 


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However, if the toxicity recovers between 7-14 
days after scheduled Day 15 dose (i.e. dose is 
delayed for 2 weeks), that dose will be 
considered missed and Day 1 of the next cycle 
should occur as originally scheduled. 
o 
Arm 3 only: the dose will be considered missed 
and dosing will continue with Day 1 of the next 
cycle when toxicity recovers (e.g. if toxicity 
recovers within 7 days, that week will be 
considered the rest week, and the next cycle can 
begin 1 week after the previously scheduled 
Day 15 dose; alternatively, if the toxicity 
recovers between 7-14 days from the scheduled 
Day 15 dose, the Day 1 dose of the next cycle 
should occur as originally scheduled).  
63,  
67-69 
90 
 
7.2.3,  
8 & 
Appendix
 3 
Only ECOG performance status to be recorded at 
Screening and within 72 hours of 
enrolment/randomization 
In additional to the ECOG performance status, KPS was also 
to be recorded at Screening and within 72 hours of 
enrolment/randomization. 
 
An additional Appendix 3 was added for evaluating the KPS. 
81-82 
12.9 
 
 
As the Study is being conducted at multiple sites, the 
Sponsor agrees that, consistent with scientific standards, 
first presentation or publication of the results of the 
Study shall be made only as part of a publication of the 
results obtained by all sites performing the Protocol. 
However, if no multicenter publication report has been 
submitted for publication in a peer reviewed journal 
within twelve (12) months of the completion of this 
Study at all sites, the Investigator shall have the right to 
publish or present independently the results of this 
Publication policy was updated as per Ipsen Bioscience 
standards: 
The sponsor encourages acknowledgement of all 
individuals/organisations involved in the funding or conduct of 
the study, including medical writers or statisticians subject to 
the consent of each individual and entity concerned, including 
acknowledgement of the sponsor. 
The results of this study may be published or communicated to 
scientific meetings by the investigators involved in the study. 
For multicentre studies, a plan for scientific publication and 
presentation of the results may be agreed and implemented by 
the study investigators or a Steering Committee. The sponsor 


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patient to the review procedure set forth herein. The 
Investigator shall provide the Sponsor with a copy of 
any such presentation or publication derived from the 
Study for review and comment at least forty-five (45) 
days in advance of any presentation or submission for 
publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be 
delayed for a limited time, not to exceed ninety (90) 
days, to allow for filing of a patent application or such 
other measures as the Sponsor deems appropriate to 
establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the Sponsor 
and/or its employees in advertising or promotional 
material or publication without the prior written consent 
of the Sponsor. The Sponsor shall not use the name(s) of 
the Investigator and/or the Collaborators in advertising 
or promotional material or publication without having 
received his/her and/or their prior written consent(s). 
The Sponsor or its designee has the right at any time to 
publish the results of the Study. 
requires that reasonable opportunity be given to review the 
content and conclusions of any abstract, presentation, or paper 
before the material is submitted for publication or 
communicated. This condition also applies to any amendments 
that are subsequently requested by referees or journal editors. 
The sponsor will undertake to comment on the draft documents 
within the time period agreed in the contractual arrangements, 
including clinical trial agreements, governing the relationship 
between the sponsor and authors (or the author’s institution). 
Requested amendments will be incorporated by the author, 
provided they do not alter the scientific value of the material. 
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. 
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. 
84-85 
13 
 
Five new references were added to the reference list. 
[28] 
R.W. Marsh, M.S. Talamonti, M.H. Katz and J.M. 
Herman, “Pancreatic cancer and FOLFIRINOX: a new era and 
new questions,” Cancer Med., vol. 4, no. 6, pp. 853–863, Jun 
2015. 
 


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[29] 
B. Chibaudel, F. Maindrault-Goebel, J.B. Bachet, C. 
Louvet, A. Zhalil, O. Dupuis, P. Hammel, M-L. Garcia, M. 
Bennamoun, D. Brusquant, C. Tournigand, T. André, C. 
Arbaud, A.K. Larsen, Y-W. Wang, C.G. Yeh, F. Bonnetain and 
A de Gramont, “PEPCOL: a GERCOR randomized phase II 
study of nanoliposomal irinotecan PEP02 (MM-398) or 
irinotecan with leucovorin/5-fluorouracil as second-line 
therapy in metastatic colorectal cancer,” Cancer Med. vol. 5, 
no. 4, pp. 676-683, Apr. 2016. 
 
[32] 
T.J. Smith, K. Bohlke, G.H. Lymann, K.R. Carson, J. 
Crawford, S.J. Cross, J.M. Goldberg, J.L. Khatcheressian, N.B. 
Leighl, C.L. Perkins, G. Somlo, J.L Wade, A.J. Wozniak, 
American Society of Clinical oncology, “Recommendations for 
the use of WBC growth factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update,” J Clin Oncol. 
Vol. 33, no. 28, pp. 3199-3212, Oct. 2015. 
 
[33] 
M.S. Aapro, J Bohlius, D.A. Cameron, L.D. Lago, J.P. 
Donnelly, N. Kearney, G.H. Lyman, R. Pettengell, V.C.Tjan-
Heijnen, J. Walewski, D.C. Weber, C. Zielinski and European 
Organisation for Research and Treatment of Cancer “2010 
update of EORTC guidelines for the use of granulocyte-colony 
stimulating factor to reduce the incidence of chemotherapy-
induced febrile neutropenia in adult patients with 
lymphoproliferative disorders and solid tumours,” Eur J 
Cancer, vol. 47, no. 1, pp. 8 32, Jan. 2011. 
 
[34] 
J. Crawford, C. Caserta J, F. Roila; ESMA Guidelines 
Working Group, “Haematopoietic growth factors: ESMO 
Clinical Practice Guidelines. Ann Oncol, vol. 21 (Suppl 5), pp. 
v248-v251, May. 2010. 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
MM-398-07-02-03 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Version 5.0, 29 September 2017 
 
SUBSTANTIAL  
 
NON-
SUBSTANTIAL  
 
 
OBJECTIVE(S) OF PROTOCOL 
AMENDMENT 
 
 
5. To optimize the NAPOX regime (irinotecan liposome injection + 5-FU/LV + oxaliplatin) in 
patients with metastatic pancreatic adenocarcinoma by assessing an additional dose for the 
combination regimen (Part 1A)  
6. To expand the study sample size (Part 1B), once the dose is selected from Part 1A, to further 
evaluate the safety and efficacy signals and update the study design accordingly 
7. To adjust the inclusion and exclusion criteria based on learnings from the three completed dose 
level cohorts. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM 
UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
REPORTING & 
ANALYSIS PLAN (RAP) 
UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 


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Appendix 7: Summary of Changes: 29 September 2017 (version 5.0) to 11 April 2018 (version 6.0) 
 
STUDY NUMBER: 
MM-398-07-02-03 
PROTOCOL TITLE: 
A RANDOMIZED, OPEN-LABEL PHASE 2 STUDY OF NANOLIPOSOMAL IRINOTECAN (NAL-
IRI)-CONTAINING REGIMENS VERSUS NAB-PACLITAXEL PLUS GEMCITABINE IN 
PATIENTS WITH PREVIOUSLY UNTREATED, METASTATIC PANCREATIC 
ADENOCARCINOMA 
AMENDED PROTOCOL 
VERSION NUMBER & DATE 
Version 6.0, 11 April 2018 
 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: Minor formatting, typos and rephrasing of text to enhance clarity have not been recorded. Underlined text 
in “Was” indicates deleted text; Bold text in “Is” indicates new text. This does not apply to tables. 
 
Version Date 
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11 APRIL 2018 (VERSION 6.0) 
Page  
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IS 
Throughout  Synopsis,1.1.1, 
1.3, all 2, all 3, 
4, 4.1, 4.2, 5.1, 
5.2, 5.3.1, 
6.1.1.3, all 6.2, 
all 6.3, 6.4, 
all 6.5, 6.7, 
7.1.2, 7.2.4, 
7.2.7, 7.3.7, 8, 
10.4-10.10 
The study is divided into two parts: Part 1 and 2. 
 
 
Part 2, which consisted in a comparison of nal-IRI-
containing regimens versus nab-paclitaxel plus gemcitabine, 
has been removed. Consequently, all mentions of Part 1, 
Part 2, nab-paclitaxel + gemcitabine and nal-IRI + 5-FU/LV 
(Arms 1 to 3 (the use of Arm 1 was reserved for use in the 
context of Part 2 only)) have been deleted. 
These changes are general and not described systematically 
in the below list of changes. 
Only Parts 1A and 1B remain unchanged. 
7 
Summary of 
changes 
The current version of the protocol (Version 5.0) was 
released on 29 September 2017. This amendment brings 
together two previous amendments into the single protocol 
version 5.0. The summary and outcome of changes are 
presented in: 
• 
Appendix 6: Summary of Changes 28 December 
2016 (Version 3.1) to 29 September 2017 (Version 5.0 
The current version of the protocol (Version 6.0) was 
released on 11 April 2018. This protocol version includes 
all amendments, with summaries of changes from 
Version 3.1 included in the following appendices. The 
main purposes of this amendment are to remove Part 2 
of the study and all related information, add inclusion 


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• 
Appendix 7: Summary of Changes: 03 April 2017 
(Version 4.0) to 29 September 2017 (Version 5.0). 
The changes for both amendments were substantial 
and exclusion criteria and some clarifications (see 
Appendix 7).  
• 
Appendix 5: Summary of Changes 28 December 
2016 (Version 3.1) to 29 September 2017 (Version 5.0) 
• 
Appendix 6: Summary of Changes: 03 April 2017 
(Version 4.0) to 29 September 2017 (Version 5.0). 
• 
Appendix 7: Summary of Changes 29 September 
2017 (Version 5.0) to 11 April 2018 (Version 6.0) 
The changes for all these amendments were substantial. 
9 
Abbreviations 
 
UDP: Uridine diphosphate  
UGT: UDP-glucuronosyltransferase 
10 
Synopsis 
Rationale 
Two combination chemotherapy regimens have emerged as 
standard of care options for first-line treatment of metastatic 
pancreatic cancer: 5-fluorouricil (5 FU)/leucovorin (LV) + 
irinotecan + oxaliplatin (FOLFIRINOX), and nab-paclitaxel 
+ gemcitabine, demonstrating a median overall survival 
(OS) of 11.1 months and 8.5 months, respectively, in 
separate Phase 3 studies. Nal-IRI (also known as MM 398) 
is a nanoliposomal formulation designed to deliver 
irinotecan to the tumor microenvironment for local drug 
activation. In a randomized phase 3 study, patients with 
metastatic pancreatic cancer who had progressed on 
gemcitabine alone (the NAPOLI-1 study), nal-IRI in 
combination with 5-FU/LV demonstrated significant 
clinical activity, increasing OS and progression free survival 
(PFS) relative to 5 FU/LV. The goal of this current study is 
to assess the preliminary efficacy and safety of nal-IRI-
containing regimens, including nal-IRI + 5-FU/LV + 
oxaliplatin and nal-IRI + 5-FU/LV, in previously untreated 
Rationale 
Nal-IRI (also known as MM 398) is a nanoliposomal 
formulation designed to deliver irinotecan to the tumor 
microenvironment for local drug activation. In a randomized 
phase 3 study, patients with metastatic pancreatic cancer 
who had progressed following gemcitabine-based therapy 
(the NAPOLI-1 study), nal-IRI in combination with 5-
FU/LV demonstrated significant clinical activity, increasing 
OS and progression free survival (PFS) relative to 5 FU/LV. 
The goal of this current study is to assess the safety, 
tolerability and preliminary efficacy of nal-IRI in 
combination with 5-FU/LV and oxaliplatin in patients not 
previously treated for metastatic pancreatic 
adenocarcinoma to select a regimen for further 
development. 


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metastatic pancreatic cancer patients to select the regimen 
for further development. 
11 
Synopsis 
Protocol Version 5.0 Update: The original plan in the study 
was to evaluate dose levels in Part 1 as described in the 
table above. Dose level cohorts 1, -1 and -2B have been 
evaluated. Dose levels 1 and -2B were considered to be not 
tolerable. Dose level -1 (oxaliplatin 60 mg/m2 + nal-IRI 60 
mg/m2) was determined to be safe and tolerable. Following 
the completion of the three predefined dose level cohorts, 
this protocol amendment introduces a new dose level -3 
(oxaliplatin 70 mg/m2 + nal-IRI 65 mg/m2) for evaluation. 
Dose levels 2 and -2A will not be evaluated in the study. 
The original plan in the study was to evaluate dose levels as 
described in the table above. Dose level cohorts 1, -1 
and -2B have been evaluated. Dose levels 1 and -2B were 
considered to be not tolerable. Dose level -1 (oxaliplatin 60 
mg/m2 + nal-IRI 60 mg/m2) was determined to be safe and 
tolerable. Following the completion of the three predefined 
dose level cohorts, a new dose level -3 (oxaliplatin 70 mg/m2 
+ nal-IRI 65 mg/m2) was introduced following a protocol 
amendment (protocol Version 5.0) to evaluate its safety 
and tolerability. Dose levels 2 and -2A were considered 
not to be evaluated in the study. Prior to this Version 5.0, 
the enrollment of dose level cohorts 1, -1 and -2B had 
been completed. 
16 
Synopsis 
Length of Study 
All patients in Part 1 and Part 2 will be treated until disease 
progression, intolerable toxicity, or at the discretion of the 
treating physician.  
A follow up clinic visit is required approximately 30 days 
after last dose of study treatment to complete the final safety 
assessments. Subsequently, patients will be followed for 
survival once every 2 months via telephone, email, or clinic 
visit until death, or study closure, whichever occurs first. 
Length of Study 
All patients in the study will be treated until disease 
progression, unacceptable drug related toxicity, or 
physician or patient’s choice.  
A follow up clinic visit is required approximately 30 days 
after last dose of study treatment to complete the final safety 
assessments. Subsequently, patients will be followed for 
survival once every 2 months via telephone, email, or clinic 
visit until death, lost to follow-up, withdrawal of consent, 
or study closure, whichever occurs first. 
16 
Synopsis 
Dosing regimens 
All regimens below will be tested in 28-day cycles, unless 
cycle duration is modified by toxicity in accordance with 
Section 6.5.5. 
Part 2:  
Arm 1: nal-IRI + 5-FU/LV + oxaliplatin 
Dosing regimen 
The regimen below will be tested in 28-day cycles, unless 
cycle duration is modified by toxicity in accordance with 
Section 6.5.3. 
 
If oxaliplatin is not well tolerated, oxaliplatin may be 
discontinued and patients may continue to receive nal-IRI + 
5-FU/LV at the discretion of the Investigator. Toxicity 


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• 
Oxaliplatin will be administered at a dose level 
identified from Part 1, IV over 120 minutes (±10 minutes), 
on Days 1 and 15 of each 28-day cycle  
• 
Nal-IRI will be administered at a dose level 
identified from Part 1 IV over 90 minutes (±10 minutes), on 
Days 1 and 15 of each 28-day cycle. 
• 
5-FU will be administered 2400 mg/m2 IV over 46-
hours (±60 minutes), on Days 1 and 15 of each 28-day cycle 
• 
Leucovorin (l + d racemic form) 400 mg/m2, IV 
over 30 minutes (±5 minutes), on Days 1 and 15 of each 28-
day cycle 
 
Note: The order of infusions on Arm 1 will be as follows: 
nal-IRI will be administered first, followed by oxaliplatin, 
then LV, followed by 5-FU. In Part 1, patients will receive 
the oxaliplatin infusion 2 hours after the completion of the 
nal IRI infusion and will receive leucovorin 30 min after 
oxaliplatin. If no infusion reactions are seen, Part 2 patients 
can receive oxaliplatin directly after completion of the nal-
IRI infusion and leucovorin directly after completion of 
oxaliplatin (see Section 6.3.1 for details). 
 
If oxaliplatin is not well tolerated in patients enrolled in 
Arm 1, oxaliplatin may be discontinued and patients may 
continue to receive nal-IRI + 5-FU/LV at the discretion of 
the Investigator. Toxicity requiring discontinuation of nal-
IRI will result in discontinuation from all study treatments. 
 
Arm 2: nal-IRI + 5-FU/LV 
The dose and regimen that is planned for Arm 2 has been 
previously studied in 117 patients who participated in the 
NAPOLI-1 trial, therefore a safety cohort in Part 1 is not 
requiring discontinuation of nal-IRI will result in 
discontinuation from all study treatments. 


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needed. The following doses will be administered in Part 2 
of the study: 
x 
nal-IRI 80 mg/m2 IV over 90 minutes (±10 
minutes), on Days 1 and 15 of each 28-day cycle 
x 
5-FU 2400 mg/m2 IV over 46-hours (±60 minutes), 
on Days 1 and 15 of each 28-day cycle 
x 
leucovorin l + d racemic form 400 mg/m2, IV over 
30 minutes (±5 minutes), on Days 1 and 15 of each 
28-day cycle 
 
Patients will be tested for UGT1A1*28 status during 
screening. However, the protocol does not contain formal 
recommendations on nal-IRI dose modifications as a 
consequence of homozygosity. The results of testing are not 
required prior to the initial dose of nal-IRI but will be made 
available for review in Part 1.  
For Part 2, all patients should receive the full starting dose 
of nal-IRI; all Arm 1 patients should start at the dose level 
identified from Part 1, while all Arm 2 patients will begin 
dosing at 80 mg/m2. The UGT1A1*28 status of each patient 
will subsequently be available to individual investigators, if 
judged clinically necessary by the investigator. 
 
Arm 3: nab-paclitaxel + gemcitabine  
x 
nab-paclitaxel 125 mg/m2 IV over 35 minutes (±5 
minutes), on Days 1, 8 and 15 of each 28-day cycle 
gemcitabine 1000 mg/m2 IV over 30 minutes (±5 
minutes), on Days 1, 8 and 15 of each 28-day cycle 


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17 
Synopsis 
Criteria for evaluation: 
Plasma samples will be analyzed for the concentration of 
nal-IRI (irinotecan) and its metabolites (SN-38 and SN-
38G) in order to derive PK parameters of nal-IRI when 
given in combination with other anticancer therapies. PK 
parameters of the combination therapies (5-FU and 
oxaliplatin) will also be analyzed to evaluate any drug 
interactions with nal-IRI. 
Efficacy in Part 1: 
Efficacy in Part 1 will be analyzed descriptively. Efficacy 
parameters summarized will include DCR at 16 weeks, 
duration of response, ORR, PFS and OS. 
Part 2 
The primary endpoint is PFS, which will be assessed in all 3 
study arms. The secondary endpoints related to efficacy will 
include median OS and overall response (CR or PR, per 
RECIST, v 1.1). Achievement of a 20%/50%/90% or 
greater decrease in CA19-9 levels compared to baseline (at 
8, 16, and 24 weeks post treatment and overall) will also be 
assessed, along with a quality of life assessment (EORTC-
QLQ-C30 and EQ-5D-5L). QTcF prolongation will be 
assessed in the Arm 2 (nal-IRI+5-FU/LV) in patients with 
PK and QTcF measurements. 
Criteria for evaluation: 
Pharmacokinetic evaluation: 
Plasma samples will be analyzed for the concentration of 
nal-IRI (irinotecan) and its metabolite (SN-38) in order to 
derive PK parameters of nal-IRI when given in combination 
with other anticancer therapies. PK parameters of the 
combination therapies (5-FU and oxaliplatin) will also be 
determined, where warranted by the data, to evaluate any 
drug interactions with nal-IRI. 
Efficacy evaluation: 
Preliminary efficacy will be analyzed descriptively. 
Efficacy parameters summarized will include DCR at 16 
weeks, duration of response, ORR, PFS and OS. 
 
 
 
 
Translational / Exploratory 
Archived tumor tissue (if available) and blood samples will 
be collected and analyzed for biomarkers (Parts 1 and 2). 
Samples will be used to explore potential markers of 
sensitivity and resistance to irinotecan, including, but not 
limited to, the following: DNA damage repair pathways 
(e.g. Topo1, BRCA1/2, and SLFN11), growth factor 
pathways (IGF1 and EGFR family receptors and ligands), 
 
Translational / Exploratory 
Archived tumor tissue (if available) and blood samples will 
be collected and analyzed for biomarkers. Samples will be 
used to explore potential markers of sensitivity and 
resistance to irinotecan, which may include, but are not 
limited to, the following: Topoisomerase-1, growth factor 
pathways (IGF1 and EGFR family receptors and ligands), 
and factors involved in CPT-11 conversion to SN-38. 


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and factors involved in CPT-11 conversion to SN-38 (e.g. 
macrophage content and CES activity). 
18 
Synopsis 
Pharmacokinetic analyses 
Part 1 and Part 2 Arm 1 
Plasma concentrations of total irinotecan, SN-38, and 
oxaliplatin in the combination therapies will be used to 
characterize PK parameters. PK parameters for individual 
patients will be estimated based on the Empirical Bayesian 
Estimation method with priors from the previously 
published parameters. The model simulated exposures, e.g., 
Cmax, AUC (area under the curve), will be compared in 
order to examine any possible interactions between nal-IRI 
and the combination therapies and to evaluate the 
relationship between dose, PK, efficacy and safety 
endpoints. 
 
Part 2 Arm 2 
Plasma concentrations of total irinotecan, SN-38 and 5-FU 
will be characterized based on the Empirical Bayesian 
Estimation method with priors from previously published 
parameters.  The relationship between dose, PK, efficacy 
and safety endpoints will be evaluated.  Moreover, the 
relationship between PK and QTcF will be used to evaluate 
the potential for QTcF prolongation (see below).  
 
QTcF Analyses 
The potential for QTcF prolongation with nal-IRI treatment 
will be evaluated in patients in Arm 2, Part 2 of this study. 
For the primary QTcF prolongation analysis, the predicted 
changes in QTcF will be obtained from the exposure-QTcF 
relationship using mixed-effect modeling. Sensitivity 
analyses will be conducted by evaluating by-timepoint and 
categorical analyses.   
 
 
Plasma concentrations of total irinotecan, SN-38, oxaliplatin 
and 5-FU in the combination therapies will be used to 
characterize corresponding PK parameters using a 
nonlinear mixed effects approach. Individual PK 
parameters will be estimated if warranted by the data. 
Graphical exploration will be performed to investigate 
any relationship between PK and pharmacodynamic 
endpoints. If a trend is shown, PK/PD modelling will be 
performed and reported separately. 


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20; 
29 
1.1.1,  
1.3 
Nal-IRI, a liposomal formulation of irinotecan, has recently 
been studied in a randomized, Phase 3, international study 
(NAPOLI-1), in metastatic pancreatic cancer patients 
previously treated with gemcitabine-based therapy, in which 
the combination of nal-IRI and 5-FU/LV significantly 
prolonged OS compared to 5-FU/LV treatment alone, in 
metastatic pancreatic cancer patients previously treated with 
gemcitabine-based therapy [9]. 
Nal-IRI, a liposomal formulation of irinotecan, has recently 
been studied in a randomized, Phase 3, international study 
(NAPOLI-1), in which the combination of nal-IRI 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 [9]. 
20, 
29 
1.1.1, 
1.3 
The goal of the present study is to assess the efficacy and 
safety of nal-IRI, in combination with other anticancer 
therapies (i.e. 5-FU/LV and/or oxaliplatin) in previously 
untreated metastatic pancreatic cancer patients, compared to 
a nab-paclitaxel + gemcitabine control arm.  
The goal of the present study is to assess the safety, 
tolerability and preliminary efficacy of nal-IRI, in 
combination with 5-FU/LV and oxaliplatin in patients not 
previously treated for metastatic pancreatic 
adenocarcinoma.  
21 
1.1.1.3 
Description of Gemcitabine 
Gemcitabine is a nucleoside metabolic inhibitor that 
exhibits antitumor 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 package insert for more details [13]). 
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. 
Deleted text 
21 
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 stabilizes microtubules by preventing depolymerization. 
Paclitaxel induces abnormal arrays or “bundles” of 
microtubules throughout the cell cycle and multiple asters 
Deleted text 


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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 package 
insert for more details [14]). 
22 
1.2.2 
Nine clinical studies of nal-IRI have been completed to 
date, with over 400 patients across multiple tumor types 
exposed to various dosing regimens, with an additional four 
studies actively recruiting patients across multiple tumor 
types 
Clinical studies of nal-IRI have been completed, with over 
400 patients across multiple tumor types exposed to various 
dosing regimens, with additional studies actively recruiting 
patients across multiple tumor types 
Foot-notes of Tables 1 and 2 have been updated with their 
creation date: Date: 28 December 2016 
29 
1.3 
1.3.1 
Rationale for Arm 1: Nal-IRI + 5-FU/LV + 
Oxaliplatin 
1.3.1 
Rationale for Nal-IRI + 5-FU/LV + Oxaliplatin 
30-32 
1.3 
1.3.2 
Rationale for Arm 2: Nal-IRI + 5-FU/LV 
Tolerability of multi-drug regimens is important in 
advanced cancer. The longer the duration of manageable 
treatment should translate into improved outcome due to 
longer drug exposure. Triplet drug regimens such as 
FOLFIRINOX are known to have significant toxicity, and 
use is limited to patients with better performance status (i.e. 
ECOG performance score of 0 or 1). With prolonged 
FOLFIRINOX treatment, oxaliplatin is often discontinued 
from the regimen due to toxicity. Therefore, if equally 
effective doublet regimens can be identified, patients may 
be able to tolerate prolonged treatment better, and even poor 
performance status patients may receive benefit. Given the 
statistically significant improvement of OS of the nal-IRI + 
5-FU/LV doublet in patients with metastatic pancreatic 
cancer previously treated with gemcitabine in the NAPOLI-
1.3.2 
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. UGT1A1*28 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 Camptosar® (nonliposomal irinotecan). 
Multiple studies have evaluated the association between 


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1 trial [11], [26], it is logical to test this combination in 
previously untreated metastatic pancreatic cancer. As 
suggested by the pre-clinical data (shown in Figure 4, 
above), it is possible that the advantages of the liposomal 
formulation of nal-IRI result in a more effective doublet, 
such that the addition of oxaliplatin may not be necessary to 
significantly impact tumor response. In this case, it may be 
possible to spare patients additional toxicity that would be 
expected with the addition of oxaliplatin. Table 5 below 
summarizes the efficacy and safety results of the NAPOLI-1 
trial compared with two standard of care options for first-
line metastatic disease. Although this is a cross-study 
comparison, the nal-IRI + 5-FU/LV doublet regimen may 
have a safety advantage over either FOLFIRINOX or nab-
paclitaxel + gemcitabine with respect to both neutropenia 
and neuropathy. 
 
Table 5: 
Comparison of Efficacy and Safety Characteristics of 
nal-IRI + 5-FU/LV versus 2 Standard of Care Regimens  
Regimens 
Nal-IRI + 
5FU-LVa 
FOLFIRINOXb 
Nab-
paclitaxel + 
gemcitabine 
+c 
Setting 
Post-
gemcitabine 
Front-line Metastatic Disease 
Efficacy 
 
 
 
Hazard Ratio 
0.57 
0.57 
0.72 
Median 
Overall 
Survival  
6.1 months 
11.1 months 
8.5 months 
Change vs. 
Control 
1.9 months 
4.3 months 
1.8 months 
Adverse 
Events ≥ 
Grade 3  
 
 
 
UGT1A1*28 7/7 homozygosity, SN-38 concentration and 
safety in patients treated with Camptosar® and suggest 
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 15-75 mg/m2 daily for 5 
days for 2 consecutive weeks (41-159% vs. 10-40%, 
respectively) [27] [28]. In a study of 66 patients who 
received single-agent non-liposomal irinotecan (350 
mg/m2 every 3 weeks), the incidence of Grade 4 
neutropenia in patients heterozygous (UGT1A1*28 6/7) 
and homozygous (7/7) for the UGT1A1*28 was 12.5% 
and up to 50% respectively (Camptosar® USPI). In a 
subsequent study, association between UGT1A1*28 
homozygosity and hematological toxicity was observed 
only in patients treated with >150 mg/m2 non-liposomal 
irinotecan. By contrast, at lower dose of non-liposomal 
irinotecan (100-125 mg/m2 every week) similar 
hematological toxicities were observed for both 
homozygous and non-homozygous patients [29]. 
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 [30]. 
 
In patients treated with irinotecan liposome injection, the 
association between UGT1A1*28 homozygosity, SN-38, 
and hematologic toxicity is primarily obtained from 
study NAPOLI-1, where UGT1A1*28 homozygous 
patients were treated at reduced dose (50 vs 70 mg/m2 


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Neutropenia 
20% 
45% 
38% 
Febrile 
neutropenia 
2% 
5% 
3% 
Fatigue 
14% 
24% 
17% 
Vomiting 
11% 
15% 
<5% 
Diarrhea 
13% 
13% 
6% 
Neuropathy 
None 
9% 
17% 
a Data from Phase 3 trial of nal-IRI + 5-FU/LV vs. 5-FU/LV [11] 
b Data from Phase 3 trial of FOLFIRNOX vs. gemcitabine [1]  
c Data from Phase 3 trial of nab-paclitaxel + gemcitabine vs. 
gemcitabine [2] 
 
every 2 weeks in combination with 5-FU/LV, or 70 vs. 
100 mg/m2 every 3 weeks monotherapy). The evaluation 
of the association between SN-38 concentration and 
UGT1A1*28 homozygosity was performed only for 
Caucasians, because homozygosity was rare in Asians 
(2/129; 1.5%). Based on the population PK and exposure-
response analysis, similar un-encapsulated SN-38 Cmax 
values were observed for homozygous and non-
homozygous Caucasian patients if both are dosed at 
70 mg/m2 (1.99 [95% CI 1.81-2.18, n=12] and 1.76 [95% 
CI 1.69-1.84, n=141] ng/mL; p=0.66; both of these values 
are approximately half of the expected SN-38 Cmax from a 
120 mg/m2 dose of non-liposomal irinotecan). 
Consequently, the predicted grade 3 or higher 
neutropenia was also similar if treated at 70 mg/m2 
monotherapy (8.7% vs. 7.4%, respectively), or if treated 
at 90 mg/m2 monotherapy (15% vs. 13%, respectively). 
Additionally, in a phase I study (UCSF 8603), no 
differences in toxicity were seen in cohorts of 
UGT1A1*28 6/7 (n=18) or 6/6 (n=16) patients, 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 hematological toxicity appear to depend on the 
incoming load of SN-38 to be metabolized 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 


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appears to spread out the incoming load of SN-38 by 
controlling the release of irinotecan. This is supported by 
a study in patients 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) [31]. 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 US package insert 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 regardless of 
UGT1A1*28 genotype. UGT1A1*28 genotype will be 
collected on all patients as a safety biomarker to further 
analyze the association between UGT1A1*228 
homozygosity, SN-38 concentration and toxicity. 
Irinotecan liposome injection dose reduction will follow 
the same dose reduction rules for all patients regardless 
of UGT1A1*28 genotype. Patients with UGT1A1*28 
homozygosity will be closely monitored for safety in 
comparison to the safety in patients with UGT1A1*28 


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non-homozygous status by the medical monitors of the 
sponsor and by the DLT committee. 
30-32 
1.3 
1.3.3 
Rationale for Arm 3: Nab-paclitaxel + Gemcitabine 
Control Arm 
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 
combination became a preferred first-line treatment option 
according to the NCCN recommendations in 2013 [27]. In a 
Phase 3, international study of 861 patients (MPACT trial), 
nab-paclitaxel + gemcitabine demonstrated a mOS of 8.5 
months versus 6.7 months for gemcitabine alone (HR 0.72; 
95% confidence interval [CI], 0.62 to 0.83; P<0.001) [2]. 
While nab-paclitaxel + gemcitabine is generally thought to 
be more tolerable than FOLFIRINOX, this combination is 
associated with neuropathy and neutropenia, and has not 
been compared directly with FOLFIRINOX (see Table 5). 
In the current study, the nab-paclitaxel + gemcitabine 
regimen will be compared to nal-IRI-containing regimens, 
including the modified triplet regimen which substitutes nal-
IRI instead of irinotecan. 
Deleted text 
10,  
32 
Synopsis, 
2.1 
The study is divided into two parts: 
Part 1 
Primary objectives: 
x 
To 
characterize 
dose-limiting 
toxicities 
(DLTs) 
associated with nal-IRI + 5 FU/LV + oxaliplatin and 
determine the Part 2 dose of the triplet combination  
 
 
Primary objectives: 
x 
To characterize dose-limiting toxicities (DLTs) associated 
with nal-IRI + 5 FU/LV + oxaliplatin and determine the 
recommended dose of the triplet combination for future 
development 
10,  
Synopsis, 
Part 2: 
Deleted text 


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32 
2.2 
Primary objectives: 
x 
To assess the efficacy of nal-IRI-containing regimens in 
first-line metastatic pancreatic cancer patients compared 
to nab-paclitaxel + gemcitabine using progression free 
survival (PFS) 
 
 
Secondary Objectives 
x 
To assess efficacy of each nal-IRI-containing regimen 
relative to nab-paclitaxel + gemcitabine using OS and 
ORR  
x 
To assess tumor marker CA19-9 response in each nal-IRI-
containing 
regimen 
relative 
to 
nab-paclitaxel 
+ 
gemcitabine 
x 
To assess health-related quality of life (HRQL) using the 
European Organization for Research and Treatment of 
Cancer (EORTC) quality-of-life core questionnaire 
(EORTC-QLQ-C30) and European Quality of Life 
Questionnaire (EQ-5D-5L) between the treatment arms 
x 
To compare the safety and adverse event profile between 
the treatment arms  
x 
To assess the potential for QTcF prolongation with nal-
IRI treatment 
 
10,  
32 
Synopsis, 
2.3 
Exploratory Objectives 
x 
To evaluate the relationship between plasma PK of nal-
IRI (total irinotecan, SN-38) oxaliplatin, and efficacy and 
safety endpoints in first-line metastatic pancreatic cancer 
x 
To evaluate blood samples and archived tumor tissue for 
potential biomarkers that may correlate with nal-IRI, PK, 
toxicity, and/or response 
Exploratory Objectives 
x 
To evaluate the relationship between plasma PK of nal-IRI 
(total irinotecan, SN-38) in combination with 5-FU and 
oxaliplatin, and safety and efficacy endpoints in first-line 
metastatic pancreatic cancer 
x 
To evaluate blood samples and archived tumor tissue for 
potential biomarkers that may correlate with nal-IRI in 
combination with 5-FU/LV and oxaliplatin, PK, 
toxicity, and/or response 
10-11, 
Synopsis, 
This is an open-label, Phase 2 comparative study to assess 
the safety, tolerability, and efficacy of nal-IRI in 
This is an open-label, Phase 2 study to assess the safety, 
tolerability, and preliminary efficacy of nal-IRI in 


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32-33 
3.1 
combination with other anticancer therapies, compared to 
nab-paclitaxel + gemcitabine, in patients with advanced 
pancreatic adenocarcinoma who have not received prior 
systemic anti-tumor therapy.  
The study will be conducted in two parts, as illustrated in 
the schematic below:  
1) an initial dose exploration (Part 1A) followed by dose 
expansion (Part 1B) of the nal-IRI + 5-FU/LV + oxaliplatin 
regimen, and  
2) a randomized, efficacy study of the nal-IRI + 5-FU/LV + 
oxaliplatin regimen (Part 2), the nal-IRI + 5-FU/LV 
combination that previously demonstrated efficacy in the 
Phase 3 NAPOLI-1 trial (i.e. the NAPOLI regimen), versus 
a nab-paclitaxel + gemcitabine control arm. 
This study will assess the following regimens in Part 2: 
• 
nal-IRI + 5-FU/LV + oxaliplatin (Arm 1) 
• 
nal-IRI + 5-FU/LV (Arm 2) 
• 
nab-paclitaxel + gemcitabine (Arm 3) 
combination with 5-FU/LV and oxaliplatin in patients not 
previously treated for metastatic pancreatic 
adenocarcinoma.  
 
The study will be conducted, as illustrated in the schematic 
below, with an initial dose exploration (Part 1A) followed by 
dose expansion (Part 1B) of the nal-IRI + 5-FU/LV + 
oxaliplatin regimen.  
 
 
 


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Part 1 will consist of an open-label dose exploration (Part 
1A) followed by dose expansion (Part 1B) of the 
combination regimen to be used in Arm 1 of Part 2: nal-IRI 
+ 5-FU/LV + oxaliplatin. The Arm 2 and Arm 3 of Part 2 
regimens have established doses, and nal-IRI + 5-FU/LV 
has been demonstrated to be tolerable, yielding antitumor 
responses in a Phase 3 study of patients with relapsed 
metastatic pancreatic cancer, and therefore will not be 
included in this part of the study. 


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11, 
33 
Synopsis,3.1 
 
 
 
 
 
 
In the absence of DLT, a minimum of 3 patients will be 
treated within each dose level cohort for a minimum of one 
cycle of therapy. Additional patients will be recruited into a 
cohort according to the DLT provisions outlined in Section 
3.2.2, or if non-DLT toxicity is identified as requiring 
further evaluation by the DLT Committee (comprising the 
Part 1 Investigators, the Medical Monitor, and the Sponsor). 
Safety evaluations are to be conducted regularly by the 
DLT committee to review all SAEs, AEs and DLTs for 
each patient to determine the safety and tolerability in 
each Cohort. The DLT Committee is comprised of the 
Investigators, the Medical Monitor, and the Sponsor. 
 
In the absence of DLT, a minimum of 3 patients will be 
treated within each dose level cohort for a minimum of one 
cycle of therapy. Additional patients will be recruited into a 
cohort according to the DLT provisions outlined in Section 
3.2.2, or if non-DLT toxicity is identified as requiring further 
evaluation by the DLT Committee. 
12, 
33 
Synopsis, 
3.1, 
4.1 
If one DLT occurs within a given dose level cohort, then the 
cohort will be expanded to a minimum of 6 patients.  
If one DLT occurs within the first 3 patients in a given 
dose level cohort, then the cohort will be expanded to a 
minimum of 6 patients.  
34 
3.1 
This protocol amendment introduces a new dose level 
cohort in Part 1A (dose level -3: oxaliplatin 70 mg/m2 + 
nal-IRI 65 mg/m2) to evaluate its safety and tolerability. 
Prior to this amendment, the enrollment of dose level 
cohorts 1, -1 and -2B has been completed 
The protocol Version 5.0 introduced a new dose level 
cohort in Part 1A (dose level -3: oxaliplatin 70 mg/m2 + nal-
IRI 65 mg/m2) to evaluate its safety and tolerability, 
following the completion of the dose level cohorts 1, -1 and 
-2B. 
12, 
34 
Synopsis, 
3.1 
At the completion of the safety evaluation period for dose 
level cohorts -1 to -3 (Part 1A) detailed in Table 6 all 
available data (DLT, SAE, and grade 3-4 adverse events, 
any available pharmacokinetic, pharmacogenomic, 
pharmacodynamic results and any initial efficacy data) are 
reviewed by the DLT Committee. 
At the completion of the safety evaluation period (as defined 
in Section 3.2.2) for the last patient enrolled for dose level 
cohorts -1 to -3 (Part 1A) detailed in Table 5, all available 
data (DLT, SAE, and grade 3-4 adverse events, any available 
pharmacokinetic, pharmacogenomic, pharmacodynamic 
results and any initial efficacy data) are reviewed by the 
DLT Committee. 


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34 
Synopsis, 
3.1 
Final determination of the Part 2 dose for Arm 1 will be 
made after all patients in the Part 1A (dose escalation) and 
Part 1B (expansion cohort) have completed two scheduled 
assessments (approximately 16 weeks of therapy; unless 
withdrawn at an earlier time point due to disease 
progression or drug-related toxicity). The DLT Committee 
will review all available data from the expansion cohort and 
also all available updated data for patients still receiving 
ongoing therapy in the other dose level cohorts.  
  
Final determination of an appropriate combination 
regimen for potential future development will be made 
after all patients in the Part 1A (dose escalation) and Part 1B 
(expansion cohort) have completed two scheduled 
assessments (approximately 16 weeks of therapy; unless 
withdrawn at an earlier time point due to disease progression 
or drug-related toxicity) and will take into account all 
available data from the expansion cohort and also all 
available updated data for patients still receiving ongoing 
therapy in the other dose level cohorts. 
34 
3.1 
Efficacy analysis (Part 1) will be performed when Week 16 
DCR classifications can be made for all patients in Part 1. 
This should occur when all patients have either achieved 
disease control at 16 weeks (i.e. have no PD up to and 
including the Week 16 assessment with documented non-
PD [SD, PR, or CR] assessment) or have discontinued from 
treatment (refer to Section 5.3 for study treatment 
discontinuation criteria). Further details on DCR analyses 
are presented in Section 10.6. 
Efficacy analysis will be performed when Week 16 DCR 
classifications can be made for all patients. This should 
occur when all patients have either achieved disease control 
at 16 weeks (i.e. have no PD up to and including the Week 
16 assessment with documented non-PD [SD, PR, or CR] 
assessment) or have discontinued from treatment (refer to 
Section 5.3 for study treatment discontinuation criteria). 
Further details on DCR analyses are presented in 
Section 10.6. 
 
13; 
34 
Synopsis, 
3.1 
Part 2: 
Part 2 will consist of an open-label, randomized, Phase 2 
study where patients will be randomized to treatment (1:1:1) 
to either nal-IRI + 5-FU/LV + oxaliplatin, nal-IRI + 5-
FU/LV, or nab-paclitaxel + gemcitabine. The randomization 
will be stratified based on region (East Asia vs. rest of the 
world) and ECOG performance status (0 vs 1). Patients 
randomized to nal-IRI + 5 FU/LV will undergo serial ECG 
recordings and time-matched pharmacokinetic sampling to 
assess any relationship between blood levels of nal-IRI and 
possible changes in QTc intervals. 
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During Part 2, a regular review of safety data will be 
conducted by an independent Data and Safety Monitoring 
Board (DSMB). The DSMB will consist of oncology and 
statistical experts, independent of the Sponsor. The timing 
of the safety reviews, and the workings of the DSMB, will 
be detailed in the DSMB charter.  The DSMB is a 
precaution in the event of unanticipated toxicities, and the 
study will not be stopped early on the basis of differences in 
efficacy, therefore no prospective adjustment of the final 
significance levels is planned on the basis of this review.   
14, 
34 
Synopsis, 3.1 
Translational Research: 
Translational research components will include collection of 
blood samples (Parts 1 and 2) and archived tumor (during 
screening, if available) to look for potential biomarkers. 
Analyses will include cytokine levels (e.g. MCSF1, and IL-
6), growth factors (e.g. IGF1 and EGFR family receptors 
and ligands), or enzyme levels (e.g. MMP9). 
Translational Research: 
Translational research components will include collection of 
blood samples and archived tumor (during screening, if 
available) to look for potential biomarkers. Analyses may 
include cytokine levels (e.g. MCSF1, and IL-6), growth 
factors (e.g. IGF1 and EGFR family receptors and ligands), 
or enzyme levels (e.g. MMP9). 
35 
3.2.1 
Considering these expected toxicities, Arm 1 will be 
evaluated for safety and tolerability in Part 1 of the study as 
described below. 
Deleted text 
13, 
35 
Synopsis, 3.2 
3.2.2 DLT Definition for Part 1 (Nal-IRI + 5-FU/LV + 
Oxaliplatin) 
As part of this study, pharmacogenomic data will be 
collected on all patients for determination of UGT1A1*28 
status. 
3.2.2 DLT Definition (Nal-IRI + 5-FU/LV + Oxaliplatin) 
 
(Deleted text) 
35 
3.2 
3.2.3 
Part 2 Dose Confirmation (Arm 1) 
The purpose of Part 1 is to determine which dose levels of 
oxaliplatin and nal-IRI are compatible when nal-IRI is used 
instead of conventional irinotecan, as described in Section 
3.1. 
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Final determination of the Part 2 dose for Arm 1 will be 
made after all patients in the Part 1A (dose escalation) and 
Part 1B (expansion cohort) have completed two scheduled 
assessments (approximately 16 weeks of therapy; unless 
withdrawn at an earlier time point due to disease 
progression or drug-related toxicity) and will take into 
account all available data from the expansion cohort and 
also all available updated data for patients still receiving 
ongoing therapy in the other dose level cohorts. Data will 
include DLT, SAE, and grade 3-4 adverse events along with 
any available pharmacokinetic, pharmacogenomic, 
pharmacodynamic results and any initial efficacy data. 
14,  
36 
Synopsis, 4 
Approximately 54 patients will be enrolled in Part 1. An 
additional 150 patients (50 patients per arm) will be enrolled 
during Part 2. Therefore, the total enrollment for the study 
will be approximately 204 patients.  
Approximately 54 patients will be enrolled in the study.  
  
36 
4 
4.1 Method of Assigning Patients to Treatment Groups 
4.1.1 Part 1 
It is expected that multiple sites will participate in Part 1 of 
this trial.  Enrollment will be based on the availability of 
patients at each site and the availability of slots in each 
cohort. Slots must be confirmed by the Sponsor, or 
designee, prior to consenting patients to Part 1.  
4.1.2 Part 2 
Three arms are planned to enroll in parallel in Part 2, and 
enrollment into Part 2 will begin once the dose has been 
confirmed for Arm 1 (see Section 3.2.3). After all screening 
assessments have been completed, patients will be 
randomized 1:1:1 using a computerized interactive web 
response system (IWRS). Randomization must occur within 
 
It is expected that multiple sites will participate in this trial.  
Enrollment will be based on the availability of patients at 
each site and the availability of slots in each cohort. Slots 
must be confirmed by the Sponsor, or designee, prior to 
consenting patients to the study.  


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7 days of planned dosing.  The randomization will be 
stratified based on region (East Asia vs. rest of the world). 
37 
4.1 
 
Protocol Version 5.0 Update: The original plan in the study 
was to evaluate dose levels in Part 1 as described in the 
table above. Dose level cohorts 1, -1 and -2B have been 
evaluated. Dose levels 1 and -2B were considered to be not 
tolerable. Dose level -1 (oxaliplatin 60 mg/m2 + nal-IRI 
60 mg/m2) was determined to be safe and tolerable.  
Following the completion of the three predefined dose level 
cohorts, this protocol amendment introduces a new dose 
level -3 (oxaliplatin 70 mg/m2 + nal-IRI 65 mg/m2) for 
evaluation Dose levels 2 and -2A will not be evaluated in 
the study.  
 
The original plan in the study was to evaluate dose levels as 
described in the table above. Dose level cohorts 1, -1 and -
2B have been evaluated. Dose levels 1 and -2B were 
considered to be not tolerable. Dose level 1 (oxaliplatin 60 
mg/m2 + nal-IRI 60 mg/m2) was determined to be safe and 
tolerable. Following the completion of the three predefined 
dose level cohorts, a new dose level -3 (oxaliplatin 70 mg/m2 
+ nal-IRI 65 mg/m2) was introduced following a protocol 
amendment (protocol Version 5.0) to evaluate its safety 
and tolerability. Dose levels 2 and -2A were considered 
not to be evaluated in the study. Prior to this Version 5.0, 
the enrollment of dose level cohorts 1, -1 and -2B has 
been completed. 
14, 
38-39 
Synopsis, 
5.1 
Inclusion Criteria for All Parts of Study: 
a) Histologically or cytologically confirmed 
adenocarcinoma of the pancreas that has not been 
previously treated in the metastatic setting: 
x 
Part 1: unresectable, locally advanced or metastatic 
disease is allowed, diagnosed within 6 weeks prior to 
enrollment 
x 
Part 2: must have metastatic disease diagnosed within 
6 weeks prior to randomization; unresectable or locally 
advanced disease is not allowed 
 
c) ECOG performance status of 0 or 1 at both Screening and 
within 72 hours prior to enrollment/randomization. Two 
observers will be required to assess ECOG. If different, the 
lowest assessment will be used for the eligibility evaluation 
at each assessment 
 
g) ECG without any clinically significant findings 
Inclusion Criteria: 
a) Histologically or cytologically confirmed 
adenocarcinoma of the pancreas that has not been previously 
treated in the metastatic setting: unresectable, locally 
advanced or metastatic disease is allowed, diagnosed within 
6 weeks prior to Screening 
 
c) ECOG performance status of 0 or 1 at Screening, and 
within 72 hours prior to first dose if first dose occurs more 
than 72 hours post screening. Two observers will be 
required to assess ECOG. If different, the lowest assessment 
will be used for the eligibility evaluation at each assessment 
(criterion applicable only for Part 1A) 
 
g) ECG without any clinically significant findings (e.g. QTc 
≤450 ms for males and ≤470 ms for females and no 
known arrhythmias) 
 


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l) Patient has a Karnofsky performance status (KPS) ≥ 
70 at Screening, and within 72 hours prior to date of first 
dose if first dose occurs more than 72 hours after 
screening. Two observers will be required to assess KPS. 
If discrepant, the one with the lowest assessment will be 
considered true (criterion applicable only for Part 1B, 
added in protocol Version 6.0) 
15-16, 
39-40 
Synopsis,5.2 
Exclusion criteria 
a) Prior treatment of pancreatic cancer in the metastatic 
setting (or locally advanced setting, Part 1 only) with 
surgery, radiotherapy, chemotherapy or investigational 
therapy (Note: placement of biliary stent is allowed) 
 
b) Prior treatment of pancreatic cancer with cytotoxic doses 
of systemic anti-tumor therapy (Note: patients receiving 
prior treatment with chemotherapy as a radiation sensitizer 
are eligible if ≥ 6 months has elapsed from completion of 
therapy) 
Exclusion criteria 
a) Prior treatment of pancreatic cancer in the metastatic 
setting (or locally advanced setting) with surgery, 
radiotherapy, chemotherapy or investigational therapy (Note: 
palliative radiotherapy is permitted; placement of biliary 
stent is allowed) 
b) 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 (modified in protocol Version 6.0) 
 
 
 
c) Uncontrolled CNS metastases (patients who require 
steroids should be on a stable or decreasing dose) 
 
c) Uncontrolled CNS metastases (Note: patients who require 
steroids should be on a stable or decreasing dose to be 
eligible) 
 
 
 
g) Known hypersensitivity to any of the components of nab-
paclitaxel or gemcitabine (Part 2 only) 
 
j) Use of strong CYP3A4 inhibitors or inducers, or presence 
of any other contraindications for irinotecan1 
 
k) Presence of any contraindications for 5-FU, leucovorin, 
oxaliplatin, gemcitabine, or nab-paclitaxel. 
 
 
g) Exclusion Criteria removed (protocol Version 6.0) 
 
j) Use of strong CYP3A4 inhibitors or inducers, or strong 
UGT1A1 inhibitors (patients are ineligible if unable to 
discontinue the use of strong CYP3A4 or UGT1A1 
inhibitors at least 1 week or strong CYP3A4 inducers at 
least 2 weeks prior to receiving first dose of irinotecan 
liposome injection), or presence of any other 
contraindications for irinotecan1 
 


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l) Use of strong CYP2C8 inhibitors or inducers, or presence 
of any other contraindications for nab-paclitaxel or 
gemcitabine (Part 2 only)2 
 
k) Presence of any contraindications for nal-IRI, 5-FU, 
leucovorin, or oxaliplatin. 
 
l) Exclusion Criteria removed (protocol Version 6.0) 
 
 
 
 
 
n) Pregnant or breast feeding; females of child-bearing 
potential must test negative for pregnancy at the time of 
enrollment based on a urine or serum pregnancy test. Both 
male and female patients of reproductive potential must 
agree to use a highly effective method of birth control, 
during the study and for 6 months following the last dose of 
study drug.3 
n) Pregnant or breast feeding; females of child-bearing 
potential must test negative for pregnancy within 7 days 
prior to the first dose based on a urine or serum pregnancy 
test. Both male and female patients of reproductive potential 
must agree to use a highly effective method of birth control, 
during the study and for 6 months following the last dose of 
study drug.2 
 
 
 
p) Documented serum albumin <3 g/dL at Screening Visit 
and within 72 hours prior to enrollment/randomization (both 
labs at screening and prior to enrollment/randomization may 
be confirmed locally) 
 
p) Documented serum albumin <3 g/dL at Screening, and 
within 72 hours prior to first dose if first dose occurs more 
than 72 hours post screening (both labs at screening and 
prior to first dose may be confirmed locally) 
 
 
 
 
1 See Section 6.8 for examples of strong CYP3A4 inhibitors or 
inducers. 
2 See Section 6.8 for examples of strong CYP2C8 inhibitors or 
inducers.  
3 For a description of highly effective contraceptive measures, 
please see Appendix 1. 
r) Previous treatment with irinotecan-based, nab-
paclitaxel-based or gemcitabine-based resulting in 
disease progression (added in protocol Version 6.0) 
 
1 See Section 6.8 for examples of strong CYP3A4 or UGT1A1 
inhibitors or CYP3A4 inducers. 
2 For a description of highly effective contraceptive measures, 
please see Appendix 1. 
40 
5.3.1 
x 
A study drug related adverse event, prior to disease 
progression, which: 
o … 
o would result in a third dose reduction in any single 
study drug (in a patient having already experienced 
2 previous dose reductions) 
x 
A study drug related adverse event, prior to disease 
progression, which: 
o … 
o would result in a fourth dose reduction in any single 
study drug (in a patient having already experienced 
3 previous dose reductions) 


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o requires discontinuation of nal-IRI (Arm 1 only) 
o requires discontinuation of nal-IRI  
 
40 
5.3.1 
A patient who discontinues study medication has not 
withdrawn from the study and must continue with all 
ongoing protocol requirements, as detailed in Section 5.3.3. 
A patient who discontinues study medication and has not 
withdrawn from the study must continue with all ongoing 
protocol requirements, as detailed in Section 5.3.3. 
41 
5.3.3 
At the time of withdrawal from the study, it should be 
clarified with the patient whether they still consent to be 
followed up for survival status only (including where 
appropriate through publicly available records) and any 
such consent to ongoing survival follow up must be 
documented in both the source hospital records and the 
eCRF. 
At the time of discontinuation from the study treatment, it 
should be clarified with the patient whether they still consent 
to be followed up for survival status only (including where 
appropriate through publicly available records) and any such 
consent to ongoing survival follow up must be documented 
in both the source hospital records and the eCRF. 
41 
6.1.1.1 
Nal-IRI must be diluted prior to administration. The diluted 
solution is physically and chemically stable for 4 hours at 
room temperature (15 – 25 °C), but it is preferred to be 
stored at refrigerated temperatures (2 – 8 °C), and protected 
from light. The diluted solution must not be frozen.  
Because of possible microbial contamination during 
dilution, it is advisable to use the diluted solution within 24 
hours if refrigerated (2 – 8 °C), and within 4 hours  if kept 
at room temperature (15 – 25 °C). 
Nal-IRI must be diluted prior to administration. The diluted 
solution is physically and chemically stable for 4 hours at 
room temperature (15 – 25 °C), but it is preferred to be 
stored at refrigerated temperatures (2 – 8 °C). The diluted 
solution must not be frozen, and must be protected from 
light until infusion. Because of possible microbial 
contamination during dilution, the diluted solution should be 
administered within 24 hours of preparation if refrigerated 
(2 – 8 °C), and within 4 hours if kept at room temperature 
(15 – 25 °C). 
42-43 
6.1.1.4 
Neutropenia 
Deaths due to sepsis following severe neutropenia have 
been reported in patients treated with irinotecan and nal-IRI.  
Neutropenic complications should be managed promptly 
with antibiotic support. G-CSF may be used to manage 
neutropenia at the investigator’s discretion, provided it is 
administered within parameters specified in Section 6.7.2. 
Neutropenia 
Deaths due to sepsis following severe neutropenia have been 
reported in patients treated with irinotecan and nal-IRI. In 
patients with metastatic pancreatic cancer in the 
NAPOLI-1 study receiving irinotecan liposome 
injection/5-FU/LV, the incidence of grade 3 or 4 
neutropenia was higher among Asian patients (18 of 33 
[55%]) compared to White patients (13 of 73 [18%]). 
Neutropenic complications should be managed promptly 
with antibiotic support. Granulocyte-colony stimulating 


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factor (G-CSF) may be used to manage neutropenia at the 
investigator’s discretion. Prophylactic use of G-CSF will 
be permitted if patients are considered high risk in the 
opinion of the investigator as specified in Section 6.7.1. 
44 
6.2 
Depending on the assigned treatment arm, patients may be 
treated with one or more of the following approved 
therapies: 
x 
5-FU/LV 
x 
oxaliplatin 
x 
nab-paclitaxel 
x 
gemcitabine 
Patients will be treated with one or more of the following 
approved therapies: 
x 
5-FU/LV 
x 
oxaliplatin 
44 
6.2.2 
Refer to the country specific package inserts or SmPC for 
details on storage and handling for 5-FU and leucovorin, 
oxaliplatin, nab-paclitaxel, and gemcitabine. 
Refer to the country specific package inserts or SmPC for 
details on storage and handling for 5-FU and leucovorin and 
oxaliplatin. 
44 
6.2.3 
Sites participating in this protocol will source their own 
combination therapy supplies. However, for sites where this 
is not possible due to country legal or regulatory 
restrictions, Ipsen will provide commercially available 5-FU 
and leucovorin, oxaliplatin, nab-paclitaxel and gemcitabine 
as required by their enrolled patients for their specific 
treatment regimen.   
Ipsen sourced combination therapy supplies will be labeled 
in accordance with local regulatory requirements, and site 
accountability for all Ipsen sourced clinical trial material is 
required. 
Sites participating in this protocol will source their own 
combination therapy supplies. However, for sites where this 
is not possible due to country legal or regulatory restrictions, 
Ipsen will provide commercially available 5-FU, leucovorin 
and oxaliplatin as required by their enrolled patients for their 
specific treatment regimen.   
Ipsen sourced combination therapy supplies will be labeled 
in accordance with local regulatory requirements, and site 
accountability for all Ipsen sourced clinical trial material is 
required and will be monitored by the sponsor or its 
representatives. 
44-45 
6.2.4 
6.2.4.3 Potential Toxicities with Nab-paclitaxel and 
Gemcitabine (Part 2 Arm 3) 
The most common adverse reactions (≥20%) for single 
agent gemcitabine are nausea/vomiting, anemia, hepatic 
transaminitis, neutropenia, increased alkaline phosphatase, 
proteinuria, fever, hematuria, rash, thrombocytopenia, 
dyspnea, and peripheral edema. 
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The following adverse events are relatively common (≥ 
20%) with nab-paclitaxel and gemcitabine combination 
treatment and are to be expected with the addition of nal-
IRI: neutropenia, fatigue, peripheral neuropathy, nausea, 
alopecia, peripheral edema, diarrhea, pyrexia, vomiting, 
decreased appetite, rash, and dehydration. 
Severe hypersensitivity reactions with fatal outcome have 
been reported with nab-paclitaxel treatment; see Section 6.4 
for guidelines on the management of infusion reactions. 
Additional adverse events may be anticipated, as described 
in the package inserts for nab-paclitaxel and gemcitabine 
[13] [14]. 
45 
6.3.1 
In Part 1, Patients will receive the oxaliplatin infusion 2 
hours after the completion of the nal-IRI infusion and will 
receive leucovorin 30 min after oxaliplatin. If no infusion 
reactions are seen, Part 2 patients can receive oxaliplatin 
directly after completion of the nal-IRI infusion and 
leucovorin directly after completion of oxaliplatin. If any 
grade 3 or higher infusion reactions are seen in Part 2 
patients, the DSMB may elect to revert back to the original 
observation periods. 
Patients will receive the oxaliplatin infusion 2 hours after the 
completion of the nal-IRI infusion and will receive 
leucovorin 30 min after oxaliplatin.   
 
45 
6.3 
6.3.2 
Part 2 Arm 2: Nal-IRI + 5-FU/LV  
The order of the infusions to be administered in the clinic 
will be as follows: nal-IRI will be administered first, 
followed by LV, followed by 5-FU. 
6.3.2.1 Part 2 Arm 2 Premedication 
All patients must be premedicated prior to nal-IRI infusion 
and 5-FU/LV infusion with standard doses of 
dexamethasone and a 5-HT3 antagonist, or equivalent other 
anti-emetics according to standard institutional practices for 
irinotecan and 5-FU administration, or the SmPC for sites 
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located in the EU. In situations where differences in 
standard institutional practices and recommendations within 
the country relevant SmPC occur, standard institutional 
practice will take precedence. Atropine may be prescribed 
prophylactically, according to standard institutional 
practices, for patients who experienced acute cholinergic 
symptoms in the previous cycles. 
45 
6.3 
6.3.3 
Doses and Administration of Nal-IRI (Part 1 and 
Part 2 Arms 1 and 2) 
Nal-IRI will be administered as follows: 
Part 1: Nal-IRI will be administered at doses of 60 mg/m2 to 
80 mg/m2 (as outlined in Section 4.2). 
Part 2: 
1. 
ARM 1 - dose of nal-IRI will be selected at the end 
of Part 1 
2. 
ARM 2 -  80mg/m2 
6.3.2 
Doses and Administration of Nal-IRI  
Nal-IRI will be administered at doses of 60 mg/m2 to 80 
mg/m2 (as outlined in Section 4.1). 
45-46 
6.3 
6.3.4 
Doses and Administration of 5-FU and Leucovorin 
(Part 1 and Part 2 Arms 1 and 2) 
Leucovorin should be administered prior to the 5-FU 
infusion (in Part 1, leucovorin will not be given 
concurrently with oxaliplatin, see Section 6.3.1). 
6.3.3 
Doses and Administration of 5-FU and Leucovorin 
 
Leucovorin should be administered prior to the 5-FU 
infusion. 
46 
6.3 
6.3.5 
Doses and Administration of Oxaliplatin (Part 1 and 
Part 2 Arm 1 only) 
x 
In Part 1, oxaliplatin will be administered at varying 
dose levels as indicated in Table 6 (from 60 mg/m2 
- 85 mg/m2), IV over 120 minutes (±10 minutes), on 
Days 1 and 15 of each 28-day cycle 
x 
In Part 2 Arm 1, oxaliplatin will be administered at 
a dose to be identified in Part 1 (as outlined in 
Section 4.2) IV over 120 minutes (±10 minutes), on 
Days 1 and 15 of each 28-day cycle  
6.3.4 
Doses and Administration of Oxaliplatin 
 
• 
Oxaliplatin will be administered at varying dose 
levels as indicated in Table 5 (from 60 mg/m2 - 85 mg/m2), 
IV over 120 minutes (±10 minutes), on Days 1 and 15 of 
each 28-day cycle 
46 
6.3 
6.3.6 
Part 2 Arm 3: Nab-paclitaxel + Gemcitabine 
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The order of the infusions to be administered in the clinic 
will be as follows: nab-paclitaxel will be administered first, 
followed by gemcitabine. 
6.3.6.1 Part 2 Arm 3 Premedication 
All patients receiving nab-paclitaxel and gemcitabine 
should be pre-medicated per the respective package inserts.  
If different institutional guidelines exist for premedication 
of weekly nab-Paclitaxel and/or gemcitabine, the 
investigator should use their standard practice or the SmPC 
for sites located in the EU.   
6.3.7 
Doses and Administration of Nab-paclitaxel and 
Gemcitabine (Part 2 Arm 3) 
• 
Nab-paclitaxel will be administered at 125 mg/m2 
IV over 35 minutes (±5 minutes), on Days 1, 8 and 15 of 
each 28-day cycle 
• 
Gemcitabine will be administered at 1000 mg/m2 IV 
over 30 minutes (±5 minutes), on Days 1, 8 and 15 of each 
28-day cycle 
46 
6.4 
The guidelines described in this section can be followed in 
case of infusion reactions to any study treatment given per 
protocol (e.g. nal-IRI, oxaliplatin, nab-paclitaxel, etc.). 
The guidelines described in this section can be followed in 
case of infusion reactions to any study treatment given per 
protocol (e.g. nal-IRI, oxaliplatin). 


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47-50 
6.5 
6.5 
Dose Modifications (Part 1 and Part 2) 
If oxaliplatin is not well tolerated in patients enrolled in 
Arm 1, oxaliplatin may be discontinued and patients may 
continue to receive nal-IRI + 5-FU/LV at the discretion of 
the Investigator.  
Any patient who has 2 dose reductions and experiences an 
adverse event that would require a third dose reduction must 
be discontinued from study treatment.  
 
For all tables below, patient should be withdrawn from 
study treatment if more than 2 dose reductions are required.  
 
Table 7: 
Part 1 and Part 2 Arm 1 (nal-IRI + 5-FU/LV + 
oxaliplatin) Dose Modifications for Hematologic Toxicities 
 
Worst Toxicity by 
CTCAE Grade 
Nal-IRI 
5-FU 
Oxaliplatin 
Grade 2 hematotoxicity 
100% of previous dose 
Grade 3- 4 neutropenia 
(ANC ≤ 1000/mm3) or 
febrile neutropenia 
and/or 
thrombocytopeniaa 
1st occurrence:  Reduce dose by 25% 
2nd occurrence:  Reduce dose another 
25% (50% of original dose) 
Other Grade 3 or 4 
hematologic toxicities 
not specifically listed 
above 
1st occurrence:  Reduce dose by 25% 
2nd occurrence:  Reduce dose another 
25% (50% of original dose) 
a Consider the use of G-CSF for patients who experience ≥ Grade 3 
neutropenia or febrile neutropenia (see Section 6.7.2 for details). 
 
 
6.5 
Dose Modifications 
If oxaliplatin is not well tolerated, oxaliplatin may be 
discontinued and patients may continue to receive nal-IRI + 
5-FU/LV at the discretion of the Investigator.  
 
Any patient who has 3 dose reductions and experiences an 
adverse event that would require a fourth dose reduction 
must be discontinued from study treatment. 
 
For all tables below, patient should be withdrawn from study 
treatment if more than 3 dose reductions are required.  
 
Table 6: 
Dose Modifications for Hematologic Toxicities(a,b,c,d) 
Worst Toxicity by 
CTCAE Grade 
Nal-IRI 
5-FU 
Oxaliplatin 
Grade 2 
hematotoxicity 
100% of previous dose 
Grade 3- 4 
neutropeniae (ANC ≤ 
1000/mm3) or febrile 
neutropenia and/or 
thrombocytopenia 
1st occurrence: Reduce dose by 20% (80% 
of original dose) 
2nd occurrence: Reduce dose by another 
15% (65% of original dose) 
3rd occurrence: Reduce dose by another 
15% (50% of original dose) 
Other Grade 3 or 4 
hematologic 
toxicities not 
specifically listed 
above 
1st occurrence:  Reduce dose by 20% (80% 
of original dose) 
2nd occurrence: Reduce dose by another 
15% (65% of original dose) 
3rd occurrence: Reduce dose by another 
15% (50% of original dose) 
Any toxicity ≥ Grade 2 can justify a dose reduction if medically 
indicated following above guidance 
b 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. 
c Patients who require more than 3 dose reductions must discontinue 
study treatment. 
d Prophylactic use of Granulocyte-colony stimulating factor (G-CSF) 
will be permitted if patients are considered high risk in the opinion of 
the investigator 


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e Consider the use of G-CSF for patients who experience ≥ Grade 3 
neutropenia or febrile neutropenia 
 
 
 
New table added: 
Table 7: Dose Modifications for Diarrheaa,b 
 
 
 
a Any toxicity ≥ Grade 2 can justify a dose reduction if medically 
indicated following above guidance 
b Patients who require more than 3 dose reductions must discontinue 
study treatment 
c Grade 1 diarrhea: 2-3 stools/day > pretreatment; Grade 2 diarrhea: 4-
6 stools/day > pretreatment 
d Grade 3 diarrhea: 7-9 stools/day > pretreatment; Grade 4 diarrhea: 
life threatening consequences 
e Prophylactic or therapeutic administration of atropine should be 
considered in patients experiencing cholinergic symptoms (acute 
diarrhea.  and abdominal cramps during or within 24 hours after nal-
IRI administration) 


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Table 8: 
Part 1 and Part 2 Arm 1 (nal-IRI + 5-FU/LV + 
oxaliplatin) Dose Modifications for Non-Hematological Toxicities 
Other than Asthenia and Grade 3 Anorexiaa,d,e 
Worst Toxicity 
by CTCAE 
Grade 
Nal-IRI 
5-FU 
Oxaliplatin 
Grade 1 or 2, 
including 
diarrheab 
100% of 
previous 
dose 
100% of 
previous dose, 
except for Grade 
2 hand foot 
syndrome, 
Grade 2 cardiac 
toxicity, or any 
grade 
neurocerebellar 
toxicity 
100% of 
previous 
dose, except 
for Grade 2 
sensory 
neuropathy 
Grade 3 or 4, 
including 
diarrheac 
(except nausea 
and vomiting) 
1st 
occurrence:  
Reduce dose 
by 25%  
2nd 
occurrence:  
Reduce dose 
another 25%  
(50% of 
original 
dose)  
1st occurrence: 
Reduce dose by 
25% 
2nd occurrence:  
Reduce dose 
another 25%  
(50% of original 
dose) 
Note: except for 
Grade 3 or 4 
hand foot 
syndrome 
1st 
occurrence:  
Reduce dose 
by 25% 
2nd 
occurrence:  
Reduce dose   
by another 
25% (50% of 
original 
dose) 
Grade 3 or 4 
nausea and/or 
vomiting 
despite anti-
emetic therapy 
 Optimize anti-emetic therapy AND 
1st occurrence:  Reduce dose by 25% 
2nd occurrence:  Reduce dose by another 25%  
(50% of original dose) 
Grade 2 hand 
foot syndrome 
100% of 
previous 
dosed 
1st occurrence: 
Reduce dose by 
25% 
2nd occurrence:  
Reduce dose 
another 25%  
(50% of original 
dose) 
100% of 
previous 
dosed 
Table 8: 
Dose Modifications for Non-Hematological Toxicities 
Other than Diarrhea, Asthenia and Grade 3 Anorexiaa,b,e 
Worst 
Toxicity by 
CTCAE 
Grade 
Nal-IRI 
5-FU 
Oxaliplatin 
Grade 3 or 4 
nausea and/or 
vomiting 
despite anti-
emetic therapy 
Optimize anti-emetic therapy AND 
1st occurrence:  Reduce dose by 20% (80% of 
original dose) 
2nd occurrence:  Reduce dose by another 15% (65% 
of original dose) 
3rd occurrence: Reduce dose by another 15% (50% 
of original dose) 
Grade 2 hand 
foot syndrome 
100% of 
previous doseb 
1st occurrence:  
Reduce dose by 
20% 
(80% of original 
dose) 
2nd occurrence:   
Reduce dose by 
another 15%  
(65% of original 
dose) 
3rd occurrence: 
Reduce dose by 
another 15% 
(50% of original 
dose) 
100% of 
previous 
doseb 
Grade 3 or 4 
hand foot 
syndrome 
100% of 
previous doseb 
Discontinue 
therapy 
100% of 
previous 
doseb 
Any grade 
neurocerebellar 
or t Grade 2 
cardiac toxicity 
100% of 
previous doseb 
Discontinue 
therapy 
100% of 
previous 
doseb 
Sensory 
neuropathy 
100% of 
previous doseb 
100% of previous 
doseb 
Grade 2, 
persistent: 
Reduce dose 
by 20% (80% 
of original 
dose) 
Grade 3, 
recovers prior 


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Grade 3 or 4 
hand foot 
syndrome 
100% of 
previous 
dosed 
Discontinue 
therapy 
100% of 
previous 
dosed 
Any grade 
neurocerebellar 
or t Grade 2 
cardiac toxicity 
100% of 
previous 
dosed 
Discontinue 
therapy 
100% of 
previous 
dosed 
Sensory 
neuropathy 
100% of 
previous 
dosed 
100% of 
previous dosed 
Grade 2, 
persistent: 
Reduce dose 
by 25% 
Grade 3, 
recovers 
prior to next 
cycle: 
Reduce dose 
by 25% 
Grade 3, 
persistent:  
Discontinue 
therapyf 
Grade 4: 
Discontinue 
therapyf 
a Asthenia and Grade 3 Anorexia do not require dose modification 
b Grade 1 diarrhea: 2-3 stools/day > pretreatment; Grade 2 diarrhea: 
4-6 stools/day > pretreatment 
c Grade 3 diarrhea: 7-9 stools/day > pretreatment; Grade 4 diarrhea: > 
10 stools/day > pretreatment. See Section 6.7.2 for therapy of 
diarrhea.  
d Any toxicity ≥ Grade 2, except asthenia and alopecia, can justify a 
dose reduction if medically indicated  
e Patients who require more than 2 dose reductions must be 
withdrawn from the study 
f Patients who discontinue therapy due to oxaliplatin-related neuropathy may 
remain on study and continue to receive nal-IRI + 5-FU/LV 
to next cycle: 
Reduce dose 
by 35% (65% 
of original 
dose) 
Grade 3, 
recurrent: 
Reduce dose 
by 15%d 
(50% of 
original dose) 
Grade 3, 
persistent or 
Grade 4: 
Discontinue 
therapyc 
 
Grade 3 or 4 
hepatic, renal, 
respiratory or 
other toxicities 
1st occurrence:  Reduce dose by 20% (80% of 
original dose) 
2nd occurrence:  Reduce dose by another 15% (65% 
of original dose) 
3rd occurrence: Reduce dose by another 15% (50% 
of original dose) 
a Asthenia and Grade 3 Anorexia do not require dose modification 
b Any toxicity ≥ Grade 2, except asthenia and alopecia, can justify a dose 
reduction if medically indicated  
c Patients who discontinue therapy due to oxaliplatin-related neuropathy may 
remain on study and continue to receive nal-IRI + 5-FU/LV  
d At the discretion of the investigator, patients can discontinue oxaliplatin 
therapy if Grade 3 persistent sensory neuropathy occurs. 
e Patients who require more than 3 dose reductions must discontinue study 
treatment  
 


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Table 9: 
Part 2 Arm 2 (nal-IRI + 5-FU/LV) Dose Modifications 
for Hematologic Toxicities 
Worst Toxicity by 
CTCAE Grade 
Nal-IRI 
5-FU 
Grade 2 neutropenia 
(ANC <1500 - 1000 
cells/mm3) 
100% of previous dose 
Grade 3 or 4 
neutropenia 
(ANC ≤ 1000/mm3) 
or febrile neutropeniaa 
1st occurrence:  
Reduce dose to 60 
mg/m2 
2nd occurrence:  
Reduce dose to 50 
mg/m2 
1st occurrence: 
Reduce dose by 
25% 
2nd occurrence:  
Reduce dose 
another 25% 
(50% of original 
dose) 
≥ Grade 2 
thrombocytopenia 
(Grade 2: platelets 
≤ 75,000/mm3 – 
50,000/mm3 
OR 
Grade 3-4: platelets < 
50,000/mm3) 
If Grade 2: 
100% of previous 
dose 
If ≥ Grade 3: 
1st occurrence:  
Reduce dose to 60 
mg/m2 
2nd occurrence:  
Reduce dose to 50 
mg/m2 
If Grade 2: 
100% of previous 
dose 
If ≥ Grade 3: 
1st occurrence: 
Reduce dose by 
25% 
2nd occurrence:  
Reduce dose 
another 25% 
(50% of original 
dose) 
Other hematologic 
toxicities not 
specifically listed above 
If Grade 2: 
100% of previous 
dose 
If ≥ Grade 3: 
1st occurrence:  
Reduce dose to 60 
mg/m2 
2nd occurrence:  
Reduce dose to 50 
mg/m2 
If ≤ Grade 2: 
100% of previous 
dose 
If ≥ Grade 3: 
1st occurrence: 
Reduce dose by 
25% 
2nd occurrence:  
Reduce dose 
another 25% 
(50% of original 
dose) 
a Consider the use of G-CSF for patients who experience ≥ Grade 3 
neutropenia or febrile neutropenia (see Section 6.7.2 for details). 
 
Deleted table 


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Table 10: Part 2 Arm 2 (nal-IRI + 5-FU/LV) Dose Modifications 
for Non-Hematological Toxicities Other than Asthenia and Grade 
3 Anorexiaa,d,e 
Worst Toxicity by 
CTCAE Grade 
Nal-IRI 
5-FU 
Grade 1 or 2,  
including diarrheab 
100% of previous 
dose 
100% of previous 
dose, except for 
Grade 2 hand foot 
syndrome, Grade 2 
cardiac toxicity, or 
any grade 
neurocerebellar 
toxicity 
Grade 3 or 4, 
including diarrheac 
(except nausea and 
vomiting) 
1st occurrence:  
Reduce dose to 
60 mg/m2 
2nd occurrence:  
Reduce dose to 
50 mg/m2 
1st occurrence: 
Reduce dose by 25% 
2nd occurrence:  
Reduce dose another 
25% (50% of original 
dose) 
Note: except for 
Grade 3 or 4 hand 
foot syndrome 
Grade 3 or 4 nausea 
and/or vomiting 
despite anti-emetic 
therapy 
Optimize anti-
emetic therapy 
AND reduce dose 
to 60 mg/m2 ; if 
the patient is 
already receiving 
60 mg/m2, reduce 
dose to 50 mg/m2 
Optimize anti-emetic 
therapy AND reduce 
dose by 25%; if the 
patient is already 
receiving a reduced 
dose, reduce dose an 
additional 25% 
Grade 2 hand foot 
syndrome 
100% of previous 
dosed 
1st occurrence: 
Reduce dose by 25% 
2nd occurrence:  
Reduce dose another 
25% (50% of original 
dose) 
Grade 3 or 4 hand 
foot syndrome 
100% of previous 
dosed 
Discontinue therapy 
Deleted table 


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Any grade 
neurocerebellar or t 
Grade 2 cardiac 
toxicity 
100% of previous 
dosed 
Discontinue therapy 
a Aesthenia and Grade 3 Anorexia do not require dose modification  
b Grade 1 diarrhea: 2-3 stools/day > pretreatment; Grade 2 diarrhea: 4-6 
stools/day > pretreatment 
c Grade 3 diarrhea: 7-9 stools/day > pretreatment; Grade 4 diarrhea: > 10 
stools/day > pretreatment 
d Any toxicity ≥ Grade 2, except anemia and alopecia, can justify a dose 
reduction if medically indicated  
e Patients who require more than 2 dose reductions must be withdrawn from the 
study 
 
50-51 
6.5 
6.5.2 Nal-IRI Dose Modifications for UGT1A1*28 Positive 
Patients (Arms 1 and 2) 
The protocol does not contain formal recommendations on 
nal-IRI dose modifications as a consequence of 
homozygosity. All patients should receive the full starting 
dose of nal-IRI. All Arm 1 patients should start at the dose 
level identified from Part 1, while all Arm 2 patients will 
begin dosing at 80 mg/m2. 
6.5.1 
Nal-IRI Dose Modifications for UGT1A1*28 
Positive Patients 
The protocol does not contain formal recommendations on 
nal-IRI dose modifications as a consequence of 
homozygosity. All patients should receive the full starting 
dose of nal-IRI.  
51 
6.5 
6.5.3 Arm 3 Dose Modifications 
Dose level reductions required due to toxicity related to 
nab-paclitaxel and gemcitabine should be made following 
the guidelines outlined in Table 11. 
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Table 11: Dose Level Reductions for Nab-paclitaxel and 
Gemcitabine 
Dose Level 
Nab-paclitaxel 
(mg/m2) 
Gemcitabine 
(mg/m2) 
Full dose 
125 
1000 
1st dose reduction 
100 
800 
2nd dose reduction 
75 
600 
If additional dose 
reductions required 
Discontinue 
Discontinue 
Recommended dose modifications for neutropenia and 
thrombocytopenia are provided in Table 12 and adjustments 
related to other toxicities are provided in Table 13.  
Table 12: 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 doses 
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 doses 
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 doses 
ANC = absolute neutrophil count 
 
Table 13: Nab-paclitaxel and Gemcitabine Dose Modifications 
for Other Adverse Drug Reactions 
Adverse Drug 
Reaction 
Nab-paclitaxel 
Gemcitabine 


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Febrile 
Neutropenia: 
Grade 3 or 4 
Withhold until fever resolves and ANC ≥ 1500; 
resume at next lower dose level 
Peripheral 
Neuropathy:     
Grade 3 or 4 
Withhold until improves ≤ 
Grade 1; resume at next 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 diarrhea 
Withhold until improves to ≤ Grade 1; 
resume at next dose level 
51 
6.5 
6.5.4 
Other Toxicities Requiring Special Attention 
For all treatment arms, QTc prolongation that occurs in the 
setting of diarrhea induced electrolyte imbalance should be 
treated with appropriate electrolyte repletion. 
6.5.2 
Other Toxicities Requiring Special Attention 
QTc prolongation that occurs in the setting of diarrhea 
induced electrolyte imbalance should be treated with 
appropriate electrolyte repletion. 


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6.5 
6.5.5 
Rules for Dose Omissions and Modified Schedules 
The following guidance should be followed when all study 
drugs in any arm are held/missed: 
For both Part 1 and Part 2, the maximum delay between the 
date of a scheduled but missed dose and the planned next 
dose should be up to 14 days.  
In Part 2, Arm 3,  
x 
If Day 1 doses are held/missed: the doses intended 
for Day 1 of a cycle should be delayed, such that 
the start of that cycle will not begin until the doses 
are actually administered to the patient 
x 
If Day 8 doses are held/missed: the cycle will 
continue per protocol and those doses will be 
considered missed. 
x 
If Day 15 doses are held/missed: the dose will be 
considered missed and dosing will continue with 
Day 1 of the next cycle when toxicity recovers.  
6.5.3 
Rules for Dose Omissions and Modified Schedules 
The following guidance should be followed when all study 
drugs are held/missed: 
The maximum delay between the date of a scheduled but 
missed dose and the planned next dose should be up to 14 
days. 
51 
6.6 
x 
Date and quantity of study drug administered to 
each patient 
 
x 
Date and quantity of study drug administered to each 
patient (the start and stop date/time of infusion of 
drug should be recorded for each patient at each 
dose) 
52 
6.6 
At the conclusion of the study, the monitor will package and 
ship all unused vials of study drug back to Sponsor for 
destruction.  
At the conclusion of the study, the monitor will perform 
accountability on all unused vials of study drug. Once 
accountability is complete, destruction may be performed 
at the site, or if the site does not have a destruction 
process, the monitor may ship the supplies back to the 
sponsor. In case of destruction at the site, the method 
should be documented in the site files. 


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6.7 
6.7.1 Antiemetic Medications 
Dexamethasone and a 5-HT3 blocker (e.g., ondansetron or 
granisetron) will be administered as premedications to all 
patients assigned to Arm 1 and Arm 2 unless 
contraindicated for the individual patient. For patients 
randomized to Arm 2, during cycle 1 ECG monitoring, 
consider alternatives to 5-HT3 blockers which have been 
associated with QT changes. Antiemetics will also be 
prescribed as clinically indicated during the study period. 
 
Deleted section 
52 
6.7 
6.7.2 
Granulocyte Colony Stimulating Factors 
Use of granulocyte colony-stimulating factors (G-CSF) is 
permitted to treat patients with neutropenia or neutropenic 
fever. In Part 1, prophylactic use of G-CSF will be 
permitted only in those patients who have had at least one 
episode of grade 3 or 4 neutropenia or neutropenic fever 
while receiving study therapy. In Part 2, prophylactic use of 
G-CSF is recommended for patients who have had at least 
one episode of grade 3 or 4 neutropenia or neutropenic fever 
while receiving study therapy, however primary prophylaxis 
with G-CSF may be considered for high risk patients, 
according to local institutional polices and/or established 
guidelines [32] [33] [34]. 
6.7.1 
Granulocyte Colony Stimulating Factors 
Deaths due to sepsis following severe neutropenia have 
been reported in patients treated with irinotecan and nal-
IRI. In patients with metastatic pancreatic cancer in the 
NAPOLI-1 study receiving irinotecan liposome 
injection/5-FU/LV, the incidence of grade 3 or 4 
neutropenia was higher among Asian patients [18 of 33 
(55%)] compared to White patients [13 of 73 (18%)]. 
Neutropenic complications should be managed promptly 
with antibiotic support. G-CSF may be used to manage 
neutropenia at the investigator’s discretion. Prophylactic 
use of G-CSF will be permitted if patients are considered 
high risk in the opinion of the investigator [33] [34] [35]. 


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53 
6.7.2 
Table 14: Recommendations for Management of Chemotherapy 
Induced Diarrhea 
Clinical Presentation 
Intervention 
Diarrhea, any grade 
Oral loperamide (2 mg every 2 hours 
for irinotecan induced diarrhea; 2 mg 
every 4 hours for 5-FU induced 
diarrhea): continue until diarrhea-free 
for t 12 hours 
Diarrhea persists on 
loperamide for > 24 
hours 
Oral fluoroquinolone x 7 days 
Diarrhea persists on 
loperamide for > 48 
hours 
Stop loperamide; hospitalize patient; 
administer IV fluids 
ANC < 500 cells/PL, 
regardless of fever or 
diarrhea  
Oral fluoroquinolone (continue until 
resolution of neutropenia) 
Fever with persistent 
diarrhea, even in the 
absence of neutropenia 
Oral fluoroquinolone (continue until 
resolution of fever and diarrhea) 
 
Table 9: 
Recommendations for Management of Chemotherapy 
Induced Diarrhea 
Clinical Presentation 
Intervention 
Diarrhea, any grade 
Oral loperamide (2 mg every 2 hours for 
irinotecan induced diarrhea; 2 mg every 4 
hours for 5-FU induced diarrhea): 
continue until diarrhea-free for t 12 
hours 
Oral electrolyte replacement 
Diarrhea persists on 
loperamide for > 24 
hours 
Oral fluoroquinolone x 7 days 
Diarrhea persists on 
loperamide for > 48 
hours 
Stop loperamide; hospitalize patient; 
administer IV fluids 
ANC < 500 cells/PL, 
regardless of fever or 
diarrhea  
Oral fluoroquinolone (continue until 
resolution of neutropenia) 
Fever with persistent 
diarrhea, even in the 
absence of neutropenia 
Oral fluoroquinolone (continue until 
resolution of fever and diarrhea) 
53 
6.8 
The following drugs are noted in the irinotecan prescribing 
information as interacting with irinotecan: St. John’s Wort, 
CYP3A4 inducing anticonvulsants (phenytoin, 
phenobarbital, and carbamazepine), ketoconazole, 
itraconazole, troleandomycin, erythromycin, diltiazem and 
verapamil.  
 
Treatment with these agents and any others that interact 
with irinotecan, 5-FU, oxaliplatin, or gemcitabine should be 
avoided wherever possible. Additionally, nab-paclitaxel is 
catalyzed by CYP2C8 and CYP3A, therefore Part 2 patients 
randomized to Arm 3 should avoid concomitant treatment 
with strong inhibitors (ketoconazole and other imidazole 
antifungals, erythromycin, fluoxetine, gemfibrozil, 
cimetidine, ritonavir, saquinavir, indinavir and nelfinavir) or 
inducers (rifampicin, carbamazepine, phenytoin, efavirenz, 
The following drugs are noted in the irinotecan prescribing 
information as interacting with irinotecan: 
• 
Strong CYP3A4 inducers, e.g., St. John’s Wort, 
CYP3A4 inducing anticonvulsants (phenytoin, 
phenobarbital, and carbamazepine), rifampin, rifabutin, 
rifapentine 
• 
Strong CYP3A4 inhibitors, e.g., clarithromycin, 
indinavir, itraconazole, ketoconazole, lopinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, 
voriconazole 
• 
Weak to moderate CYP3A4 inhibitors, e.g., 
troleandomycin, erythromycin, diltiazem, verapamil 
• 
Strong UGT1A1 inhibitors, e.g., atazanavir, 
gemfibrozil, indinavir, ketoconazole 
 


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and nevgirapine) of CYP2C8 or CYP3A. Because 5-FU 
interacts with warfarin, caution should be exercised if 
concomitant use is necessary. No live attenuated vaccines 
should be given to patients randomized to any arm of the 
study (e.g., yellow fever vaccine and polio virus vaccine). 
Refer to the country specific package inserts of 5-FU, 
leucovorin, oxaliplatin, nab-paclitaxel, or gemcitabine for 
any other drug interactions. 
Treatment with these agents and any others that interact with 
irinotecan, 5-FU, or oxaliplatin should be avoided wherever 
possible. Because 5-FU interacts with warfarin, caution 
should be exercised if concomitant use is necessary. No live 
attenuated vaccines should be given to patients of the study 
(e.g., yellow fever vaccine and polio virus vaccine). Refer to 
the country specific package inserts of 5-FU, leucovorin, or 
oxaliplatin for any other drug interactions. 
54 
7.1.2 
Patients who are confirmed to meet all inclusion and 
exclusion criteria will be enrolled in Part 1 and randomized 
via an IWRS in Part 2. The first dose (Cycle 1 Day 1) must 
be given within 7 days of enrollment/randomization. 
Patients who are confirmed to meet all inclusion and 
exclusion criteria will be enrolled in the study and receive 
the first dose (Cycle 1 Day 1). 
54-55 
7.2.3 
The Eastern Cooperative Oncology Group (ECOG) 
Performance Status will be obtained at Screening and within 
72 hours of enrollment/randomization by the Investigator or 
his/her designee via questioning of the patient about their 
functional capabilities. Additionally, Karnofsky 
Performance Status (KPS) will be recorded at Screening and 
within 72 hours of enrollment/randomization. 
The Eastern Cooperative Oncology Group (ECOG) 
Performance Status will be obtained at Screening, and within 
72 hours prior to first dose if first dose occurs more than 
72 hours post screening, by the Investigator or his/her 
designee via questioning of the patient about their functional 
capabilities. Additionally, Karnofsky Performance Status 
(KPS) will be recorded at Screening, and within 72 hours 
prior to first dose if first dose occurs more than 72 hours 
post screening. 
55 
7.2.4 
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  
In Part 2, patients randomized to Arm 2 will be enrolled in a 
QTc study evaluating sequential collection of ECGs. For 
these patients, ECG readings should be collected as outlined 
in Appendix 5. 
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 (see Section 6.5.2 
for QTc in relation to diarrhea). 


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7.2.5 
 
Added text: 
Patients who continue infusion of 5-FU in home settings 
for the extended durations during the study, should keep 
a record of date/time of infusion start and stop and 
report any adverse events to the site. The Investigator or 
medically qualified person should call the patients who 
are discharged home for extended infusions to record the 
start and stop date/time for infusion and to assess 
adverse events reported by the patient (see Section 
6.2.4.1). 
55 
7.2 
7.2.7 
EORTC-QLQ-C30 and EQ-5D-5L (Part 2 Only) 
Health-related quality of life (HRQL) will be assessed by 
the EORTC-QLQ-C30 and EQ-5D-5L instruments. The 
EORTC-QLQ-C30 is a reliable and widely used measure of 
the quality of life of cancer patients in multicultural clinical 
research settings. It incorporates nine multi-item scales: five 
functional scales (physical, role, cognitive, emotional, and 
social); three symptom scales (fatigue, pain, and nausea and 
vomiting); and a global health and quality-of-life scale. 
Several single-item symptom measures are also included. 
EQ-5D is a generic, preference-based measurement of 
HRQL. The 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: no problems, slight problems, moderate 
problems, severe problems, and unable to do. 
Patients will be required to complete both questionnaires at 
timepoints outlined in the Schedule of Assessments. On 
days that the patient is to receive study drug, assessments 
should be completed prior to study drug administration. 
Only those patients for whom validated translations of the 
questionnaires are available will be required to complete the 
questionnaire. 
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55 
7.3 
 
Laboratory assessments required for screening and 
enrolment eligibility can be performed locally for 
evaluating patient eligibility and enrolment only. 
56 
7.3.5 
Whole blood, serum and plasma will be collected to 
potentially identify factors that may correlate with tumor 
response, sensitivity or resistance to nal-IRI, and nal-IRI 
PK. 
Archived tissue samples, whole blood, serum and plasma 
will be collected to potentially identify factors that may 
correlate with tumor response, sensitivity or resistance to 
nal-IRI, and nal-IRI PK. 
56 
7.3.7 
7.3.7.2 
Arm 2 
Patients who are randomized to Arm 2 will undergo 
collection of blood samples in order to assess the 
relationship between blood levels of nal-IRI, SN-38 and 5-
FU and ECG findings. Directions for collecting, processing 
and shipping the PK plasma samples can be found in the 
study manual. PK samples will be collected in Cycle 1 only 
as outlined in Table 16 below. 
Table 16: Summary of PK Timepoints for Arm 2 
Sample 
Time-point 
Window 
Number 
of 
Drawsa 
1 
Pre-dose Day 1  
-24 hours 
2 
2 
After the ECG conducted 
following completion of the 90 
minute nal-IRI infusion on Day 
1 
+ 5 mins 
1 
3 
After the ECG conducted 60 
minutes into the 5-FU infusion 
on Day 1 
+ 5 mins 
2 
4 
After the ECG conducted 60 
minutes following completion of 
the 46-hour 5-FU infusion on 
Day 3 
+ 5 mins 
1 
5 
Pre-dose Day 15  
-24 hours 
2 
6 
After the ECG conducted 
following completion of the nal-
IRI infusion on Day 15 
+ 5 mins 
1 
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7 
After the ECG conducted 60 
minutes into the 5-FU infusion 
on Day 15 
+ 5 mins 
2 
8 
After the ECG conducted 
following completion of the 46-
hour 5-FU infusion on Day 15 
+ 5 mins 
1 
a The number of draws corresponds to the number of analytes that will be 
measured; for example, sample #3 at the 60 minute mark of the 5-FU infusion 
will be used to measure nal-IRI and 5-FU. 
 
57-58 
8 
See below 
See below 
 


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Section 8 WAS 
Procedure 
Screening 
Phase 
Treatment Phase 
Follow Up Phase 
-28d 
Cycle 121 
Additional Cycles21 
Every 8w after 
1st dose 
End of Treatment 
Visit22 
Every 2 months from EoT 
Follow-up visit 
D1 
D3 
D8 
D15 
D1 
D8 
D15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
 
 
 
 
 
Demographics 
X1 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
 
ECOG PS 
XX2, 26 
X 
 
 
 
X 
 
 
 
X 
 
KPS PS 
XX2, 27 
 
 
 
 
 
 
 
 
 
 
EORTC-QLQ-C309 
X2 
X3 
 
 
 
X3 
 
 
 
 
 
EQ-5D-5L9 
X2 
X3 
 
 
 
X3 
 
 
 
X 
 
CBC4 
X2 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Serum chemistry4,  
X2, 28 
X 
 
X 
X 
X 
 
X 
 
X 
 
CA19-9 
X2 
 
 
 
 
 
 
 
X19 
X20 
 
UGT1A1*28 
X2, 5 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X2 
X 
 
 
 
X 
 
 
 
X 
 
ECG6 
X1,7 
X25 
 
 
X25 
 
 
 
 
X 
 
Archived slides8 
X 
 
 
 
 
 
 
 
 
 
 
Randomization9 
X2 
 
 
 
 
 
 
 
 
 
 
Plasma for PK10 
 
X11 
X12 
X13 
X14 
 
 
 
 
X 
 
Biomarker analysis15, 14 
 
X15 
 
 
 
X 
 
 
 
X 
 
Concomitant meds and 
procedures 
X1 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Arms 1 & 2 dosing16 
 
X 
 
 
X 
X 
 
X 
 
 
 
Arm 3 dosing16 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
AE / Hospitalization 
assessment & reporting 
X17 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Disease evaluation18 
X1 
 
 
 
 
 
 
 
X19 
X20 
X23 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
X24 
1 Procedures to be completed within 28 days of 1st dose of study drug 
2 Procedures to be completed within 7 days of 1st dose of study drug 
3 HRQL questionnaires must be completed before study treatment administration 
4 After screening, samples should be obtained within 2 days from scheduled date of collection 
5 Result not required prior to enrollment in the study or prior to receiving the initial dose of nal-IRI 
6 To be repeated as clinically indicated during the study 
7 Two independent readings at least 1 minute apart 
8 Collection of archived tumor block or paraffin embedded slides is required, if available 
9 Part 2 only 
10 PK sampling will only be collected from patients enrolled in Arm 1 (Part 1) or randomized to Arm 1 or Arm 2 in Part 2 


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11 Samples collected at the following timepoints in Arm 1: pre-dose (within 24 hours prior to nal-IRI infusion); at the end of the nal-IRI infusion (+30 mins) and at the end of the oxaliplatin infusion (+5 mins). Samples 
collected at the following timepoints in Arm 2: pre-dose nal-IRI infusion, after the ECG conducted following completion of the 90 minute nal-IRI infusion, after the ECG conducted 60 minutes into the 5-FU infusion. 
All samples will be collected within 5 minutes after completion of the ECG recordings. 
12 In Arm 1, sample collected within 2 hours prior to the completion of the 5-FU infusion. In Arm 2, sample collected after the ECG conducted 60 minutes following completion of the 5-FU infusion. 
13 Sample collected +168 hours/7 days after the completion of the nal-IRI infusion (±24 hours) in Arm 1 only.  
14 In Arm 1, sample collected just prior to dosing with nal-IRI (within 24 hours). Samples collected at the following timepoints in Arm 2: pre-dose nal-IRI infusion, after the ECG conducted following completion of 
the 90 minute nal-IRI infusion, after the ECG conducted 60 minutes into the 5-FU infusion on Day 15, and after the ECG conducted 60 minutes following completion of the 5-FU infusion (Day 17). All samples will 
be collected within 5 minutes after completion of the ECG recordings. 
15 Blood will be collected for biomarker analyses: plasma samples will be collected at all timepoints; additionally, whole blood and serum samples will be collected on Cycle 1 Day 1 only 
16 Study drug administration should occur ±2 days from scheduled date of administration 
17 Adverse events that occur during screening should be documented as pre-existing conditions; only SAEs that are felt by the Investigator to be directly related to a study procedure should be reported during screening. 
18 Disease evaluation according to RECIST v. 1.1 (see Section 7.2.6) 
19 Disease evaluations and CA19-9 should be done every 8 weeks (± 7 days) after 1st dose  
20 Unless completed in the prior 8 weeks 
21 All cycles are 28-day cycles, unless modified due to toxicity 
22 The End of Treatment (EoT) Follow-Up visit should occur 30 days (± 14 days) after last dose  
23 For patients who discontinue the study for reasons other than radiologically confirmed disease progression only (e.g. patients who are removed due to adverse events), imaging studies should be continued until 
documented progression of disease per RECIST v1.1 (see Section 7.2.6). 
24 Follow-up contacts should be made every 8 weeks (± 7 days) until death or study completion; data collected should include overall survival status as well as subsequent treatment information. 
25 In Arm 2, ECG recordings will be collected via Holter monitor as outlined in Appendix 5 at the following timepoints: Cycle 1, Day 1: -30, -20 and -10 minutes pre-dose nal-IRI, immediately following nal-IRI 
infusion, immediately following the LV infusion, 60 minutes after beginning the 5-FU infusion and 60 minutes after completion of the 46-hour 5-FU infusion. Cycle 1, Day 15: -10 minutes pre-dose nal-IRI, 
immediately following nal-IRI infusion, immediately following the LV infusion, 60 minutes after beginning the 5-FU infusion and 60 minutes after completion of the 46-hour 5-FU infusion. Patients must be in a 
supine/semi-recumbent resting position for 10 minutes prior to collection times. 
26 ECOG to be performed at Screening and within 72 hours of enrollment/randomization. ECOG assessment requires determination by two independent assessors. In the case of a discrepancy between the 2 assessments, 
the one with a lower score will be selected at each assessment. 
27 KPS to be performed at Screening and within 72 hours of enrollment/randomization. KPS assessment requires determination by two independent assessors. In the case of a discrepancy between the 2 assessments, 
the one with a lower score will be selected at each assessment. 
28 Serum albumin needs to be collected at Screening Visit and within 72 hours prior to enrollment/ randomization to confirm exclusion criteria ‘p’ (both labs at screening and prior to enrollment/randomization may be 
confirmed locally) (Section 5.2). 
 
 


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Section 8 IS 
Procedure 
Screening 
Phase 
Treatment Phase 
Follow Up Phase 
-28d 
Cycle 119 
Additional Cycles19 
Every 8w after 
1st dose 
End of Treatment 
Visit18 
Every 2 months from EoT 
Follow-up visit 
D1 
D3 
D8 
D15 
D1 
D8 
D15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
 
 
 
 
 
Demographics 
X1 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
 
ECOG PS 
XX2, 23 
X 
 
 
 
X 
 
 
 
X 
 
KPS PS 
XX2, 24 
 
 
 
 
 
 
 
 
 
 
CBC4 
X2 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Serum chemistry4 
X2, 25 
X 
 
X 
X 
X 
 
X 
 
X 
 
CA19-9 
X2 
 
 
 
 
 
 
 
X17 
X20 
 
UGT1A1*28 
X2, 5 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X2 
X 
 
 
 
X 
 
 
 
X 
 
ECG6 
X1,7 
 
 
 
 
 
 
 
 
X 
 
Archived slides8 
X 
 
 
 
 
 
 
 
 
 
 
Plasma for PK 
 
X9 
X10 
X11 
X12 
 
 
 
 
X26 
 
Biomarker analysis12, 13 
 
X13 
 
 
 
X 
 
 
 
X 
 
Concomitant meds and 
procedures 
X1 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Dosing14 
 
X 
 
 
X 
X 
 
X 
 
 
 
AE / Hospitalization 
assessment & reporting 
X15 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Disease evaluation16 
X1 
 
 
 
 
 
 
 
X17 
X18 
X21 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
X22 
1 Procedures to be completed within 28 days of 1st dose of study drug 
2 Procedures to be completed within 7 days of 1st dose of study drug 
3 HRQL questionnaires must be completed before study treatment administration 
4 After screening, samples should be obtained within 2 days from scheduled date of collection 
5 Result not required prior to enrollment in the study or prior to receiving the initial dose of nal-IRI 
6 To be repeated as clinically indicated during the study 
7 Two independent readings at least 1 minute apart 
8 Collection of archived tumor block or paraffin embedded slides is required, if available 
9 Samples collected at the following timepoints: pre-dose (within 24 hours prior to nal-IRI infusion); at the end of the nal-IRI infusion (+30 mins) and at the end of the oxaliplatin infusion (+5 mins).  
10 Sample collected within 2 hours prior to the completion of the 5-FU infusion.  
11 Sample collected +168 hours/7 days after the completion of the nal-IRI infusion (±24 hours).  
12 Sample collected just prior to dosing with nal-IRI (within 24 hours). 
13 Blood will be collected for biomarker analyses: plasma samples will be collected at all timepoints; additionally, whole blood and serum samples will be collected on Cycle 1 Day 1 only. 
14 Study drug administration should occur ±2 days from scheduled date of administration 
15 Adverse events that occur during screening should be documented as pre-existing conditions; only SAEs that are felt by the Investigator to be directly related to a study procedure should be reported during screening. 
16 Disease evaluation according to RECIST v. 1.1 (see Section 7.2.6) 


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17 Disease evaluations and CA19-9 should be done every 8 weeks (± 7 days) after 1st dose  
18 Unless completed in the prior 8 weeks 
19 All cycles are 28-day cycles, unless modified due to toxicity 
20 The End of Treatment (EoT) Follow-Up visit should occur 30 days (± 14 days) after last dose  
21 For patients who discontinue the study for reasons other than radiologically confirmed disease progression only (e.g. patients who are removed due to adverse events), imaging studies should be continued until 
documented progression of disease per RECIST v1.1 (see Section 7.2.6). 
22 Follow-up contacts should be made every 8 weeks (± 7 days) until death or study completion; data collected should include overall survival status as well as subsequent treatment information. 
23 ECOG to be performed at Screening, and within 72 hours prior to first dose if first dose occurs more than 72 hours post screening. ECOG assessment requires determination by two independent assessors. In the 
case of a discrepancy between the 2 assessments, the one with a lower score will be selected at each assessment. 
24 KPS to be performed at Screening, and within 72 hours prior to first dose if first dose occurs more than 72 hours post screening. KPS assessment requires determination by two independent assessors. In the case of 
a discrepancy between the 2 assessments, the one with a lower score will be selected at each assessment. 
25 Serum albumin needs to be collected at Screening, and within 72 hours prior to first dose if first dose occurs more than 72 hours post screening to confirm exclusion criteria ‘p’ (both labs at screening and prior to 
first dose may be confirmed locally) (Section 5.2). 
26 Sample to be collected within 5 minutes after ECG recording 
 


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62 
10.4 
Part 1 and Part 2 will be analyzed separately, according to 
safety and efficacy parameters.  
Patient populations defined for this study are described 
below: 
x 
Intent-to-Treat (ITT) population (Part 2 only):  This 
population includes all randomized patients.  
Patients will be analyzed according to the 
randomized arm.   
x 
Safety (SAF) population:  
o Part 1: The Part 1 safety population 
includes patients receiving at least one dose 
of any study drug  
o Part 2: The Part 2 safety population 
includes patients receiving at least one dose 
of any study drug. The SAF population will 
be summarized according to arm actually 
received. 
x 
EQ-5D-5L population (Part 2 only): Treated 
patients, defined as patients who received at least 
one dose of study treatment, that have provided 
baseline and at least 1 post-baseline assessment for 
EQ-5D. 
x 
EORTC-QLQ-30 population (Part 2 only): Treated 
patients, defined as patients who received at least 
one dose of study treatment, that have provided 
baseline and at least 1 post-baseline assessment for 
EORTC-QLQ-30. 
x 
PK Population: The PK population will include all 
nal-IRI treated patients with at least one post-study 
drug PK assessment. 
 
Patient populations defined for this study are described 
below: 
x 
Safety (SAF) population: The safety population 
includes patients receiving at least one dose of any 
study drug  
x 
PK Population: The PK population will include all 
nal-IRI treated patients who received at least 1 
dose and who have at least 1 plasma 
concentration and no major protocol deviations 
affecting PK variables. 
 


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62 
10.5 
Study populations (enrolled, safety, PK) will be summarized 
and displayed as frequencies. Disposition of patients will be 
summarized including patients screened, randomized, 
treated, and discontinued. 
Study populations (safety, PK) will be summarized and 
displayed as frequencies. Disposition of patients will be 
summarized including patients screened, treated, and 
discontinued. 
17, 
63 
Synopsis, 
10.6 
In the assessments of efficacy of Part 2, each nal-IRI-
containing arm will be compared to the control arm. 
Efficacy comparisons will use stratified analyses, 
incorporating randomization strata. Each comparison will be 
use 0.10 level one-sided testing to evaluate whether the nal 
IRI containing arm improves the efficacy parameter. 
Confidence intervals will be presented at two-sided 95% 
level for descriptive purposes. Hypothesis tests and 
confidence intervals will not be adjusted for multiple 
comparisons and consequently the experiment-wise type I 
error may be greater than the 0.10 level. The primary 
efficacy comparisons will be based on the ITT population, 
which will include all randomized patients. 
Deleted text 
17, 
63 
Synopsis, 
10.6 
Tumor evaluation will be measured according to RECIST 
v1.1. For each patient, progression free survival time will be 
determined as the time from randomization (for patients in 
Part 1, the reference start time will be date of first study 
drug) to the first documented radiographical progression of 
disease (PD), per investigator using RECIST 1.1, or death 
from any cause, whichever comes first. 
 
Efficacy analyses will be performed on Safety 
population. 
Tumor evaluation will be measured according to RECIST 
v1.1. For each patient, progression free survival time will be 
determined as the time from the date of first study drug to 
the first documented radiographical progression of disease 
(PD), per investigator using RECIST 1.1, or death from any 
cause, whichever comes first. 
17, 
63 
 
Synopsis, 
10.6 
For Part 2, a primary analysis will be conducted when there 
are at least 70 PFS events for each comparison to the control 
arm. A subsequent analysis for PFS and other endpoints will 
be performed when PFS events have occurred in at least 120 
(i.e. 80% of randomized patients) patients. 
 
Deleted text 
 


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17, 
63 
Synopsis, 
10.6 
Primary Efficacy Analysis 
PFS will be descriptively summarized for each dose level 
cohort (Part 1) and treatment arm (Part 2) using Kaplan-
Meier methodology. Median PFS time and corresponding 
95% confidence limits will be presented. For Part 2, PFS of 
each nal-IRI-containing arm will be compared to the control 
arm. Hypothesis tests will be conducted for differences in 
PFS using a one-sided stratified log-rank test. Hazard ratios 
(with 95% confidence interval) for PFS will be estimated 
using stratified Cox models. 
Secondary Efficacy Analyses 
Best Overall Response (BOR) is defined as the best 
response as recorded from the start of study drug until 
disease progression. Patients without a post-baseline tumor 
assessment will be considered to be non-evaluable for BOR. 
To classify BOR as stable disease (SD), there should be a 
qualifying SD assessment at least 6 weeks from enrollment 
(Part 1) or randomization (Part 2). Overall Response Rate 
(ORR) is defined as the proportion of patients with a BOR 
characterized as either a Complete Response (CR) or Partial 
Response (PR) relative to the total number of evaluable 
patients. Only patients with measurable disease at baseline 
will be included in the analysis of the objective response. 
For Part 1 and Part 2, estimates of overall response rate and 
its corresponding 95% CI will be calculated for each dose 
level cohort (Part 1) and treatment arm (Part 2). For Part 2, 
ORR of each nal-IRI-containing arm will be compared to 
the control arm. Differences in overall response rate 
between each nal-IRI-containing arm and control arm will 
be provided with 95% CIs. Cochran-Mantel-Haenszel tests, 
adjusting by randomization strata, will be used to compare 
overall response rates. 
Efficacy Analysis 
PFS will be analyzed using Kaplan-Meier method and 
descriptively summarized at 3 months interval for each 
dose level cohort. Median PFS time and corresponding 95% 
confidence limits will be presented. 
 
 
 
 
 
 
Best Overall Response (BOR) is defined as the best 
response as recorded from the start of study drug until 
disease progression. Patients without a post-baseline tumor 
assessment will be considered to be non-evaluable for BOR. 
To classify BOR as stable disease (SD), there should be a 
qualifying SD assessment at least 6 weeks from the first 
dose of study drug. Overall Response Rate (ORR) is 
defined as the proportion of patients with a BOR 
characterized as either a Complete Response (CR) or Partial 
Response (PR) relative to the total number of evaluable 
patients. Only patients with measurable disease at baseline 
will be included in the analysis of the objective response. 
The estimates of overall response rate and its corresponding 
95% CI will be calculated for each dose level cohort. 
 
 
 


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18, 
63 
Synopsis, 
10.6 
The maximum reduction (% change from baseline) in 
CA19-9 will be computed, including analyses by time 
period (up to Week 8, 16 and 24 visits). CA 19-9 response 
analyses will be carried out using 3 thresholds for maximum 
reduction: ≥ 20%, ≥50%, ≥90%. A patient without post-
baseline CA19-9 measurement will be considered as a non-
responder. Only patients with CA 19-9 elevated (>37 U/mL) 
at baseline will be included in the analysis of the CA19-9 
response. For each threshold and time period, the proportion 
of CA19-9 response will be estimated, along with 
corresponding 95% confidence intervals, by treatment arm. 
 
Deleted text 
18, 
63 
Synopsis, 
10.6 
Overall Survival (OS) is the time from enrollment (Part 1) 
or randomization (Part 2) to the date of death from any 
cause. Patients who are alive or lost to follow-up at the time 
of the analysis will be censored at the last known alive date. 
OS will be descriptively summarized for each dose level 
cohort (Part 1) and treatment arm (Part 2) using Kaplan-
Meier methodology. For Part 2, OS of each nal-IRI-
containing arm will be compared to the control arm. 
Hypothesis tests will be conducted for differences in OS 
using a one-sided stratified log-rank test. Hazard ratios 
(with 95% confidence interval) for PFS will be estimated 
using stratified Cox models. 
 
Overall Survival (OS) is the time from the date of first 
study drug to the date of death from any cause. Patients 
who are alive or lost to follow-up at the time of the analysis 
will be censored at the last known alive date. Similar to 
PFS, OS will be analyzed using Kaplan-Meier method and 
descriptively summarized for each dose level cohort. 
 


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18, 
63 
Synopsis,
10.6 
Quality of Life Analyses 
Quality of life analyses will be performed using patients in 
the analysis populations for each quality of life instrument 
(EORTC-QLC-C30, EQ-5D-5L). EORTC-QLQ-30 and EQ-
5D-5L results will be summarized at each visit by treatment 
group 
For each EORTC QLQ-C30 administered, scores will be 
computed for the following scales: 
• 
Global Health Status 
• 
Physical Functioning 
• 
Role Functioning 
• 
Emotional Functioning 
• 
Cognitive Functioning 
• 
Social Functioning 
• 
Fatigue 
• 
Nausea and vomiting 
• 
Pain 
• 
Dyspnea 
• 
Insomnia 
• 
Appetite Loss 
• 
Constipation 
• 
Diarrhea 
• 
Financial difficulties. 
Scoring will be carried out as described in the EORTC 
QLQ-C30 Scoring Manual (Fayers, Aaronson, Bjordal, 
Curran, & Groenvald, 2001). Linear transformations will be 
applied to the raw scores so that the reported score will have 
range 0-100 for all scales. Summary statistics will be 
presented for each subscale. A summary health state index 
value will be computed for each EQ-5D-5L assessment. 
Summary statistics will be presented for summary health 
state index. For each EQ-5D-5L attribute (mobility, self-
care, usual activities, pain/discomfort, and 
anxiety/depression), responses will be tabulated. 
Deleted text 


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Version Date 
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Page  
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64 
10.7 
Details on the analyses to assess the potential of QTcF 
prolongation with nal-IRI treatment are provided in 
Appendix 5. 
Deleted text (and corresponding Appendix 5) 
64 
10.9 
10.9.1 Part 1 and Part 2 Arm 1 
Plasma concentrations of total irinotecan, SN-38 and 
oxaliplatin will be used to characterize PK parameters. Due 
to the sparse PK sampling schedule, PK parameters for 
individual patients will be estimated based on the Empirical 
Bayesian Estimation method with priors from the previously 
estimated (nal-IRI) or published (oxaliplatin) population PK 
model parameters. The model simulated exposures, e.g., 
Cmax, AUC (area under the curve), will be used to examine 
any possible interactions between nal-IRI and oxaliplatin by 
comparing the least squares geometric mean ratios (LS-
GMR) of drug exposures. The relationship between dose, 
PK, efficacy and safety endpoints will be evaluated. 
NONMEM®, Version 7.3, will be used to estimate 
individual PK parameters and simulate plasma exposures. 
 
10.9.2 Part 2 Arm 2 
Plasma concentrations of total irinotecan, SN-38 and 5-FU 
will be used to characterize PK parameters. Due to the 
sparse PK sampling schedule, PK parameters for individual 
patients will be estimated based on the Empirical Bayesian 
Estimation method with priors from the previously 
estimated population PK models. The model simulated 
exposures, e.g., Cmax, AUC (area under the curve), will be 
used to evaluate the relationship between dose, PK, efficacy 
and safety endpoints. Moreover, the potential for QTcF 
prolongation will be evaluated from the relationship 
between PK and QTcF. 
Plasma concentrations of total irinotecan, SN-38, and 
oxaliplatin and 5-FU in the combination therapies will be 
used to characterize corresponding PK parameters using a 
nonlinear mixed effects approach. Individual PK 
parameters will be estimated if warranted by the data. 
Graphical exploration will be performed to investigate 
any relationship between PK and pharmacodynamic 
endpoints. If a trend is shown, PK/PD modelling will be 
performed and reported separately. 


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64-65 
10.10 
Part 2 of this study will include a comparison of the 
progression-free survival for each lip IRI containing arm 
versus the control arm. In the Phase 3 MPACT study of 
nab-paclitaxel plus gemcitabine versus gemcitabine alone, a 
significant OS advantage was observed with nab paclitaxel 
with the median PFS of 5.5 months (compared with 3.7 
months, i.e. 16 weeks, in the gemcitabine alone arm) [2]. 
The table below illustrates the power to detect differences in 
PFS between an experimental arm and the control arm with 
at least 70 PFS events using a one-sided comparison at an 
unadjusted 0.10 level of significance. If the true hazard ratio 
for an experimental arm relative to the control arm is 0.60, 
the study would have 80% power to detect an improvement 
with a pairwise one-sided 0.10 level test. 
Table 18: 
Power to Detect Treatment Effect 
Hazard ratio 
for PFS 
(experimental 
vs control) 
Power 
(≥ 70 events between 2 arms 
for comparison) 
0.75 
47% 
0.70 
58% 
0.65 
70% 
0.60 
80% 
0.55 
88% 
 
Below text added was in the synopsis and have been added in 
Section 10.10. 
A selected dose level cohort will be expanded to include 
30 patients in total. An estimate of the DCR at Week 16 
will be tabulated and summarized. The following table 
displays the probabilities of outcomes for DCR16 with 
n=30 as a function of the true DCR16: 
Table 12: 
Probability probabilities of outcomes for 
DCR16 
 
True 
DCR16 
Probability 
observed 
DCR16 ≥ 50% 
Probability 
observed 
DCR16 ≥ 55% 
Probability 
observed 
DCR16 ≥ 60% 
45% 
0.36 
0.14 
0.07 
50% 
0.57 
0.29 
0.18 
55% 
0.77 
0.50 
0.36 
60% 
0.90 
0.71 
0.58 
65% 
0.97 
0.87 
0.78 
70% 
0.99 
0.96 
0.92 
 
 


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70-72 
13 
Three references, listed below, were deleted. References 
cited in the text have been updated accordingly. 
[13] 
“Gemcitabine for injection U.S. Package Insert,” 
2014. [Online]. Available: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/
020509s077lbl.pdf. 
[14] 
“ABRAXANE® for Injectable Suspension 
(paclitaxel protein-bound particles for injectable 
suspension),” 2014. [Online]. Available: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/
021660s040lbl.pdf. 
[39] 
Sarapa, N., Britto, M.R. Challenges of 
characterizing proarrhythmic risk due to QTc prolongation 
induced by nonadjuvant anticancer agents. Expert Opin 
Drug Saf. vol. 7, no. 3, pp 305-318, 2008. 
The five following new references were added to the 
reference list. References cited in the text have been 
updated accordingly. 
[27] 
Iyer L1, Das S, Janisch L, Wen M, Ramírez J, 
Karrison T, Fleming GF, Vokes EE, Schilsky RL, Ratain 
MJ. UGT1A1*28 polymorphism as a determinant of 
irinotecan disposition and toxicity. Pharmacogenomics J. 
2002;2(1):43-7.  
[28] 
Stewart CF, Panetta JC, O'Shaughnessy MA, Throm 
SL, Fraga CH, Owens T, Liu T, Billups C, Rodriguez-
Galindo C, Gajjar A, Furman WL, McGregor LM. UGT1A1 
promoter genotype correlates with SN-38 pharmacokinetics, 
but not severe toxicity in patients receiving low-dose 
irinotecan. J Clin Oncol. 2007 Jun 20; 25(18):2594-600. 
[29] 
Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, 
McLeod HL. UGT1A1*28 genotype and irinotecan-induced 
neutropenia: dose matters. J Natl Cancer Inst. 2007 Sep 5; 
99(17):1290-5. 
[30] 
Toffoli G, Cecchin E, Corona G, Russo A, 
Buonadonna A, D'Andrea M, Pasetto LM, Pessa S, Errante 
D, De Pangher V, Giusto M, Medici M, Gaion F, Sandri P, 
Galligioni E, Bonura S, Boccalon M, Biason P, Frustaci S. 
The role of UGT1A1*28 polymorphism in the 
pharmacodynamics and pharmacokinetics of irinotecan in 
patients with metastatic colorectal cancer. J Clin Oncol. 
2006 Jul 1; 24(19):3061-8. 
[31] 
Roy AC, Park SR, Cunningham D, Kang YK, Chao 
Y, Chen LT, Rees C, Lim HY, Tabernero J, Ramos FJ, 
Kujundzic M, Cardic MB, Yeh CG, de Gramont A. A 
randomized phase II study of PEP02 (MM-398), irinotecan 
or docetaxel as a second-line therapy in patients with locally 
advanced or metastatic gastric or gastro-oesophageal 
junction adenocarcinoma. Ann Oncol. 2013 Jun; 
24(6):1567-73. 
74 
14 
Bin Zhang. 
Fiona Maxwell 


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Version Date 
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Page  
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IS 
Senior Medical Development Director 
Oncology and Endocrinology 
Ipsen Bioscience, Inc. 
Medical Development Director 
Oncology 
Ipsen Bioinnovation 
76 
Appendix Appendix 2 Proposed Algorithm for Diarrhea Management: 
Reference in the footnote was incorrect [30] 
Reference in the footnote has been corrected: [36] 
79 
Appendix Appendix 5 QTc Sub-study Protocol (see at the end of this 
summary of changes) 
Deleted appendix 
 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
MM-398-07-02-03 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Version 6.0, 11 April 2018 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
OBJECTIVE(S) OF PROTOCOL 
AMENDMENT 
 
 
• 
To remove the comparative Part 2 (regimens: nal-IRI + 5FU/LV and nab-paclitaxel + 
gemcitabine) and all related information (e.g., comparison versus nab-paclitaxel plus 
Gemcitabine; Arms 1, 2 and 3, randomization). 
• 
To add or modify inclusion criteria 
• 
To add, remove or modify exclusion criteria 
• 
To add clinical data in UGT1A1*28 homozygous patients 
• 
To update dose modification rules 
• 
To modify granulocyte Colony Stimulating Factors  
• 
To specify treatment infusion of 5-FU continued at home 
• 
To remove QTcF assessments and Appendix 5 (QT specific), which were specific to Part 2 
• 
Other changes were made for clarification or correction 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM 
UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN 
(RAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 


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Appendix 5: QTc Sub-study Protocol (Deleted in Protocol Version 6.0) 
The objective of the QTc sub-study is to evaluate the potential of QTcF prolongation with nal-
IRI treatment. Patients randomized to Arm 2 in Part 2 of the study will be enrolled in a QTc 
sub-study. For these patients, ECGs should be collected following the schedule outlined 
below. For each collection point, patients should be in a supine/semi-recumbent, resting 
position for at least 15 minutes. Recording should begin 10 minutes prior to the nominal 
collection time, as only the last 5 minutes of each recording will be used for analysis. 
Moreover, PK samples will be collected within 5 min after each ECG collections as specified 
in Table A and Figure A. 
Table A: Schedule of ECG and PK Sampling Times 
Cycle/Day 
Number of ECG 
Readings 
ECG Time Points 
PK Collection 
Cycle 1 Day 1 
3 
Pre-dose -30, -20 and -10 minutes 
Yes 
Cycle 1 Day 1 
1 
Post-dose nal-IRI 
Yes 
Cycle 1 Day 1 
1 
Post-dose LV infusion 
No 
Cycle 1 Day 1 
1 
60 minutes after initiating 5-FU 
infusion 
Yes 
Cycle 1 Day 3 
1 
60 minutes after completing 5-FU 
infusion 
Yes 
Cycle 1 Day 15 
1 
Pre-dose -10 minutes 
Yes 
Cycle 1 Day 15 
1 
Post-dose nal-IRI 
Yes 
Cycle 1 Day 15 
1 
Post-dose LV infusion 
No 
Cycle 1 Day 15 
1 
60 minutes after initiating 5-FU 
infusion 
Yes 
Cycle 1 Day 17 
1 
60 minutes after completing 5-FU 
infusion 
Yes 
 


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Figure A: Timing of ECG and PK Sampling in Arm 2 
 
The 12-lead Holter and ECG equipment will be supplied and supported by iCardiac 
Technologies, Inc. All ECG data will be collected using a Global Instrumentation (Manlius, 
NY, USA) M12R ECG continuous 12 lead digital recorder. The continuous 12-lead digital 
ECG data will be stored on SD memory cards. ECGs to be used in the analyses will be read 
centrally by iCardiac Technologies, Inc. 
The following principles will be followed in iCardiac’s core laboratory: 
x ECG analysts are blinded to the patient and visit allocation 
x Baseline and on-treatment ECGs for a particular patient will be over-read on the same 
lead and will be analyzed by the same reader. 
x The primary analysis lead is lead II.  If lead II is not analyzable, then primary lead of 
analysis will be changed to another lead for the entire patient data set. 
A description of ECG extraction and interval measurements with the High Precision QT 
technique is given in the iCardiac's ECG manual. 
Planned Statistical Methods 
Detailed plans for the statistical methods of the sub-study will be provided in a statistical 
analysis plan which will be finalized prior to database lock.  


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1. Determination of Sample Size 
Evaluation of QTcF will be performed in approximately 20 patients with evaluable QT and 
PK samples.  
The sample size of the QT sub-study is not based on a formal power calculation but is based 
on what is deemed feasible in this patient population. An estimate of the power can be 
obtained by looking at one test (one sided, one group), with a threshold of the QT effect 
(∆QTcF) of 20 ms and variability of ∆QTcF that is assumed to be substantially higher than in 
healthy volunteer studies. The table below gives the power of a test for non-inferiority (single 
group) against a threshold of 20 ms based on 20 patients at a one-sided 5% level assuming 
various values for the SD of the change from baseline. The threshold of 20 ms was selected 
based on regulatory feedback on other oncology programs [39]. With 20 evaluable patients, 
the probability that the upper bound of the 90% confidence interval to be less than 20 ms as a 
function of assumed underlying effects and standard deviation of the ∆QTcF is provided in 
Table B which show high precision in evaluating QTcF effects.   
Table B: Power to exclude a QT effect (∆QTcF) exceeding 20 ms 
Assumed Underlying Effect 
SD of ∆QTcF 
Power to Exclude 20 ms QTc Effecta 
0 
12 
1.00 
0 
15 
1.00 
0 
20 
1.00 
0 
25 
0.96 
3 
12 
1.00 
3 
15 
1.00 
3 
20 
0.98 
3 
25 
0.90 
5 
12 
1.00 
5 
15 
1.00 
5 
20 
0.94 
5 
25 
0.83 
10 
12 
0.97 
10 
15 
0.89 
10 
20 
0.70 
10 
25 
0.53 
a The upper bound of the 90% confidence interval will fall below 20 ms 
2. Analysis Populations 
Safety Set: consists of all patients enrolled in the sub-study, who received at least one dose of 
study drug. 
QTc Analysis Set: consists of all patients in the safety set who had ECG measurements at 
baseline as well as on-treatment data with at least 1 post-dose time point with a QTcF value.  
Pharmacokinetic (PK) Analysis Set: consists of all patients enrolled in the sub-study, which 
received the study drug and have at least one valid PK concentration measurement for study 
drug. 
PK/QTc Analysis Set: contains all patients in the QTc analysis and the PK analysis sets with 
at least one pair of post-dose PK and QTc data from the same timepoint. 
3. General Methodology 
All statistical analysis of the sub-study will be performed using the statistical software SAS 
for Windows Version 9.3 (SAS Institute, Inc., Cary, NC). Data collected from all patients 


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enrolled in the sub-study will be presented in data listings. Both absolute values and change 
from baseline for each patient will be given where applicable. All continuous data will be 
listed with the same precision as will be presented in the database. Data listings will be sorted 
by treatment, patient ID, and timepoint. Missing values will be represented by an empty cell 
and no imputation will be made. 
Continuous data will be summarized in tables using missing data count, mean, median, range, 
standard deviation (SD), standard error (SE), and 90% 2-sided confidence interval (CI; based 
on a t-distribution if not otherwise stated) by treatment and timepoint. All continuous data will 
be rounded to the nearest tenth. Categorical data (including the missing data category) will be 
summarized by treatment and timepoint using counts and percentages. Percentages will be 
rounded up or down to next integer percentage. Population counts for the sub-study will be 
used as the denominator in the calculation of percentages unless otherwise specified. 
4. Statistical Procedures and Descriptive Summaries 
The primary analysis to evaluate the potential of QTcF prolongation is based on the exposure-
response analysis with the objective to exclude a QT effect (∆QTcF) exceeding 20 ms. 
Additional analyses, including by-timepoint and categorical analyses, will be used as 
sensitivity analyses.  
Exposure-Response Analysis: The relationship between nal-IRI, SN-38 and 5-FU plasma 
concentrations and 'QTcF (change-from-baseline QTcF) will be investigated by a linear 
mixed effects modeling approach, that is: 
ΔQTcF ~ Intercept+C1 + C2 + C3 
with C1 is the concentration of total irinotecan, C2 is that of SN-38 and C3 is that of 5-FU. 
Any concentrations below BQL will be set to 0. Patients will be included in the model as a 
random effect for both intercept and slope, when applicable. Starting from this model, simpler 
models will be explored by removing those concentrations whose effects are not significant. 
In particular, a model without C3 (5-FU) will be explored, since this drug has a very short 
half-life. 
The model with the lowest AIC (the Akaike information criterion) will be used for predicting 
ΔQTcF. For each analyte (a) included in this model, a prediction will be made at the 
geometric mean Cmax of this analyte and the geometric mean concentration of the other 
analytes observed at Tmax of analyte (a). For each prediction, the predicted effect and its 2-
sided 90% CI for ΔQTcF will be obtained.  
Appropriateness of a linear model: To assess the appropriateness of a linear model, normal 
QQ-plots for the residuals and plots of weighted residuals vs. concentration and vs. fitted 
values will be produced. Examples of these plots are shown below: 
 
In addition, a model with interactions and quadratic terms in concentration will be fitted.  If 
there is an indication that a linear model is inappropriate or there is a relevant interaction 
between drugs, further exploratory modelling will be performed. This may include, but is not 
limited to: 
-3
-2
-1
0
1
2
3
-20
0
20
40
Normal Q-Q Plot
Theoretical Quantiles
Sample Quantiles
0
200
400
600
800
-2
0
2
4
Concentration
Standardized Residuals
-20
-10
0
10
20
-2
0
2
4
Fitted Values
Standardized Residuals


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x replacing the concentration C in the primary model by a log-transformation of C, e.g., 
log(C/C0), where C0 is the limit of quantification of the assay used to determine C and 
all values below C0 are replaced by C0 (i.e., log[C0/C0] = 0). 
x fitting a nonlinear model such as an Emax model. 
The exposure-response analysis will then be repeated for the model found to best 
accommodate the nonlinearity detected. 
By-Timepoint Analysis: 
In addition to the summaries described in Section 3, a model based by-timepoint analysis will 
be performed. The analysis for QTcF will be based on a linear mixed-effects model with 
'QTcF as the dependent variable, baseline QTcF as covariate, and time (categorical) as 
factor. An unstructured covariance matrix will be specified for the repeated measures at post-
dose timepoints within patient. If the model with unstructured covariance matrix fails to 
converge, other covariance matrix such as compound symmetry can be considered. For each 
timepoint, the LS-means will be given together with SE and 90 % CI. For change-from-
baseline HR, PR, QRS, QT and RR, the same model will be used as described for QTcF and 
the same results will be tabulated. The By-Timepoint-Analysis will be interpreted 
descriptively. 
The presence of hysteresis, i.e. a time-lag between Cmax and the largest QTc effect, will be 
graphically evaluated on an exploratory basis.  
Categorical Analysis: The analysis results for categorical outliers and T-wave morphology 
will be summarized in frequency tables with counts and percentages for both number of 
patients and number of timepoints. For categorical outliers, the number (percentage) of 
patients as well as timepoints with increases in QTcF from baseline of >30 and >60 msec and 
absolute QTcF values >450, >480, and >500 msec; increase in PR interval from baseline 
>25% and a PR interval >200 msec; increase in QRS interval from baseline >25% and a QRS 
interval >120 msec; decrease in HR from baseline >25% and a HR <50 bpm; and increase in 
HR from baseline >25% and a HR >100 bpm will be determined by each treatment group, 
respectively. For T-wave morphology, the analysis will be focused on the treatment-emergent 
changes. The T-wave morphology categories are described as follows: 
Category 
Description 
Normal T wave (+) 
Any positive T wave not meeting any criterion below 
Flat T wave 
T amplitude ≤1 mm (either positive or negative), including flat 
isoelectric line 
Notched T wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on 
ascending or descending arm of the positive T wave 
Biphasic 
T wave that contains a second component with an opposite 
phase that is at least 0.1 mV deep (both positive/negative and negative/positive and 
polyphasic T waves included) 
Normal T wave (-) 
T amplitude is negative, without biphasic T wave or notches 
Notched T wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on 
descending or ascending arm of the negative T wave 
All outliers will be summarized on the basis of incidence rates. A patient will be counted only 
once for a particular outlier event if the patient experiences more than one incidence of that 
event. 
 


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Appendix 8: Summary of Changes: 11 April 2018 (version 6.0) to 27 September 2019 (version 7.0) 
 
STUDY NUMBER: 
MM-398-07-02-03 
PROTOCOL TITLE: 
A RANDOMIZED, OPEN-LABEL PHASE 2 STUDY OF NANOLIPOSOMAL IRINOTECAN (NAL-IRI)-
CONTAINING REGIMENS VERSUS NAB-PACLITAXEL PLUS GEMCITABINE IN PATIENTS WITH 
PREVIOUSLY UNTREATED, METASTATIC PANCREATIC ADENOCARCINOMA 
AMENDED PROTOCOL 
VERSION NUMBER & DATE 
Version 7.0, 27 September 2019 
 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: Underlined text in “Was” indicates deleted text; Bold text in “Is” indicates new text. This does not apply to 
tables. 
 
Version Date 
11 APRIL 2018 (VERSION 6.0) 
27 SEPTEMBER 2019 (VERSION 7.0) 
Page  
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16 
Synopsis 
 
Length of Study 
Following fulfilment of analysis requirements for the 
primary and/or secondary endpoints, the sponsor may elect 
to transition patients that are still receiving treatment or 
are being followed for OS to an extension phase of the 
study. 
65 
11 
Following fulfillment of analysis requirements for the primary 
and/or secondary endpoints, the Sponsor may elect to close the 
study. At that time, all patients receiving treatment will be 
permitted to transition into the extension phase of the study, 
and will continue to receive treatment until disease progression, 
death, unacceptable study drug related toxicity, patient refusal, 
or start of any new anticancer treatment, whichever occurs first 
(see Section 5.3 for other discontinuation criteria). 
Central collection of data will not be required for patients 
entering the extension phase of the study; only serious adverse 
events will be collected. Investigators may perform standard 
procedures and tests needed to treat and evaluate patients; 
Following fulfillment of analysis requirements for the primary 
and/or secondary endpoints, the Sponsor may elect to 
transition patients that are still receiving treatment or are 
being followed for OS to an extension phase of the study.  
Patients will continue to be followed for OS every 4 months.  
Patients still receiving treatment will continue to receive this 
until disease progression, death, unacceptable study medication 
related toxicity or withdrawal of consent (see Section 5.3 for 
other discontinuation criteria). 
For patients receiving treatment in the extension phase of 
the study only OS and treatment-related SAEs will be 


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however, the results of these assessments will not be routinely 
reported. In the event that an SAE occurs, additional 
information (such as local laboratory results, concomitant 
medications, and procedures) may be requested by the Sponsor 
in order to evaluate the reported SAE. The patient’s 
participation in the study extension will be completed once 
study treatment is discontinued. There will be no post 
discontinuation period in the extension phase of the protocol. 
collected in the eCRF. In the event that an SAE occurs, 
additional information (such as local laboratory results, 
concomitant medications, and procedures) may be requested by 
the Sponsor in order to evaluate the reported SAE, although 
this additional information does not need to be captured in 
the eCRF. Investigators may perform standard procedures and 
tests needed to treat and evaluate patients; however, the results 
of these assessments will not be routinely reported. The 
extension phase of the study will be completed once all 
patients have died, withdraw consent, or lost to follow-up 
after two attempts on OS follow-up. 


IPSEN GROUP 
PROTOCOL MM-398-07-02-03 
VERSION 7.0 – 27 SEPTEMBER 2019 
 
Proprietary and Confidential 
 
Page 168 of 168 
SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
MM-398-07-02-03 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Version 7.0, 27 September 2019 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
OBJECTIVE(S) OF PROTOCOL 
AMENDMENT 
 
 
• 
To clarify the extension part of the study will collect very limited data (only treatment-related SAEs 
and OS) with no study procedures apart from patients continuing on study medication for as long their 
treating physician feels they derive benefit. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
No 
 
 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN 
(RAP) UPDATE 
Yes 
 
No 
 
 
 
(tick one) 
 
 


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Summary of Changes 
Regarding compound MM-398, this is a Summary of Changes for Protocol MM-398-07-02-03, 
“A Randomized, Open-label Phase 2 Study of Nanoliposomal Irinotecan (nal-IRI)-containing 
Regimens versus nab-Paclitaxel plus Gemcitabine in Patients with Previously Untreated, 
Metastatic Pancreatic Adenocarcinoma”, from Version 1.0 to Version 2.1.  
General Changes and Note 
Protocol MM-398-07-02-03 is being amended to address changes to the planned statistical 
analyses and to incorporate the addition of electrocardiogram studies paired with time-matched 
pharmacokinetic sampling to assess possible changes in QTc intervals. 
In addition to the two protocol changes, several administrative changes have been made.  
 
 
Version No: 
Version Date 
Replaced Approved Protocol 
1.0 
26 Jun 2015 
Current Approved Protocol  
2.0 
24 Mar 2016 


 
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Changes to Protocol MM-398-07-02-03 Version 1.0 to Version 2.0 
Section No. or Title 
Current Protocol Text: 
Version 2.1 
Amended Protocol Text: 
Version 2.2 
Rationale 
List of Abbreviations 
N/A 
QTcF:  QT interval, Fridericia 
correction 
The addition of calculations of QT 
interval measurement to the protocol. 
Section 1.2.1.1:  Nal-IRI Pre-Clinical 
Pharmacokinetics 
Section 1.2.2.1:  Nal-IRI PK in Humans 
Section 1.3.1:  Rationale for Arm 1: Nal-
IRI + 5-FU/LV + 
Oxaliplatin 
Free irinotecan 
Non-liposomal irinotecan 
All instances of “free irinotecan” have 
been changed to “non-liposomal 
irinotecan” to more accurately reflect 
irinotecan that is not encapsulated in a 
nanoliposome drug delivery system. 
Section 2.2.1:  Primary Objectives 
To assess efficacy of nal-IRI-
containing regimens in first-line 
metastatic pancreatic cancer 
patients compared to nab-
paclitaxel + gemcitabine using 
the progression free survival 
(PFS) rate at 24 weeks 
To assess efficacy of nal-IRI-
containing regimens in first-line 
metastatic pancreatic cancer 
patients compared to nab-
paclitaxel + gemcitabine using 
progression free survival (PFS) 
The primary endpoint was changed to 
PFS to enable a more sensitive analysis 
of the primary endpoint analysis. 
Assuming a median PFS time of 5.5 
months in the control arm and 
exponential distribution for PFS, an 
increase in PFS at 24 weeks from 50% 
to 70% implies a hazard ratio of 0.55. 
The amendment planned analysis of 
PFS has 88% power for HR=0.55.  
Consequently, the endpoint was 
changed to the more informative 
standard PFS endpoint. 


 
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Section No. or Title 
Current Protocol Text: 
Version 2.1 
Amended Protocol Text: 
Version 2.2 
Rationale 
Section 2.2.2:  Secondary Objectives 
•  To assess the efficacy of each 
nal-IRI-containing regimen 
relative to nab-paclitaxel + 
gemcitabine using overall 
survival (OS), PFS, and 
objective response rate (ORR; 
CR + PR, per RECIST v1.1) 
•  To assess tumor marker 
CA19-9 response in each nal-
IRI-containing regimen 
relative to nab-paclitaxel + 
gemcitabine  
•  To assess health-related 
quality of life (HRQL) using 
the European Organization for 
Research and Treatment of 
Cancer (EORTC) quality-of-
life core questionnaire 
(EORTC-QLQ-C30) and 
European Quality of Life 
Questionnaire (EQ-5D-5L) in 
each arm 
•  To compare the safety and 
adverse event profile between 
the treatment arms 
•  To assess the efficacy of each 
nal-IRI-containing regimen 
relative to nab-paclitaxel + 
gemcitabine using overall 
survival (OS) and objective 
response rate (ORR; CR + PR, 
per RECIST v1.1) 
•  To assess tumor marker 
CA19-9 response in each nal-
IRI-containing regimen 
relative to nab-paclitaxel + 
gemcitabine  
•  To assess health-related 
quality of life (HRQL) using 
the European Organization for 
Research and Treatment of 
Cancer (EORTC) quality-of-
life core questionnaire 
(EORTC-QLQ-C30) and 
European Quality of Life 
Questionnaire (EQ-5D-5L) in 
each arm 
•  To compare the safety and 
adverse event profile between 
the treatment arms  
•  To assess the potential for 
QTcF prolongation with nal-
IRI treatment 
The primary endpoint was changed to 
PFS to enable a more sensitive analysis 
at the planned timing of the primary 
endpoint analysis and so this endpoint 
was removed from secondary endpoints. 
  
The addition of ECG readings and time-
matched PK sample collections for 
evaluation of QTc prolongation. 


 
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Section No. or Title 
Current Protocol Text: 
Version 2.1 
Amended Protocol Text: 
Version 2.2 
Rationale 
Section 2.2.3:  Exploratory Objectives 
•  To evaluate blood samples and 
archived tumor tissue for 
potential biomarkers that may 
correlate with nal-IRI PK, 
toxicity, and/or response 
•  To evaluate the relationship 
between plasma PK of nal-IRI 
(total irinotecan, SN-38), 
oxaliplatin and efficacy and 
safety endpoints in first-line 
metastatic pancreatic cancer 
•  To evaluate blood samples and 
archived tumor tissue for 
potential biomarkers that may 
correlate with nal-IRI PK, 
toxicity, and/or response 
To more fully characterize the PK 
profile of the nal-IRI +5-FU/LV 
regimen in first-line treatment for 
metastatic pancreatic cancer. 
Section 3.0:  Study Design 
 
 
Amended to reflect the change from 
PFS at 24 weeks to PFS. 
Section 3.1:  Study Design Overview 
(Part 2, Paragraph 1) 
Part 2 will consist of an open-
label, randomized, Phase 2 study 
where patients will be 
randomized to treatment (1:1:1) 
to either nal-IRI + 5-FU/LV + 
oxaliplatin, nal-IRI + 5-FU/LV, 
Part 2 will consist of an open-
label, randomized, Phase 2 study 
where patients will be 
randomized to treatment (1:1:1) 
to either nal-IRI + 5-FU/LV + 
oxaliplatin, nal-IRI + 5-FU/LV, 
The addition of ECG readings and time-
matched PK sample collections for 
evaluation of any possible QTc 
prolongation by nal-IRI in Arm 2. 


 
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Section No. or Title 
Current Protocol Text: 
Version 2.1 
Amended Protocol Text: 
Version 2.2 
Rationale 
or nab-paclitaxel + gemcitabine. 
The randomization will be 
stratified based on region (East 
Asia  vs. rest of the world) and 
performance status (ECOG 0 vs. 
1).  During Part 2, a regular 
review of safety data will be 
conducted by an independent 
Data and Safety Monitoring 
Board (DSMB). The DSMB will 
consist of oncology and 
statistical experts, independent 
of the Sponsor. The timing of the 
safety reviews, and the workings 
of the DSMB, will be detailed in 
the DSMB charter.  The DSMB 
is a precaution in the event of 
unanticipated toxicities, and the 
study will not be stopped early 
on the basis of differences in 
efficacy, therefore no 
prospective adjustment of the 
final significance levels is 
planned on the basis of this 
review.   
or nab-paclitaxel + gemcitabine. 
The randomization will be 
stratified based on region (East 
Asia  vs. rest of the world) and 
performance status (ECOG 0 vs. 
1). Patients randomized to nal-
IRI + 5-FU/LV will undergo 
serial ECG recordings and time-
matched pharmacokinetic 
sampling to assess any 
relationship between blood 
levels of nal-IRI and possible 
changes in QTc intervals. 
During Part 2, a regular review 
of safety data will be conducted 
by an independent Data and 
Safety Monitoring Board 
(DSMB). The DSMB will 
consist of oncology and 
statistical experts, independent 
of the Sponsor. The timing of the 
safety reviews, and the workings 
of the DSMB, will be detailed in 
the DSMB charter.  The DSMB 
is a precaution in the event of 
unanticipated toxicities, and the 
study will not be stopped early 
on the basis of differences in 
efficacy, therefore no 
prospective adjustment of the 
final significance levels is 
planned on the basis of this 
review.   
Section 5.1:  Inclusion Criteria 
f)  Adequate renal function as 
f)  Adequate renal function as 
Creatinine clearance was changed to 


 
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Section No. or Title 
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Amended Protocol Text: 
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Rationale 
evidenced by serum 
creatinine ≤ 1.5 x ULN, and 
calculated clearance ≥60 
mL/min/1.72 m2 for patients 
with serum creatinine levels 
above or below the 
institutional normal value. 
Actual body weight should be 
used for calculating creatinine 
clearance using the 
Cockcroft-Gault Equation 
(CreatClear = Sex * ((140 - 
Age) / (SerumCreat)) * 
(Weight / 72); for patients 
with body mass index (BMI) 
>30 kg/m2, lean body weight 
should be used instead. 
evidenced by serum 
creatinine ≤ 1.5 x ULN, and 
calculated clearance ≥60 
mL/min/1.73 m2 for patients 
with serum creatinine levels 
above or below the 
institutional normal value. 
Actual body weight should be 
used for calculating creatinine 
clearance using the 
Cockcroft-Gault Equation 
(CreatClear = Sex * ((140 - 
Age) / (SerumCreat)) * 
(Weight / 72); for patients 
with body mass index (BMI) 
>30 kg/m2, lean body weight 
should be used instead. 
correct the value to the accepted 
standard. 
Section 5.2:  Exclusion Criteria 
c)  Known metastasis to the 
central nervous system. 
n)  Pregnant or breast feeding; 
females of child-bearing 
potential must test negative 
for pregnancy at the time of 
enrollment based on a urine 
or serum pregnancy test. Both 
male and female patients of 
reproductive potential must 
agree to use a highly effective 
method of birth control, 
during the study and for 3 
months following the last 
dose of study drug. 
c)  Uncontrolled CNS metastases 
(patients who require steroids 
should be on a stable or 
decreasing dose) 
n)  Pregnant or breast feeding; 
females of child-bearing 
potential must test negative 
for pregnancy at the time of 
enrollment based on a urine 
or serum pregnancy test. 
Both male and female 
patients of reproductive 
potential must agree to use a 
highly effective method of 
birth control, during the study 
and for 4 months following 
the last dose of study drug. 
CNS metastases, as long as they are 
controlled, should not be a de novo 
exclusion for patients with solid tumors 
on clinical studies. 
 
To align with the Onivyde (irinotecan 
liposome injection) USPI. 


 
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Section No. or Title 
Current Protocol Text: 
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Amended Protocol Text: 
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Rationale 
Section 6.1.1:  Description of Nal-IRI 
Nal-IRI (irinotecan liposome 
injection, also known MM-398) 
is irinotecan in the form of the 
sucrosofate salt, encapsulated in 
liposomes for intravenous 
infusion.  It will be supplied in 
sterile, single-use vials 
containing 10 mL or 9.5 mL of 
nal-IRI at a concentration of 5 
mg/mL. nal-IRI must be stored 
refrigerated at 2 to 8°C, with 
protection from light. The 
appearance of MM-398 is white 
to slightly yellow opaque liquid. 
Nal-IRI (irinotecan liposome 
injection, also known MM-398) 
is irinotecan in the form of the 
sucrosofate salt, encapsulated in 
liposomes for intravenous 
infusion.  It will be supplied in 
sterile, single-use vials 
containing 10 mL of nal-IRI at a 
concentration of 5 mg/mL. nal-
IRI must be stored refrigerated at 
2 to 8°C, with protection from 
light. The appearance of MM-
398 is white to slightly yellow 
opaque liquid. 
To align with current investigational 
drug supply. 
Section 6.1.1.1:  Storage and Handling of 
Nal-IRI 
Nal-IRI must be diluted prior to 
administration.  The diluted 
solution is physically and 
chemically stable for 6 hours at 
room temperature (15-30°C), but 
it is preferred to be stored at 
refrigerated temperatures (2-
8°C), and protected from light. 
The diluted solution must not be 
frozen.  Because of possible 
microbial contamination during 
dilution, it is advisable to use the 
diluted solution within 24 hours 
if refrigerated (2-8°C), and 
within 6 hours if kept at room 
temperature (15-30°C). 
Nal-IRI must be diluted prior to 
administration.  The diluted 
solution is physically and 
chemically stable for 4 hours at 
room temperature (15-25°C), but 
it is preferred to be stored at 
refrigerated temperatures (2-
8°C), and protected from light. 
The diluted solution must not be 
frozen.  Because of possible 
microbial contamination during 
dilution, it is advisable to use the 
diluted solution within 24 hours 
if refrigerated (2-8°C), and 
within 4 hours if kept at room 
temperature (15-25°C). 
To align with the Onivyde (irinotecan 
liposome injection) USPI. 
Section 6.3.1:  Arm 1: Nal-IRI + 5-
FU/LV + Oxaliplatin 
The order of the infusions to be 
administered in the clinic will be 
as follows: nal-IRI will be 
administered first, followed by 
The order of the infusions to be 
administered in the clinic will be 
as follows: nal-IRI will be 
administered first, followed by 
Language change to clarify the timing 
of administration of leucovorin. 


 
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Section No. or Title 
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oxaliplatin, then LV, followed 
by 5-FU. 
In Part 1, patients will receive 
the oxaliplatin infusion 2 hours 
after the completion of the MM-
398 infusion. If no infusion 
reactions are seen, Part 2 patients 
can receive oxaliplatin directly 
after completion of the MM-398 
infusion. If any grade 3 or higher 
infusion reactions are seen in 
Part 2 patients, the DSMB may 
elect to revert back to 
administration of oxaliplatin two 
hours after the completion of the 
MM-398 infusion. 
oxaliplatin, then LV, followed 
by 5-FU. 
In Part 1, patients will receive 
the oxaliplatin infusion 2 hours 
after the completion of the MM-
398 infusion and will receive 
leucovorin 30 min after 
oxaliplatin. If no infusion 
reactions are seen, Part 2 patients 
can receive oxaliplatin directly 
after completion of the MM-398 
infusion and leucovorin directly 
after completion of oxaliplatin. 
If any grade 3 or higher infusion 
reactions are seen in Part 2 
patients, the DSMB may elect to 
revert back to the original 
observation periods. 


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Section No. or Title 
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Amended Protocol Text: 
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Section 6.3.3:  Doses and Administration 
of Nal-IRI
(Arms 1 and 2) 
Nal-IRI will be administered by 
intravenous (IV) infusion over 
90 minutes (±10 minutes) every 
two weeks.  The first cycle Day 
1 is a fixed day; subsequent 
doses should be administered on 
the first day of each cycle +/- 2 
days.     
Prior to administration, the 
appropriate dose of nal-IRI must 
be diluted in 5% Dextrose 
Injection solution (D5W) or 
normal saline to a final volume 
of 500 mL. Care should be taken 
not to use in-line filters or any 
diluents other than D5W or 
normal saline.  Nal-IRI can be 
administered at a rate of up to 1 
mL/sec (30 mg/sec). 
Nal-IRI will be administered at a 
dose of 80 mg/m2 as an IV 
infusion over 90 minutes (±10 
minutes), on Days 1 and 15 of 
each 28-day cycle.  The first 
cycle Day 1 is a fixed day; 
subsequent doses should be 
administered on the first day of 
each cycle +/- 2 days.     
Prior to administration, the 
appropriate dose of nal-IRI must 
be diluted in 5% Dextrose 
Injection solution (D5W) or 
0.9% Sodium Chloride Injection 
to a final volume of 500 mL. 
Care should be taken not to use 
any diluents other than D5W or 
0.9% sodium chloride.   
Language change to clarify the 
preparation and administration of nal-
IRI.
Section 6.3.4:  Doses and Administration 
of 5-FU and Leucovorin 
(Arms 1 and 2) 
Leucovorin should be 
administered prior to the 5-FU 
infusion (on Arm 1, leucovorin 
will be given concurrently with 
oxaliplatin, see Section 7.3.1).  
Actual dose of 5-FU and 
leucovorin to be administered 
will be determined by 
calculating the patient’s body 
surface area prior to each cycle.  
A +/- 5% variance in the 
calculated total dose will be 
allowed for ease of dose 
administration. 
Leucovorin should be 
administered prior to the 5-FU 
infusion (on Arm 1, leucovorin 
will not be given concurrently 
with oxaliplatin, see Section 
7.3.1).  Actual dose of 5-FU and 
leucovorin to be administered 
will be determined by 
calculating the patient’s body 
surface area prior to each cycle.  
A +/- 5% variance in the 
calculated total dose will be 
allowed for ease of dose 
administration. 
Language change to clarify the timing 
of leucovorin administration relative to 
oxaliplatin.
Section 6.7.1:  Antiemetic Medications 
Dexamethasone and a 5-HT3 
Dexamethasone and a 5-HT3 
To avoid the possible confounding 


 
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Rationale 
blocker (e.g., ondansetron or 
granisetron) will be administered 
as premedications to all patients 
assigned to Arm 1 and Arm 2 
unless contraindicated for the 
individual patient. Antiemetics 
will also be prescribed as 
clinically indicated during the 
study period. 
blocker (e.g., ondansetron or 
granisetron) will be administered 
as premedications to all patients 
assigned to Arm 1 and Arm 2 
unless contraindicated for the 
individual patient. For patients 
randomized to Arm 2, during 
cycle 1 ECG monitoring, 
consider alternatives to 5-HT3 
blockers which have been 
associated with QT changes.  
Antiemetics will also be 
prescribed as clinically indicated 
during the study period. 
effects of 5-HT3 blockers during QTc 
monitoring. 
Section 7.2.4:  Electrocardiogram (ECG) 
A 12 lead ECG will include a 
description of the cardiac rate, 
rhythm, interval durations and an 
overall impression. If ECG is 
abnormal, clinical significance 
should be indicated. 
A 12 lead ECG will include a 
description of the cardiac rate, 
rhythm, interval durations and an 
overall impression. If ECG is 
abnormal, clinical significance 
should be indicated. 
In Part 2, patients randomized to 
Arm 2 will be enrolled in a QTc 
study evaluating sequential 
collection of ECGs. For these 
patients, ECG readings should 
be collected as outlined in 
Appendix 5. 
Serial ECG testing added to Arm 2 to 
assess for possible changes in QTc 
intervals caused by nal-IRI. 
Section 7.3.5:  Biomarker Samples 
Whole blood and plasma will be 
collected to potentially identify 
factors that may correlate with 
tumor response, sensitivity or 
resistance to nal-IRI, and nal-IRI 
PK.  Examples of potential 
analyses include cytokine levels 
Whole blood, serum and plasma 
will be collected to potentially 
identify factors that may 
correlate with tumor response, 
sensitivity or resistance to nal-
IRI, and nal-IRI PK.  Examples 
of potential analyses include 
To clarify that serum samples will also 
be collected for biomarker analysis. 


 
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Section No. or Title 
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Amended Protocol Text: 
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Rationale 
(e.g. MCSF1, and IL-6), growth 
factors (e.g. IGF1 and EGFR 
family receptors and ligands), 
enzyme levels (e.g. MMP9). 
cytokine levels (e.g. MCSF1, 
and IL-6), growth factors (e.g. 
IGF1 and EGFR family 
receptors and ligands), enzyme 
levels (e.g. MMP9). 
Section 7.3.7:  Pharmacokinetic 
Assessments 
8.3.7:  Pharmacokinetic 
Assessments (Arm 1 
Only) 
Since the combination of nal-IRI 
and oxaliplatin has not yet been 
tested in the clinic, plasma 
samples will be collected to 
determine the levels of nal-IRI 
and SN-38, as well as 5-FU and 
oxaliplatin, in Arm 1 patients.  
Additional analytes which may 
impact the pharmacokinetics of 
nal-IRI may also be measured 
from this sample. Directions for 
processing and shipping the PK 
plasma samples can be found in 
the study manual. The PK time 
points outlined in the Table 12 
below will be drawn during 
Cycle 1 only. PK samples will 
be collected during Parts 1 and 2 
of the study. 
 
 
 
 
 
 
 
7.3.7:  Pharmacokinetic 
Assessments 
7.3.7.1: Arm 1 
Since the combination of nal-IRI 
and oxaliplatin has not yet been 
tested in the clinic, plasma 
samples will be collected to 
determine the levels of nal-IRI 
and SN-38, as well as 5-FU and 
oxaliplatin, in Arm 1 patients.  
Additional analytes which may 
impact the pharmacokinetics of 
nal-IRI may also be measured 
from this sample. Directions for 
processing and shipping the PK 
plasma samples can be found in 
the study manual. The PK time 
points outlined in Table 12 
below will be drawn during 
Cycle 1 only. PK samples will 
be collected during Parts 1 and 2 
of the study. 
 
 
 
 
 
 
 
Pharmacokinetic sampling added to 
Arm 2 to evaluate any relationship 
between blood levels of nal-IRI and 
possible changes in QTc intervals. 


 
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Table 12:  Summary of PK 
Timepoints for Arm 
1 
Sample 
Time-point  
1 
Prior to nal-IRI infusion o
2 
At the end of the nal-IRI 
3 
At the end of the oxalipla
4 
Within 2 hours prior to th
5 
+168 hours/7 days after t
6 
Prior to nal-IRI infusion o
7 
End of Treatment visit (3
*The number of draws corresponds to 
the number of analytes that will be 
measured; for example, sample #3 at the 
end of the oxaliplatin infusion will be 
used to measure nal-IRI and oxaliplatin.  
 
Table 12:  Summary of PK 
Timepoints for Arm 
1 
Sample 
Time-point  
1 
Prior to nal-IRI infusion 
2 
At the end of the nal-IRI 
3 
At the end of the oxalipla
4 
Within 2 hours prior to th
5 
+168 hours/7 days after t
6 
Prior to nal-IRI infusion 
7 
End of Treatment visit (3
*The number of draws corresponds to 
the number of analytes that will be 
measured; for example, sample #3 at the 
end of the oxaliplatin infusion will be 
used to measure nal-IRI and oxaliplatin.  
7.3.7.2 Arm 2 
Patients who are randomized to 
Arm 2 will undergo collection of 
blood samples in order to assess 
the relationship between blood 
levels of nal-IRI, SN-38 and 5-
FU and ECG findings. 
Directions for collecting, 
processing and shipping the PK 
plasma samples can be found in 
the study manual. PK samples 
will be collected in Cycle 1 only 
as outlined in Table 13 below. 
 
 
 


 
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Table 13:  Summary of PK 
Timepoints for Arm 
2 
Sample 
Time-point  
1 
Pre-dose Day 1  
2 
After the ECG conducte
nal-IRI infusion on Day 
3 
After the ECG conducte
Day 1 
4 
After the ECG conducte
46-hour 5-FU infusion o
5 
After the pre-dose ECG 
15  
6 
After the ECG conducte
infusion on Day 15 
7 
After the ECG conducte
Day 15 
8 
After the ECG conducte
FU infusion on Day 15 
*The number of draws corresponds to 
the number of analytes that will be 
measured; for example, sample #3 at the 
60 minute mark of the 5-FU infusion 
will be used to measure nal-IRI and 5-
FU.  
Section 8.0:  Schedule of Assessments 
N/A 
See Table 
The schedule of assessments was 
updated to reflect the addition of ECG 
and PK testing to Arm 2, and to add the 
collection of serum for biomarker 
analysis. 
Section 10.6: Efficacy Analysis 
In the assessments of efficacy, 
each nal-IRI-containing arm will 
In the assessments of efficacy, 
each nal-IRI-containing arm will 
The primary endpoint was changed to 
PFS to enable a more sensitive analysis 


 
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be compared to the control arm. 
Efficacy comparisons will use 
stratified analyses, incorporating 
randomization strata. Each 
comparison will be use 0.10 
level one-sided testing to 
evaluate whether the nal-IRI-
containing arm improves the 
efficacy parameter. Confidence 
intervals will be presented at 
two-sided 95% level for 
descriptive purposes. Hypothesis 
tests and confidence intervals 
will not be adjusted for multiple 
comparisons. The primary 
efficacy comparisons will be 
based on the ITT population, 
which will included all 
randomized patients.  
Tumor evaluation will be 
measured according to RECIST 
v1.1. For each patient, 
progression free survival time 
will be determined as the time 
from randomization (for patients 
in Part 1, the reference start time 
will be date of first study drug) 
to the first documented 
radiographical progression of 
disease (PD), per investigator 
using RECIST 1.1, or death from 
any cause, whichever comes 
first. If the progression or death 
occurs at a time point that is 
be compared to the control arm. 
Efficacy comparisons will use 
stratified analyses, incorporating 
randomization strata. Each 
comparison will be use 0.10 
level one-sided testing to 
evaluate whether the nal-IRI-
containing arm improves the 
efficacy parameter. Confidence 
intervals will be presented at 
two-sided 95% level for 
descriptive purposes. Hypothesis 
tests and confidence intervals 
will not be adjusted for multiple 
comparisons and consequently 
the experiment-wise type I error 
may be greater than the 0.10 
level. The primary efficacy 
comparisons will be based on the 
ITT population, which will 
included all randomized patients.  
Tumor evaluation will be 
measured according to RECIST 
v1.1. For each patient, 
progression free survival time 
will be determined as the time 
from randomization (for patients 
in Part 1, the reference start time 
will be date of first study drug) 
to the first documented 
radiographical progression of 
disease (PD), per investigator 
using RECIST 1.1, or death from 
any cause, whichever comes 
of the primary endpoint analysis. 
Assuming a median PFS time of 5.5 
months in the control arm and 
exponential distribution for PFS, an 
increase in PFS at 24 weeks from 50% 
to 70% implies a hazard ratio of 0.55. 
The amendment planned analysis of 
PFS has 88% power for HR=0.55.  
Consequently, the endpoint was 
changed to the more informative 
standard PFS endpoint. 
 


 
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greater than 12 weeks after the 
non-PD last tumor assessment, 
then progression-free survival 
time will be censored at the time 
of the last non-PD tumor 
assessment. 
A primary analysis will be 
conducted when the Week 24 
progression-free status for all 
randomized patients can be 
determined, anticipated at 
approximately 24 weeks after the 
last patient is randomized. A 
subsequent analysis for PFS and 
other endpoints will be 
performed when PFS events 
have occurred in at least 120 (i.e. 
80% of randomized patients) 
patients. 
 
Primary Efficacy Analysis 
In the intention-to-treat (ITT) 
analysis, a patient will be 
considered to have achieved 
progression-free survival at 24 
weeks if the patient has data to 
indicate the patient has not 
progressed at 24 weeks. That is, 
a patient will be considered a 
responder if there is at least one 
non-PD assessment, prior to 
progression or new anticancer 
therapy, at Week 24 or later.  
Patients who do not meet the 24-
first. If the progression or death 
occurs at a time point that is 
greater than 12 weeks after the 
non-PD last tumor assessment, 
then progression-free survival 
time will be censored at the time 
of the last non-PD tumor 
assessment. Details on censoring 
rules will be provided in the 
study statistical analysis plan.  
A primary analysis will be 
conducted when there are at least 
70 PFS events for each 
comparison to the control arm. A 
subsequent analysis for PFS and 
other endpoints will be 
performed when PFS events 
have occurred in at least 120 (i.e. 
80% of randomized patients) 
patients. 
 
Primary Efficacy Analysis 
For each arm, PFS will be 
descriptively summarized for 
each arm using Kaplan-Meier 
methodology. Median PFS time 
and corresponding 95% 
confidence limits will be 
presented. For each nal-IRI-
containing arm, PFS will be 
compared to the control arm. 
Hypothesis tests will be 
conducted for differences in PFS 
using a one-sided stratified log-


 
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week progression-free 
achievement criteria (e.g. 
patients progressed/died up to 
Week 24, patients censored prior 
to Week 24), If progression or 
death occurs at a time point that 
is greater than 12 weeks after the 
non-PD last tumor assessment.   
For each arm, the progression-
free survival achievement rate at 
24 weeks will be estimated by 
the number of patients meeting 
the 24 week achievement criteria 
divided by the number of ITT 
patients in the arm. The rate 
estimates will  be presented with 
corresponding 95% confidence 
intervals. Each nal-IRI 
containing arm will be assessed 
for increase in rate relative to the 
control arm using a one-sided 
Cochran-Mantel-Haenszel test, 
incorporating randomization 
stratification factors, at 0.10 
level of significance. 
 
Secondary Efficacy Analyses 
Progression-free Survival (PFS) 
will be descriptively summarized 
for each arm using Kaplan-Meier 
methodology. Median PFS time 
and corresponding 95% 
confidence limits will be 
presented. For each nal-IRI-
rank test. Hazard ratios (with 
95% confidence interval) for 
PFS will be estimated using 
stratified Cox models. 
 
Secondary Efficacy Analyses 
Best Overall Response (BOR) is 
defined as the best response as 
recorded from the start of study 
drug until disease progression. 
Patients without a post-baseline 
tumor assessment will be 
considered to be non-evaluable 
for BOR. To classify BOR as 
stable disease (SD), there should 
be a qualifying SD assessment at 
least 6 weeks from 
randomization. Objective 
Response Rate (ORR) is defined 
as the proportion of patients with 
a BOR characterized as either a 
Complete Response (CR) or 
Partial Response (PR) relative to 
the total number of evaluable 
patients. Only patients with 
measurable disease at baseline 
will be included in the analysis 
of the objective response. 
Estimates of objective response 
rate and its corresponding 95% 
CI will be calculated for each 
treatment arm.  For each nal-IRI-
containing arm, ORR will be 
compared to the control arm. 


 
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containing arm, PFS will be 
compared to the control arm. 
Hypothesis tests will be 
conducted for differences in PFS 
using a one-sided stratified log-
rank test. Hazard ratios (with 
95% confidence interval) for 
PFS will be estimated using 
stratified Cox models. 
Best Overall Response (BOR) is 
defined as the best response as 
recorded from the start of study 
drug until disease progression. 
Patients without a post-baseline 
tumor assessment will be 
considered to be non-evaluable 
for BOR. To classify BOR as 
stable disease (SD), there should 
be a qualifying SD assessment at 
least 6 weeks from 
randomization. Objective 
Response Rate (ORR) is defined 
as the proportion of patients with 
a BOR characterized as either a 
Complete Response (CR) or 
Partial Response (PR) relative to 
the total number of evaluable 
patients. Only patients with 
measurable disease at baseline 
will be included in the analysis 
of the objective response. 
Estimates of objective response 
rate and its corresponding 95% 
CI will be calculated for each 
Differences in objective 
response rate between each nal-
IRI-containing arm and control 
arm will be provided with 95% 
CIs. Cochran-Mantel-Haenszel 
tests, adjusting by randomization 
strata, will be used to compare 
objective response rates. 
The maximum reduction (% 
change from baseline) in CA19-
9 will be computed, including 
analyses by time period (up to 
Week 8, 16 and 24 visits).  CA 
19-9 response analyses will be 
carried out using 3 thresholds for 
maximum reduction: ≥ 20%, 
≥50%, ≥90%. A patient without 
post-baseline CA19-9 
measurement will be considered 
as a non-responder. Only 
patients with CA 19-9 elevated 
(>37 U/mL) at baseline will be 
included in the analysis of the 
CA19-9 response. For each 
threshold and time period, the 
proportion of CA19-9 response 
will be estimated, along with 
corresponding 95% confidence 
intervals, by treatment arm.  
Overall Survival (OS) is the time 
from randomization to the date 
of death from any cause. Patients 
who are alive or lost to follow-
up at the time of the analysis will 


 
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treatment arm.  For each nal-IRI-
containing arm, ORR will be 
compared to the control arm. 
Differences in objective 
response rate between each nal-
IRI-containg arm and control 
arm will be provided with 95% 
CIs. Cochran-Mantel-Haenszel 
tests, adjusting by randomization 
strata, will be used to compare 
objective response rates. 
The maximum reduction (% 
change from baseline) in CA19-
9 will be computed, including 
analyses by time period (up to 
Week 8, 16 and 24 visits).  CA 
19-9 response analyses will be 
carried out using 3 thresholds for 
maximum reduction: ≥ 20%, 
≥50%, ≥90%. A patient without 
post-baseline CA19-9 
measurement will be considered 
as a non-responder. Only 
patients with CA 19-9 elevated 
(>37 U/mL) at baseline will be 
included in the analysis of the 
CA19-9 response. For each 
threshold and time period, the 
proportion of CA19-9 response 
will be estimated, along with 
corresponding 95% confidence 
intervals, by treatment arm.  
Overall Survival (OS) is the time 
from randomization to the date 
be censored at the last known 
alive date. OS  will be 
descriptively summarized for 
each arm using Kaplan-Meier 
methodology. For each nal-IRI-
containing arm, OS will be 
compared to the control arm. 
Hypothesis tests will be 
conducted for differences in OS 
using a one-sided stratified log-
rank test. Hazard ratios (with 
95% confidence interval) for 
PFS will be estimated using 
stratified Cox models. 


 
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of death from any cause. Patients 
who are alive or lost to follow-
up at the time of the analysis will 
be censored at the last known 
alive date. OS  will be 
descriptively summarized for 
each arm using Kaplan-Meier 
methodology. For each nal-IRI-
containing arm, OS will be 
compared to the control arm. 
Hypothesis tests will be 
conducted for differences in OS 
using a one-sided stratified log-
rank test. Hazard ratios (with 
95% confidence interval) for 
PFS will be estimated using 
stratified Cox models. 
Section 10.8:  Biomarker Subgroup 
Analysis 
Analyses will be performed to 
assess the associations between 
potential biomarkers (from 
plasma and archived tissue) and 
efficacy parameters (ORR, 
percent change in target lesion 
size, and PFS or as appropriate).  
Graphical displays will be 
performed when appropriate. 
Analyses will be performed to 
assess the associations between 
potential biomarkers (from 
plasma, serum and archived 
tissue) and efficacy parameters 
(ORR, percent change in target 
lesion size, and PFS or as 
appropriate).  Graphical displays 
will be performed when 
appropriate. 
To clarify that serum samples will also 
be analyzed. 
Section 10.7:  Safety Analysis 
Safety analyses (adverse events 
and laboratory analyses) will be 
performed using the safety 
population.  Adverse events will 
be reported by the MedDRA 
version 17.1 or higher. Toxicity 
will be graded according to the 
Safety analyses (adverse events 
and laboratory analyses) will be 
performed using the safety 
population.  Adverse events will 
be reported by the MedDRA 
version 17.1 or higher. Toxicity 
will be graded according to the 
To address the addition of the QTcF 
analyses. 


 
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NCI CTCAE version 4.03. 
Safety analysis of patients in 
Part 1 will include a summary of 
dose-limiting toxicity events. 
The period for treatment-
emergent adverse events and 
safety findings will be from the 
time of first study drug 
administration to 30 days after 
the date of last study drug 
administration. If an adverse 
event begins on the date of first 
study drug administration with 
no time recorded, the event will 
be considered as treatment-
emergent. 
Tabular summaries will be 
presented for all adverse events, 
pre-treatment adverse events, 
treatment-emergent adverse 
events (TEAE), serious adverse 
events, adverse events leading to 
study drug discontinuation, 
TEAE-related to study drug and 
TEAE Grade 3/4. Adverse 
events will be summarized by 
System Organ Class and 
preferred term.  All adverse 
event data will be listed by 
patient. 
Laboratory data will be 
presented by cycle.  Abnormal 
laboratory values will be 
assessed using all available data 
NCI CTCAE version 4.03. 
Safety analysis of patients in 
Part 1 will include a summary of 
dose-limiting toxicity events. 
The period for treatment-
emergent adverse events and 
safety findings will be from the 
time of first study drug 
administration to 30 days after 
the date of last study drug 
administration. If an adverse 
event begins on the date of first 
study drug administration with 
no time recorded, the event will 
be considered as treatment-
emergent. 
Tabular summaries will be 
presented for all adverse events, 
pre-treatment adverse events, 
treatment-emergent adverse 
events (TEAE), serious adverse 
events, adverse events leading to 
study drug discontinuation, 
TEAE-related to study drug and 
TEAE Grade 3/4. Adverse 
events will be summarized by 
System Organ Class and 
preferred term.  All adverse 
event data will be listed by 
patient. 
Laboratory data will be 
presented by cycle.  Abnormal 
laboratory values will be 
assessed using all available data 


 
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and toxicity grading will be 
assigned according to NCI 
CTCAE toxicity scale, where 
criteria are available to do so. 
Maximum and minimum 
decrease/increase in continuous 
laboratory data will be reported.  
Frequency and percent of 
abnormal laboratory values 
(L/ULN, 2*L/ULN) will be 
assessed.  Shift to most severe 
toxicity grade will be 
summarized.  
Vital signs and ECG will be 
tabulated for the change from 
baseline by time point.  
Additional analyses may be 
performed as described in detail 
within the SAP. 
and toxicity grading will be 
assigned according to NCI 
CTCAE toxicity scale, where 
criteria are available to do so. 
Maximum and minimum 
decrease/increase in continuous 
laboratory data will be reported.  
Frequency and percent of 
abnormal laboratory values 
(L/ULN, 2*L/ULN) will be 
assessed.  Shift to most severe 
toxicity grade will be 
summarized.  
Vital signs and ECG will be 
tabulated for the change from 
baseline by time point.  
Additional analyses may be 
performed as described in detail 
within the SAP. 
Details on the analyses to assess 
the potential of QTcF 
prolongation with nal-IRI 
treatment are provided in 
Appendix 5. 
Section 10.9:  Pharmacokinetics 
Analysis 
10.9:  Pharmacokinetics 
Analysis 
Plasma concentrations of nal-IRI 
and oxaliplatin will be used to 
characterize PK parameters. Due 
to the sparse PK sampling 
schedule, PK parameters for 
individual patients will be 
estimated based on the Empirical 
Bayesian Estimation method 
10.9:  Pharmacokinetics 
Analysis 
10.9.1: Arm 1 
Plasma concentrations of total 
irinotecan, SN-38 and oxaliplatin 
will be used to characterize PK 
parameters. Due to the sparse PK 
sampling schedule, PK 
parameters for individual 
patients will be estimated based 
New analysis included to address the 
addition of pharmacokinetic sampling 
in Arm 2, and to further characterize the 
profile of the nal-IRI + 5-FU/LV + 
oxaliplatin regimen in Arm 1. 


 
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with priors from the previously 
estimated (nal-IRI) or published 
(oxaliplatin) population PK 
model parameters. The model 
simulated exposures, e.g., Cmax, 
AUC (area under the curve), will 
be used to examine any possible 
interactions between nal-IRI and 
oxaliplatin by comparing the 
least squares geometric mean 
ratios (LS-GMR) of drug 
exposures. NONMEM®, 
Version 7.3, will be used to 
estimate individual PK 
parameters and simulate plasma 
exposures. 
on the Empirical Bayesian 
Estimation method with priors 
from the previously estimated 
(nal-IRI) or published 
(oxaliplatin) population PK 
model parameters. The model 
simulated exposures, e.g., Cmax, 
AUC (area under the curve), will 
be used to examine any possible 
interactions between nal-IRI and 
oxaliplatin by comparing the 
least squares geometric mean 
ratios (LS-GMR) of drug 
exposures. The relationship 
between dose, PK, and safety 
endpoints will be evaluated. 
NONMEM®, Version 7.3, will 
be used to estimate individual 
PK parameters and simulate 
plasma exposures. 
10.9.2: Arm 2 
Plasma concentrations of total 
irinotecan, SN-38 and 5-FU will 
be used to characterize PK 
parameters. Due to the sparse PK 
sampling schedule, PK 
parameters for individual 
patients will be estimated based 
on the Empirical Bayesian 
Estimation method with priors 
from the previously estimated 
population PK models. The 
model simulated exposures, e.g., 
Cmax, AUC (area under the 


 
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curve), will be used to evaluate 
the relationship between dose, 
PK, efficacy and safety 
endpoints.  Moreover, the 
potential for QTcF prolongation 
will be evaluated from the 
relationship between PK and 
QTcF. 
Section 10.10:  Sample Size Justification 
The total number of patients 
enrolled in Part 1 of the study 
will depend on the number of 
dose cohorts required to identify 
the Part 2 dose. Escalation to the 
next dose cohort will depend on 
the background toxicity rate (i.e., 
probability of DLT at a given 
dose). When 1 of 3 patients 
develops a DLT and the cohort is 
expanded to 6 subjects, the 
proposed plan for dose 
escalation provides a 91% 
probability that dose escalation 
will proceed at doses associated 
with DLT probability of <10%. 
The table below shows the 
probability of escalation from 
cohort to cohort with various 
toxicity rates. 
 
 
Background  
Toxicity Rate 
1% 
5%
Probability of Dose 
Escalation 
0.999 
0.97
The total number of patients 
enrolled in Part 1 of the study 
will depend on the number of 
dose cohorts required to identify 
the Part 2 dose. Escalation to the 
next dose cohort will depend on 
the background toxicity rate (i.e., 
probability of DLT at a given 
dose). When 1 of 3 patients 
develops a DLT and the cohort is 
expanded to 6 subjects, the 
proposed plan for dose 
escalation provides a 91% 
probability that dose escalation 
will proceed at doses associated 
with DLT probability of <10%. 
The table below shows the 
probability of escalation from 
cohort to cohort with various 
toxicity rates. 
Background  
Toxicity Rate 
1% 
5%
Probability of Dose 
Escalation 
0.999 
0.97
Part 2 of this study will include a 
The language regarding power 
calculations was changed to reflect the 
new primary PFS endpoint in Part 2. 
 


 
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Part 2 of this study will include a 
comparison of the progression-
free survival achievement rate at 
24 weeks for each nal-IRI-
containing arm versus the 
control arm.. In the phase 3 
MPACT study of nab-paclitaxel 
plus gemcitabine versus 
gemcitabine alone, a significant 
OS advantage was observed with 
nab-paclitaxel with the median 
PFS of 5.5 months (compared 
with 3.7, i.e. 16 weeks, in the 
gemcitabine alone arm) [2]. The 
median PFS of 5.5 months 
corresponds to a PFS rate of 24 
weeks of 50%.  
The table below illustrates the 
power to detect differences in 
PFS achievement rate at 24 
weeks between an experimental 
arm and the control arm using a 
one-sided comparison at an 
unadjusted 0.10 level of 
significance. If the true rate for 
the control arm is 50%, the study 
would have 78% power to detect 
an improvement in an 
experimental arm that has a true 
rate of 70%.  
Reference %  
Experimenta
50 
60 
50 
65 
comparison of the progression-
free survival for each nal-IRI-
containing arm versus the 
control arm. In the Phase 3 
MPACT study of nab-paclitaxel 
plus gemcitabine versus 
gemcitabine alone, a significant 
OS advantage was observed with 
nab-paclitaxel with the median 
PFS of 5.5 months (compared 
with 3.7 months, i.e. 16 weeks, 
in the gemcitabine alone arm) 
[2]. 
The table below illustrates the 
power to detect differences in 
PFS between an experimental 
arm and the control arm with at 
least 70 PFS events using a one-
sided comparison at an 
unadjusted 0.10 level of 
significance. If the true hazard 
ratio for an experimental arm 
relative to the control arm is 
0.60, the study would have 80% 
power to detect an improvement 
with a pairwise one-sided 0.10 
level test. 
Hazard ratio for PFS 
 (experimental vs control) 
0.75 
0.70 
0.65 
0.60 
0.55 


 
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50 
70 
20 
78% 
50 
71 
21 
80% 
50 
75 
25 
91% 
 
 
 
Section 12.7.2:  Confidentiality of 
Biomarker Samples 
Blood samples collected as part 
of the biomarker analysis will be 
identified only by a number 
assigned to the patient at the 
study site; this number will be 
used in lieu of the patient’s name 
in order to protect the patient’s 
identity. The samples will be 
stored at a facility designated by 
the Sponsor. Other than the 
patient’s unique identifying 
number, no additional patient 
information that could 
potentially disclose the patient’s 
identity will be stored with these 
samples. Samples will be kept 
until they are used completely 
for the specified biomarker 
analyses, or, in the event there is 
remaining tissue or blood sample 
available, such specimens will 
be stored for a maximum of 5 
years after approval of the final 
study report for the clinical trial; 
at that time, any remaining 
samples will be destroyed. At the 
time of informed consent, 
patients will be able to refuse 
long-term storage (i.e. 5 years 
beyond initial specified 
analyses) of these remaining 
Blood samples collected as part 
of the biomarker analysis will be 
identified only by a number 
assigned to the patient at the 
study site; this number will be 
used in lieu of the patient’s name 
in order to protect the patient’s 
identity. The samples will be 
stored at a facility designated by 
the Sponsor. Other than the 
patient’s unique identifying 
number, no additional patient 
information that could 
potentially disclose the patient’s 
identity will be stored with these 
samples. Samples will be kept 
until they are used completely 
for the specified biomarker 
analyses, or, in the event there is 
remaining tissue or blood sample 
available, such specimens will 
be stored for a maximum of 5 
years after approval of the final 
study report for the clinical trial; 
at that time, any remaining 
samples will be destroyed. 
Patients may withdraw consent 
from the study at any time, 
however, data already collected 
will not be removed from the 
study dataset.  
To clarify there will not be long term 
(i.e. 5 years beyond initial specified 
analyses) or indefinite storage of 
samples. 


 
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samples. If long-term  storage is 
refused, any remaining samples 
will be destroyed following the 
initial specified analyses. 
Similarly, patients may withdraw 
approval at any time by 
submitting a written request to 
their study site Investigator. 
Upon receipt of this withdraw of 
consent, no further analyses will 
be completed and the patient’s 
remaining samples will be 
destroyed, however, data already 
collected will not be removed 
from the study dataset.  
Any samples that a patient 
consents to be stored indefinitely 
may be used by the Sponsor for 
future research. The results from 
these exploratory analyses may 
not necessarily be shared with 
the Investigators or the 
participating patients. 
The results from these 
exploratory analyses may not 
necessarily be shared with the 
Investigators or the participating 
patients. 
Appendix 4:  QTc Substudy Protocol 
N/A 
Addition of QTc Substudy 
Protocol 
Appendix 4 has been added to detail the 
instructions for the conduct of the QTc 
substudy. 


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Study Synopsis 
This document will serve to detail all changes made to the protocol. Throughout this document 
deleted text will be indicated with strikethrough and added text will be bold and underlined. 
Rationale: The synopsis has been updated to reflect all additions and deletions in the main body 
of the protocol. 
Sponsor: Merrimack Pharmaceuticals 
Protocol Title: 
A randomized, open-label, Phase 2 study of nanoliposomal irinotecan (nal-
IRI)-containing regimens versus nab-paclitaxel plus gemcitabine in patients 
with previously untreated, metastatic pancreatic adenocarcinoma  
Protocol 
Number: MM-398-07-02-03 
Trial Location: International; multiple sites 
Study 
Rationale: 
Two combination chemotherapy regimens have emerged as standard of care 
options for first-line treatment of metastatic pancreatic cancer: 5-fluorouricil 
(5-FU)/leucovorin (LV) + irinotecan + oxaliplatin (FOLFIRINOX), and nab-
paclitaxel + gemcitabine, demonstrating a median overall survival (OS) of 
11.1 months and 8.5 months, respectively, in separate Phase 3 studies. Nal-
IRI (also known as MM-398) is a nanoliposomal formulation designed to 
deliver irinotecan to the tumor microenvironment for local drug activation. In 
a randomized phase 3 study, patients with metastatic pancreatic cancer who 
had received and progressed on gemcitabine (the NAPOLI-1 study), nal-IRI 
in combination with 5-FU/LV demonstrated significant clinical activity, 
increasing OS and PFS relative to 5-FU/LV. The goal of this current study is 
to assess the preliminary efficacy and safety of nal-IRI-containing regimens, 
including nal-IRI + 5-FU/LV + oxaliplatin  and nal-IRI + 5-FU/LV, in 
previously untreated metastatic pancreatic cancer patients to assess the most 
promising regimen for further development.  
Primary 
Objectives: 
The study is divided into two parts: 
Part 1: 
x To evaluate the safety and tolerability of nal-IRI + 5FU/LV + 
oxaliplatin  
x To characterize dose-limiting toxicities (DLTs) associated with nal-
IRI + 5FU/LV + oxaliplatin and determine the Part 2 dose of the 
triplet combination  
Part 2: 
x To assess the efficacy of nal-IRI-containing regimens in first-line 
metastatic pancreatic cancer patients compared to nab-paclitaxel + 
gemcitabine using the progression-free survival (PFS) rate at 24 weeks  
Secondary 
Objectives: 
Part 1: 
x To characterize the pharmacokinetics (PK) of nal-IRI in combination 
with 5-FU and oxaliplatin 
Part 2: 
x To assess efficacy of each nal-IRI-containing regimen relative to nab-
paclitaxel + gemcitabine using overall survival (OS) ,  PFS, and 
objective response rate (ORR; CR + PR, per RECIST v1.1) 


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x To assess tumor marker CA19-9 response in each nal-IRI-containing 
regimen relative to nab-paclitaxel + gemcitabine 
x To assess health-related quality of life (HRQL) using the European 
Organization for Research and Treatment of Cancer (EORTC) quality-
of-life core questionnaire (EORTC-QLQ-C30) and European Quality 
of Life Questionnaire (EQ-5D-5L) in each arm 
x To compare the safety and adverse event profile between the treatment 
arms 
x To assess the potential for QTcF prolongation with nal-IRI 
treatment 
Exploratory 
Objectives: 
x To evaluate the relationship between plasma PK of nal-IRI (total 
irinotecan, SN-38), oxaliplatin, and efficacy and safety endpoints 
in first-line metastatic pancreatic cancer 
x To evaluate blood samples and archived tumor tissue for potential 
biomarkers that may correlate with nal-IRI PK, toxicity, and/or 
response nal-IRI 
Study Design: 
This is an open-label, Phase 2 comparative study to assess the safety, 
tolerability, and efficacy of nal-IRI in combination with other anticancer 
therapies, compared to nab-paclitaxel + gemcitabine, in patients with 
advanced pancreatic adenocarcinoma who have not received prior 
chemotherapy. This study will assess the following regimens: 
x nal-IRI + 5-FU/LV + oxaliplatin (Arm 1) 
x nal-IRI + 5-FU/LV (Arm 2) 
x nab-paclitaxel + gemcitabine (Arm 3) 
The study will be conducted in two parts, as illustrated in the schematic 
below:  
1)  a safety run-in of the nal-IRI + 5-FU/LV + oxaliplatin  regimen, and  
2)  a randomized, efficacy study of  the nal-IRI + 5-FU/LV + oxaliplatin 
regimen, the nal-IRI + 5-FU/LV combination that previously 
demonstrated efficacy in the Phase 3 NAPOLI-1 trial (i.e. the NAPOLI 
regimen), versus a nab-paclitaxel + gemcitabine control arm. 


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Part 1:  
Part 1 will consist of an open-label safety run-in of the combination regimen 
in Arm 1: nal-IRI + 5-FU/LV + oxaliplatin. The Arm 2 and Arm 3 regimens 
have established doses, and nal-IRI + 5-FU/LV has been demonstrated 
tolerable, yielding antitumor responses in a Phase 3 study of patients with 
relapsed metastatic pancreatic cancer, and therefore will not be included in 
this part of the study. The safety run-in will enroll small cohorts of patients 
following a traditional 3 + 3 dose escalation design in order to confirm the 
target dose of oxaliplatin. Dose limiting toxicities (DLTs) will be evaluated 
during the first cycle of treatment (i.e. 28 days per cycle; or 14 days after the 
2nd dose of study treatment if there is a treatment delay according to Section
7.5) in cohorts of patients to determine if the target  combination dose is 
tolerable (note: the target combination dose is based on the established 
oxaliplatin dose of the FOLFIRINOX regimen, as published by Conroy et al. 
[1]). If there are no DLTs within the safety evaluation period, then the 
subsequent cohort will be initiated following agreement between the 
Investigators, the Medical Monitor, and the Sponsor. If one DLT occurs, then 
the cohort will be expanded to 6 patients. If 2 or more patients have DLTs 
within a given dose level, that dose will be considered to exceed the optimal 
safety and tolerability criteria of the combination, and the dose will not be 
escalated further; however, lower doses may be explored. The Part 2 dose will 
then be defined as the next lower dose level in which 6 patients were treated 
and ≤ 1 patient experienced a DLT.  
Since the individual chemotherapies included in the proposed combinations 
have been studied in previous clinical trials, it is important that the safety 
assessment takes into account the expected safety profile of the standard dose 
regimen (e.g. FOLFIRINOX). Any toxicity that is related to disease 
progression will not be considered a DLT. The following adverse events will 
be considered as DLTs if they occur during the first cycle of treatment and are 
deemed related to the study treatment regimen: 


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x Grade 4 neutropenia or thrombocytopenia that does not resolve within 
7 days despite optimal therapy (withholding study drug and 
administering concomitant medication, e.g. G-CSF administration for 
neutropenia) 
x Grade 4 neutropenia complicated by fever ≥ 38.5 °C (i.e. febrile 
neutropenia) and/or Grade 3 neutropenia with infection 
x Inability to begin subsequent treatment course within 14 days of the 
scheduled date, due to drug-related toxicity  
x Any grade 4 non-hematologic toxicity with the specific exclusion of:  
o Fatigue/asthenia < 2 weeks in duration 
o Increases in alkaline phosphatase levels 
o Nausea and vomiting ≤3 days duration (only considered dose 
limiting if they last > 72 hours after treatment with an optimal 
anti-emetic regimen) 
o Diarrhea ≤3 days duration (only considered dose limiting if 
diarrhea lasts > 72 hours after treatment with an optimal anti-
diarrheal regimen) 
The final determination of DLTs will be made following discussion between 
the DLT review committee (i.e. the Part 1 Investigators, the Medical Monitor, 
and the Sponsor). As part of this study, pharmacogenomic data will be 
collected on all patients for determination of UGT1A1*28 status. If a patient 
in any cohort experiences a DLT, and is found to be homozygous for the 
UGT1A1*28 allele, the Investigators, Medical Monitor, and Sponsor will 
assess if the adverse event was attributable to the patient’s UGT1A1*28 
homozygous status prior to being assigned the category of DLT. Additionally, 
adverse events meeting the criteria above which are also known adverse 
reactions of either 5-FU or oxaliplatin based on reported safety data, and 
unexpected of nal-IRI, will be discussed between the Investigators, Medical 
Monitor and Sponsor before being assigned the category of DLT in the first 
cycle of treatment.  
Following the Cycle 1 safety evaluation period, dose escalation for the next 
cohort may occur. Patients will continue to be monitored for safety beyond 
Cycle 1 in order to determine if multiple cycles of treatment are tolerable.  
Part 2: 
Part 2 will consist of an open-label, randomized, Phase 2 study in which 
patients will be randomized to treatment (1:1:1) to either nal-IRI + 5-FU/LV + 
oxaliplatin, nal-IRI + 5-FU/LV, or gemcitabine + nab-paclitaxel (control 
regimen). The randomization will be stratified based on region (East Asia  vs. 
rest of the world) and performance status (ECOG 0 vs. 1). Patients 
randomized to nal-IRI + 5-FU/LV will undergo serial electrocardiogram 
recordings and time-matched pharmacokinetic sampling in order to 
assess any relationship between blood levels of nal-IRI and its metabolite 
SN-38 and possible QTc interval changes. An independent Data and Safety 
Monitoring Board (DSMB) will be utilized to monitor emerging safety data.  


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Full details will be listed in a DSMB charter.     
Translational Research: 
Translational research components will include collection of blood samples 
(Parts 1 and 2) and archived tumor (during screening, if available) to look for 
potential biomarkers. Analyses include cytokine levels (e.g. MCSF1, and IL-
6), growth factors (e.g. IGF1 and EGFR family receptors and ligands), or 
enzyme levels (e.g. MMP9).  
Number of 
Patients: 
Approximately 6-18 patients will be enrolled in Part 1. An additional 150 
patients (50 patients per arm) will be enrolled during Part 2. Therefore, the 
total enrollment for the study will be approximately 156-168 patients.  
Inclusion 
Criteria: 
a) Pathologically confirmed adenocarcinoma of the pancreas that has not 
been previously treated in the metastatic setting.  
x Part 1: unresectable, locally advanced or metastatic disease is 
allowed, diagnosed within 6 weeks prior to enrollment 
x Part 2: must have metastatic disease diagnosed within 6 weeks 
prior to randomization; locally advanced disease is not allowed 
b) Measurable or non-measurable disease as defined by RECIST v1.1 
c) ECOG performance status of 0 or 1 
d) Adequate biological parameters as evidenced by the following blood 
counts: 
x ANC > 1,500 cells/μl without the use of hematopoietic growth 
factors, 
x Platelet count > 100,000 cells/μl, and 
x Hemoglobin > 9 g/dL  
e) Adequate hepatic function as evidenced by: 
x Serum total bilirubin ≤ ULN (biliary drainage is allowed for biliary 
obstruction), and 
x AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver 
metastases are present) 
f) Adequate renal function as evidenced by serum creatinine ≤ 1.5 x 
ULN, and calculated clearance ≥60 mL/min/1.72 1.73 m2 for patients 
with serum creatinine levels above or below the institutional normal 
value. Actual body weight should be used for calculating creatinine 
clearance using the Cockcroft-Gault Equation (CreatClear = Sex * 
((140 - Age) / (SerumCreat)) * (Weight / 72); for patients with body 
mass index (BMI) >30 kg/m2, lean body weight should be used 
instead. 
g) Normal ECG or ECG without any clinically significant findings  
h) Recovered from the effects of any prior surgery or radiotherapy   
i) ≥ 18 years of age  
j) Agreeable to submit unstained archived tumor tissue for analysis, if 
available  
k) Able to understand and sign an informed consent (or have a legal 
representative who is able to do so) 
l)  


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Exclusion 
Criteria: 
a) Prior treatment of pancreatic cancer in the metastatic setting with 
surgery, radiotherapy, chemotherapy or investigational therapy (note: 
placement of biliary stent is allowed) 
b) Prior treatment of pancreatic cancer with cytotoxic doses of 
chemotherapy (patients receiving prior treatment with chemotherapy 
as a radiation sensitizer are eligible if ≥ 6 months has elapsed from 
completion of therapy)   
c) Known metastasis to the central nervous system  Uncontrolled CNS 
metastases (patients who require steroids should be on a stable or 
decreasing dose) 
d) Clinically significant gastrointestinal disorder including hepatic 
disorders, bleeding, inflammation, occlusion, diarrhea > grade 1, 
malabsorption syndrome, ulcerative colitis, inflammatory bowel 
disease, or partial bowel obstruction   
e) History of any second malignancy in the last 3 years; patients with 
prior history of in-situ cancer or basal or squamous cell skin cancer are 
eligible.  Patients with a history of other malignancies are eligible if 
they have been continuously disease free for at least 3 years. 
f) Known hypersensitivity to any of the components of nal-IRI, other 
liposomal products, or any components of 5-FU, leucovorin or 
oxaliplatin 
g) Known hypersensitivity to any of the components of nab-paclitaxel or 
gemcitabine (Part 2 only) 
h) Concurrent illnesses that would be a relative contraindication to trial 
participation such as active cardiac or liver disease, including:  
x Severe arterial thromboembolic events (myocardial infarction, 
unstable angina pectoris, stroke) less than 6 months before 
inclusion 
x NYHA Class III or IV congestive heart failure, ventricular 
arrhythmias or uncontrolled blood pressure  
x Known historical or active infection with HIV, hepatitis B, or 
hepatitis C 
i) 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, patients with tumor fever may be enrolled), which in the 
investigator’s opinion might compromise the patient’s participation in 
the trial or affect the study outcome 
j) Use of strong CYP3A4 inhibitors or inducers, or presence of any other 
contraindications for irinotecan1 
k) Presence of any contraindications for 5-FU, leucovorin, or oxaliplatin 
l) Use of strong CYP2C8 inhibitors or inducers, or presence of any other 
contraindications for nab-paclitaxel or gemcitabine (Part 2 only)1 
m) Any other medical or social condition deemed by the Investigator to be 
likely to interfere with a patient’s ability to sign informed consent, 
cooperate and participate in the study, or interfere with the 
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n) Pregnant or breast feeding; females of child-bearing potential must test 
negative for pregnancy at the time of enrollment based on a urine or 
serum pregnancy test. Both male and female patients of reproductive 
potential must agree to use a highly effective method of birth control, 
during the study and for 43 months following the last dose of study 
drug2. 
1. See Section 7.8 for examples of strong CYP3A4 and CYP2C8 inhibitors or 
inducers. 
2. For a description of highly effective contraceptive measures, please see 
Appendix 2. 
Length of 
Study: 
Patients will be treated until disease progression (radiologic or clinical 
deterioration), intolerable toxicity, or at the discretion of the treating 
physician.  A follow up clinic visit is required approximately 30 days after 
last dose of study treatment to complete the final safety assessments. 
Subsequently, patients will be followed for survival once every 2 months via 
telephone, email, or clinic visit until death or study closure, whichever occurs 
first. 
Investigational 
Product: 
Nal-IRI (irinotecan liposome injection; also known as MM-398) is irinotecan 
in the form of the sucrosofate salt, encapsulated in liposomes for intravenous 
infusion.  It will be supplied in sterile, single-use vials containing 10 mL or 
9.5 mL of nal-IRI at a concentration of 5 mg/mL. Nal-IRI must be stored 
refrigerated at 2 to 8°C, with protection from light. 
Additional 
Anti-cancer 
Therapies: 
Depending on the assigned treatment arm, patients may be treated with one or 
more of the following approved therapies: 
x 5-FU/LV  
x oxaliplatin  
x nab-paclitaxel 
x gemcitabine  
Please reference the respective package inserts for additional information. 
Dosing 
Regimens: 
All regimens below will be tested in 28-day cycles. Planned cohorts for the 
Arm 1 safety assessment are described below (Part 1). Dosing will begin at 
dose level 1, with planned escalation to dose level 2, the target dose of 
oxaliplatin based on the established FOLFIRINOX regimen [1]. One drug in 
the triplet combination will be escalated, while the other two drugs are held 
constant, as indicated in the table below. The dose of nal-IRI and 5-FU/LV in 
Dose Level 1 and 2 is the same dose and schedule that was previously used in 
the NAPOLI-1 Phase 3 study. 
Arm 1: nal-IRI + 5-FU/LV + oxaliplatin 
x In Part 1, oxaliplatin will be administered at increasing dose levels as 
indicated in Table 5 (from 60 mg/m2 - 85 mg/m2), IV over 120 
minutes (±10 minutes), on Days 1 and 15 of each 28-day cycle 
x In Part 2, oxaliplatin will be administered at a dose of 85 mg/m2, IV 
over 120 minutes (±10 minutes), on Days 1 and 15 of each 28-day 
cycle (if target dose is confirmed in accordance with Section 4.2.3) 
x nal-IRI 80 mg/m2 IV over 90 minutes (±10 minutes), on Days 1 and 15 


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of each cycle 
x 5-FU 2400 mg/m2 IV over 46-hours (±60 minutes), on Days 1 and 15 
of each cycle 
x leucovorin l + d racemic form 400 mg/m2, IV over 30 minutes (±5 
minutes), on Days 1 and 15 of each cycle 
Note: The order of infusions on Arm 1 will be as follows: nal-IRI will be 
administered first, followed by oxaliplatin, then LV, followed by 5-FU. 
Patients dosed in Part 1 will receive oxaliplatin infusion 2 hours after the 
completion of the MM-398 infusion (see Section 7.3.1 for details). 
Dose 
Level* 
Oxaliplatin 
(mg/m2) 
5-FU/LV 
(mg/m2) 
nal-
IRI(mg/m2) 
1 
60 
(starting dose) 
2400/400 
80 
2** 
85 
2400/400 
80 
*Additional dose levels and dose de-escalation plans are presented in 
protocol section 5.2 
**Dose level 2 is the target dose of oxaliplatin, based on the 
established FOLFIRINOX regimen published by Conroy et al. [1], and 
will be used in Part 2 of the study following dose confirmation 
according to Section 4.2.3. 
Arm 2: nal-IRI + 5-FU/LV 
The dose and regimen that is planned for Arm 2 has been previously studied 
in 117 patients who participated in the NAPOLI-1 trial, therefore a safety 
cohort in Part 1 is not needed. The following doses will be administered in 
Part 2 of the study: 
x nal-IRI 80 mg/m2 IV over 90 minutes (±10 minutes), on Days 1 and 15 
of each cycle 
x 5-FU 2400 mg/m2 IV over 46-hours (±60 minutes), on Days 1 and 15 
of each cycle 
x leucovorin l + d racemic form 400 mg/m2, IV over 30 minutes (±5 
minutes), on Days 1 and 15 of each cycle 
Arm 3: nab-paclitaxel + gemcitabine  
x nab-paclitaxel 125 mg/m2 IV over 35 minutes (±5 minutes), on Days 
1, 8 and 15 of each 28-day cycle 
x gemcitabine 1000 mg/m2 IV over 30 minutes (±5 minutes), on Days 1, 
8 and 15 of each 28-day cycle 
Criteria for 
Evaluation: 
Part 1: Assessments for safety will include all treated patients and will be 
based on adverse events, laboratory data, and study treatment related dose-
limiting toxicities. Patients who discontinue prior to completion of Cycle 1 
due to events that are not related to study treatment toxicity will not be 
considered in the assessment for DLT, and will be replaced for the purposes 
of DLT evaluation. Plasma samples will be analyzed for the concentration of 
nal-IRI (irinotecan) and its metabolites (SN-38 and SN-38G) in order to 
derive PK parameters of nal-IRI when given in combination with other 
anticancer therapies. PK parameters of the combination therapies (5-FU and 


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oxaliplatin) will also be analyzed to evaluate any drug interactions with nal-
IRI. 
Part 2: The primary endpoint is progression free survival achievement rate at 
24 weeks, which will be assessed in all 3 study arms. The secondary 
endpoints related to efficacy will include overall survival, PFS time, and 
objective response (CR or PR, per RECIST, v 1.1). Achievement of a 
20%/50%/90% or greater decrease in CA19-9 levels compared to baseline (at 
8, 16, and 24 weeks post-treatment and overall) will also be assessed, along 
with a quality of life assessment (EORTC-QLQ-C30 and EQ-5D-5L). QTcF 
prolongation will be assessed in the Arm 2 (nal-IRI+5-FU/LV) in patients 
with PK and QTcF measurements.  
Translational / Exploratory:  
Archived tumor tissue (if available) and blood samples will be collected and 
analyzed for biomarkers (Parts 1 and 2). Samples will be used to explore 
potential markers of sensitivity and resistance to irinotecan, including, but not 
limited to, the following: DNA damage repair pathways (e.g. Topo1, 
BRCA1/2, and SLFN11), growth factor pathways (IGF1 and EGFR family 
receptors and ligands), and factors involved in CPT-11 conversion to SN-38 
(e.g. macrophage content and CES activity). 
Statistical 
Analyses: 
The safety population will include all patients receiving any part of at least 
one dose of study drug.   
Efficacy and safety analyses will be presented separately for Part 1 and Part 2 
of the study. Efficacy comparisons to the control arm, i.e. nab-paclitaxel + 
gemcitabine, will include only patients enrolled in Part 2. 
Categorical variables will be summarized by frequency distributions (number 
and percentages of patients) and continuous variables will be summarized by 
descriptive statistics (mean, standard deviation, median, minimum, 
maximum).   
Tumor evaluation will be measured according to RECIST v1.1. For each 
patient, progression free survival time will be determined as the time from 
randomization (for part 1 patients, the reference time will be date of first 
study drug) to the first documented radiographical progression of disease 
(PD), per investigator using RECIST 1.1, or death from any cause, whichever 
comes first. If the progression or death occurs at a time point that is greater 
than 12 weeks after the non-PD last tumor assessment, then progression-free 
survival time will be censored at the time of the last non-PD tumor 
assessment. 
In the assessments of efficacy, each nal-IRI-containing arm will be compared 
to the control arm. Efficacy comparisons will use stratified analyses, 
incorporating randomization strata. Each comparison will use 0.10 level one-
sided testing to evaluate whether the nal-IRI-containing arm improves the 
efficacy parameter. Confidence intervals will be presented at two-sided 95% 
level for descriptive purposes. Hypothesis tests and confidence intervals will 
not be adjusted for multiple comparisons and consequently the experiment-


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wise type I error rate may exceed the 0.10 level. The primary efficacy 
comparisons will be based on the ITT population, which will included all 
randomized patients.  
A primary analysis will be conducted when there are at least 70 PFS events 
for each comparison to the control arm. Week 24 progression-free status 
for all randomized patients can be determined, anticipated at approximately 
24 weeks after the last patient is randomized. A subsequent analysis for PFS 
and other endpoints will be performed when PFS events have occurred in at 
least 120 patients (i.e. 80% of randomized patients). 
Primary Efficacy Analysis 
In the intention-to-treat (ITT) analysis, a patient will be considered to have 
achieved progression-free survival at 24 weeks if the patient has data to 
indicate the patient has not progressed at 24 weeks. That is, a patient will be 
considered a responder if there is at lease one non-PD assessment, prior to 
progression or new anticancer therapy, at Week 24 or later.  
For each arm, the progression-free survival achievement rate at 24 weeks will 
be estimated by the number of patients meeting the 24 week achievement 
criteria divided by the number of ITT patients in the arm. The rate estimates 
will  be presented with corresponding 95% confidence intervals. Each nal-IRI 
containing arm will be assessed for increase in rate relative to the control arm 
using a one-sided Cochran-Mantel-Haenszel test, incorporating randomization 
stratification factors, at 0.10 level of significance. PFS will be descriptively 
summarized for each arm using Kaplan-Meier methodology. Median PFS 
time and corresponding 95% confidence limits will be presented. For 
each nal-IRI-containing arm, PFS will be compared to the control arm. 
Hypothesis tests will be conducted for differences in PFS using a one-
sided stratified log-rank test. Hazard ratios (with 95% confidence 
interval) for PFS will be estimated using stratified Cox models. 
Secondary Efficacy Analyses 
Progression-free survival (PFS) will be descriptively summarized for each 
arm using Kaplan-Meier methodology. Median PFS time and corresponding 
95% confidence limits will be presented. For each nal-IRI-containing arm, 
PFS will be compared to the control arm. Hypothesis tests will be conducted 
for differences in PFS using a one-sided stratified log-rank test. Hazard ratios 
(with 95% confidence interval) for PFS will be estimated using stratified Cox 
models. 
Best Overall Response (BOR) is defined as the best response as recorded 
from the start of study drug until disease progression. Patients without a post-
baseline tumor assessment will be considered to be non-evaluable for BOR. 
To classify BOR as stable disease (SD), there should be a qualifying SD 
assessment at least 6 weeks from randomization. Objective Response Rate 
(ORR) is defined as the proportion of patients with a BOR characterized as 
either a Complete Response (CR) or Partial Response (PR) relative to the total 


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number of evaluable patients. Only patients with measurable disease at 
baseline will be included in the analysis of the objective response. Estimates 
of objective response rate and its corresponding 95% CI will be calculated for 
each treatment arm.  For each nal-IRI-containing arm, ORR will be compared 
to the control arm. Differences in objective response rate between each nal-
IRI-containing arm and control arm will be provided with 95% CIs. Cochran-
Mantel-Haenszel tests, adjusting by randomization strata, will be used to 
compare objective response rates. 
The maximum reduction (% change from baseline) in CA19-9 will be 
computed, including analyses at timepoints (up to Week 8, 16 and 24 visits) 
and overall. Summaries of CA19-9 response will be computed based on three 
thresholds for magnitude of the maximum reduction: ≥20%, ≥50%, ≥ 90%. A 
patient without post-baseline CA19-9 measurement will be considered as a 
non-responder. The proportion of CA19-9 response will be estimated, along 
with corresponding 95% confidence intervals, for each arm.  
Overall Survival (OS) is the time from randomization to the date of death 
from any cause. Patients who are alive or lost to follow-up at the time of the 
analysis will be censored at the last known alive date. OS  will be 
descriptively summarized for each arm using Kaplan-Meier methodology. For 
each nal-IRI-containing arm, OS will be compared to the control arm. 
Hypothesis tests will be conducted for differences in OS using a one-sided 
stratified log-rank test. Hazard ratios (with 95% confidence interval) for PFS 
will be estimated using stratified Cox models 
Quality of Life Analyses 
Analyses of quality of life will be carried out on treated patients who provide 
baseline and at least 1 post-baseline assessment for the assessment (i.e. there 
will be an EORTC-QLQ-C30 analysis population and an EQ-5D-5L analysis 
population). EORTC-QLQ-C30 and EQ-5D-5L results will be summarized at 
each visit by treatment group 
Subscale scoring will be carried out as described in the EORTC QLQ-C30 
Scoring Manual (Fayers, Aaronson, Bjordal, Curran, & Groenvald, 2001). 
Linear transformations will be applied to the raw scores so that the reported 
score will have range 0 100 for all scales. Summary statistics will be 
presented for each subscale. 
A summary health state index value will be computed for each EQ-5D-5L 
assessment. Summary statistics will be presented for summary health state 
index. For each EQ-5D-5L attribute (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression), responses will be tabulated. 
Safety Analyses 
Safety analyses (adverse events and laboratory analyses) will be performed 
using the safety population.  Adverse events will be reported by the MedDRA 
version 17.1 or higher. Toxicity will be graded according to the NCI CTCAE 


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version 4.03. 
Safety analysis of patients in Part 1 will include a summary of dose-limiting 
toxicity events. 
The period for treatment-emergent adverse events and safety findings will be 
from the time of first study drug administration to 30 days after the date of 
last study drug administration. If an adverse event begins on the date of first 
study drug administration with no time recorded, the event will be considered 
as treatment-emergent. 
Tabular summaries will be presented for all adverse events, pre-treatment 
adverse events, treatment-emergent adverse events (TEAE), serious adverse 
events, adverse events leading to study drug discontinuation, TEAE-related to 
study drug and TEAE Grade 3/4. Adverse events will be summarized by 
System Organ Class and preferred term.  All adverse event data will be listed 
by patient. 
Laboratory data will be presented by cycle.  Abnormal laboratory values will 
be assessed using all available data and toxicity grading will be assigned 
according to NCI CTCAE toxicity scale, where criteria are available to do so.  
Laboratory, vital signs, and ECG data will be summarized according to 
parameter type. 
Pharmacokinetic Analyses 
Arm 1 
Plasma concentrations of nal-IRI total irinotecan, SN-38, and oxaliplatin in 
the combination therapies will be used to characterize PK parameters. PK 
parameters for individual patients will be estimated based on the Empirical 
Bayesian Estimation method with priors from the previously published 
parameters. The model simulated exposures, e.g., Cmax, AUC (area under the 
curve), will be compared in order to examine any possible interactions 
between nal-IRI and the combination therapies and to evaluate the 
relationship between dose, PK and safety endpoints. 
Arm 2 
Plasma concentrations of total irinotecan, SN-38 and 5-FU will be 
characterized based on the Empirical Bayesian Estimation method with 
priors from previously published parameters.  The relationship between 
dose, PK, efficacy and safety endpoints will be evaluated.  Moreover, the 
relationship between PK and QTcF will be used to evaluate the potential 
for QTcF prolongation (see below).  
QTcF Analyses 
The potential of QTcF prolongation with nal-IRI treatment will be 
evaluated in patients in Arm 2, Part 2 of this study. For the primary 
QTcF prolongation analysis, the predicted changes in QTcF will be 
obtained from the exposure-QTcF relationship using mixed-effect 


MM-398 – Protocol MM-398-07-02-03
Summary of Changes: Version 1.0 to 2.0
 
Proprietary and Confidential  
Page 39 of 40 
modeling. Sensitivity analyses will be conducted by evaluating by-
timepoint and categorical analyses.   
Sample Size 
Justification: 
The total number of patients enrolled in Part 1 of the study will depend on the 
number of dose cohorts required to confirm the optimal dose. Escalation to 
the next dose cohort will depend on the background toxicity rate (i.e., 
probability of DLT at a given dose). When 1 of 3 patients develops a DLT 
and the cohort is expanded to 6 subjects, the proposed plan for dose escalation 
provides a 91% probability that dose escalation will proceed at doses 
associated with DLT probability of <10%. The table below shows the 
probability of escalation from cohort to cohort with various toxicity rates. 
Background  
Toxicity  
Rate 
1% 
5% 
10% 
20% 
30% 40% 
 
50% 
 
Probability 
of Dose 
Escalation 
0.999 0.973 
0.906 
0.709 
0.494 0.309 0.172 
Part 2 of this study will include a comparison of the progression-free survival 
achievement rate at 24 weeks for each nal-IRI-containing arm versus the 
control arm. In the phase 3 MPACT study of nab-paclitaxel plus gemcitabine 
versus gemcitabine alone, a significant OS advantage was observed with nab-
paclitaxel with the median PFS of 5.5 months (compared with 3.7 months, i.e. 
16 weeks, in the gemcitabine alone arm) [2]. The median PFS of 5.5 months 
corresponds to a PFS rate at 24 weeks of approximately 50%.  
 
The table below illustrates the power to detect differences in PFS achievement 
rate at 24 weeks between an experimental arm and the control arm with at 
least 70 PFS events using a one-sided comparison at an unadjusted 0.10 level 
of significance. If the true hazard ratio rate for an experimental arm 
relative to the control arm is 50%0.60, the study would have 70%80% power 
to detect an improvement with a pairwise one-sided 0.10 level test. in an 
experimental arm that has a true rate of 70%.  
 
Hazard ratio 
(experimental 
vs control) 
Power 
(≥ 70 events 
between 2 arms 
for comparison) 
0.75 
47% 
0.70 
58% 
0.65 
70% 
0.60 
80% 
0.55 
88% 
 
Reference  
% 
Experimental 
% 
Delta 
% pts 
 
Power 
N=50/arm 


MM-398 – Protocol MM-398-07-02-03
Summary of Changes: Version 1.0 to 2.0
 
Proprietary and Confidential  
Page 40 of 40 
50 
60 
10 
39% 
50 
65 
15 
59% 
50 
70 
20 
78% 
50 
71 
21 
80% 
50 
75 
25 
91% 
 
 
 


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 Electronic Signature Page 
This page is the manifestation of the electronic signature(s) used in compliance with 
 
International’s electronic signature policies and procedures and in compliance with applicable regulations. 
UserName: 
 
Title:  
 
Date: Tuesday, 18 May 2021, 09:31 PM   GMT Standard Time 
Meaning: Document contents approved. 
================================================
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