Clinical trial NCT03088813
Conditions: Small Cell Lung Cancer
Sponsor: Ipsen
Start date: 2018-04-25; Completion date: 2023-07-27
Enrollment: 491 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, open label phase 3 study of irinotecan liposome injection (ONIVYDE®) versus topotecan in patients with small cell lung cancer who have progressed on or after platinum-based first-line therapy

The study was conducted in two parts:

1. Dose determination of irinotecan liposome injection
2. A randomized, efficacy study of irinotecan liposome injection versus topotecan

Detailed description:
The study was conducted in two parts:

Part 1: Open-label dose-finding study of irinotecan liposome injection. 30 patients were planned to be enrolled.

Part 1 Primary Objectives:

* Describe the safety and tolerability of irinotecan liposome injection monotherapy administered every 2 weeks
* Determine the optimal irinotecan liposome injection monotherapy dose for Part 2 of this study

Part 2: A randomized, efficacy study of irinotecan liposome injection versus intravenous (IV) topotecan.

Approximately 450 patients were planned to be enrolled in part 2.

Part 2 objectives: To compare overall survival following treatment with irinotecan liposome injection with overall survival following treatment with IV topotecan.

Arms: arm 1: Irinotecan liposome injection arm 2: Irinotecan liposome injection arm 3: Irinotecan liposome injection arm 4: Topotecan
Interventions: intervention 1: Irinotecan liposome injection intervention 2: Topotecan
Intervention descriptions: intervention 1: IV intervention 2: IV

Protocol documents:
Prot_000.pdf: 
 
 
RESILIENT: A Randomized, Open Label Phase 3 
Study of Irinotecan Liposome Injection (ONIVYDE®) 
versus Topotecan in Patients with Small Cell Lung 
Cancer Who Have Progressed on or after Platinum-
based First-Line Therapy 
IPSEN Bioscience, Inc 
Version 1.0: 13 DEC 2016 
Version 1.1: 31 JAN 2017 
Version 2.0: 03 APR 2017 
Version 3.0: 14 NOV 2017 
Version 4.0: 14 SEP 2018 
Version 5.0: 04 DEC 2019 
Version 6.0: 15 APR 2020 
Version 7.0: 24 NOV 2020 
Version 8.0: 07 OCT 2021 
EUDRA CT #: 2017-004261-26 
ClinicalTrials.gov ID: NCT03088813 
Emergency Contact:  
Global Patient Safety Head 
Ipsen Innovation 
Zone Industrielle de Courtaboeuf, 5 avenue du Canada, 91940 Les Ulis, France 
Mobile:  
for emergency contact) 
For serious adverse event (SAE) reporting and pregnancy notification: 
E-mail: 
 
If email reporting is not possible: 
Fax:
Fax:
 
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.  
PPD
PPD
PPD


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TABLE OF CONTENTS 
SUMMARY OF CHANGES ............................................................................................... 7 
LIST OF ABBREVIATIONS .............................................................................................. 9 
SYNOPSIS .......................................................................................................................... 11 
1 
BACKGROUND INFORMATION AND RATIONALE ..................................... 26 
1.1 
Small Cell Lung Cancer ........................................................................................... 26 
1.2 
Study Rationale ......................................................................................................... 27 
1.2.1 
Rationale for Evaluating Irinotecan Liposome Injection in SCLC ...... 27 
1.2.2 
Rationale for Evaluating 85 mg/m2 Every 2 Weeks Monotherapy Dose 
of Irinotecan Liposome Injection ........................................................... 28 
1.2.3 
Rationale for Intravenous Topotecan as Control .................................. 29 
1.2.4 
Nonclinical Data Supporting Evaluation of Irinotecan Liposome 
Injection in Small Cell Lung Cancer ..................................................... 29 
1.2.4.1 
Extended Exposure of SN-38 Leads to Increased Cell Death In Vitro .... 30 
1.2.4.2 
Irinotecan Liposome Injection Effectively Delivers Irinotecan and SN-38 
to SCLC Tumors In Vivo .......................................................................... 30 
1.2.4.3 
Irinotecan Liposome Injection Has Improved Anti-Tumor Activity as 
Compared to Non-liposomal Irinotecan HCl and Topotecan In Vivo ..... 31 
1.3 
Irinotecan Liposome Injection Clinical Experience .............................................. 33 
1.3.1 
United States Food and Drug Administration Approval of ONIVYDE® 
and Determination of Irinotecan Liposome Injection Strength ........... 33 
1.3.2 
Clinical Pharmacology ........................................................................... 34 
1.3.2.1 
Association Between Exposure and Efficacy with Irinotecan Liposome 
Injection ................................................................................................... 34 
1.3.2.2 
Association between Exposure and Safety with Irinotecan Liposome 
Injection ................................................................................................... 34 
1.3.3 
Clinical Data Supporting Evaluation of Dose ....................................... 34 
1.3.3.1 
Clinical Data Supporting Evaluation of 85 mg/m2 Every 2 Weeks ......... 34 
1.3.3.2 
Clinical Data to Justify 70 mg/m2 Every 2 Weeks in Part 2 .................... 35 
1.3.4 
Clinical Data in UGT1A1*28 Homozygous Patients ............................ 35 
2 
OBJECTIVES ........................................................................................................... 37 
2.1 
Part 1 .......................................................................................................................... 37 
2.1.1 
Primary Objectives .................................................................................. 37 
2.1.2 
Secondary Objectives .............................................................................. 37 
2.1.3 
Exploratory Objectives ............................................................................ 37 
2.2 
Part 2 .......................................................................................................................... 38 
2.2.1 
Primary Objective .................................................................................... 38 
2.2.2 
Secondary Objectives .............................................................................. 38 
2.2.3 
Exploratory Objectives ............................................................................ 38 
3 
STUDY DESIGN ....................................................................................................... 38 
3.1 
Overview of Study Design ........................................................................................ 38 


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3.1.1 
Part 1 ....................................................................................................... 39 
3.1.2 
Part 2 ....................................................................................................... 42 
3.2 
Study Duration and Study Closure ......................................................................... 43 
3.3 
Safety Review Committee and Independent Data Monitoring Committee ......... 43 
4 
STUDY POPULATION ........................................................................................... 44 
4.1 
Inclusion Criteria ...................................................................................................... 44 
4.2 
Exclusion Criteria ..................................................................................................... 45 
4.3 
Patient Discontinuation ............................................................................................ 47 
4.3.1 
Permanent Discontinuation of Study Treatment ................................... 47 
4.3.2 
Withdrawal from the Study ..................................................................... 47 
4.3.3 
Procedures following Study Drug Discontinuation or Study Withdrawal
.................................................................................................................. 48 
4.4 
Enrollment of Additional Patients (Patient Replacement) ................................... 48 
4.5 
Method of Assigning Patients to Treatment Groups ............................................. 48 
5 
INVESTIGATIONAL PRODUCTS ....................................................................... 49 
5.1 
Description of Irinotecan Liposome Injection........................................................ 49 
5.1.1 
Storage and Handling of Irinotecan Liposome Injection ..................... 49 
5.1.2 
Packaging and Labelling of Irinotecan Liposome Injection ................ 49 
5.1.3 
Administration of Irinotecan Liposome Injection ................................. 49 
5.1.3.1 
Irinotecan Liposome Injection Premedication......................................... 50 
5.1.3.2 
Toxicity of Irinotecan Liposome Injection ............................................... 50 
5.2 
Description of Topotecan for Injection ................................................................... 54 
5.2.1 
Storage and Handling of Topotecan ...................................................... 55 
5.2.1.1 
US package insert/EU SmPC ................................................................... 55 
5.2.2 
Packaging and Labelling of Topotecan ................................................. 55 
5.2.3 
Administration of Topotecan .................................................................. 55 
5.3 
Rules for Dose Modification of Irinotecan Liposome Injection and Topotecan . 55 
5.3.1 
Irinotecan Liposome Injection ............................................................... 55 
5.3.2 
Topotecan for Injection .......................................................................... 56 
5.4 
Concomitant and Prohibited Therapies ................................................................. 57 
5.4.1 
Concomitant and Supportive Care Therapies ........................................ 57 
5.4.1.1 
Antiemetic Medications ............................................................................ 57 
5.4.1.2 
Myelosuppression .................................................................................... 58 
5.4.1.3 
Therapy for Diarrhea ............................................................................... 58 
5.4.2 
Prohibited Therapies ............................................................................... 58 
5.5 
Accountability of Study Drug .................................................................................. 59 
6 
STUDY ASSESSMENTS ......................................................................................... 59 
6.1 
Screening Visit ........................................................................................................... 59 
6.2 
Treatment/Active Follow-up Visits ......................................................................... 59 
6.2.1 
Pauses in Treatment................................................................................ 60 
6.3 
30-day Follow-up Visit .............................................................................................. 60 


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6.4 
Survival or Long-Term Follow-up .......................................................................... 61 
7 
SCHEDULE OF ASSESSMENTS .......................................................................... 62 
7.1 
Irinotecan Liposome Injection ................................................................................. 63 
7.2 
IV Topotecan ............................................................................................................. 65 
8 
CLINICAL PROCEDURES AND ASSESSMENTS ............................................ 67 
8.1 
Medical History ......................................................................................................... 67 
8.2 
Adverse Event Assessment and Reporting ............................................................. 67 
8.3 
Physical Exam ........................................................................................................... 67 
8.4 
Vital Signs .................................................................................................................. 67 
8.5 
Performance Status Assessment .............................................................................. 67 
8.6 
Quality of Life Assessments ..................................................................................... 67 
8.7 
Electrocardiogram and Pharmacokinetic-Matched Holter Monitoring ............. 68 
8.8 
Disease Evaluation .................................................................................................... 68 
9 
LABORATORY PROCEDURES AND ASSESSMENTS .................................... 69 
9.1 
Complete Blood Count ............................................................................................. 69 
9.2 
Serum Chemistry ...................................................................................................... 69 
9.3 
Pregnancy Test .......................................................................................................... 69 
9.4 
UGT1A1*28 ............................................................................................................... 69 
9.5 
Pharmacokinetic Sampling ...................................................................................... 70 
9.6 
Biobanking ................................................................................................................. 70 
10 
ADVERSE EVENT REPORTING ......................................................................... 71 
10.1 Definitions .................................................................................................................. 71 
10.1.1 
Adverse Events ........................................................................................ 71 
10.1.2 
Serious Adverse Events ........................................................................... 71 
10.2 Assessing and Documenting Adverse Events ......................................................... 72 
10.3 Reporting Serious Adverse Events .......................................................................... 73 
10.4 Determining the Severity and Relatedness of an Event ........................................ 73 
10.4.1 
Grading the Severity of an Adverse Event ............................................. 73 
10.4.2 
Relationship to Study Drug .................................................................... 74 
10.4.3 
Reporting and Follow-up of Pregnancy ................................................. 74 
11 
STATISTICAL METHODS .................................................................................... 74 
11.1 General Considerations ............................................................................................ 74 
11.2 Statistical Hypothesis and Determination of Sample Size .................................... 74 
11.3 Analysis Populations ................................................................................................. 75 
11.4 Disposition, Demographics, and Baseline Characteristics .................................... 76 
11.5 Efficacy Analysis ....................................................................................................... 76 
11.5.1 
Primary Efficacy Analysis (Part 2) ........................................................ 76 
11.5.2 
Key Secondary Analyses (Part 2)............................................................ 76 
11.5.2.1 
Progression-free Survival ........................................................................ 76 
11.5.2.2 
Objective Response .................................................................................. 77 
11.5.2.3 
Change From Baseline in Dyspnea and Cough Symptoms ..................... 77 


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11.5.3 
Exploratory Objectives Analyses ............................................................ 77 
11.5.3.1 
Time to treatment failure ......................................................................... 77 
11.5.3.2 
EORTC-QLQ outcomes ........................................................................... 77 
11.5.3.3 
Patient Global Impression of Change and Severity ................................. 78 
11.5.3.4 
EQ-5D-5L ................................................................................................ 78 
11.5.3.5 
Time to CNS Progression......................................................................... 78 
11.5.3.6 
Biomarkers ............................................................................................... 78 
11.6 Safety Analysis .......................................................................................................... 78 
11.7 Pharmacokinetic Analysis ........................................................................................ 79 
11.7.1 
Listings and Summary Statistics of Concentrations .............................. 79 
11.7.2 
Pharmacokinetic Data Analysis ............................................................. 79 
11.7.3 
Pharmacokinetics/Pharmacodynamics Relationship ............................ 79 
12 
STUDY ADMINISTRATION ................................................................................. 79 
12.1 Pre-Study Documentation ........................................................................................ 79 
12.2 Source Documents ..................................................................................................... 79 
12.3 Trial Ethics ................................................................................................................ 80 
12.4 Patient Informed Consent ........................................................................................ 80 
12.5 Investigational Review Board and Independent Ethics Committee Approval ... 80 
12.6 Monitoring ................................................................................................................. 81 
12.7 Data Quality Assurance ............................................................................................ 81 
12.8 Confidentiality ........................................................................................................... 82 
12.9 Protocol Amendments .............................................................................................. 82 
12.10 Publication ................................................................................................................. 82 
12.11 Records Retention ..................................................................................................... 83 
12.12 Study Termination .................................................................................................... 83 
13 
INVESTIGATOR SIGNATURE PAGE ................................................................ 85 
14 
REFERENCES .......................................................................................................... 86 
15 
APPENDIX ................................................................................................................ 90 
15.1 Appendix I: Recommendations for Management of Chemotherapy Induced 
Diarrhea ..................................................................................................................... 90 
15.2 Appendix II: ECOG Performance Status ............................................................... 92 
15.3 Appendix III: Response Criteria for CNS Metastases .......................................... 93 
15.4 Appendix IV: Temporary Measures and Procedures Related to COVID-19 
Pandemic .................................................................................................................... 94 
15.5 Appendix V: Summary of Changes 03 April 2017 (Version 2.0) to 
14 November 2017 (Version 3.0) .............................................................................. 96 
15.5.1 
Appendix Va Summary of Changes 14 November 2017 (Version 3.0) to 
25 April 2018 (Version 3.1 France)...................................................... 125 
15.5.2 
Appendix Vb Summary of Changes 14 November 2017 (Version 3.0) to 
10 May 2018 (Version 3.1 Germany) ................................................... 127 
15.6 Appendix VI: Summary of Changes 14 November 2017 (Version 3.0) to 
14 September 2018 (Version 4.0) ........................................................................... 131 


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15.7 Appendix VII: Summary of Changes 14 September 2018 (Version 4.0) to 
04 December 2019 (Version 5.0) ............................................................................ 158 
15.8 Appendix VIII: Summary of Changes 04 December 2019 (Version 5.0) to 
15 April 2020 (Version 6.0) .................................................................................... 181 
15.9 Appendix IX: Summary of Changes 15 April 2020 (Version 6.0) to 
24 November 2020 (Version 7.0) ............................................................................ 191 
15.10 Appendix X: Summary of Changes 24 November 2020 (Version 7.0) to 07 
October 2021 (Version 8.0) .................................................................................... 218 
 
LIST OF TABLES 
Table 1: 
Recommended Dosea Modifications for Irinotecan Liposome Injection .... 56 
Table 2: 
Recommended Topotecan Dose Modification Scheme for Subsequent 
Cycles ................................................................................................................ 57 
Table 3: 
Schedule of Assessments for Patients Receiving Irinotecan Liposome 
Injection ............................................................................................................ 63 
Table 4: 
Schedule of Assessments for Patients Receiving IV Topotecan .................. 65 
Table 5: 
Part 1 PK and ECG Extraction Time Points ................................................ 68 
Table 6: 
Pharmacokinetic Sampling Plan .................................................................... 70 
Table 7: 
Type I (α) and Type II (β) Error Spending for the Planned OS Analyses . 75 
Table 8 
Recommendations for Management of Chemotherapy Induced Diarrhea
 ........................................................................................................................... 90 
 
LIST OF FIGURES 
Figure 1: Increased SN-38 Exposure Leads to Increased Cell Death In Vitro .......... 30 
Figure 2: Irinotecan Liposome Injection-mediated Tumor Delivery of Irinotecan and 
SN-38 In Vivo ................................................................................................... 31 
Figure 3: Anti-tumor Activity of Irinotecan Liposome Injection, Non-liposomal 
Irinotecan and Topotecan at Clinically Relevant Doses in DMS-114 and 
NCI-H1048 SCLC Xenograft Models ............................................................ 32 
Figure 4: Anti-tumor Activity of Irinotecan Liposome Injection, Non-Liposomal 
Irinotecan and Topotecan in a Preclinical Model of Second Line SCLC .. 32 
Figure 5: Study Schema ................................................................................................... 39 
Figure 6: Description of Treatment Stages .................................................................... 39 
Figure 7: Treatment Cohorts: Safety Run-in ................................................................ 40 
 


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SUMMARY OF CHANGES 
The current version of the protocol (Version 8.0) was released on 07 October 2021. This 
protocol Version 8.0 includes all amendments, with summaries of changes from the protocol 
Version 2.0 included in the following appendices: 
• 
Appendix V: Summary of Changes 03 April 2017 (Version 2.0) to 14 November 2017 
(Version 3.0)  
- 
To streamline the phase II/III study design and allow sufficient statistical power 
for interim analysis 
• 
Appendix Va: Summary of Changes 14 November 2017 (Version 3.0) to 
25 April 2018 (Version 3.1 France) 
- 
To incorporate country-specific request from French regulatory authority 
received during the clinical trial submission process 
• 
Appendix Vb: Summary of Changes 14 November 2017 (Version 3.0) to 
10 May 2018 (Version 3.1 Germany) 
- 
To incorporate country-specific requests from German regulatory authority 
received during the clinical trial submission process 
• 
Appendix VI: Summary of Changes: 14 November 2017 (Version 3.0) to 
14 September 2018 (Version 4.0) 
- 
To incorporate country-specific requests from regulatory authorities received 
during the clinical trial submission process 
- 
To clarify eligibility criteria and protocol procedures 
• 
Appendix VII: Summary of Changes 14 September 2018 (Version 4.0) to 
04 December 2019 (Version 5.0). 
- 
To provide justification for dose level chosen for Part 2 
- 
To clarify protocol procedures 
- 
To update recommendations for management of chemotherapy-induced diarrhea 
- 
To clarify pregnancy follow-up period 
- 
To revise adverse event management guidelines 
- 
To update disease specific inclusion criteria. 
• 
Appendix VIII: Summary of Changes 04 December 2019 (Version 5.0) to 15 April 2020 
(Version 6.0). 
- 
To remove the futility interim PFS analysis as not required for decision on 
continuity of the study. 
- 
To clarify definition of length of SAE reporting (expressed differently in two 
different sections) 
- 
To clarify the sourcing of topotecan 
- 
Administration change to front cover fax number 
• 
Appendix IX: Summary of Changes 15 April 2020 (Version 6.0) to 24 November 2020 
(Version 7.0). 
- 
To update the statistical analysis to allow an assessment of the interim efficacy 
signal, confirming the promising results observed during the Part 1 by adding a 
descriptive analysis of ORR for efficacy at the time of the interim analysis of OS 
futility 


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- 
To amend the secondary and exploratory objectives for patient reported outcomes 
(PRO). 
- 
To include reporting requirements and detail specifics to conduct of the study 
during the COVID-19 pandemic. 
- 
To clarify eligibility criterion and protocol procedures. 
• 
Appendix X: Summary of Changes 24 November 2020 (Version 7.0) to 
07 October  2021 (Version 8.0). 
- 
To include supplemental interim analysis of the efficacy and safety based on 
intent-to treat (ITT) population to fulfill FDA recommendation. 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
5-FU 
5-fluoruracil 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BICR 
Blinded independent central review 
BLQ 
Below the limit of quantification 
BOR 
Best overall response 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CAV 
Cyclophosphamide, doxorubicin, and vincristine 
CBC 
Complete blood count 
CDX 
Cell line derived xenograft 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum serum concentration 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Contract research organization 
CT  
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
C#D# 
Cycle #, Day # 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
D5W 
Dextrose 5% in water 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EORTC-QLQ-C30 
EORTC quality-of-life core 30 questionnaire 
EORTC-QLQ-LC13 
EORTC quality-of-life questionnaire; lung cancer supplement 
ESMO 
European Society of Medical Oncology 
EQ-5D-5L 
EuroQol 5 dimension health status questionnaire (5 level) 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
HR  
Hazard ratio 
IASLC 
International Association for the Study of Lung Cancer 
IB 
Investigator’s Brochure 


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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology System 
ITT 
Intent to treat 
IV 
Intravenous 
LV 
Leucovorin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
Nal-IRI 
Irinotecan liposome injection; Liposomal irinotecan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease or disease progression 
PFS 
Progression free survival 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic(s) 
PRO 
Patient reported outcome 
QoL 
Quality of life 
QTcF 
QT interval, Fridericia correction 
RANO-BM 
Response assessment in neuro-oncology brain metastases 
RBC 
Red blood cell 
RECIST  
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
Small cell lung cancer 
SmPC 
Summary of medical product characteristics 
SRC 
Safety Review Committee 
TEAE 
Treatment emergent adverse event 
TOP1 
Topoisomerase-1 
TTF 
Time to treatment failure 
ULN 
Upper limit of normal 
UGT 
Uridine diphosphate glucuronosyl transferase 
UGT1A1 
Uridine diphosphate glucuronosyl transferase 1A1 
UGT1A1*28 
UGT1A1 pharmacogenetic variant *28 
US 
United States 
USP 
United States Pharmacopeia 
USPI 
United States package insert 
VAS 
Visual analog scale 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
 


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SYNOPSIS 
Sponsor: 
IPSEN Bioscience, Inc 
650 East Kendall Street, 
Cambridge MA 02142- USA 
Protocol 
Title: 
RESILIENT: A Randomized, Open Label Phase 3 Study of Irinotecan Liposome 
Injection (ONIVYDE®) versus Topotecan in Patients with Small Cell Lung 
Cancer Who Have Progressed on or after Platinum-based First-Line Therapy 
Protocol 
Number: MM-398-01-03-04 
Phase of 
Development: 3 
Trial 
Locations: Worldwide 
Number of 
sites: Approximately 137 sites will participate in the study.   
Patient 
Population: 
Patients with small cell lung cancer who have progressed on or after 
platinum-based first line therapy. 
Estimated 
Number of 
Patients: 
In Part 1 of the study, approximately 24 to 36 patients will be enrolled and in 
Part 2 of the study approximately 450 patients will be enrolled. 
Objectives  
Part 1  
 
Part 1 (single-arm; dose-ranging) Objectives: 
Primary Objectives: 
• 
Describe the safety and tolerability of irinotecan liposome injection 
monotherapy administered every 2 weeks 
• 
To determine the irinotecan liposome injection monotherapy dose 
(85 mg/m2 or 70 mg/m2 administered every 2 weeks) for Part 2 of this 
study.  
(Note: all doses of irinotecan liposome injection refer to free base unless 
otherwise stated) 
Secondary Objectives: 
To assess the preliminary efficacy of irinotecan liposome injection (at either the 
85 mg/m2 dose level or the 70 mg/m2 dose level) as determined by:  
• 
Objective response rate (ORR) 
• 
Progression free survival (PFS) 
• 
Overall survival (OS). 
Exploratory Objectives: 
• 
To describe QTcF following treatment with irinotecan liposome injection. 
• 
To explore the biomarkers associated with toxicity and efficacy following 
treatment with irinotecan liposome injection in this patient population. 
• 
To describe the association between UGT1A1*28 and other UGT1A1 
genotypes, SN-38 concentration and safety. 


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• 
To evaluate the pharmacokinetics (PK) and the relationship between PK 
exposure and efficacy and safety following irinotecan liposome injection in 
this patient population. 
• 
To explore patient-reported outcomes (PROs) using the European 
Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC-QLQ-C30) and European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire Lung 
Cancer 13 (EORTC-QLQ-LC13), Patient Global Impression of Severity 
(PGI-S), 
Patient 
Global 
Impression 
of 
Change 
(PGI-C), 
and 
EuroQol 5- dimension health status questionnaire (5 level) (EQ-5D-5L). 
Objectives  
Part 2 
Part 2 (two-arm randomized) Objectives: 
Primary Objective: 
To compare overall survival (OS) following treatment with irinotecan liposome 
injection with OS following treatment with IV topotecan.  
Secondary Objectives: 
To compare the following between the treatment arms: 
• 
Progression free survival (PFS) 
• 
Objective response rate (ORR) 
• 
Patient Reported Outcomes (PRO) 
• 
Safety profile. 
Exploratory Objectives: 
• 
To explore the biomarkers associated with toxicity and efficacy following 
treatment with irinotecan liposome injection in this patient population. 
• 
To describe the association between UGT1A1*28 and other UGT1A1 
genotypes, SN-38 concentration (irinotecan liposome injection treated 
patients only) and safety. 
• 
To evaluate the pharmacokinetics and the relationship between 
pharmacokinetic exposure and efficacy and safety following irinotecan 
liposome injection in this patient population.  
• 
To compare the rate of development/time to development of central nervous 
system (CNS) progression and development of new CNS metastases 
between treatment arms. 
• 
To compare time to treatment failure between treatment arms. 
• 
To assess the proportion of patients with improvement in symptoms as 
measured by EORTC QLQ-C30/LC13 dyspnea scale. 
• 
To assess the proportion of patients with improvement in symptoms as 
measured by the EORTC QLQ-LC13. 
• 
To compare the effect of irinotecan liposome injection versus. topotecan on 
symptoms (other than dyspnea and cough), functioning and global health 
status as measured by EORTC-QLQ-C30, EORTC-QLQ-LC13 and 
EQ-5D-5L. 
Study Design: This study will be conducted in two parts: an open-label, single-arm, safety run-in 
period (Part 1) followed by a randomized period (Part 2) assessing irinotecan 


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liposome injection versus IV topotecan in patients with small cell lung cancer 
(SCLC) who have progressed on or after platinum-based first line therapy. 
Details of the study design for each part are as follows: 
Note: Onivyde is also known as irinotecan liposome injection, liposomal injection or nal-IRI.  
Each part will consist of three stages: screening stage, treatment/active follow-up 
stage and long-term follow-up stage. Once consented, patients will enter a screening 
stage. Upon first dose of study treatment in Part 1 or randomization (Part 2), patients 
will enter the treatment/active follow-up stage. Once a decision is made to 
permanently discontinue the patient from study treatment, a 30-day follow-up visit 
will occur and the patient will enter the long-term follow-up stage. The stages for 
this trial are outlined in the schematic below.
Part 1:
Part 1 is an open-label, single-arm, safety run-in evaluation of irinotecan liposome 
injection administered every 2 weeks intended to confirm the anticipated Part 2 
regimen (85 mg/m2), based on safety and preliminary efficacy. A contingency has 
been included for evaluation of irinotecan liposome injection at a dose level of 
70 mg/m2, should the higher dose level of 85 mg/m2 result in unacceptable toxicity. 
At either dose level of irinotecan liposome injection up to 24 patients will be 
enrolled.
The safety assessment and the corresponding expansion will be conducted 
according to a “6+6” design followed by enrollment of an additional 12 patients (as 
described below). Patients will initially be treated with irinotecan liposome 
injection 85 mg/m2 every 2 weeks. Dose limiting toxicities (DLTs) will be evaluated 
for the first 12 patients treated during the first 28 days of treatment (or up to 14 days 
after the second dose of study treatment if there is a treatment delay due to non-
DLT related reasons).
•
Among the first 6 patients receiving irinotecan liposome injection 
85 mg/m2 (i.e 85 mg/m2 cohort), if ≤ 2 patients experience a DLT, another 
6 patients will be enrolled into this cohort. Otherwise, enrollment into the 
70 mg/m2 cohort will be initiated.
•
Among the first 12 patients receiving irinotecan liposome injection 
85 mg/m2, if ≤ 2 patients experience a DLT, this cohort will be expanded 
by 12 additional patients. Otherwise, the enrollment of the 85 mg/m2 cohort 
will be stopped and the enrollment of the 70 mg/m2 cohort will be initiated. 


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Note: all doses described are irinotecan liposome injection free base. 
If the 70 mg/m2 cohort is enrolled, the same “6+6” design followed by enrollment 
of an additional 12 patients, and the same DLT guidelines will be used as that for 
the 85 mg/m2 cohort. If ≤ 2 patients among the first 12 patient receiving irinotecan 
liposome injection 70 mg/m2 experience a DLT, then that dose level will be declared 
tolerable and this cohort will be expanded by 12 additional patients. Otherwise, 
additional dose reduction(s) may be considered.  
Note that in either the 85 mg/m2 cohort or the 70 mg/m2 cohort, there will be no 
stopping rules based on DLT assessment; however, DLTs will continue to be 
assessed among the additional 12 patients recruited after the first 12 patients have 
completed DLT evaluation. 
The decision of which dose to use for Part 2 will be made based on the totality of 
data from all patients treated in Part 1. 
If a decision is made to terminate the irinotecan liposome injection 85 mg/m2 dose 
level cohort (and instead initiate enrollment into the 70 mg/m2 cohort) patients who 
are tolerating the 85 mg/m2 dose level will remain at that dose level (unless 
subsequent toxicity requires a dose modification). 
During the DLT evaluation period in either 85 mg/m2 and 70 mg/m2 cohort, the 
following adverse events (AEs) should be considered as DLTs if they occur during 
the first 28 days of treatment (or 14 days after the second dose of study treatment if 
there is a treatment delay and are deemed related to the study treatment by the 
investigator: 
• 
Grade 4 neutropenia or thrombocytopenia that does not resolve within 
7 days despite optimal supportive therapy, 
• 
Inability to begin subsequent treatment course within 14 days of the 
scheduled date, due to drug-related toxicity,  
• 
Grade 3-4 neutropenia complicated by fever ≥ 38.5 °C (i.e. febrile 
neutropenia) and/or by infection, 
• 
Any Grade 4 non-hematologic toxicity with the exception of the following: 
o Fatigue/asthenia lasting < 14 days, 
o Nausea and vomiting lasting ≤ 72 hours duration (only considered 
dose limiting if they last > 72 hours after treatment with an optimal 
anti-emetic treatment), 


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o Diarrhea ≤ 72 hours duration (only considered dose limiting if 
diarrhea lasts > 72 hours after treatment with an optimal 
anti-diarrheal regimen), 
• 
Grade 3 non-hematologic toxicity with the exception of the following: 
o Any gastrointestinal disorder and dehydration (with associated 
signs and symptoms) unless Grade 3 toxicity persists despite 
optimal medical management for > 72 hours, 
o Pain unless Grade 3 toxicity persists despite optimal medical 
management, 
o Fatigue, fever, flu like symptoms, infections and infestations, 
o Infusion reaction (and associated symptoms) unless it occurs 
following steroid premedication, 
o Hepatic and kidney function abnormalities, and electrolyte 
abnormalities unless they persist, despite optimal medical 
management. 
The determination of whether an AE is considered a DLT will be made by the Safety 
Review Committee (SRC) comprising the Part 1 Investigators and the Medical 
Monitor(s) of the Sponsor. Other AEs, not meeting the DLT criteria above, that are 
deemed related to study treatment can also be considered a DLT event at the 
discretion of the SRC. Safety review meetings between investigators and sponsor 
will occur regularly during Part 1 of the study with at least monthly meetings, or 
more frequently, if required. 
Safety and efficacy results from Part 1 will determine if the study proceeds to Part 2. 
The final decision to proceed to Part 2 will be made by the Sponsor in consultation 
with the study steering committee of the study, after consideration of all available 
efficacy and safety data from Part 1 of the study. 
All patients in Part 1 will follow the same schedule of assessments as required for 
Part 2 detailed below. 
Part 2: 
Part 2 will be randomized, and assess the efficacy of irinotecan liposome injection 
versus IV topotecan. Approximately 450 eligible patients will be randomized in a 
1:1 ratio between the experimental arm (Arm A: based on the findings of Part 1 
[i.e. likely to be either 85 mg/m2 or 70 mg/m2 of irinotecan liposome injection]) and 
the control arm (Arm B: topotecan). Note that following assessment of the available 
safety and efficacy data from Part 1 the 70 mg/m2 dose was chosen for Arm A. 
Patients will be randomized to the treatment arms using an Interactive Response 
Technology System (IRT) at a central location. Randomization will be stratified, 
based on the following factors: 
• 
Region (North America vs. Asia vs. Other) 
• 
Platinum sensitivity (sensitive vs. resistant) 
• 
Performance status (ECOG 0 vs. 1) 
• 
Prior immunotherapy (yes vs. no) 
(Note: for platinum sensitivity, progression within 90 days from the completion of 
first-line platinum therapy is considered “platinum resistant” and the others 
“platinum sensitive”. Prior immunotherapy sensitivity should not be confused with 
platinum sensitivity). 
Only region (North America vs. Asia vs. Other) and platinum sensitivity (sensitive 
vs. resistant) will be used for the stratified efficacy analysis. 


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It is intended that all patients in Parts 1 and 2 will be treated until progressive disease 
or unacceptable toxicity (see Section 4.3.1). Patients may take a treatment holiday 
and resume study treatment under certain instances. Detailed rule for pausing and 
resuming study treatment can be found in Section 6.2.1. A modified visit schedule 
will operate during this treatment pause, however, tumor and quality of life 
assessments must be evaluated at the same frequency as during active treatment. 
Cross-over between treatment arms is not permitted. 
Upon permanent discontinuation of study treatment (defined as patients with 
progressive disease whilst receiving study treatment and/or those assessed by the 
Investigator as unable to continue or resume study treatment due to unacceptable 
toxicity), patients will return to the study site for a 30-day follow-up visit. After this 
visit, patients will continue to be followed for OS status by phone, email or a visit 
to the study site once every month until death or study closure, whichever occurs 
first. 
Tumor assessments will be performed every 6 weeks (± 1 week), using the 
Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (Version 1.1) 
(Parts 1 and 2) and Response Assessment in Neuro-oncology Brain Metastases 
(RANO-BM) criteria for CNS lesions (Part 2). Tumor assessment at screening and 
for all subsequent visits will be computed tomography (CT) with contrast 
(chest/abdomen required and pelvis [or other areas] if clinically indicated) and brain 
magnetic resonance imaging (MRI) with contrast. For patients who are allergic to 
IV contrast or cannot tolerate IV contrast due to impaired renal function or other 
issues, a non-enhanced CT or MRI is acceptable. Each follow-up tumor assessment 
should use the same assessment method as performed at screening, unless medically 
contraindicated. Patients who discontinue study treatment, for reasons other than 
disease progression, should continue to be followed-up until radiological 
documentation of progressive disease with the same schedule of tumor assessments 
(every 6 weeks ± 1 week) until radiological documentation of progressive disease 
or until the start of new anti-neoplastic therapy. The Sponsor will collect and store 
all tumor assessment images on all patients throughout the study. Progressive 
disease will be determined by local radiology review and/or investigator 
assessment. An independent central review of the scans will be performed at the 
discretion of the Sponsor to support potential early filing to regulatory authorities. 
All patients will be followed at least monthly for survival status until death, loss to 
follow-up or study closure, whichever comes first. 
A quality of life assessment will be performed using the EORTC-QLQ-C30, 
EORTC-QLQ-LC13, PGI-S, PGI-C and EQ-5D-5L questionnaires. Although the 
PGI-C and PGI-S are not specified as exploratory objectives in Part 2 they will serve 
as anchors deriving a within-patient meaningful change threshold in Part 2. All PRO 
instruments are required to be completed at screening, prior to dosing at 6-week 
intervals (and prior to any other assessment procedures) following start of treatment, 
at treatment discontinuation, at the 30-day follow-up visit. Patients who discontinue 
study treatment, for reasons other than disease progression, should continue to 
complete all QoL assessments every 6 weeks until radiological documentation of 
progressive disease or until the start of  new anti-neoplastic therapy. The PGI-C is  
not included in the screening assessment. Adverse events will be evaluated 
according to the National Cancer Institute’s (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0. For summary of AEs, events will be 
coded using the latest Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary (Version 21.0 or later) at the start of the study. 
The primary analysis is planned when at least 350 OS events have occurred in 
Part 2. An interim analysis for OS futility is planned at approximately the 29% 


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information time, after at least 100 OS events have occurred. A supplemental 
interim analysis is planned on data collected 24 weeks after the last patient has been 
randomized based on the ITT Population. At the timepoints of the interim analysis 
and supplemental interim analysis, ORR by blinded independent central review 
(BICR) tumor assessments will be analyzed descriptively: 
• 
by the independent DMC for the first 200 patients randomized in Part 2 of 
the study  
• 
for the full ITT population in the supplemental interim analysis.  
Details of BICR tumor assessment process and approach will be described in the 
imaging charter document. Details of the study-level type I error control are 
provided in the section on statistical methods and in the Statistical Analysis Plan 
(SAP).  
An independent DMC will be established to monitor data in Part 2 of the study, to 
evaluate the planned interim analysis for OS futility and to make recommendation 
to the Sponsor based on the results of this interim analysis over continuation or 
stoppage of the study. During the course of the study, regular review of safety data 
will be conducted in accordance with the DMC charter. The first safety review by 
the DMC will take place after the 30th patient is randomized and treated for at least 
one cycle or permanently discontinues study drug, whichever occurs first. The 
timing and details of subsequent data reviews will be detailed in the DMC charter. 
Items reviewed will include (but not limited to) safety events, results of interim 
analysis, any available results of PK testing and UGT1A1*28 genotype. Attention 
will be paid to determining whether any study procedure needs to be modified for 
patients who are homozygous for UGT1A1*28. 
Pharmacokinetics 
Sparse plasma samples for PK will be collected from all patients receiving 
irinotecan liposome injection (Part 1 and Part 2).  
Biobanking 
The exploratory endpoint comprises biobanking of samples for further analysis 
among patients who consent. Patient participation to consent to biobanking samples 
is optional. Analysis from the biobank samples will be performed outside the scope 
of the main study and reported separately. 
Estimated 
Number of 
Patients 
In Part 1 of the study, approximately 24 to 36 evaluable patients will be enrolled 
and in the Part 2 of the study approximately 450 patients will be enrolled. 
Inclusion 
Criteria: 
To participate in the study patients must meet the following inclusion criteria, and 
none of the exclusion criteria: 
General Inclusion Criteria  
1. At least 18 years of age. 
2. Able to understand and provide the study informed consent. 
3. ECOG performance status of 0 or 1. 
4. Life expectancy >12 weeks. 
 


I P S E N G R O U P 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
V E R SI O N 8. 0 –  0 7 O C T O B E R 2 0 2 1  
 
Pr o prietar y a n d C o nfi de ntial  
P a ge 1 8  
 
 
Dise ase S pecific I ncl usi o n Criteri a  
5.  Hist o pat h ol o gicall y or c yt ol o gicall y c o nfir me d s mall cell l u n g ca ncer acc or di n g 
t o t he I nter nati o nal Ass ociati o n f or t he St u d y of L u n g Ca ncer (I A S L C) 
hist o pat h ol o gical classificati o n. Mi xe d or c o m bi ne d s u bt y pes acc or di n g t o t he 
I A S L C are n ot all o we d. 
6.  E val ua ble disease as defi ne d b y R E CI S T Ver si o n 1. 1 g ui deli nes ( patie nts wit h 
n o n -meas ura ble lesi o ns are eli gi ble).  
7.  Ra di ol o gicall y c o nfir me d pr o gressi o n o n or after first -li ne plati n u m base d 
c he m ot hera p y (car b o plati n or cis plati n), or c he m o -ra diati o n i ncl u di n g 
plati n u m -base d c he m ot hera p y f or treat m e nt of li mite d or e xte nsi ve sta ge 
S C L C. I n a d diti o n t o plati n u m -base d re gi me n,  o ne li ne of i m m u n ot hera p y as 
m o n ot hera p y or i n c o m bi nati o n i n first or i n sec o n d li ne setti n g is all o we d.  
8.  Rec o vere d fr o m t he effects of a n y pri or c he m ot hera p y, s ur ger y, ra di ot he ra p y or 
ot her a nti -ne o plastic t hera p y (rec o vere d t o Gra de  1 or better, wit h t he e xce pti o n 
of al o pecia, peri p heral ne ur o pat h y, or ot ot o xicit y).  
He m at ol o gic, Bi oc he mic al a n d Or g a n F u ncti o n I ncl usi o n Criteri a  
9.  D uri n g t he Scree ni n g peri o d, a de q uate b o ne marr o w reser ves as e vi de nce d b y: 
a. A bs ol ute ne utr o p hil c o u nt > 1, 5 0 0 cells/ µ L ( 1. 5 x 1 0 9/ L) wit h o ut 
t he use of he mat o p oietic gr o wt h fact ors wit hi n t he i m me diatel y 
prece di n g 1 4  da ys;  
b.  Platelet c o u nt > 1 0 0, 0 0 0 cells/ µ L ( 1 0 0 x 1 0 9/ L);  
c. He m o gl o bi n > 9 g/ d L; tra nsf usi o ns ar e all o we d. 
1 0.  A de q uate he patic f u ncti o n as e vi de nce d b y:  
a. Ser u m t otal bilir u bi n wit hi n n or mal ra n ge f or t he i nstit uti o n;  
b.  As partate 
a mi n otra nsferase 
a n d 
ala ni ne 
a mi n otra nsferase 
≤ 2. 5  x  u p per li mit of n or mal ( U L N) ( ≤ 5 x U L N is acce pta ble if 
li ver metastases is prese nt); 
c. Ser u m al b u mi n ≥3. 0 g/ d L ( ≥ 3 0 g/ L).  
1 1.  A de q uate re nal f u ncti o n as e vi de nce d b y a ser u m creati ni ne ≤1. 5 x U L N a n d 
creati ni ne cleara nce ≥4 0 m L/ mi n.  Act ual b o d y wei g ht s h o ul d be use d f or 
calc ulati n g creati ni ne cleara nce usi n g t he C oc kcr oft -Ga ult E q uati o n (e xce pt f or 
patie nts wit h b o d y mass i n de x > 3 0 k g/ m 2 w he n lea n b o d y wei g ht s h o ul d be 
use d i nstea d):  
 
 
 
 
w here Se x = 1 f or male a n d 0. 8 5 f or fe males  
 
1 2.  Electr ocar di o gra m wit h o ut a n y cli nicall y si g nifica nt fi n di n gs at scree ni n g, as 
per i n vesti gat or’s assess me nt.  
 
 
( 1 4 0 –  A ge ( years)) × ( Wei g ht ( k g))  
7 2 × Ser u m Creati ni ne ( m g/ d L)  
 
 
×  Se x  
Ser u m Creati ni ne ( m g/ mi n) =  


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Additional Disease Specific Inclusion Criteria 
13a Patients with certain types of asymptomatic CNS metastases that meet ALL the 
following criteria are eligible.  
a. Patients with asymptomatic CNS metastases prior to enrollment 
b. Prior radiation for CNS metastatic disease is completed ≥4 weeks 
prior to enrollment  
c. CNS metastases that are stable or have decreased according to the 
post radiation follow-up scan that is conducted at least 4 weeks 
after completion of radiation treatment for CNS lesion. 
d.  Patients have discontinued corticosteroids or are on stable low-
dose steroids (prednisone or equivalent 10 mg daily or less) for at 
least 1 week after completion of radiation for CNS lesion prior to 
enrollment. 
Exclusion 
Criteria: 
Patients must meet all the inclusion criteria listed above and none of the following 
exclusion criteria: 
General Exclusion Criteria 
1. Any 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. 
2. Pregnant or breast feeding; females of child-bearing potential must test negative 
for pregnancy at the time of enrollment based on a serum pregnancy test. 
Females of childbearing potential are defined as fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Postmenopausal 
women are defined as those that have an absence of menstruation for at least 
2 years. If necessary, follicle stimulating hormone results >50 IU/L at screening 
are confirmatory in the absence of a clear postmenopausal history. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. 
Male patients must agree to use condoms during the study and for 4 months 
following the last dose of study drug. Female patients of reproductive potential 
must agree to use a highly effective method of birth control, during the study 
and for 1 month following the last dose of study drug. 
Disease Specific Exclusion Criteria  
3. Patients with large cell neuroendocrine lung carcinoma. 
4. Patients who have received any of the following treatments: 
a. Prior treatment regimens with irinotecan, topotecan or any other 
topoisomerase I inhibitor including investigational topoisomerase I 
inhibitors; 
b. Retreatment with platinum-based regimen after relapse of first-line 
platinum-containing therapy; 
c. Any antibody-drug conjugates or molecular targeted agents (e.g. poly 
ADP-ribose polymerase inhibitors), either alone or in combination with 
other treatments; 


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d. More than one line of prior immunotherapy; 
e. Any other additional regimen of prior cytotoxic chemotherapy, not 
described above.  
5. Patients with a history (any grade) of immunotherapy induced colitis or 
pneumonitis, based on clinical assessment and/or confirmed by biopsy. 
6. Patients with any of the following CNS metastases:  
a. Patients who have developed new or progressive brain metastasis 
within three months following prophylactic and/or therapeutic cranial 
radiation (whole brain or stereotactic radiation) as defined by imaging; 
b. Patients with symptomatic CNS metastases; 
c. Patients with carcinomatous meningitis. 
7. 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 the first 
dose of irinotecan liposome injection. 
8. Have a previous or concurrent cancer that is distinct in primary 
(non-pulmonary) site or histology, except carcinoma in situ, treated basal cell 
carcinoma, superficial bladder tumors (Ta and Tis [carcinoma in situ]) or any 
previous cancer curatively treated with last specific treatment >3 years ago 
without evidence of recurrence. 
9. Investigational therapy administered within 4 weeks, or within a time interval 
less than at least 5 half-lives (whichever is less) of the investigational agent 
prior to the first scheduled day of dosing in this study. 
Hematologic, Biochemical and Organ Function Exclusion Criteria 
10. Severe cardiovascular and pulmonary disease (e.g. myocardial infarction, 
unstable angina pectoris, coronary angioplasty or stenting, deep vein 
thrombosis, stroke, pulmonary fibrosis, active uncontrolled bleeding, or a 
known bleeding diathesis) less than 6 months before inclusion. 
11. New York Heart Association Class III or IV congestive heart failure, ventricular 
arrhythmias or uncontrolled blood pressure.  
12. Active infection (e.g. acute bacterial infection, tuberculosis, active hepatitis B/C 
or active human immunodeficiency virus) which in the Investigator’s opinion 
might compromise the patient’s participation in the trial or affect the study 
outcome. 
13. Known hypersensitivity to any of the components of irinotecan liposome 
injection, other liposomal products, or topotecan. 
14. Clinically significant gastrointestinal disorder including hepatic disorders, 
bleeding, inflammation, occlusion, or diarrhea > Grade 1. 
Additional Disease Specific Exclusion Criterion (only applicable in France, per 
request of French Regulatory Authorities) 
15. Patients who, per investigator assessment, are suitable for a second line 
platinum-based regimen following relapse after first-line platinum-based 
therapy. 
Length of 
Study: 
The study will end when all patients are off study drug treatment and at least 
350 OS events have occurred in Part 2  


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Study 
Assessments: See Schedule of Assessments 
Study 
Treatment 
Irinotecan liposome injection: 
Part 1: (single-arm, dose-ranging) 
• 
Irinotecan liposome injection 85 mg/m2 (strength expressed as irinotecan 
free base; approximately equivalent to 100 mg/m2 of the hydrochloric 
trihydrate salt) IV over 90 minutes, every 2 weeks in a 6-week cycle 
OR 
• 
Irinotecan liposome injection 70 mg/m2 (strength expressed as irinotecan 
free base; approximately equivalent to 80 mg/m2 of the hydrochloric 
trihydrate salt) IV over 90 minutes, every 2 weeks in a 6-week cycle. 
Part 2 (two-arm, randomized): 
• Irinotecan liposome injection 85 mg/m2 (strength expressed as irinotecan 
free base; approximately equivalent to 100 mg/m2 of the hydrochloric 
trihydrate salt) IV over 90 minutes, every 2 weeks in a 6-week cycle (unless 
deemed unacceptable in Part 1, in which case the 70 mg/m2 dose level 
[strength expressed based on irinotecan free base; approximately equivalent 
to 80 mg/m2 of the hydrochloric trihydrate salt] will be utilized IV over 
90 minutes, every 2 weeks in a 6-week cycle). Note that following 
assessment of the available safety and efficacy data from Part 1 the 70 mg/m2 
dose level will be utilized for Part 2. 
• Topotecan 1.5 mg/m2: IV over 30 minutes daily for 5 consecutive days, every 
3 weeks in a 6-week cycle. 
Up to three dose reductions of irinotecan liposome injection or up to two dose 
reductions of topotecan per patient are permitted due to toxicities. Dose delays are 
permitted to allow recovery from treatment-associated toxicities. Prophylactic 
antibiotics are recommended for patients at high risk of infectious complications. 
Prophylactic granulocyte colony stimulating factors should be considered. For 
further details on dose reductions and supportive care measures, please refer to 
Section 5.3. 
Investigational 
Product: 
Irinotecan liposome injection (also known as liposomal irinotecan, nal-IRI, 
MM-398, PEP02, BAX2398 and ONIVYDE®) is a sterile, white to slightly yellow 
opaque isotonic liposomal dispersion. Each 10 mL single-dose vial contains 43 mg 
irinotecan free base at a concentration of 4.3 mg/mL. The liposome is a unilamellar 
lipid bilayer vesicle, approximately 110 nm in diameter, which encapsulates an 
aqueous space containing irinotecan in a gelated or precipitated state as the 
sucrosofate salt. It will be supplied as sterile, single-use vials containing 43 mg 
irinotecan free base at a concentration of 4.3 mg/mL. 
Irinotecan liposome injection must be stored refrigerated (2 to 8°C, 36 to 46°F) with 
protection from light. Do not freeze. 
Sample Size 
Part 1: 
Up to 36 patients will be evaluated in Part 1. Up to 12 patients per dose level of 
irinotecan liposome injection may be treated at either 85 mg/m2 or 70 mg/m2 and 
one of these two dose levels will subsequently be expanded to a total of 24 patients. 
A dose level of irinotecan liposome injection will be determined to have an 
acceptable toxicity profile if there are ≤2 DLTs in the first 12 patients evaluated. 


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A total of 24 patients (at the eventually selected dose level of irinotecan liposome 
injection) is considered sufficient to provide a preliminary assessment of efficacy 
endpoints, for the purposes of determining whether to proceed to Part 2. 
 
Part 2: 
The primary endpoint is OS.  
A total of 450 patients will be randomized in a 1:1 ratio to the two treatment arms. 
Follow-up until at least 350 OS events are observed across the two treatment arms 
provides at least 87% power to detect a true hazard ratio of HR ≤ 0.714 (median 
OS: 7.5 vs 10.5 months) using a stratified log-rank test (stratified by region 
(North America vs. Asia vs. Other) and platinum sensitivity (sensitive vs. resistant)) 
with overall 1-sided significance level of 0.025 (adjusted for the interim analysis).  
Assuming enrollment over 24 months with a ramp-up to a maximum of 21 patients 
per month and lost-to-follow-up rate of 5% across both treatment arms, the timing 
of the primary analysis is expected to be at 37 months. 
An interim OS analysis for futility will be conducted when approximately 29% of 
the planned final number of OS events (i.e., approximately 100 of 350 OS events) 
has been observed in the ITT population. 
At the timepoint of the interim analysis, ORR by BICR tumor assessments will be 
analyzed descriptively by the independent DMC for the first 200 patients 
randomized in Part 2 of the study. The independent DMC will notify the Sponsor if 
pre-specified criteria for ORR are met. 
A supplemental interim analysis is planned on data collected 24 weeks after the last 
patient has been randomized based on the ITT population to fulfill FDA 
recommendation.  At this timepoint, OS and ORR (supported by DOR) will be 
summarized descriptively. 
Note: detailed methodology is further described in the SAP. 
Statistical 
Considerations 
and Data 
Reporting: 
General: 
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). 
Part 1: 
The efficacy and safety of irinotecan liposome injection in Part 1 will be reported 
descriptively. In addition, AEs occurring in Part 1 of the study will be described in 
detail. 
Patients enrolled and treated with at least one dose of irinotecan liposome injection 
will comprise the Part 1 safety and efficacy population.  
Part 2: 
Patients randomized in Part 2 will comprise the ITT population. This will be the 
population used to evaluate the efficacy (OS, PFS, ORR) of the experimental arm. 
In the ITT analyses of efficacy, each patient will be considered according to the 
randomized treatment assignment. Patients who received any part of any study drug 
will define the Part 2 safety population. 


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For stratified analyses, stratification factors will be the randomization stratification 
factors of region (North America, Asia, Other) and platinum sensitivity (sensitive, 
resistant).  
 
Primary Efficacy Analysis (Part 2): 
Overall Survival 
Overall survival is defined as the number of months from randomization in Part 2 
to the date of death. Patients without observed death at the time of the primary 
analysis will have OS censored according to the last recorded date alive. 
The primary analysis will be performed using a stratified log-rank test (stratified by 
region and platinum sensitivity) comparing the OS difference between two 
treatment arms with level of significance controlled at the one-sided 0.025 level. 
Kaplan-Meier methods will be used to estimate median OS (with 95% confidence 
intervals (CI)) and to display OS time graphically. A stratified Cox proportional 
hazards model will be used to estimate hazard ratio and its corresponding 95% CI. 
Sensitivity analyses for OS will be described in the SAP.  
An interim analysis of OS for futility (at approximately 29% of planned OS events) 
is planned. To control type I and type II errors, the planned interim analysis will 
utilize an alpha and (non-binding) beta spending function approach with Hwang-
Shih-Decani spending and γ parameter equal to -4.5 for each type I error and γ = -1 
for type II error (Hwang, 1990). 
A supplemental interim analysis is planned on data collected 24 weeks after the last 
patient has been randomized based on the ITT population to fulfill FDA 
recommendation. At this timepoint, OS and ORR (supported by DOR) will be 
summarized descriptively. 
 
Key Secondary Efficacy Analyses (Part 2): 
Key secondary endpoints are PFS, ORR and change from baseline in patient 
reported symptoms (dyspnea and cough). 
Key secondary endpoints will be tested no more than once. To control the overall 
Type I error rate for the comparison between irinotecan liposome injection and 
topotecan for the primary and secondary endpoints, a hierarchical approach will be 
applied to the statistical testing of the secondary endpoints. The statistical inference 
for the first secondary endpoint of PFS (by BICR) will only be performed if the 
primary endpoint (OS), is statistically significant. The second secondary endpoint 
of ORR (by BICR) will only be tested if PFS is statistically significant. Similarly, 
the PRO endpoints will only be tested if ORR is statistically significant. Any 
parameter which is not statistically significant will be regarded as descriptive and 
exploratory. 
Progression-free survival: 
Progression-free survival is the time from randomization in Part 2 to the first 
documented objective disease progression (PD) using RECIST Version 1.1 (or 
RANO-BM criteria for CNS lesions) or death due to any cause, whichever occurs 
first. Determination of PFS will be based on BICR tumor assessment, with PFS 
based on investigator tumor assessments as a sensitivity analysis. If neither death 
nor progression is observed, data will be censored on the date of the last observed 
tumor assessment date. Patients without a valid tumor response evaluation at 
enrollment/randomization 
will 
be 
censored 
on 
the 
date 
of 


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enrollment/randomization. Patients starting a new anti-cancer treatment prior to 
documented PD will be censored at the date of the last observed tumor assessment 
prior to start of the new treatment. Patients with documented PD or death after an 
unacceptable long interval (i.e. 2 or more missed or indeterminate scheduled 
assessments) will be censored at the time of the last observed non-PD tumor 
assessment date prior to progression or death. Details of data handling for censoring 
of PFS will be provided in the SAP.  
The difference in PFS between treatments will be evaluated using a stratified log-
rank test (stratified by region and platinum sensitivity). Kaplan-Meier methods will 
be used to estimate median PFS (with 95% CI) and to display PFS time graphically. 
A stratified Cox proportional hazards model will be used to estimate the PFS hazard 
ratio and its corresponding 95% CI. Sensitivity analyses for PFS will be described 
in the SAP. 
Objective Response: 
Objective response rate is the proportion of patients who achieve partial response  
(PR) or complete response (CR) according to RECIST Version 1.1 guidelines (or 
RANO-BM criteria for CNS lesions, Part 2). An estimate of the ORR and its 95% 
CI will be calculated. The difference in ORR between treatment groups will be 
compared using Cochran-Mantel-Haenszel method, stratified by region and 
platinum sensitivity. 
In addition to investigator assessment, a BICR review of the tumor assessment 
images will be performed for all patients included in the study, and more 
specifically at the time of: 
• 
the interim analysis, for the descriptive analysis of ORR based on the first 
200 patients randomized in both arms (i.e. approximately 100 patients from 
each arm) as well as for the patients included in Part 1 and treated with the 
selected dose for Part 2. 
• 
the supplemental analysis, for tumor images for all randomized patients 
collected 24 weeks after the last patient has been randomized.  
A final formal test on secondary endpoint ORR will be based on BICR tumor 
assessment, with ORR based on investigator tumor assessments as a sensitivity 
analysis. 
Patient Reported Outcomes: 
The secondary endpoints below are included in the testing hierarchy: 
• 
Change from baseline to Week 12 in EORTC QLQ-C30/LC13 dyspnea 
scale  
• 
Change from baseline to Week 12 in EORTC QLQ-LC13 cough scale 
 
Safety Analysis: 
Safety analyses (AEs and laboratory analyses) will be performed using the safety 
population, defined as all patients receiving any study drug. Treatment assignment 
will be according to actual treatment received. Adverse events will be coded using 
MedDRA (Version 21.0 or later). Severity will be graded according to the NCI 
CTCAE Version 5.0. 
Treatment-emergent adverse events (TEAEs) are defined as any AEs reported from 
the date of first study drug exposure to 30 days after the last date of study drug 
exposure. Frequency and percentages of patients will be summarized for: any grade 
TEAE, Grade 3 or higher TEAE, study-drug related TEAE, serious TEAE, TEAE 


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leading to dose modification, TEAE leading to study drug discontinuation, death 
and TEAE leading to death. Adverse events will be summarized by system organ 
class and preferred term. All AE data will be listed by patient.   
Laboratory data will be summarized according to parameter type. Where applicable, 
toxicity grading for laboratory safety parameters will be assigned based on NCI 
CTCAE Version 5.0 criteria. 
QTcF Analyses: 
The potential of QTcF prolongation with irinotecan liposome injection treatment 
will be evaluated in patients receiving irinotecan liposome injection in Part 1 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. 
Pharmacokinetics and Pharmacodynamics Analysis: 
Pharmacokinetics of total irinotecan and SN-38 will be quantified from the 
concentrations from plasma samples using nonlinear mixed effect modeling. The 
initial PK analysis will use the empirical Bayesian estimation, however, additional 
covariate analyses will be performed to evaluate alternative baseline factors specific 
to SCLC. The resulting PK estimates will be used to evaluate the association 
between PK and pharmacodynamics (efficacy and safety endpoints).  


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1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Small Cell Lung Cancer 
Lung cancer is the leading cause of cancer deaths worldwide. Small cell lung cancer (SCLC) 
accounts for about 15% of lung cancers overall and is a particularly aggressive neoplasm with 
a 5-year survival of <10%. Little progress has been made in improving outcome for this 
malignancy over the last 30 years.  
Small cell lung cancer is classified into limited and extensive stage disease based on the extent 
of the disease. Approximately 30% of patients with SCLC are diagnosed with limited stage 
disease, and are typically treated with a combination of radiation and chemotherapy 
(Morabito  2014). With current treatments only ~20% of patients with limited stage disease 
have potential to be cured (Dowell, 1999). Extensive stage disease remains incurable with an 
expected median survival of 7 to 9 months (Morabito, 2014). Extensive stage disease is 
typically first treated with a combination of a platinum (carboplatin or cisplatin) plus etoposide 
in the US and EU (NCCN guidelines; Früh et al, 2013) or irinotecan plus cisplatin in Japan 
(NCC Japan Annual Report, 2013). About 50-90% of patients with extensive stage disease 
respond to initial treatment (Morabito, 2014); however, patients rapidly relapse and develop 
resistance. Those that have progressed within 90 days from the completion of first-line platinum 
therapy are considered “platinum resistant” and the others “platinum sensitive” (prior 
immunotherapy sensitivity should not be confused with platinum sensitivity). Because most 
patients experience relapse or disease progression after initial response to chemotherapy, 
subsequent therapy is often required with the hope of symptom palliation or prolongation of 
survival. For patients who progress >6 months from the completion of first-line therapy, 
re-challenge with the same drugs used as the initial treatment has been reported to result in 
potential benefit. Although both the European Society for Medical Oncology (ESMO) 
guidelines (Früh et al, 2013) and the 2020 NCCN guidelines suggest the use of the original first 
line regimen when relapse occurs after 6 months, the level of evidence for this recommendation 
is based on studies conducted in the 1980s (Postmus, 1987; Giaccone, 1987) with small 
numbers of patients (level V evidence in the ESMO guideline, e.g. studies without control 
group, case reports, experts’ opinion). Additionally, a recent study by Wakuda (2015) showed 
that relapsed patients re-challenged with the first line regimen had similar outcomes to those 
receiving single-agent chemotherapy. This platinum re-challenge approach is utilized mainly 
due to very limited treatment options for recurrent SCLC. 
The topoisomerase I (TOP 1) inhibitor topotecan is the only agent approved for second-line 
therapy in the United States (US) and Europe. A study by von Pawel (1999) compared 
intravenous topotecan with a regimen of cyclophosphamide, doxorubicin, and vincristine 
(CAV) for patients with recurrent SCLC. Topotecan treatment reduced symptoms to a greater 
degree than CAV and was associated with less hematologic toxicity, although it failed to 
provide a survival benefit. The combination of oral topotecan plus best supportive care has 
shown both survival and quality-of-life benefits compared with best supportive care alone in 
patients with relapsed SCLC (O’Brien, 2006). In Japan, in addition to topotecan, amrubicin is 
also approved but it failed to gain approval elsewhere, following its failure to demonstrate 
superior efficacy in a large phase III study conducted in Western patients (von Pawel, 2014). 
Irinotecan is also an active and useful agent in SCLC. Superior overall survival (OS) for 
irinotecan plus cisplatin over cisplatin plus etoposide was noted in a Phase 3 study conducted 
in first line extensive stage patients in Japanese patients (Noda, 2002). Irinotecan is not 
approved for SCLC outside of Japan because a study in Western patients failed to replicate the 
superior efficacy seen in Japanese patients (Hanna, 2006). However, three additional phase III 
studies of irinotecan plus a platinum versus etoposide plus a platinum in the first line setting 


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have shown a trend of increased OS for patients receiving irinotecan combinations including 
one study that met statistical significance (Zatloukal, 2010; Lara, 2009; Hermes, 2008). In the 
second line setting, single agent irinotecan has been evaluated in a few small studies with 
reported objective response rate (ORR), time to treatment progression, and OS in the range of 
0-47%, 1.7-2.6 months and 4.6 months, respectively, (Pallis, 2009; Masuda, 1992; 
Sevinc, 2011) with similar outcomes to that of topotecan (von Pawel, 2014). Based on these 
and other studies, irinotecan is included in major treatment guidelines for the treatment of 
patients with SCLC. Irinotecan plus either cisplatin or carboplatin is listed as possible first line 
regimen as well as irinotecan monotherapy in second line in the National Comprehensive 
Cancer Network (NCCN) guidelines (2020 NCCN guidelines). ESMO guidelines list irinotecan 
plus cisplatin as an alternative first line regimen for those patients for whom etoposide is 
contraindicated (Früh, 2013). 
1.2 
Study Rationale 
1.2.1 
Rationale for Evaluating Irinotecan Liposome Injection in SCLC 
The rationale for testing irinotecan liposome injection (also known as liposomal irinotecan, 
nal-IRI, MM-398, PEP02, BAX2398, and ONIVYDE®) in patients with SCLC is based on 
targeting a validated drug target (TOP1), supportive non-clinical data, the concordance between 
SCLC biology and the proposed irinotecan liposome injection mechanism of action and prior 
clinical data for non-liposomal irinotecan in other indications. Based on these factors it is 
hypothesized that irinotecan liposome injection has the potential to improve upon the clinical 
activity of both topotecan and non-liposomal irinotecan. 
Topoisomerase I is a validated drug target in SCLC and is the target of topotecan, an approved 
agent in SCLC. SN-38, the active metabolite of irinotecan (and irinotecan liposome injection), 
is also known to target TOP1. Deoxyribonucleic acid (DNA) topoisomerases are a class of 
enzymes involved in the regulation of DNA supercoiling. Type I topoisomerases change the 
degree of supercoiling of DNA by causing single-strand breaks and re-ligation. Inhibition of 
TOP1 stabilizes the complex between TOP1 and DNA which collides with moving DNA 
replication forks, eventually leading to double stranded DNA damage and ultimately cell death. 
It is well established that increased cytotoxicity of TOP1 inhibitors is associated with sustained 
exposure. Liposomal delivery of irinotecan, a prodrug of SN-38, provide a mechanism for 
sustained inhibition of TOP1. 
Nonclinical data support the use of irinotecan liposome injection in SCLC, as described in 
Section 1.2.4. The biology of SCLC is well-matched with the irinotecan liposome injection 
proposed mechanism of action, which involves liposomal deposition in tumor tissue through 
leaky vasculature, followed by drug release either interstitially or after cellular uptake by 
phagocytic cells and subsequent conversion of irinotecan to SN-38. Irinotecan liposome 
injection deposits in and delivers irinotecan to tumors in SCLC models to a similar or greater 
extent than other tumor types and results in therapeutically relevant levels of tumor SN-38. 
Irinotecan liposome injection demonstrated anti-tumor activity in multiple xenograft models of 
SCLC at clinically-relevant dose levels and, importantly, demonstrated greater anti-tumor 
activity than irinotecan and topotecan. Finally, irinotecan liposome injection demonstrated 
greater anti-tumor activity than irinotecan and topotecan in a model of second line SCLC in 
which tumor has previously progressed on prior carboplatin plus etoposide. 
Irinotecan liposome injection has not yet been evaluated in clinical trials in patients with SCLC. 
However, the availability of clinical efficacy data for non-liposomal irinotecan monotherapy in 
this indication (described in Section 1.1), the overlapping mechanism of action of 
(non-liposomal) irinotecan and irinotecan liposome injection [mediated through the same active 
SN-38) metabolite] and the anticipated predictable safety profile of irinotecan liposome 


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injection collectively suggest that extrapolation from previous experience with non-liposomal 
irinotecan is an appropriate means of identifying a suitable starting dose level of irinotecan 
liposome injection in the context of SCLC. Based on these considerations, the current study 
comprises an initial non-randomized portion (safety run-in) where patients will be treated with 
irinotecan liposome injection at a dose level of 85mg/m2 every 2 weeks in Part 1 in order to 
ensure that the safety of the proposed regimen (85 mg/m2) is acceptable prior to proceeding to 
the randomized Part 2 of the study. Additional data (discussed in Section 1.2.2) derived from 
clinical experience of irinotecan liposome injection in malignant indications other than SCLC, 
at dose levels comparable to, or in excess of those included within the current study, further 
support the proposed dose level of 85mg/m2.  
However, a contingency has been included for subsequent safety evaluation of a lower dose 
level of irinotecan liposome injection (70 mg/m2 every 2 weeks) should the 85 mg/m2 level 
prove to have unacceptable toxicity. Additionally, preliminary efficacy will be defined in a total 
of 24 patients at the eventual Part 2 dose level of irinotecan liposome injection, in order to 
permit an overall assessment of safety and efficacy prior to commencement of Part 2. It is, 
therefore, considered that the initial safety and preliminary efficacy evaluation of irinotecan 
liposome injection, at one of two possible dose levels, provides a robust basis for progressing 
to Part 2 of the study. Additional risk control measures have been incorporated into Part 2 
through a futility analysis for OS combined with a prospective program of safety review by an 
independent Data Monitoring Committee (DMC). Therefore, the study design facilitates rapid 
progression to a registration directed trial phase in this difficult to treat disease, whilst retaining 
sequential ongoing risk-benefit assessment during the conduct of the study, thus protecting 
patient safety and preserving the scientific integrity of the study. 
1.2.2 
Rationale for Evaluating 85 mg/m2 Every 2 Weeks Monotherapy Dose of Irinotecan 
Liposome Injection 
The rationale for evaluating 85 mg/m2 free base dose every 2 weeks is supported by clinical 
studies for non-liposomal irinotecan HCl, the clinical pharmacology of irinotecan liposome 
injection and data from clinical studies of irinotecan liposome injection. 
In early clinical studies of non-liposomal irinotecan HCl there is convincing evidence of a 
dose-response relationship (Van Cutsem, 2005). In phase I studies of non-liposomal irinotecan 
HCl, increased tumor responses were seen at higher doses (Merrouche, 1997; Abigerges, 1995) 
and the dose-efficacy relationship has been further supported by subsequent population 
pharmacokinetic (PK) analyses (Chabot, 1995). 
The clinical pharmacology of irinotecan liposome injection indicates a dose-efficacy 
relationship supporting the evaluation of a higher than currently approved biweekly dose of 
70 mg/m2 (approved in combination with 5-fluorouracil (5-FU) and leucovorin (LV)). In 
metastatic pancreatic cancer, patients in the NAPOLI-1 study treated with irinotecan liposome 
injection 70 mg/m2 + 5-FU/LV, a higher exposure of unencapsulated SN-38 (uSN38; in the 
form of time above effective concentration and average concentration) was found to have 
association with better efficacy in terms of OS, PFS, and ORR therefore, a higher dose of 
irinotecan liposome injection has the potential for further improved efficacy. In the irinotecan 
liposome injection arm of the randomized phase II PEP0206 study, 44 patients with metastatic 
gastric cancer were treated with irinotecan liposome injection monotherapy dosed at 100 mg/m2 
free base every 3 weeks. The ORR in the intent to treat (ITT) population in the irinotecan 
liposome injection arm was 13.6%. Intra-patient dose escalation was permitted for patients who 
tolerated 100 mg/m2 irinotecan liposome injection (every 3 weeks) without Grade 2 or above 
toxicity. Five patients received 130 mg/m2 free base dose after first receiving the 100 mg/m2 
dose. Three out of the five patients exhibited confirmed partial response and two had stable 


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disease. These results are suggestive of dose-efficacy relationship and provide further support 
for evaluation of an 85 mg/m2 every 2 weeks regimen of irinotecan liposome injection in this 
trial in patients with SCLC. 
Clinical studies of irinotecan liposome injection and clinical pharmacology support the 
potential safety of the 85 mg/m2 dose of irinotecan liposome injection administered every two 
weeks. In a phase I study (PIST-CRC-01), in patients with advanced refractory colorectal 
carcinoma, a dose of irinotecan liposome injection monotherapy of 86 mg/m2 every 2 weeks 
was well tolerated and active. In a cohort of 6 patients treated at this dose level, there was 1 dose 
limiting toxicity (DLT) (Grade 3 diarrhea) and 1 partial response noted (see Section 1.3.2). 
1.2.3 
Rationale for Intravenous Topotecan as Control  
The choice of intravenous topotecan as the control arm for the randomized portion of this study 
was based on its inclusion in multiple clinical practice guidelines, its approval in both the US 
for use in platinum-sensitive patients who progressed after first-line chemotherapy and in the 
European Union (EU) for patients with relapsed SCLC for whom re-treatment with the first-line 
regimen is not considered appropriate, and its widespread clinical use in this disease setting. In 
patients with relapsed or refractory SCLC, the administration of second line single agent 
chemotherapy, including topotecan, is recommended by the NCCN (2020 NCCN guidelines) 
and by the American Society of Clinical Oncology guidelines (Rudin, 2016). The European 
Society of Medical Oncology guidelines (Früh, 2013) recommend oral or intravenous topotecan 
for patients who have platinum-resistant or sensitive relapsed SCLC. Intravenous topotecan is 
approved in the US for patients with SCLC that are platinum-sensitive and have progressed on 
first-line therapy (Topotecan USPI), and in the EU for patients with relapsed SCLC for whom 
re-treatment with the first-line regimen is not considered appropriate (Topotecan SmPC).  
It is worth noting that the use of intravenous topotecan for platinum-sensitive patients is 
potentially controversial due to guidelines suggesting re-challenge with the first line regimen. 
Although both the ESMO guidelines (Fruh et al, 2013) and the 2020 NCCN guidelines suggest 
the use of the original first line regimen when relapse occurs after 6 months, the level of 
evidence for this recommendation is based on studies conducted in the 1980s (Postmus, 1987; 
Giaccone, 1987) with small numbers of patients (level V evidence in the ESMO guideline, 
e.g. studies without control group, case reports, experts’ opinion). Additionally, a recent study 
by Wakuda, et al (2015) showed that relapsed patients re-challenged with the first line regimen 
had similar outcomes to those receiving monotherapy chemotherapy. Finally, intravenous 
topotecan has been used as a control arm in recently completed phase II and phase III studies 
in second-line SCLC (cabazitaxel vs. intravenous topotecan (Evans, 2015) and amrubicin vs. 
intravenous topotecan (von Pawel, 2014)) indicating both its acceptability to the clinical 
community and the feasibility of enrolling a study with this control arm.  
Oral topotecan will not be allowed in the control arm, as intravenous topotecan is the 
predominantly prescribed topotecan formulation (>90%) in US clinical practice 
(Intercontinental Marketing Services claims data) and appears to be the preferred topotecan 
formulation in clinical practice outside of the US as well, as indicated to the Sponsor by lung 
cancer clinical experts. Finally, intravenous topotecan will result in greater control over 
compliance than oral administration and will further minimize heterogeneity in the control arm. 
1.2.4 
Nonclinical Data Supporting Evaluation of Irinotecan Liposome Injection in Small 
Cell Lung Cancer 
The mechanism of action of irinotecan liposome injection comprises extended plasma 
circulation (as compared to non-liposomal irinotecan HCl), deposition into tumor tissue via the 
vasculature, uptake by phagocytic cells, release of drug and conversion of irinotecan to its active 


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metabolite SN-38. Sustained tumor-derived SN-38 delivery by irinotecan liposome injection 
leads to sustained TOP1 inhibition, resulting in subsequent DNA damage and tumor cell death 
(Kalra, 2014).  
The following in vitro and in vivo data highlight aspects of the proposed mechanism of action 
of irinotecan liposome injection and illustrate the potential activity of irinotecan liposome 
injection in comparison to non-liposomal irinotecan and topotecan in models of SCLC.  
1.2.4.1 
Extended Exposure of SN-38 Leads to Increased Cell Death In Vitro 
Topoisomerase I inhibition has potent effects on a wide range of cancer cell lines. The activity 
of SN-38, the active metabolite of irinotecan, against various SCLC cell lines was investigated 
using in vitro growth and viability assays. Figure 1 shows that treatment with SN-38 decreased 
cell viability by > 90% in SCLC cell lines (DMS114, NCI-H1048). Effective cell growth 
inhibition was observed between 1-10 nM, with increased cell killing with increased time of 
exposure. The concentration range of SN-38 in which cell killing begins to occur coincides with 
the amount of SN-38 measured from tumor biopsies taken from patients with various solid 
tumors 72 hours after administration of irinotecan liposome injection (range: 3 - 163 nM; 
Ramanathan, 2014), which is depicted in Figure 1 as the grey shaded area. These data suggest 
that the prolonged duration of SN-38 TOPO1 inhibition in tumors due to irinotecan liposome 
injection pharmacological characteristics would be likely to result in activity in patients with 
SCLC. 
Figure 1: Increased SN-38 Exposure Leads to Increased Cell Death In Vitro 
1 0 -3
1 0 -2
1 0 -1
1 0 0
1 0 1
1 0 2
1 0 3
1 0 4
1 0 5
0
2 5
5 0
7 5
1 0 0
1 2 5
D M S -1 1 4  (S C L C )
C o n c e n tra tio n  (n M )
C e ll N u m b e r (% )
1 0 -3
1 0 -2
1 0 -1
1 0 0
1 0 1
1 0 2
1 0 3
1 0 4
1 0 5
0
2 5
5 0
7 5
1 0 0
1 2 5
N C I-H 1 0 4 8  (S C L C )
C o n c e n tra tio n  (n M )
C e ll N u m b e r (% )
0 h
2 4 h
4 8 h
7 2 h
8 8 h
1 2 h
T u m o r S N -3 8
T u m o r S N -3 8
 
Concentration and exposure-dependent growth inhibition of SCLC cell lines by SN-38 at select time points. 
Range of SN-38 detected in tumor biopsies (grey box) from a previous clinical study (Ramanathan, 2014) in 
patients with various solid tumors is overlaid on the time-dependent SN-38 growth inhibition curves. Cell 
growth inhibition kinetics of SN-38 in 2 SCLC cell lines (DMS-114 and NCI-H1048) using an IncuCyte® 
ZOOM System over a time-course of up to 88 hours. 
1.2.4.2 
Irinotecan Liposome Injection Effectively Delivers Irinotecan and SN-38 to SCLC 
Tumors In Vivo 
Liposomes require leaky vasculature to gain entry into tumor tissue. Greater than 80% of SCLC 
tumor lesions express detectable levels of vascular endothelial growth factor (VEGF) 
(Dowell, 2004). VEGF expression is involved in angiogenesis and vessel permeability that may 
indicate the ability to achieve effective liposome delivery into SCLC tumors. Macrophages are 
the primary cell type believed to phagocytose irinotecan liposome injection within the tumor 
tissue. While little data on macrophages in SCLC are available, macrophages have been 
detected in SCLC biopsy samples and ranged from few cells to heavy infiltration of the tissues 
(Hedbrant, 2015). Macrophages express high levels of carboxylesterase 2, which is one of the 
enzymes needed to convert irinotecan to its active metabolite, SN-38. 


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The ability of irinotecan liposome injection to deliver irinotecan and SN-38 into tumors was 
evaluated in SCLC cell-line derived xenograft (CDX) models (NCI-H1048, DMS-114, H841) 
in comparison to CDX and patient-derived xenograft models of other tumor types. Irinotecan 
liposome injection was administered intravenously to xenograft tumor bearing mice. At 
24 hours post administration, mice were sacrificed and tumors were harvested. Irinotecan and 
SN-38 levels in tumors were measured by high performance liquid chromatography (HPLC). 
Figure 2 demonstrates that tumors derived from SCLC cell lines have similar or higher levels 
of irinotecan liposome injection deposition, as assessed by irinotecan content, than other tumor 
types. Furthermore, analysis of SN-38 levels indicates that increased irinotecan delivery was 
associated with increased levels of SN-38. These findings are consistent with a proposed 
mechanism of liposome deposition and local conversion of irinotecan to SN-38 within the 
tumor. 
Figure 2: Irinotecan Liposome Injection-mediated Tumor Delivery of Irinotecan and SN-38 In Vivo 
H 1 0 4 8
D M S - 5 3
H 8 4 1
C T G - 0 1 5 8
A 5 4 9
H 1 5 7
L o V o
H T - 2 9
C T G - 0 0 6 2
C T G - 0 0 7 9
A s P C - 1
C T G - 0 2 8 3
C T G - 0 2 8 8
A 2 7 8 0
C T G - 0 2 5 2
M D A - M B - 2 3 1
H C C 3 8
S K - E S - 1
0 . 0 1
0 . 1
1
1 0
1 0 0
T u m o r  I r i n o t e c a n  @  2 4  h  ( % I D / g )
B r e a s t
S C L C
C o l o r e c t a l
P a n c r e a t i c
O v a r i a n
E w i n g s
N S C L C
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
T u m o r  I r i n o t e c a n   @  2 4  h   ( n g / g )
T u m o r  S N - 3 8  @  2 4  h  ( n g / g )
H 8 4 1
H 1 0 4 8
D M S - 5 3
A
B
 
(a) 
Irinotecan delivered by irinotecan liposome injection was measured by HPLC at 24 h post administration 
in various mouse xenograft models, as shown. Data were normalized to injected dose per tumor weight. 
Shown here includes data obtained from SCLC CDX models. (B) Tumor irinotecan and tumor SN-38 
levels, shown as ng of SN-38 per tumor weight, were measured by HPLC at 24 h post administration for 
three SCLC xenograft models. Increased levels of SN-38 were associated with increased levels of tumor 
irinotecan delivered by irinotecan liposome injection. 
1.2.4.3 
Irinotecan Liposome Injection Has Improved Anti-Tumor Activity as Compared to 
Non-liposomal Irinotecan HCl and Topotecan In Vivo 
The activity of irinotecan liposome injection, non-liposomal irinotecan and topotecan were 
directly compared at clinically relevant doses in two CDX models. Clinically relevant doses 
were calculated by using standard surface area to weight ratios conversion per National Cancer 
Institute (NCI) guidelines. Figure 3 presents tumor growth kinetics of mice bearing SCLC 
xenograft tumors that were treated weekly with irinotecan liposome injection, non-liposomal 
irinotecan or topotecan. In both the DMS-114 and NCI-H1048 models, irinotecan liposome 
injection displayed significantly greater anti-tumor activity than both non-liposomal irinotecan 
and topotecan. Furthermore, 10 out of 10 mice treated in NCI-H1048 model treated with 
irinotecan liposome injection experienced complete regressions of their tumors as compared to 
0 out of 10 mice treated with topotecan. 


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Figure 3: Anti-tumor Activity of Irinotecan Liposome Injection, Non-liposomal Irinotecan and 
Topotecan at Clinically Relevant Doses in DMS-114 and NCI-H1048 SCLC Xenograft Models
A
B
NOD/SCID mice with (A) DMS-114 or (B) NCI-H1048 SCLC xenograft tumors were treated with IV irinotecan 
liposome injection, IV irinotecan, IP topotecan or vehicle control. Vertical dotted lines indicate start of weekly 
dosing. Irinotecan liposome injection dose is shown on irinotecan HCl basis. Following treatment, irinotecan 
liposome injection displayed significant anti-tumor activity compared to topotecan (p <0.0001 for DMS-114 on 
day 52 and p <0.0001 for NCI-H1048 on day 59; non-parametric t-test) and irinotecan (p <0.0001 for DMS-114 
on day 65 and p<0.0001 for NCI-H1048 on day 84; non-parametric t-test).
Note: nal-IRI = irinotecan liposome injection or liposomal irinotecan
Finally, the activity of irinotecan liposome injection, non-liposomal irinotecan and topotecan 
were directly compared in a second line setting of SCLC. Mice bearing NCI-H1048 SCLC 
tumors were treated with a carboplatin plus etoposide, a first line regimen in SCLC. Once the 
tumors escaped growth control by carboplatin plus etoposide, mice were randomized to either 
continue treatment with carboplatin plus etoposide or switch to second line treatment with either 
irinotecan liposome injection, non-liposomal irinotecan or topotecan. As shown in Figure 4, 
irinotecan liposome injection had anti-tumor activity in the second line setting and, furthermore, 
had significantly greater anti-tumor activity than both non-liposomal and topotecan.
Figure 4: Anti-tumor Activity of Irinotecan Liposome Injection, Non-Liposomal Irinotecan and 
Topotecan in a Preclinical Model of Second Line SCLC
2 0
3 0
4 0
5 0
6 0
7 0
8 0
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
N C I - H 1 0 4 8
D a y s  p o s t  i m p l a n t a t i o n
T u m o r  V o l u m e  ( m m
3 )
1 L  C o n t r o l
1 L  C a r b o p l a t i n  +  E t o p o s i d e
2 L  C o n t r o l
2 L  C a r b o p l a t i n  +  E t o p o s i d e
2 L  N a l - I R I  ( 1 6  m g / k g / w k ,  d 1 )
2 L  I r i n o t e c a n  ( 3 3  m g / k g / w k ,  d 1 )
2 L  T o p o t e c a n  ( 1 . 6 6  m g / k g / w k ,  d 1 - 2 )
NOD/SCID mice with NCIH1048 SCLC xenograft tumors were treated weekly with the combination of 
30 mg/kg carboplatin plus 25 mg/kg etoposide. When tumor reached approximately 1200 mm3, mice were 
randomized to receive weekly treatment with topotecan (1.66 mg/kg/wk administered IP in equal fractions on 


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days 1 and 2), non-liposomal irinotecan (33 mg/kg/wk administered IV on day 1) irinotecan liposome injection 
(16 mg/kg/wk administered IV on day 1), continue treatment with carboplatin plus etoposide or vehicle control. 
Vertical dotted lines indicate start of weekly dosing. Irinotecan liposome injection dose is shown on irinotecan 
HCl basis. After tumors progressed on first-line treatment with carboplatin plus etoposide, irinotecan liposome 
injection displayed significant anti-tumor activity compared to topotecan and irinotecan (p=0.0002 on day 70 
and p=0.0002 on day 84 for topotecan and irinotecan, respectively). 
Note: nal-IRI = irinotecan liposome injection or liposomal irinotecan 
1.3 
Irinotecan Liposome Injection Clinical Experience 
Irinotecan liposome injection has been studied in patients with solid tumors, including cervical 
cancer, gastric cancer, pancreatic cancer, and colorectal cancer. Irinotecan liposome injection 
under the tradename ONIVYDE®, was approved in the United States and Taiwan in 2015 and 
in the EU and Australia in 2016 and in Canada, Switzerland, and South Korea in 2017 in 
combination with 5-FU and LV, for the treatment of patients with metastatic pancreatic 
adenocarcinoma after disease progression following gemcitabine-based therapy. The 
registration for this indication is under review in several other countries. Disease areas currently 
being studied include front-line pancreatic cancer, glioma, breast cancer and several pediatric 
solid tumors, including Ewing's sarcoma, rhabdomyosarcoma, neuroblastoma, and 
osteosarcoma. Details of completed and ongoing studies are presented in the Investigator's 
Brochure (IB). 
1.3.1 
United States Food and Drug Administration Approval of ONIVYDE® and 
Determination of Irinotecan Liposome Injection Strength  
ONIVYDE® (irinotecan liposome injection, liposomal irinotecan, or nal-IRI) is formulated with 
irinotecan hydrochloride trihydrate into a liposomal dispersion for intravenous use.   
ONIVYDE® in combination with 5-FU/LV was approved by the US Food and Drug 
Administration (FDA) in October 2015 for the treatment of patients with metastatic 
adenocarcinoma of the pancreas after disease progression following gemcitabine-based 
therapy. Prior to FDA approval of ONIVYDE®, the compound was identified as MM-398 (or 
PEP02), and MM-398 dosing has been expressed on the basis of irinotecan hydrochloride 
trihydrate salt. At the time of approval, the FDA applied the USP Salt Policy; therefore, the 
drug strength of ONIVYDE® in the United States is now expressed in terms of the active moiety 
rather than the salt.  
Converting ONIVYDE® dose from irinotecan hydrochloride trihydrate salt base (as 
traditionally has been described for MM-398 until the US approval) to a dose based on 
irinotecan free base is accomplished by substituting the molecular weight of irinotecan 
hydrochloride trihydrate (677.19 g/mole) with the molecular weight of irinotecan free base 
(586.68 g/mole), which results in a conversion factor of 0.866. Therefore, the 80 mg/m2 based 
on irinotecan hydrochloride trihydrate salt is equivalent to a 69.3 mg/m2 based on irinotecan 
free base. This value was rounded to 70 mg/m2 in the United States Product Information to 
minimize any potential dosing errors. 
ONIVYDE® was approved by the European Medicines Agency (EMA) in October 2016 for the 
treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-FU/LV, in adult 
patients who have progressed following gemcitabine based therapy. As approved in the EU, 
ONIVYDE® dosing strength is expressed on the basis of irinotecan hydrochloride trihydrate 
salt. Therefore, the dose of ONIVYDE® described in the Summary of Product Characteristics 
(SmPC) is 80 mg/m2 based on irinotecan hydrochloride trihydrate salt (versus 70 mg/m2 when 
expressed on irinotecan free base). 


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For the purpose of this protocol, all applicable ONIVYDE® (irinotecan liposome injection or 
liposomal irinotecan or nal-IRI) dose regimens, descriptions and modifications are based on the 
irinotecan free base. 
1.3.2 
Clinical Pharmacology  
1.3.2.1 
Association Between Exposure and Efficacy with Irinotecan Liposome Injection 
Population PK analysis of data from the irinotecan liposome injection + 5-FU/LV arm in the 
NAPOLI-1 trial (patients with advanced metastatic pancreatic cancer) (Adiwijaya et al, 2016) 
was suggestive of a relationship between exposure and efficacy. In the irinotecan liposome 
injection+5-FU/LV arm of NAPOLI-1, longer OS and PFS were associated with longer time of 
exposure of un-encapsulated SN-38, the active metabolite of irinotecan, above a threshold 
(>0.03 ng/mL) and with higher AUC of un-encapsulated SN-38. Longer duration of exposure 
of un-encapsulated SN-38 above 0.03 ng/mL was associated with a higher probability of 
achieving an objective response in the irinotecan liposome injection+5-FU/LV arm. 
1.3.2.2 
Association between Exposure and Safety with Irinotecan Liposome Injection 
The exposure-safety relationship for irinotecan liposome injection is based on population PK 
analysis of data from 353 patients (Adiwijaya et al, 2016). Higher total irinotecan maximum 
serum concentration (Cmax) was associated with higher probability of observing Grade 3 or 
higher diarrhea. Higher Cmax of un-encapsulated SN-38 was associated with higher probability 
of both incidence and severity of neutropenia treatment-emergent adverse events (TEAEs), with 
different probabilities of observing Grade 3 or higher neutropenia with and without 
co-administration with 5-FU/LV.  
1.3.3 
Clinical Data Supporting Evaluation of Dose 
1.3.3.1 
Clinical Data Supporting Evaluation of 85 mg/m2 Every 2 Weeks 
The maximum tolerated dose of irinotecan liposome injection in a Phase 1 study was established 
to be 104 mg/m2 (dose expressed as free base) administered every three weeks.  
The safety of irinotecan liposome injection monotherapy given every 2 weeks was evaluated in 
an open-label phase I dose finding study conducted in Taiwanese patients with colorectal cancer 
“Phase I and Pharmacokinetic Study of Biweekly PEP02 (Liposome Irinotecan) in Patients with 
Metastatic Colorectal Cancer Refractory to First-line Oxaliplatin-based Chemotherapy 
(PIST-CRC-01)”.  
The starting dose level was 69 mg/m2 and escalated to 77 and then to 86 mg/m2 (doses expressed 
as irinotecan free base). 
Eighteen patients were enrolled at the dose levels of 69, 77 and 86 mg/m2 of irinotecan liposome 
injection (doses expressed as irinotecan free base) with 6 patients at each dose level. Of the 
total of 18 patients, the average age was 58.6 years old; 9 (50%) patients were female and 
9 (50%) patients were male. The average weight at screening was 61.8 kg. Twelve (66.7%) and 
6 (33.3%) patients had an ECOG 0 and 1 performance status, respectively. All patients had 
received prior oxaliplatin-based treatment for their metastatic colorectal cancer. All patients 
were Chinese.  
A total of 109 cycles of treatment (2 weeks per cycle in this study) were administered, with a 
mean of 6 cycles per patient (range 2-18, median 4 cycles/patient). There was 1 DLT at each 
dose level (Grade 3 neutropenia with infection and Grade 3 diarrhea).  
The most commonly reported TEAEs occurring in >20% of patients were diarrhea, decreased 
appetite, and alopecia (each in 16 patients, 88.9%); anemia and nausea (each in 14 patients, 
77.8%); vomiting (13 patients, 72.2%); mucosal inflammation (12 patients, 66.7%); 


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leukopenia, constipation (each in 11 patients, 61.1%); neutropenia (10 patients, 55.6%), fatigue 
(9 patients, 50.0%); alkaline phosphatase increased, hypokalemia (each in 8 patients, 44.4%); 
dizziness (7 patients, 38.9%); abdominal distension, pain (each in 6 patients, 33.3%); 
abdominal pain, urinary tract infection, gamma-glutamyl transferase increased, insomnia, skin 
hyperpigmentation (each in 5 patients, 27.8%); abdominal pain upper, influenza like illness, 
aspartate aminotransferase (AST) increased, weight decreased, cholinergic syndrome, cough 
(each in 4 patients, 22.2%). Overall, 13 patients (72.2%) experienced at least one (TEAE) of 
Grade 3 or higher severity. The most common Grade 3 or TEAEs were vomiting (5 patients, 
27.8%) and diarrhea and nausea (each in 3 patients, 16.7%). 
In terms of efficacy, there were 4 partial responses (22%), two in the 69 mg/m2 (dose expressed 
as irinotecan free base) cohort, and 1 in each of the other two cohorts. 
In conclusion, irinotecan liposome injection 69 – 86 mg/m2 (doses expressed as irinotecan free 
base, corresponding to 80-100 mg/m2 irinotecan liposome injection strength expressed as 
irinotecan hydrochloride) given every two weeks appeared generally well tolerated and active 
when administered as a single agent in patients with advanced colorectal carcinoma refractory 
to first line oxaliplatin-based regimens.  
1.3.3.2 
Clinical Data to Justify 70 mg/m2 Every 2 Weeks in Part 2 
Based on the safety and tolerability of irinotecan liposome injection monotherapy observed at 
the two different dose levels of 85 mg/m2 and 70 mg/m2 (free base equivalent) in Part 1, the 
recommended dose was determined to be 70 mg/m2 administered every two weeks.  
The assessment of the available safety and efficacy data from Part 1 is presented in detail in the 
IB. Thirty patients were treated for more than 12 weeks in Part 1.  
Five patients received irinotecan liposome injection at 85 mg/m2 on a bi-weekly basis. This 
dose was deemed not tolerable due to DLT (defined in Section 3.1.1). Once the first two DLT 
events were reported in two patients in the 85 mg/m2 treatment group, enrollment at 85 mg/m2 
dose level was stopped and dose reduction to 70 mg/m2 was recommended for patients who 
continued to receive treatment in the 85 mg/m2 treatment group, (total of five patients), and the 
70 mg/m2  treatment group was initiated. 
As presented in the IB at an interim data cut-off of 08 May 2019, 25 patients received irinotecan 
liposome injection at 70 mg/m2 on a biweekly basis. The 70 mg/m2 dose was deemed tolerable: 
40% of patients at the 70 mg/m2 dose level experienced Grade 3 or higher treatment-related 
TEAEs. Diarrhea was the most common gastrointestinal adverse event. 
Preliminary efficacy at 70 mg/m2 dose level identified 11 patients with partial responses 
(ORR 44%). Best overall response BOR (partial response +stable disease) was 72%. 
Part 1 demonstrated encouraging anti-tumor activity of irinotecan liposome injection at 
70 mg/m2 in patients with SCLC (ORR: 44%, BOR: 72%). Irinotecan liposome injection at 
70 mg/m2 was generally well tolerated. 
1.3.4 
Clinical Data in UGT1A1*28 Homozygous Patients 
Human uridine diphosphate glucuronosyl transferase (UGT) 1A1 is the enzyme that detoxifies 
neurotoxic bilirubin by conjugating it with glucuronic acid and 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® 
(non-liposomal irinotecan) (Camptosar® USPI 2019). 


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Multiple studies have evaluated the association between UGT1A1*28 homozygosity, SN-38 
concentration, and safety in patients treated with non-liposomal irinotecan and suggest the 
associations are dose and inter-patient variability dependent. Higher increase in SN-38 
concentrations were observed for UGT1A1 *1/*28 (6/7) (heterozygous) and UGT1A1 *28/*28 
(7/7) (homozygous) genotypes compared to UGT1A1 *1/*1 (6/6) (wild type) genotype when 
non-liposomal irinotecan was administered at a high dose of 300 mg/m2 (Iyer 2002) than when 
it was administered at a low dose of 20 mg/m2 (Stewart 2007). Although absolute neutrophil 
count (ANC) nadirs significantly correlated with SN-38 exposure at the higher dose of 
300 mg/m2 of non-liposomal irinotecan, the difference between the severe grades of 
neutropenia (Grade 3 higher or above) were not found to be statistically significant amongst the 
three genotypes (Iyer 2002). Evaluation of lower dosing regimens of non-liposomal irinotecan 
(15 to 75 mg/m2 daily for 5 days for 2 weeks) found that despite the increase of SN-38 
concentrations observed, UGT1A1 genotype was not a significant single predictor for 
irinotecan toxicity. 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 for 
UGT1A1*28 (6/7) and homozygous (7/7) for the UGT1A1*28 was 12.5% and up to 50% 
respectively (Camptosar® USPI 2019). 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 to 125 mg/m2 every week) similar hematological toxicities were observed for 
both UGT1A1*28/*28 and those with a UGT1A1*1/*28 or UGT1A1*1/*1 (Hoskins 2007). 
Publications from prospective trials of 250 metastatic colorectal cancer patients studying the 
FOLFIRI regimen (irinotecan dose of 180 mg/m2) and the role of UGT1A1*28 polymorphism 
in toxicity and efficacy did not support a dose reduction in patients with UGT1A1*28 
homozygosity and further suggest that the data are insufficient for recommending specific dose 
adjustments based on the UGT1A1 genotype (Toffoli 2006). More recently, a study in 
2982 patients with colorectal cancer from trial PETACC-3, found that a complex set of risk 
factors is involved in the development of toxicity, including UGT1A1. However, other 
parameters that are readily available in clinical practice, notably sex, age and performance 
score, were stronger predictors than the UGT1A1*28 genotype (Tejpar 2018). 
In patients treated with irinotecan liposome injection, the association between UGT1A1*28 
(7/7) homozygosity, SN-38, and hematologic toxicity is primarily obtained from the NAPOLI-1 
study, where UGT1A1*28 homozygous patients were treated at a reduced dose (50 mg/m2 
versus 70 mg/m2 (FBE) every 2 weeks in combination with 5-FU/LV, or 70 mg/m2 versus 
100 mg/m2 (FBE) every 3 weeks monotherapy). The NAPOLI-1 study Population PK results 
concluded that no significant association was observed between UGT1A1*28 homozygosity 
and SN-38 exposure. In addition, the UGT1A1*28 homozygous Caucasian patients were 
predicted to have an approximately 2% higher incidence of neutropenia Grade 3 or higher 
TEAEs compared to nonhomozygous Caucasian patients. An additional pooled Population PK 
study showed that overall exposure to SN‑38 was deemed similar between Japanese and 
non-Japanese populations with unrecognisable influence of UGT1A1 genotype. 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 Camptosar® administration is consistent with this 
hypothesis. Furthermore, liposomal encapsulation appears to spread out the incoming load of 


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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) (Roy, 2013). Reduced load of SN-38 may allow for metabolism by 
UGT enzymes even in patients with reduced UGT enzyme activities (for example, UGT1A1*28 
homozygous patients). 
Despite the lack of associations between UGT1A1*28 homozygosity, safety, and PK, the 
irinotecan liposome injection 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*28 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 DMC. 
2 
OBJECTIVES 
This study will be conducted in two parts: an open-label, single-arm, safety run-in (Part 1) to 
confirm the Part 2 dose of irinotecan liposome injection, followed by a randomized, open-label 
comparison of irinotecan liposome injection and topotecan in patients with SCLC. 
2.1 
Part 1 
2.1.1 
Primary Objectives 
The primary objectives of Part 1 are: 
• 
Describe the safety and tolerability of irinotecan liposome injection monotherapy 
administered every 2 weeks 
• 
To determine the irinotecan liposome injection monotherapy dose (85 mg/m2 or 
70 mg/m2 administered every 2 weeks) for Part 2 of this study. 
2.1.2 
Secondary Objectives 
The secondary objectives of Part 1 are to assess the preliminary efficacy of irinotecan liposome 
injection (at either the 85 mg/m2 dose level or the 70 mg/m2 dose level) as determined by:  
• 
Objective response rate (ORR) 
• 
Progression free survival (PFS) 
• 
Overall survival (OS). 
2.1.3 
Exploratory Objectives 
• 
To describe QTcF following treatment with irinotecan liposome injection. 
• 
To explore the biomarkers associated with toxicity and efficacy following treatment with 
irinotecan liposome injection in this patient population. 
• 
To describe the association between UGT1A1*28 and other UGT1A1 genotypes, 
SN-38 concentration and safety. 


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• 
To evaluate the pharmacokinetics and the relationship between pharmacokinetic 
exposure and efficacy and safety following irinotecan liposome injection in this patient 
population. 
• 
To explore patient-reported outcomes (PROs) using European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) 
and European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Lung Cancer 13 (EORTC-QLQ-LC13), Patient Global Impression of 
Severity (PGI-S), Patient Global Impression of Change (PGI-C), and EuroQol 
5-dimension health status questionnaire (5 level) (EQ-5D-5L). 
2.2 
Part 2 
2.2.1 
Primary Objective 
The primary objective of Part 2 is to compare overall survival following treatment with 
irinotecan liposome injection with overall survival following treatment with intravenous (IV) 
topotecan. 
2.2.2 
Secondary Objectives 
The secondary objectives of Part 2 are to compare the following between the treatment arms: 
• 
Progression free survival (PFS) 
• 
Overall response rate (ORR)  
• 
Patient reported outcomes (PRO) 
• 
Safety profile. 
2.2.3 
Exploratory Objectives  
The exploratory objectives include: 
• 
To explore the biomarkers associated with toxicity and efficacy following treatment with 
irinotecan liposome injection in this patient population. 
• 
To describe the association between UGT1A1*28 and other UGT1A1 genotypes, SN-38 
concentration (irinotecan liposome injection treated patients only) and safety. 
• 
To evaluate the pharmacokinetics and the relationship between pharmacokinetic 
exposure and efficacy and safety following irinotecan liposome injection in this patient 
population.  
• 
To compare the rate of development/time to development of central nervous system 
(CNS) progression and development of new CNS metastases.  
• 
To compare time to treatment failure (TTF) between treatment arms. 
• 
To assess the proportion of patients with improvement in symptoms as measured by 
EORTC QLQ-C30/LC13 dyspnea scale 
• 
To assess the proportion of patients with improvement in symptoms as measured by the 
EORTC QLQ-LC13 cough scale 
• 
To compare the effect of irinotecan liposome injection vs. topotecan on symptoms (other 
than dyspnea and cough), functioning and global health status as measured by EORTC 
QLQ-C30, EORTC QLQ-LC13 and EQ-5D-5L. 
3 
STUDY DESIGN 
3.1 
Overview of Study Design 
This study will be conducted in two parts: an open-label, single-arm, safety run-in period 
(Part 1) followed by a randomized period (Part 2) assessing irinotecan liposome injection versus 


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IV topotecan in patients with SCLC who have progressed on or after platinum-based first line 
therapy (see Figure 5). 
Part 1 is an open-label, single-arm, safety run-in evaluation of irinotecan liposome injection 
administered every 2 weeks, intended to confirm the anticipated Part 2 regimen (85 mg/m2), 
based on safety and preliminary efficacy. A contingency has been included for evaluation of 
irinotecan liposome injection at a dose level of 70 mg/m2, should the higher dose level of 
85 mg/m2 result in unacceptable toxicity.
Part 2 will be randomized, and assess the efficacy of irinotecan liposome injection versus 
IV topotecan.
Figure 5: Study Schema
Note: ONIVYDE is also known as irinotecan liposome injection, liposomal irinotecan or nal-IRI.
Each part will consist of three stages: screening stage, treatment/active follow-up stage and 
long-term follow-up stage. Once consented, patients will enter a screening stage. Upon first 
dose of study treatment in Part 1 or randomization (Part 2), patients will enter the 
treatment/active follow-up stage. Once a decision is made to permanently discontinue the 
patient from study treatment, a 30-day follow-up visit will occur and the patient will enter the 
long-term follow-up stage. The stages for this trial are outlined in the schematic below.
Figure 6: Description of Treatment Stages
It is intended that all patients in Parts 1 and 2 will be treated until progressive disease or 
unacceptable toxicity. Patients may take a treatment holiday and resume study treatment under 
certain instances. Detailed rule for pausing and resuming study treatment can be found in 
Section 6.2.1. Cross-over between treatment arms is not permitted.
Upon permanent discontinuation of study treatment (defined as patients with progressive 
disease whilst receiving study treatment and/or those assessed by the Investigator as unable to 
continue or resume study treatment due to unacceptable toxicity), patients will return to the 
study site for a 30-day follow-up visit. After this visit, patients will continue to be followed for 
OS status by phone, email or a visit to the study site once every month until death or study 
closure, whichever occurs first.
3.1.1
Part 1
Part 1 is an open-label, single-arm, safety run-in evaluation of irinotecan liposome injection 
administered every 2 weeks, intended to confirm the anticipated Part 2 regimen (85 mg/m2), 
based on safety and preliminary efficacy. A contingency has been included for evaluation of 


I P S E N G R O U P 
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E O R T C -Q L Q -L C 1 3, P GI -S, P GI -C a n d t he E Q -5 D -5 L i n Part 1. All  patie nt -re p ort i nstr u me nts 
will be a d mi nistere d at scree ni n g a n d pri or t o d osi n g at 6 -wee k i nter vals ( pri or t o a n y ot her 
assess me nt pr oce d ure) f oll o wi n g start of treat me nt, at treat me nt disc o nti n uati o n a n d at t he 
3 0 -da y f oll o w -u p visit. T he P GI -C is n ot i ncl u de d i n t he scree ni n g assess me nt.  
T he safet y assess me nt a n d t he c orres p o n di n g r ule of e x pa nsi o n will be c o n d ucte d acc or di n g t o 
a “ 6 + 6 ” desi g n f oll o we d b y e nr oll me nt of a n a d diti o nal 1 2 patie nts (as descri be d bel o w). 
Patie nts will i nitiall y be treate d wi t h iri n oteca n li p os o me i njecti o n 8 5 m g/ m2 e ver y 2 wee ks. 
D ose li miti n g t o xicities will be e v al uate d f or t he first 1 2 patie nts tr eate d d uri n g t he first 2 8  da ys 
of treat me nt ( or u p t o 1 4 da ys after t he s ec o n d d ose of st u d y treat me nt if t here is a tr eat me nt 
d ela y d ue t o n o n -D L T rel ate d reas o ns).  
 
• 
A m o n g t h e first 6 p atie nts recei vi n g iri n ot eca n li p os o me i njecti o n 8 5  m g/ m 2, 
(i.e. 8 5  m g/ m 2 c o h ort) if ≤2  patie nts e x perie n ce a D L T, a n ot her 6  p atie nts will be 
e nr olle d. Ot her wise, e nr oll me nt i nt o t he 7 0 m g/ m 2 c o h ort will be i nitiate d.  
• 
A m o n g t he first 1 2 patie nts recei vi n g iri n oteca n li p os o me i njecti o n 8 5  m g/ m 2, if 
≤2  patie nts e x perie nce a D L T, t his c o h ort will be e x pa n de d b y 1 2 a d diti o nal patie nts. 
Ot her wise, t he e nr oll me nt of t he 8 5 m g/ m 2 c o h ort will be st o p pe d a n d t he e nr oll me nt of 
t he 7 0 m g/ m2 c o h ort will be i nitiate d.  
  
Fi g ure  7 : Tre at me nt C o h orts: S afet y R u n -i n 
 
 
If t he 7 0 m g/ m2 c o h ort is e nr olle d, t he sa me “ 6 + 6” desi g n f oll o w e d b y e nr oll me nt of a n 
a d diti o nal 1 2 patie nts, a n d t he sa me D L T g ui deli nes will be use d as t hat f or t he 8 5  m g/ m 2 
c o h ort. If ≤2  patie nts a m o n g t he first 1 2 p atie nt recei vi n g iri n oteca n li p os o me i njecti o n 
7 0  m g/ m 2 e x perie nce a D L T, t he n t hat d ose le vel will be dec lare d t olera ble a n d t his c o h ort will 
be e x pa n de d b y 1 2 a d diti o nal patie nts. Ot her wise, a d diti o nal d ose re d ucti o n(s) ma y be 
c o nsi dere d.  


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NOTE that in either the 85 mg/m2 cohort or the 70 mg/m2 cohort, there will be no stopping 
rules based on the DLT assessment; however, DLTs will continue to be assessed among the 
additional 12 patients recruited after the first 12 patients have completed DLT evaluation. 
The decision of which dose to use for Part 2 will be made based on the totality of data from all 
patients treated in Part 1.  
If a decision is made to terminate the irinotecan liposome injection 85 mg/m2 dose level cohort 
(and instead initiate enrollment into the 70 mg/m2 cohort) patients who are tolerating the 
85 mg/m2 dose level will remain at that dose level (unless subsequent toxicity requires a dose 
modification). 
During the DLT evaluation period in either the 85 mg/m2 or 70 mg/m2 cohort, the following 
adverse events (AEs) should be considered as DLTs if they occur during the first 28 days of 
treatment (or 14 days after the 2nd dose of study treatment if there is a treatment delay according 
to Section 6.2) and are deemed related to the study treatment by the Investigator: 
• 
Grade 4 neutropenia or thrombocytopenia that does not resolve within 7 days despite 
optimal supportive therapy 
• 
Inability to resume subsequent treatment within 14 days of the scheduled date, due to 
drug-related toxicity  
• 
Grade 3-4 neutropenia complicated by fever ≥ 38.5 °C (i.e. febrile neutropenia) and/or 
by infection 
• 
Any Grade 4 non-hematologic toxicity with the exception of the following: 
- 
Fatigue/asthenia lasting < 14 days  
- 
Nausea and vomiting lasting ≤ 72 hours duration (only considered dose limiting if 
they last > 72 hours after treatment with an optimal anti-emetic treatment) 
- 
Diarrhea ≤ 72 hours duration (only considered dose limiting if diarrhea lasts 
> 72 hours after treatment with an optimal anti-diarrheal regimen) 
• 
Grade 3 non-hematologic toxicity with the exception of the following: 
- 
Any gastrointestinal disorder and dehydration (with associated signs and 
symptoms) unless Grade 3 toxicity persists despite optimal medical management 
for > 72 hours  
- 
Pain unless Grade 3 toxicity persists despite optimal medical management  
- 
Fatigue, fever, flu like symptoms, infections and infestations  
- 
Infusion reaction (and associated symptoms) unless it occurs following steroid 
premedication 
- 
Hepatic and kidney function abnormalities, and electrolyte abnormalities unless 
they persist, despite optimal medical management. 
The determination of whether an AE is considered a DLT will be made by the safety review 
committee (i.e. the Part 1 Investigators and the Medical Monitor(s) of the Sponsor). Other AEs, 
not meeting the DLT criteria above, that are deemed related to study treatment can also be 
considered a DLT event at the discretion of the safety review committee. Safety review 
meetings between investigators and sponsor will occur regularly during Part 1 of the study with 
at least monthly meetings, or more frequently, if required. 
The decision on Part 2 dose level, as per Part 1 outcome, will be communicated to all 
participating investigators prior to initiating Part 2 recruitment. 


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3.1.2 
Part 2 
Approximately 450 eligible patients will be randomized in a 1:1 ratio between the experimental 
arm (Arm A: based on the findings of Part 1 [either 85 mg/m2 or 70 mg/m2 of irinotecan 
liposome injection]) and the control arm (Arm B: IV topotecan). Note that following assessment 
of the available safety and efficacy data from Part 1 the 70 mg/m2 dose was chosen for Arm A 
(see Section 1.3.3.2). Patients will be randomized to the treatment arms using an Interactive 
Response Technology System (IRT) at a central location. Randomization will be stratified, 
based on the following factors: 
• 
Region (North America vs. Asia vs Other) 
• 
Platinum sensitivity (sensitive vs. resistant) 
• 
Performance status (ECOG 0 vs. 1) 
• 
Prior immunotherapy (yes vs. no) 
(Note: for platinum sensitivity, progression within 90 days from the completion of first-line 
platinum therapy is considered “platinum resistant” and the others “platinum sensitive”. Prior 
immunotherapy sensitivity should not be confused with platinum sensitivity). 
Only region (North America vs. Asia vs. Other) and platinum sensitive vs. resistant will be used 
for the stratified efficacy analysis. 
Tumor assessments will be performed every 6 weeks (± 1 week), using the Response Evaluation 
Criteria in Solid Tumors (RECIST) guidelines Version 1.1 (Parts 1 and 2) and Response 
Assessment in Neuro-oncology Brain Metastases (RANO-BM) criteria for CNS lesions 
(Part 2). Tumor assessment at screening and for all subsequent visits will be computed 
tomography (CT) with contrast (chest/abdomen required and pelvis [or other areas] if clinically 
indicated) and brain magnetic resonance imaging (MRI) with contrast. For patients who are 
allergic to IV contrast or cannot tolerate IV contrast due to impaired renal function or other 
issues, a non-enhanced CT or MRI is acceptable. Each follow-up tumor assessment should use 
the same assessment method as performed at screening, unless medically contraindicated. All 
patients will have imaging of the brain at screening and at each assessment. Patients who 
discontinue study treatment, for reasons other than disease progression per RECIST Version 1.1 
or RANO-BM criteria (for CNS lesions, Part 2) should continue to be followed with the same 
schedule of tumor assessments (every 6 weeks ± 1 week) until radiological documentation of 
progressive disease.  
Progressive disease will be determined by local radiology review and/or by investigator 
assessment, to ensure optimal and timely medical management. The Sponsor will collect and 
store all tumor assessment images on all patients throughout the study. An independent central 
review of the scans will be performed at the discretion of the Sponsor to support potential early 
filing to regulatory authorities. All patients will be followed at least monthly for survival status 
until death, loss to follow-up or study closure, whichever comes first. 
A quality of life assessment will be performed using the EORTC-QLQ-C30, 
EORTC-QLQ-LC13, PGI-C, PGI-S, and the EQ-5D-5L in Part 2. Although the PGI-C and 
PGI-S are not specified as exploratory objectives in Part 2, they will serve as anchors for 
deriving a within-patient meaningful change threshold in Part 2. All patient-reported outcome 
(PRO) instruments will be administered at screening and prior to dosing at 6-week intervals 
(and prior to any other assessment procedures) following start of treatment, at treatment 
discontinuation and at the 30-day follow-up visit. Patients who discontinue study treatment, for 
reasons other than disease progression, should continue to complete all QoL assessments every 
6 weeks until radiological documentation of progressive disease or until the start of alternative 
anti-neoplastic therapy. The PGI-C is not included in the screening assessment. Adverse events 


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will be evaluated according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. For summary of AEs, events will be coded using the latest Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary (Version 21.0 or later) at the start 
of the study. 
The primary analysis is planned when at least 350 OS events have occurred in Part 2. An interim 
analysis of OS for futility is planned at approximately 29% information time, after at least 
100 OS events have occurred. At the time of the interim analysis, ORR by blinded independent 
central review (BICR) tumor assessments will be analyzed descriptively by the independent 
DMC for the first 200 patients randomized in Part 2 of the study (i.e. approximately 100 patients 
from each arm). The independent DMC will notify the Sponsor if pre-specified criteria for ORR 
are met, as detailed in the DMC charter. A supplemental interim analysis is planned on data 
collected 24 weeks after the last patient has been randomized based on the ITT Population. 
Details of the ORR by BICR analysis are provided in the section on statistical methods and in 
the Statistical Analysis Plan (SAP).  
Pharmacokinetics 
Sparse plasma samples for PK of irinotecan liposome injection and SN-38 will be collected 
from all patients receiving irinotecan liposome injection (Part 1 and Part 2). 
Biomarker Exploratory Endpoint and Evaluation 
The exploratory endpoint comprises biobanking of samples for future analyses, among patients 
who consent for optional exploratory biomarker analysis. Analysis of biobank samples will be 
performed outside the scope of the main study and will be reported separately. Biobank samples 
may be stored for up to 15 years.  
Archival tumor tissue samples will be collected at baseline (C1D1), if available. 
Blood and stool samples will be collected as follows in both the ONIVYDE® and Topotecan 
arms: 
• 
At baseline (C1D1) 
• 
At week 6 (C2D1) 
• 
Treatment pause or Week 12 (C3D1) or end of treatment (whichever occurs first). 
3.2 
Study Duration and Study Closure 
Upon completion of screening (up to 28 days) all patients in Parts 1 and 2 will be treated until 
progressive disease or unacceptable toxicity. Each patient’s participation in the study treatment 
phase will end at the time of their 30-day follow-up assessment. Then, each patient will enter 
the long-term follow-up when they should continue to be followed for survival status via 
telephone, email, clinic visit, or medical record review until death, lost to follow-up, withdrawal 
of consent or study closure, whichever occurs first as described in Section 6.4 
The overall duration of the entire study is anticipated to be approximately 5 years. The study 
will be considered to have started when the first patient has provided signed informed consent 
and to have ended once all patients are off study treatment and at least 350 OS events have 
occurred in randomized patients. 
3.3 
Safety Review Committee and Independent Data Monitoring Committee 
Safety Review Committee 
A Safety Review Committee (SRC) (comprising the Part 1 Investigators and the Medical 
Monitor(s) of the Sponsor) will be responsible for supervising review of DLT and other safety 
data during Part 1 and the decision whether or not to implement enrollment into an irinotecan 
liposome injection 70 mg/m2 cohort. 


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The final decision to proceed to Part 2 (and the dose level of irinotecan liposome injection), 
will be made by the Sponsor in consultation with the study steering committee, after 
consideration of all available efficacy and safety data from Part 1 of the study. 
Independent Data Monitoring Committee 
An independent DMC will be established to monitor data in Part 2 of the study, to evaluate the 
planned interim analysis and to make recommendation to the Sponsor based on the results of 
the interim analysis over continuation or stoppage of the study. During the course of the study, 
regular review of safety data will be conducted in accordance with the DMC charter. The first 
safety review by the DMC will take place after the 30th patient is randomized and treated for 
at least one cycle or permanently discontinues study drug, whichever occurs first. The timing 
and details of subsequent data reviews will be detailed in the DMC charter. Items reviewed will 
include (but not limited to) safety events, results of interim analysis, any available results of PK 
testing and UGT1A1*28 genotype. Attention will be paid to determining whether any study 
procedure needs to be modified for patients who are homozygous for UGT1A1*28. 
4 
STUDY POPULATION 
4.1 
Inclusion Criteria  
To participate in the study patients must meet the following inclusion criteria, and none of the 
exclusion criteria: 
General Inclusion Criteria  
(1) 
At least 18 years of age. 
(2) 
Able to understand and provide the study informed consent. 
(3) 
ECOG performance status of 0 or 1. 
(4) 
Life expectancy >12 weeks. 
Disease Specific Inclusion Criteria  
(5) 
Histopathologically or cytologically confirmed small cell lung cancer according to the 
International Association for the Study of Lung Cancer (IASLC) histopathological 
classification. Mixed or combined subtypes according to the IASLC are not allowed. 
(6) 
Evaluable disease as defined by RECIST Version 1.1 guidelines (patients with 
non-measurable lesions are eligible). 
(7) 
Radiologically confirmed progression on or after first-line platinum based chemotherapy 
(carboplatin or cisplatin), or chemo-radiation including platinum-based chemotherapy 
for treatment of limited or extensive stage SCLC. In addition to platinum-based regimen, 
one line of immunotherapy as monotherapy or in combination, in first or in second line 
setting is allowed. 
(8) 
Recovered from the effects of any prior chemotherapy, surgery, radiotherapy or other 
anti-neoplastic therapy (recovered to Grade 1 or better, with the exception of alopecia, 
peripheral neuropathy, or ototoxicity). 
Hematologic, Biochemical and Organ Function Inclusion Criteria 
(9) 
During the Screening period, adequate bone marrow reserves as evidenced by: 
(a) 
Absolute neutrophil count >1,500 cells/µL (1.5 x 109/L) without the use of 
hematopoietic growth factors within the immediately preceding 14 days;  
(b) 
Platelet count >100,000 cells/µL (100 x 109/L); 
(c) 
Hemoglobin >9 g/dL; transfusions are allowed 


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(10) Adequate hepatic function as evidenced by: 
(a) 
Serum total bilirubin within normal range for the institution  
(b) 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 x upper limit of normal (ULN) (≤5 x ULN is acceptable if liver metastases 
are present) 
(c) 
Serum albumin ≥3.0 g/dL (≥30 g/L) 
(11) Adequate renal function as evidenced by a serum creatinine ≤1.5 x ULN and creatinine 
clearance ≥40 mL/min. Actual body weight should be used for calculating creatinine 
clearance using the Cockcroft-Gault Equation (except for patients with body mass 
index >30 kg/m2 when lean body weight should be used instead): 
 
(12) Electrocardiogram (ECG) without any clinically significant findings at screening, as per 
investigator’s assessment. 
Additional Disease Specific Inclusion Criteria 
(13a) Patients with certain types of asymptomatic CNS metastases that meet ALL the following 
criteria are eligible.  
a) 
Patients with asymptomatic CNS metastases prior to enrollment 
b) 
Prior radiation for CNS metastatic disease is completed ≥4 weeks prior to 
enrollment  
c) 
CNS metastases that are stable or have decreased according to the post radiation 
follow-up scan that is conducted at least 4 weeks after completion of radiation 
treatment for CNS lesion. 
d) 
Patients have discontinued corticosteroids or are on stable low-dose steroids 
(prednisone or equivalent 10 mg daily or less) for at least 1 week after completion 
of radiation for CNS lesion prior to enrollment. 
4.2 
Exclusion Criteria 
Patients must meet all the inclusion criteria listed above and none of the following exclusion 
criteria: 
General Exclusion Criteria 
(1) 
Any 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 
(2) 
Pregnant or breast feeding; females of child-bearing potential must test negative for 
pregnancy at the time of enrollment based on a serum pregnancy test. Females of 
childbearing potential are defined as fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Postmenopausal women are defined as those 
that have an absence of menstruation for at least 2 years. If necessary, follicle stimulating 
hormone results >50 IU/L at screening are confirmatory in the absence of a clear 
postmenopausal history. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy.  
Male patients must agree to use condoms during the study and for 4 months following 
the last dose of study drug. Female patients of reproductive potential must agree to use a 


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highly effective method of birth control, during the study and for 1 month following the 
last dose of study drug.  
Disease Specific Exclusion Criteria  
(3) 
Patients with large cell neuroendocrine lung carcinoma. 
(4) 
Patients who have received any of the following treatments:  
(a) 
Prior treatment regimens with irinotecan, topotecan or any other TOP I inhibitor 
including investigational TOP I inhibitors; 
(b) 
Retreatment 
with 
platinum-based 
regimen 
after 
relapse 
of 
first-line 
platinum-containing therapy; 
(c) 
Any antibody-drug conjugates or molecular targeted agents (e.g. poly ADP-ribose 
polymerase inhibitors), either alone or in combination with other treatments; 
(d) 
More than one line of prior immunotherapy; 
(e) 
Any other additional regimen of prior cytotoxic chemotherapy, not described 
above. 
(5) 
Patients with a history (any grade) of immunotherapy induced colitis or pneumonitis 
based on clinical assessment and/or confirmed by biopsy. 
(6) 
Patients with any of the following CNS metastases: 
(a) 
Patients who have developed new or progressive brain metastasis within 
three months following prophylactic and/or therapeutic cranial radiation (whole 
brain or stereotactic radiation) as defined by imaging; 
(b) 
Patients with symptomatic CNS metastases;  
(c) 
Patients with carcinomatous meningitis. 
(7) 
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 the first dose of irinotecan 
liposome injection. (See Section 5.4.2 for list of prohibited therapies). 
(8) 
Have a previous or concurrent cancer that is distinct in primary (non-pulmonary) site or 
histology, except carcinoma in situ, treated basal cell carcinoma, superficial bladder 
tumors (Ta and Tis [carcinoma in situ]) or any previous cancer curatively treated with 
last specific treatment >3 years ago without evidence of recurrence. 
(9) 
Investigational therapy administered within 4 weeks, or within a time interval less than 
at least 5 half-lives (whichever is less) of the investigational agent prior to the first 
scheduled day of dosing in this study. 
Hematologic, Biochemical and Organ Function Exclusion Criteria 
(10) Severe cardiovascular and pulmonary disease (e.g. myocardial infarction, unstable 
angina pectoris, coronary angioplasty or stenting, deep vein thrombosis, stroke, 
pulmonary fibrosis, active uncontrolled bleeding, or a known bleeding diathesis) less 
than 6 months before inclusion. 
(11) New York Heart Association Class III or IV congestive heart failure, ventricular 
arrhythmias, or uncontrolled blood pressure. 
(12) Active infection (e.g. acute bacterial infection, tuberculosis, active hepatitis B or active 
human immunodeficiency virus) which in the Investigator’s opinion might compromise 
the patient’s participation in the trial or affect the study outcome. 
(13) Known hypersensitivity to any of the components of irinotecan liposome injection, other 
liposomal products, or topotecan. 


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(14) Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, 
inflammation, occlusion, or diarrhea > Grade 1. 
Additional Disease Specific Exclusion Criterion (only applicable in France, per request of 
French Regulatory Authorities) 
(15) Patients who, per investigator assessment, are suitable for a second line platinum-based 
regimen following relapse after first-line platinum-based therapy. 
4.3 
Patient Discontinuation 
4.3.1 
Permanent Discontinuation of Study Treatment 
It is intended that patients will be treated until radiologically determined progressive disease 
per local radiology review and/or investigator assessment, per RECIST Version 1.1 criteria (or 
RANO-BM for CNS lesions in Part 2) or unacceptable toxicity. However, a patient may 
permanently discontinue study treatment at any point. Criteria for permanent discontinuation 
of study treatment for patients receiving irinotecan liposome injection (Part 1 and Part 2) and 
those receiving topotecan (Part 2) include: 
• 
Radiologically determined progressive disease local radiology review and/or per 
investigator assessment, per RECIST Version 1.1 (or RANO-BM for CNS lesions in 
Part 2); 
• 
Clinical deterioration sufficient to prevent further radiological assessment; 
• 
Unacceptable toxicity, defined as a study drug related AE, prior to disease progression, 
which: 
- 
in the opinion of the Investigator, precludes ANY further treatment with study 
drug 
- 
requires treatment with study drug 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 third dose reduction in study drug (in a patient having already 
experienced 2 previous dose reductions) Detailed rule of dose modification can be 
found in Section 5.3. 
• 
Development of an intercurrent medical condition or need for concomitant therapy that 
precludes ANY further treatment with study drug; 
• 
Withdrawal of consent for further treatment; 
• 
Pregnancy. 
A patient who permanently discontinues study treatment and has not withdrawn from the study 
and must continue with all ongoing protocol requirements, as detailed in Section 4.3.3. 
4.3.2 
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 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. 


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4.3.3 
Procedures following Study Drug Discontinuation or Study Withdrawal 
Following permanent study drug discontinuation all procedures and evaluations required at the 
30-day (End of Treatment) follow-up visit should be completed. All patients who permanently 
discontinue study medication as a result of an AE must be followed until resolution or 
stabilization of the AE. Patients who permanently discontinue study drug prior to radiologically 
determined disease progression should continue to be assessed radiologically and complete 
QoL assessments every 6 weeks, until radiologically determined progressive disease per 
RECIST Version 1.1 (or RANO-BM for CNS lesions) has been documented or until the start 
of new anti-neoplastic therapy. Overall survival follow-up contacts should continue every 
month 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. 
Since OS is the primary endpoint it is extremely important to capture the date of death. 
If a patient discontinues from the study treatment, the patient will continue to be followed up 
for survival status (including where appropriate through publicly available records). Ongoing 
survival follow-up must be documented in both the source hospital records and the electronic 
case report form (eCRF).  
If a patient withdraws consent to participate in 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.  
Patients participating to the optional research biobanking program have the right to withdraw 
their consent from the optional research biobanking program at any time and for any reason 
during the study or during the period of sample storage (i.e. the entire 15 years during which 
the sample is kept). If a patient wishes to withdraw consent for biobanking, and the samples are 
still at the Investigator site at that time, the Investigator must inform the Medical Monitor in 
writing of the patient’s decision and destroy the samples. If the samples are in the Sponsor’s 
repository, the Investigator must inform Ipsen directly using the e-mail address, 
, mentioning only the patient ID. Ipsen will ensure the destruction 
of the samples and all corresponding aliquots and issue confirmation of the destruction, which 
will be forwarded to the Investigator. Analyses conducted before withdrawal will not be 
affected. 
4.4 
Enrollment of Additional Patients (Patient Replacement) 
For Part 1, if a patient discontinues study treatment before completing two doses of study 
treatment, for reasons other than a DLT, then that patient may be replaced by a new patient at 
the same dose level. For Part 2, there is no patient replacement. 
4.5 
Method of Assigning Patients to Treatment Groups 
Part 1: 
Patients will initially be allocated to the irinotecan liposome injection 85 mg/m2 dose cohorts 
(according to the 6+6 design followed by enrollment of an additional 12 patients as described 
in Section 3.1). According to the DLT rules detailed in Section 3.1, patients may subsequently 
be allocated in cohorts to an irinotecan liposome injection dose level of 70 mg/m2, as 
determined by the SRC. 
Part 2: 
Part 2 will be initiated upon passing the stopping criteria and based on the decision of the 
Sponsor in consultation with the study steering committee. 
PPD


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After all screening assessments have been completed and the first patient reported outcome 
assessment has been completed, eligible patients will be randomized using a computerized IRT, 
in a 1:1 ratio, to one of the following treatment arms: 
• 
Arm A (experimental arm): irinotecan liposome injection (70 mg/m2 based on the 
findings of Part 1) 
• 
Arm B (control arm): IV topotecan. 
Randomization must occur within 7 days of planned dosing when all eligibility criteria are 
confirmed. The randomization will be stratified based on the following factors: 
• 
Region (North America vs. Asia vs. Other) 
• 
Platinum sensitivity (sensitive vs. resistant) 
• 
Performance status (ECOG 0 vs. 1) 
• 
Prior immunotherapy (yes vs. no). 
Platinum resistant patients are defined as patients with disease that either progressed during 
first-line platinum containing therapy or within 90 days of its completion. Platinum sensitive 
patients are defined as patients with disease that progressed after 90 days of completion of first 
line platinum containing therapy.  
5 
INVESTIGATIONAL PRODUCTS 
5.1 
Description of Irinotecan Liposome Injection 
Irinotecan liposome injection is a sterile, white to slightly yellow opaque isotonic liposomal 
dispersion. Each 10 mL single-dose vial contains 43 mg irinotecan free base at a concentration 
of 4.3 mg/mL. The liposome is a unilamellar lipid bilayer vesicle, approximately 110 nm in 
diameter, which encapsulates an aqueous space containing irinotecan in a gelated or 
precipitated state as the sucrosofate salt. It will be supplied as sterile, single-use vials containing 
43 mg irinotecan free base at a concentration of 4.3 mg/mL. 
5.1.1 
Storage and Handling of Irinotecan Liposome Injection 
Irinotecan liposome injection must be stored refrigerated at 2 to 8°C, with protection from light. 
Diluted solution must be protected from light prior to infusion. Irinotecan liposome injection 
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. 
Irinotecan liposome injection must be diluted prior to administration. Because of the potential 
for microbial contamination during dilution, the solution for infusion should be used 
immediately, but may be stored at room temperature (15° to 30°C) for up to 4 hours prior to the 
start of the infusion. If necessary, the solution for infusion may be refrigerated (2° to 8°C) for 
up to 24 hours prior to use. The diluted solution must not be frozen, and should be protected 
from light. 
5.1.2 
Packaging and Labelling of Irinotecan Liposome Injection 
Irinotecan liposome injection will be packaged in a multi-vial cardboard container. The 
individual vials, as well as the outside of the cardboard container, will be labelled in accordance 
with local regulatory requirements. 
5.1.3 
Administration of Irinotecan Liposome Injection 
Irinotecan liposome injection will be administered at a dose of 85 mg/m2 (strength expressed 
based on irinotecan free base; approximately equivalent to 100 mg/m2 of the hydrochloric 
trihydrate salt) IV over 90 minutes, every 2 weeks in a 6-week cycle. Should the 85 mg/m2 dose 


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be deemed to have unacceptable toxicity, the 70 mg/m2 will be utilized (strength expressed 
based on irinotecan free base; approximately equivalent to 80 mg/m2 of the hydrochloric 
trihydrate salt) IV over 90 minutes, every 2 weeks in a 6-week cycle. Note that following 
assessment of the available safety and efficacy data from Part 1 the 70 mg/m2 dose was chosen 
for Part 2 (see Section 1.3.3.2). 
Prior to administration, the appropriate dose of irinotecan liposome injection 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 irinotecan liposome injection to be administered will be determined by 
calculating the patient’s body surface area (BSA) prior to each IP administration. Use of BSA 
calculation formula according to institutional standards is allowed. The Du Bois formula, which 
has been shown to be effective for estimating body fat in both obese and non-obese patients, is 
widely used in clinical practice, and may be utilized in the study at investigator discretion, if 
different from institutional standard. BSA is represented in m2, W is weight in kg, and H is 
height in cm, 
 
BSA = 0.007184 × W0.425 × H0.725 
Du Bois D, Du Bois EF (Jun 1916). "A formula to estimate the approximate surface area if height and weight be known". Archives of 
Internal Medicine 17 (6): 863-71. PMID 2520314. Retrieved 2012-09-09. 
 
A ±5% variance in the calculated total dose will be allowed for ease of dose administration. 
Caution should be exercised when using irinotecan liposome injection in patients with body 
mass index <18.5 kg/m2. 
Irinotecan liposome injection vials are single-use vials; therefore, site staff must not store any 
unused portion of a vial for future use and they must discard unused portions of the product. 
Dose reduction and supportive care measures are described in Sections 5.3 and 5.4.1, 
respectively. 
5.1.3.1 
Irinotecan Liposome Injection Premedication 
All patients must be pre-medicated prior to irinotecan liposome injection infusion with at least 
standard doses of dexamethasone or equivalent other steroids, and a 5-HT3 antagonist, and/or 
equivalent other anti-emetics according to standard institutional practices. Use of 
diphenhydramine hydrochloride and acetaminophen is allowed as per institutional guidelines 
and as clinically indicated. Atropine may be prescribed prophylactically for patients who 
experienced acute cholinergic symptoms in the previous cycles 
5.1.3.2 
Toxicity of Irinotecan Liposome Injection  
The most clinically important adverse reactions of irinotecan liposome injection are 
summarized below. For more detailed description of the additional adverse reactions, the IB 
should be consulted. 


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Diarrhea 
Irinotecan liposome injection can cause severe and life-threatening diarrhea, which must be 
treated at first signs of onset. Patients may experience late onset diarrhea (after 24 hours 
following chemotherapy) and early onset diarrhea (within 24 hours of chemotherapy, 
sometimes occurring with other symptoms of cholinergic reaction). An individual patient may 
experience both early and late-onset diarrhea. Irinotecan liposome injection is prohibited to be 
administered to patients with bowel obstruction. 
Early onset diarrhea (occurring during or shortly after infusion of irinotecan) is usually 
cholinergic in nature. It may be accompanied by symptoms of rhinitis, increased salivation, 
miosis, lacrimation, diaphoresis, flushing, and intestinal hyper-peristalsis that can cause 
abdominal cramping. Early onset diarrhea of any severity is treated with IV or subcutaneous 
atropine 0.25 to 1 mg (unless clinically contraindicated). 
Late onset 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 onset diarrhea should be treated promptly with loperamide, and 
octreotide should be considered if diarrhea persists after loperamide. 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. A Clostridium 
difficile test per institutional guidelines is recommended if clinically indicated. 
Neutropenia 
Irinotecan liposome injection can cause severe or life-threatening neutropenia and fatal 
neutropenic sepsis. 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. 
Hypersensitivity 
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been 
observed with irinotecan, however, have not been observed with irinotecan liposome injection 
to date. This could be due to the limited cumulative patient exposure to date of irinotecan 
liposome injection, or the use of appropriate premedication and early recognition and treatment 
of expected AEs. There is insufficient evidence to know whether these known adverse reactions 
of irinotecan are also associated with irinotecan liposome injection. Suspected drugs should be 
withheld immediately and aggressive therapy should be given if hypersensitivity reactions 
occur. 
Interstitial Lung Disease 
Irinotecan HCl can cause severe and fatal interstitial lung disease. This adverse reaction has not 
yet been described with irinotecan liposome injection. Irinotecan liposome injection should be 
withheld in patients with new or progressive dyspnea, cough, and fever, pending diagnostic 
evaluation. Irinotecan liposome injection should be discontinued in patients with confirmed 
diagnosis of interstitial lung disease. 


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Embryo-Fetal Toxicity 
Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE®, 
ONIVYDE® can cause fetal harm when administered to a pregnant woman. Embryotoxicity 
and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in 
irinotecan exposures lower than those achieved with irinotecan liposome injection 70 mg/m2 in 
humans, administered to pregnant rats and rabbits during organogenesis. Pregnant women 
should be advised of the potential risk to a fetus. Females of reproductive potential should use 
a highly effective contraception method during treatment with irinotecan liposome injection 
and for one month following the final dose. Highly effective contraceptive methods include: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (e.g. oral, intravaginal, transdermal) 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(e.g. oral, implantable, injectable) 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Male partner has had a vasectomy. 
Total abstinence from intercourse with male partners (periodic abstinence is not acceptable). 
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. 
Patients at Particular Risk 
In clinical trials of the weekly schedule of irinotecan, it has been noted that patients with 
modestly elevated screening 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. 
The PKs of irinotecan liposome injection have not been studied in patients with hepatic 
impairment. In a population PK analysis, patients with screening bilirubin concentrations of 
1-2 mg/dL (N=19) had average steady state concentrations for total SN-38 that were increased 
by 37% compared to patients with screening bilirubin concentrations of <1 mg/dL (N=329); 
however, there was no effect of elevated ALT/AST concentrations on total SN-38 
concentrations. No data are available in patients with bilirubin >2 mg/dL. 
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. 
Infusion reactions, consisting of rash, urticarial, periorbital edema, or pruritus, occurring on the 
day of irinotecan liposome injection administration were reported in 3% of patients receiving 


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irinotecan liposome injection monotherapy or irinotecan liposome injection/5-FU/LV 
combination in the NAPOLI-1 study. 
Management of Infusion Reactions 
The guidelines described in this section can be followed in case of infusion reactions to either 
study treatment given per protocol (irinotecan liposome injection and topotecan). Infusion 
reactions will be defined according to the NCI CTCAE (Version 5.0) 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 hours 
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): 
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 
irinotecan liposome injection), 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 500 or 650 mg orally. 


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• 
Future infusions may be administered at a reduced rate (e.g. over 120 minutes for 
irinotecan liposome injection), 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 500 or 650 mg orally 
or as per institutional guidelines. 
UGT1A1*28 Monitoring 
UGT1A1*28 genotype will be collected on all patients and assessed centrally. Results will be 
provided to the site and to the Sponsor. Sites will be asked to include the result from the 
UGT1A1*28 genotyping on the adverse events reporting form. 
All patients treated with irinotecan liposome injection, regardless of the results of the 
UGT1A1*28 genotype, will be treated with the same starting dose of irinotecan liposome 
injection and will follow the same dose reduction rules. During the regular safety monitoring 
of patients during the study, as will be conducted by the Sponsor Medical Monitor(s) and by 
the SRC (Part 1) and the DMC (Part 2), the safety and PK of UGT1A1*28 homozygous patients 
will be compared to those who are non-homozygous for UGT1A1*28 to determine whether any 
different dosing strategy (such as a lower starting dose and/or different dose reduction for 
irinotecan liposome injection) is required for patients who are homozygous for UGT1A1*28. 
The first safety DMC meeting will occur after the 30th patient completed one cycle of treatment 
or discontinued treatment, whichever occurs first. No association between UGT1A1*28 and 
safety is expected in patients treated with topotecan. 
Other Potential Toxicities 
Irinotecan liposome injection, the liposomal formulation of irinotecan is different from 
irinotecan in unencapsulated formulation, so there is 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. 
5.2 
Description of Topotecan for Injection 
The following information has been obtained from the HYCAMTIN® (topotecan) for injection 
US and EU package inserts. In the US, topotecan for injection, as a single agent, is indicated 
for the treatment of patients with SCLC with platinum-sensitive disease who progressed after 
first-line chemotherapy (Topotecan USPI). In the EU, IV topotecan is indicated for the 


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treatment of patients with relapsed SCLC for whom re-treatment with the first-line regimen is 
not considered appropriate (Topotecan SmPC). 
5.2.1 
Storage and Handling of Topotecan 
5.2.1.1 
US package insert/EU SmPC 
Instructions for storage and handling of topotecan are provided in the pharmacy manual and the 
commercial package inserts and SmPCs. 
5.2.2 
Packaging and Labelling of Topotecan 
Commercial topotecan sourced centrally by the Sponsor or sourced locally by the sites, where 
allowed by local regulations and approved by the Sponsor, will be labeled as investigational 
medicinal product in accordance with local country requirements. 
5.2.3 
Administration of Topotecan 
Topotecan is administered at an initial dose of 1.5 mg/m2 IV over 30 minutes daily for 
5 consecutive days, every 3 weeks in a 6-week cycle. 
Patients randomized to the topotecan arm should be considered for prophylactic G-CSF in all 
cycles starting 24 hours following the last dose (both short and long acting growth factor is 
acceptable, based on investigator preference). 
5.3 
Rules for Dose Modification of Irinotecan Liposome Injection and Topotecan 
Dose modifications of irinotecan liposome injection and topotecan are allowed as clinically 
indicated (Section 5.3.1 and Section 5.3.2 respectively). If a patient’s dose is reduced during 
the study, it should remain reduced for the duration of the study, dose re-escalation is not 
permitted. 
5.3.1 
Irinotecan Liposome Injection 
Dose reduction and supportive care measures are described in Table 1, below. 
Prior to initiating a new dose of treatment, a patient must have: 
• 
Absolute neutrophil count (ANC)  1500/mm3 (1.5x109/L) 
• 
Platelet count  100,000/mm3 (100x109/L) 
• 
All local lab results assessed. 
All clinical decisions will be based on local laboratory assessments. Treatment should be 
delayed for recovery from toxicity and upon recovery to at least Grade 1, treatment should be 
administered according to the guidelines in Table 1 below. If the patient had febrile neutropenia, 
the ANC must have resolved to 1500/mm3 (1.5x109/L) and the patient must have recovered 
from infection. 


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Table 1: Recommended Dosea Modifications for Irinotecan Liposome Injection 
Toxicity NCI CTCAE Gradeb 
Occurrence 
Starting Dose  
70 mg/m2 
85 mg/m2 
Hematological toxicities:  
Neutropenia, leukopenia, or 
thrombocytopenia Grade 3 
or 4 Neutropenic fever 
First 
occurrence 
56 mg/m2 
 (80% of original 
dose) 
68 mg/m2 
(80% of original 
dose) 
Second 
occurrence 
46 mg/m2 
(65% of original 
dose) 
55 mg/m2 
(65% of original 
dose) 
Third 
occurrence 
35 mg/m2 
(50% of original 
dose) 
43 mg.m2 
(50% of original 
dose) 
• A new dose of treatment should not begin until the absolute neutrophil count is ≥1500/mm3 
(1.5x109/L) 
• A new dose of treatment should not begin until the platelet count is ≥100,000/mm3 
(100x109/L) 
Nonhematological toxicities:  
All nonhematological 
toxicities (except asthenia and 
anorexia): Grade 3 or 4 
Withhold irinotecan liposome injection. Upon recovery to 
≤ Grade 1, resume irinotecan liposome injection as below: 
First 
occurrence 
56 mg/m2  
(80% of original 
dose) 
68 mg/m2 
(80% of original 
dose) 
Second 
occurrence 
46 mg/m2 
(65% of original 
dose) 
55 mg/m2 
(65% of original 
dose) 
Third 
occurrence 
35 mg/m2 
(50% of original 
dose) 
43 mg/m2 
(50% of original 
dose) 
• A new dose of treatment should not begin until serum chemistry parameters resolve to 
≤ Grade 1 
• A new dose of treatment should not begin until nonhematological toxicities resolve to 
≤ Grade 1 
• For Grade ≥ 3 nausea and vomiting, reduce dose only if occur despite optimal anti-emetic 
therapy 
• Asthenia and Grade 3 anorexia do not require any dose modifications 
Interstitial lung disease  
First 
occurrence 
Discontinue treatment 
Severe hypersensitivity 
reaction 
First 
occurrence 
Discontinue treatment 
a All doses mentioned are based on irinotecan free base  
b National Cancer Institute Common Terminology Criteria for Adverse Events Version 5 
5.3.2 
Topotecan for Injection 
It is important to ensure that patients randomized to topotecan achieve the maximum possible 
exposure to ensure that they derive the most benefit from the treatment. Dose modifications 
(dose delays, including dose holidays, dose reductions), prophylactic use of myeloid growth 
factors, antibiotics for high risk patients and all other appropriate supportive care measures 
should be used to ensure that patients receive the highest tolerated dose and duration possible. 


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In exceptional circumstances (e.g. long holidays), where administration of the topotecan IV is 
not possible for 5 consecutive days, after discussion with study medical monitor, the 
Investigator can adjust the dosing regimen based on their clinical judgment to ensure: 
(1) 
The patient is receiving highest tolerable dose and duration possible, and  
(2) 
The highest daily dose does not exceed 1.5 mg/m2. 
The recommended dose modifications are described in this section (Section 5.3.2) for topotecan 
and the recommended supportive care measures are described in Section 5.4.1. 
Topotecan should only be started in patients with a screening neutrophil count of greater than 
or equal to 1,500/mm3 (1.5x109/L) and a platelet count greater than or equal to 100,000/mm3 
(100x109/L). 
In subsequent cycles topotecan should not be administered unless the neutrophil count 
is ≥1x109/L, the platelet count is ≥100 x 109/L, and the hemoglobin level is ≥9 g/dL 
(after transfusion if necessary). Treatment should be administered according to the guidelines 
in Table 2 below. 
Dose reduction of topotecan is allowed at investigator discretion during the treatment cycle as 
clinically indicated after the starting dose of 1.5 mg/m2 is initiated.  
Dose reduction from dose level 0 to dose level -2 is permitted. The reduced dose should 
continue to be administered over 5 consecutive days per topotecan prescribing information. 
Prophylactic antibiotics are recommended for patients at high risk of infectious complications. 
Up to two dose reductions of topotecan per patient are permitted due to toxicities (see Table 2). 
If a third dose reduction is needed to manage a toxicity, topotecan treatment can be adjusted 
per clinical assessment after discussion with the Medical Monitor and documented 
appropriately.  
Table 2: Recommended Topotecan Dose Modification Scheme for Subsequent Cycles 
Dose Level Dose Modifications 
0 
1.5 mg/m2 IV days 1-5 
-1 
1.25 mg/m2 IV days 1-5 
-2 
1.0 mg/m2 IV days 1-5 
The dose of topotecan in patients should be reduced to 0.75 mg/m2/day for 5 consecutive days 
if the creatinine clearance is between 20 and 39 mL/min. 
Topotecan should be discontinued if a new diagnosis of interstitial lung disease is confirmed. 
Please note that for both irinotecan liposome injection and topotecan, all dose 
modifications should be based on worst preceding toxicity and a patient may permanently 
discontinue study treatment if he/she meets any of the criteria for permanent 
discontinuation of study treatment listed in Section 4.3.1.  
5.4 
Concomitant and Prohibited Therapies 
5.4.1 
Concomitant and Supportive Care Therapies 
5.4.1.1 
Antiemetic Medications 
Irinotecan Liposome Injection: Dexamethasone and a 5-HT3 blocker (e.g., ondansetron or 
granisetron) will be administered as premedications to all patients receiving irinotecan liposome 
injection. Antiemetics may be prescribed as clinically indicated during the study period. An 
NK1 inhibitor, such as rolapitant (with no CYP3A4 interactions), for delayed nausea and 
vomiting for moderately emetogenic chemotherapy may be used in addition to 5-HT3 
antagonist, as per institutional standards and as clinically indicated, with consideration of 
potential drug-drug interaction (please refer to list of prohibited medications in Section 5.4.2). 


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Topotecan: Antiemetic therapy for topotecan per institutional standard of care, including 5-HT3 
antagonists and NK-1 inhibitor Rolapitant, may be prescribed as clinically indicated during the 
study period. 
5.4.1.2 
Myelosuppression 
Use of G-CSF is permitted. All patients randomized to the topotecan arm are recommended to 
receive prophylactic G-CSF in all cycles starting 24 hours following the last dose (both short 
and long acting growth factor is acceptable, based on investigator preference). For patients 
receiving irinotecan liposome injection the use of prophylactic G-CSF (both short and long 
acting growth factor is acceptable, based on investigator preference) is allowed, based on 
investigator judgment. History of prior abdominal radiation increases the risk of severe 
neutropenia and febrile neutropenia following irinotecan liposome injection treatment. Close 
monitoring of blood counts is recommended, and the use of myeloid growth factors should be 
considered for patients with a history of radiation. Caution should be exercised in patients 
receiving concurrent administration of irinotecan liposome injection with irradiation. 
Prophylactic antibiotics are recommended for patients at high risk of infectious complications. 
5.4.1.3 
Therapy for Diarrhea 
Acute diarrhea and abdominal cramps, developing during or within 24 hours after irinotecan 
liposome injection administration, may occur as part of a cholinergic syndrome. The syndrome 
can be treated with atropine. Prophylactic or therapeutic administration of atropine, according 
to institutional standards, should be considered in patients experiencing cholinergic symptoms 
during the study. 
Diarrhea can be debilitating and on rare occasions is potentially life-threatening. Anti-diarrhea 
management should be initiated at the first episode of poorly formed or loose stools or the 
earliest onset of bowel movements that are more frequent than normal. For both arms, diarrhea 
should be managed according to institutional guidelines, or according to the guidelines 
developed by an American Society of Clinical Oncology panel and ESMO Clinical Practice 
Guidelines for treating chemotherapy-induced diarrhea (Benson 2004, Ustaris 2015, 
Bossi 2018). 
For a detailed algorithm of diarrhea management for chemotherapy-induced diarrhea see 
Appendix 1. 
5.4.2 
Prohibited Therapies 
In the prescribing information for the treatment of patients with metastatic adenocarcinoma of 
the pancreas, after disease progression following gemcitabine-based therapy, the following 
drugs are noted as interacting with irinotecan liposome injection when administered in 
combination with 5-FU and LV (including but not limited to): 
• 
Strong CYP3A4 inducers, e.g., St. John’s Wort, CYP3A4 inducing anticonvulsants 
(phenytoin, phenobarbital, and carbamazepine), rifampin, rifabutin, rifapentine, 
mitotane, avasimibe, enzalutamide. 
• 
Strong CYP3A4 inhibitors, e.g. clarithromycin, indinavir, itraconazole, ketoconazole, 
lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole, 
tipranavir, troleandomycin, danoprevir, mibefradil, pozaconazole, conivaptan, grapefruit 
juice. 
• 
Weak to moderate CYP3A4 inhibitors, e.g., troleandomycin, erythromycin, diltiazem, 
verapamil, fosaprepitant. 
• 
Strong UGT1A1 inhibitors, e.g., atazanavir, gemfibrozil, indinavir, ketoconazole. 


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Treatment with these agents and any others that interact with irinotecan or topotecan should be 
avoided wherever possible. Refer to the IB for ONIVYDE® and topotecan instructions leaflet 
(as prepared and packaged for this study) for any other drug interactions. 
The following therapies are not permitted during the study treatment phase: 
• 
Other 
systematic 
anti-neoplastic 
therapy, 
(e.g. 
cytotoxics, 
targeted 
agents, 
immunotherapy, or antibodies, etc.). 
• 
Radiotherapy, unless given for palliative reason and with the approval of the Medical 
Monitor. Study treatment must be held during palliative radiation and for 2 weeks after 
completion of radiation. 
• 
Any other investigational therapy is not permitted. 
5.5 
Accountability of Study Drug 
Investigator and investigational site staff are responsible for maintaining an accurate inventory 
and accounting of all study drugs used throughout the study, including locally sourced and 
centrally sourced supplies, as applicable. 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 
• 
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. 
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 end 
study, all used and unused vials can be destroyed on site as per local regulations and 
instructions, or shipped to the Sponsor’s storage facility for destruction. A certificate of 
destruction will be provided by the site or the storage facility for filling in the Investigator’s 
file. 
6 
STUDY ASSESSMENTS 
See Section 7.1 and Section 7.2 for schedule of assessments. 
6.1 
Screening Visit 
The screening phase will begin once the patient signs the informed consent form. All procedures 
for screening are outlined in Section 8. For further descriptions of the clinical and laboratory 
assessments required, please refer to Section 9. Rescreening is only allowed after discussion 
and approval from the Sponsor’s Medical Monitor. 
6.2 
Treatment/Active Follow-up Visits 
Patients who are confirmed to meet all inclusion and exclusion criteria will be enrolled in Part 1 
and randomized via an IRT in Part 2. The first dose (Cycle 1 Day 1) must be given within 7 days 
of enrollment/randomization. All study procedures and assessments are outlined in Section 8 


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and Section 9. During the treatment period, a window of ±2 days will apply to all visits, unless 
otherwise stated. 
While in the Treatment/Active Follow-up phase, pauses in study drug treatment may be 
allowed, at the discretion of the Investigator. If a pause occurs in treatment, patients should 
continue to follow the same schedule of assessments, however, once 30 days have passed since 
last study drug administration, visits may be limited to every 3 weeks rather than weekly. 
6.2.1 
Pauses in Treatment 
It is intended that all patients will be treated until progressive disease or unacceptable toxicity. 
Patients may take a treatment holiday and resume study treatment under one of the following 
instances: 
• 
Patients with at least stable disease at the end of Cycle 3 may take a treatment holiday or 
may continue study treatment at the Investigator discretion as long as the Investigator 
believes that there is clinical benefit from continued study treatment. 
• 
Patients who discontinue study treatment due to unacceptable toxicity prior to disease 
progression may resume study treatment if their underlying disease progresses and they 
recovered from the toxicity following discussion with the Investigator and in agreement 
with the Sponsor Medical Monitor. 
• 
Patients who require palliative radiotherapy must withhold study treatment during 
palliative radiation and for 2 weeks after completion of radiation. These patients may 
resume study treatment following completion of radiotherapy, regardless of whether 
progression occurred or not, if continuation of study treatment is felt to be in the best 
interest of the patient in the judgment of the Investigator. 
• 
In case of suspected or confirmed COVID-19 infection, administration of study treatment 
may be temporarily discontinued depending on the patient clinical presentation. In some 
cases, the Investigator may request a patient to be retested before administration of study 
treatment is resumed. (See also Section 10.1.2 for the reporting of COVID-19 infection). 
In exceptional circumstances (e.g. long holidays), where administration of the topotecan IV is 
not possible for 5 consecutive days, after discussion with the study medical monitor, the 
Investigator can adjust the dosing regimen based on their clinical judgment to ensure:  
(1) 
The patient is receiving highest tolerable dose and duration possible, and  
(2) 
The highest daily dose does not exceed 1.5 mg/m2. 
Please note that the duration of a treatment holiday should NOT be longer than 1 cycle 
(6 weeks). More than one treatment holiday is allowed as long as the above criteria are satisfied. 
During treatment breaks, QoL assessments and RECIST (or RANO-BM for CNS lesions in 
Part 2) scans should continue to follow the same frequency (every 6 weeks). All remaining 
assessments only need to be completed when/if the patient comes in to clinic for a scan or QoL 
assessment during this break, with the exception of safety monitoring, complete blood counts 
(CBCs) and serum chemistry collection. Safety monitoring and labs should be collected at a 
reduced rate of a minimum of every 3 weeks since last clinic visit, or at a higher frequency 
based on investigator judgment. If/when a patient restarts treatment, the cycle 2 and beyond 
schedule should be resumed. 
6.3 
30-day Follow-up Visit 
All patients are expected to complete a 30-day follow-up assessment upon permanent 
discontinuation of study treatment. This assessment should occur approximately 30 days 
(± 1 week) after a decision is made to permanently discontinue study treatment (defined as 
patients with progressive disease whilst receiving study treatment and/or those assessed by 


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the Investigator as unable to continue or resume study treatment due to unacceptable toxicity) 
All procedures and assessments are outlined in Section 7. 
6.4 
Survival or Long-Term Follow-up 
After the 30-day follow-up visit, patients should continue to be followed for survival status 
once every month (± 14 days) via clinic visit, telephone, email, or medical record review until 
death, lost to follow-up, withdrawal of consent (to further survival follow-up), or study closure, 
whichever occurs first. Additionally, data on subsequent anti-cancer treatments and the date of 
progression associated with subsequent anti-cancer treatment should be collected during these 
contacts and documented in the eCRF. In the case of patients who discontinue protocol 
treatment, for reasons other than progressive disease per RECIST Version 1.1 and/or RANO-
BM criteria, and remain on study, disease evaluations (including imaging studies) and QoL 
assessments should continue into the follow-up period, as described in the Section 7. 
If a patient does not respond to attempts to contact for OS follow-up, at least three 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 
should be captured from public records if available. 
 


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7 
SCHEDULE OF ASSESSMENTS 
The schedule of assessments for irinotecan liposome injection is shown in Section 7.1 (Table 3) and IV topotecan in Section 7.2 (Table 4). 
If the COVID-19 pandemic prevents patients from coming to the site, patients can have their study visit assessments performed remotely as judged 
appropriate by the Investigator. Please also refer to Appendix 15.4. Of note, as the adapted visit deviates from the regular protocol plan, the changes 
will be recorded as protocol deviations related to COVID-19. 


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7.1 
Irinotecan Liposome Injection  
The schedule of assessments shown in Table 3 below, only applies to patients receiving irinotecan liposome injection: 
Table 3: Schedule of Assessments for Patients Receiving Irinotecan Liposome Injection 
Procedure 
Screening 
Visit 
Treatment/Active Follow-up Visits 
30 Day 
Follow-
up10 
LTFU 
(q1mo)15 
Cycle 1 
Cycle 2 and beyond 
Treatment 
Pause16 
D1 
D8 
D15 
D22 
D29 
D36 
D1 
D15 
D22 
D29 
Informed consent 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs & weight 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam3 
X1 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
ECOG PS Scoring 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with differential4 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistry4, 5 
X2 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
Pregnancy test6 
X2 
X2 
 
 
 
 
 
X 
 
 
 
 
X 
 
UGT1A1*28 genotype 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment7 
X1 
Every 6 weeks from C1D1 
X 
X 
 
QoL Questionnaires8, 13 
X17 
Every 6 weeks from C1D1 
X 
X 
 
ECG8 
X2 
X12, 14 
X12, 14 
X12, 14 
 
 
 
 
 
 
 
 
 
 
Archived tumor tissue 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant procedures 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization (Part 2) 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking9 
 
X8 
Collected at 6 and 12 weeks8 
 
 
 
PK samples11 
 
X 
X 
X 
 
 
 
 
 
X11 
 
 
 
 
Irinotecan liposome 
injection administration18 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
Adverse event reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall survival reporting15 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; C=cycle; CBC=cell blood count; D=day; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; LDH=lactate dehydrogenase; LTFU=long-term follow-up; PK=pharmacokinetic; PS=performance status; 
QoL=quality of life; RECIST=Response Evaluation Criteria in Solid Tumors; RANO-BM=Response Assessment in Neuro-oncology brain metastases; RBC=red blood cell; RNA=ribonucleic 
acid; WBC=white blood cell 
1 Within 28 days of C1D1. 
2 Within 7 days of C1D1.  
3 Physical Exams should occur on days of dosing prior to study drug administration.  Height should be collected at screening only. 
4 Day 1: within 3 days prior to infusion for all cycles, as applicable. Investigators must document their review of each laboratory report. The CBC will include the following: hemoglobin, 
hematocrit, platelet count, RBC, WBC with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and other cells). Serum chemistry will include electrolytes (sodium, 
potassium, chloride and bicarbonate), BUN, serum creatinine, glucose, bilirubin, AST, ALT, alkaline phosphatase, LDH, uric acid, total protein, albumin, calcium, magnesium and phosphate.    
5 A chemistry sample must be sent to the central lab; local lab results may be used for enrollment and dosing decisions if central lab results are not available. 
6 Pregnancy tests should be performed via serum β-HCG within 7 days of C1D1 in the Screening period. During the Treatment period on D1 of every cycle and at the 30 day follow-up visit, 
a urine or serum β-HCG pregnancy test should be administered.  
7CT and Brain MRI to be assessed at screening and every 6 weeks after the first dose of study drug regardless if the subsequent dose is delayed or interrupted.  Please see Section 8.8 for 
further details. 
In the event the patient permanently discontinues study treatment for reasons other than disease progression, a tumor assessment should be completed as soon as possible relative to the date of 
study termination, unless performed within the prior 4 weeks, to ensure disease progression is not present and to assess overall disease status. In such patients, tumor assessment should occur 
no later than the date of the 30-day follow-up visit and future assessments should continue to take place every 6 weeks during the follow-up period until objective disease progression or 
commencement of new anti-neoplastic therapy (in accordance with RECIST Version 1.1, (or RANO-BM for Part 2). Tumor assessment comprises imaging of both peripheral disease and the 
brain at each assessment. 
8 To be assessed or collected prior to dosing. 
9 Biobanking samples, whole blood for DNA, RNA, circulating free DNA and plasma and stool samples will only be collected for those individuals who have signed the optional biobanking 
informed consent for exploratory biomarkers at baseline (C1D1), as well as 6 and 12 weeks, (end of study. If a patient progresses prior to 12 weeks, a sample should be taken at time of 
discontinuation. “X" at D1 in Cycle 2 and beyond to include C3D1. 
10 The 30-day follow-up visit should occur 30 days after discontinuation of the study treatment (± 1 week). 
11 Please refer to Section 9.5 for details on PK sampling. An optional sample may also be provided during Days 2 to 6 (Part 2). Cycle 1 Day 8 sampling may occur ±1day. 
12 Replicate ECG readings (Holter monitoring) will be collected on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15 at the same time point at PK assessments for patients in Part 1 only 
unless also required for Part 2 at the discretion of the Sponsor.  Please refer to Section 8.7 for time points 
13 Quality of life questionnaires (EQ5D and EORTC-QLQ-C30 +LC13, Patient Global Impression of Change, and Patient Global Impression of Severity) are collected in Part 1 and Part 2 
and intended to be collected on day of dosing, prior to dosing every 6 weeks, and prior to any other assessment procedures. In the event the patient permanently discontinues study treatment 
for reasons other than disease progression, QoL assessments should continue to take place every 6 weeks during the follow-up period until objective disease progression or commencement of 
new anti-neoplastic therapy. A ±1-week window is permitted in order to sync assessment with clinic visit. The Patient Global Impression of Change is omitted at the screening assessment. 
14 Part 1 only 
15 Follow-up should occur every 1 month (± 2 weeks). 
16 Treatment Pause Modified Schedule: During treatment breaks, QoL assessments and radiological assessments should continue to follow the same frequency (every 6 weeks).  All 
remaining assessments only need to be completed when/if the patient comes in to clinic for a scan or QoL assessment during this break with the exception of safety monitoring, CBCs and 
serum chemistry collection.  Safety monitoring and labs should be collected at a reduced rate of a minimum of every 3 weeks since last clinic visit, or at a higher frequency based on 
investigator judgment.  If/when a patient restarts treatment, the cycle 2 and beyond schedule should be resumed. 
17 Within 14 days of C1D1. 
18 Between 48 and 72 hours after completion of the irinotecan liposome injection infusion, a safety follow-up phone call will be made by a study nurse. 


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7.2 
IV Topotecan  
The schedule of assessments shown in Table 4, below, only applies to patients receiving IV topotecan: 
Table 4: Schedule of Assessments for Patients Receiving IV Topotecan 
Procedure 
Screening 
Visit 
Treatment/Active Follow-up Visits 
30 Day 
Follow-
up10 
LTFU 
(q1mo)12 
Cycle 1 
Cycle 2 and beyond 
Treatment 
Pause13 
D1 
D8 
D15 
D22 
D29 
D36 
D1 
D15 
D22 
D29 
Informed consent 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs & weight 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam3 
X1 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
ECOG PS Scoring 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with differential 4 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistry4, 5 
X2 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
Pregnancy test6 
X2 
X2 
 
 
 
 
 
X 
 
 
 
 
X 
 
UGT1A1*28 genotype 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment7 
X1 
Every 6 weeks from C1D1 
X 
X 
 
QoL Questionnaires8, 11 
X14 
Every 6 weeks from C1D1 
X 
X 
 
ECG8 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived tumor tissue 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant procedures 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobanking9 
 
X8 
Collected at 6 and 12 weeks8 
 
 
 
Topotecan Administration 
(5 consecutive days) 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Adverse event reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall survival reporting12 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; C=cycle; CBC=cell blood count; D=day; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; LDH=lactate dehydrogenase; PK=pharmacokinetic; PS=performance status; QoL=quality of life; RECIST=Response 
Evaluation Criteria in Solid Tumors; RANO-BM=Response Assessment in Neuro-oncology brain metastases; RBC=red blood cell; RNA=ribonucleic acid; WBC=white blood cell 
 
1 Within 28 days of C1D1. 
2 Within 7 days of C1D1.  
3 Physical Exams should occur on days of dosing prior to study drug administration.  Height should be collected at screening only. 
4 Day 1: within  3 days prior to infusion for all cycles, as applicable. Investigators must document their review of each laboratory report. The CBC will include the following: hemoglobin, 
hematocrit, platelet count, RBC, WBC with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and other cells). Serum chemistry will include electrolytes (sodium, 
potassium, chloride and bicarbonate), BUN, serum creatinine, glucose, bilirubin, AST, ALT, alkaline phosphatase, LDH, uric acid, total protein, albumin, calcium, magnesium and phosphate.   
5 A chemistry sample must be sent to the central lab; local lab results may be used for enrollment and dosing decisions if central lab results are not available. 
6 Pregnancy tests should be performed via serum β-HCG within 7 days of C1D1 in the Screening period. During the Treatment period on D1 of every cycle and at the 30 day follow-up visit, 
a urine or serum β-HCG pregnancy test should be administered.  
7 CT and Brain MRI to be assessed at screening and every 6 weeks first dose of study drug even if subsequent dose is delayed or interrupted.  Please see Section 8.8 for further details. 
In the event the patient permanently discontinues study treatment for reasons other than disease progression, a tumor assessment should be completed as soon as possible relative to the date 
of study termination, unless performed within the prior 4 weeks, to ensure disease progression is not present and to assess overall disease status. In such patients, tumor assessment should 
occur no later than the date of the 30-day follow-up visit and future assessments should continue to take place every 6 weeks during the follow-up period until objective disease progression or 
commencement of new anti-neoplastic therapy (in accordance with RECIST Version 1.1 (or RANO-BM) for Part 2). Tumor assessment comprises imaging of both peripheral disease and the 
brain at each assessment. 
8 To be assessed or collected prior to dosing. 
9 Biobanking samples, whole blood for DNA, RNA, circulation free DNA, plasma, and stool samples will only be collected for those individuals who have signed the optional biobanking 
informed consent for exploratory biomarkers at baseline (C1D1), as well as 6 and 12 weeks, (end of study).  If a patient progress prior to 12 weeks, a sample should be taken at time of 
discontinuation. "X" at D1 in Cycle 2 and beyond to include C3D1. 
10 The 30-day follow-up visit should occur 30 days after discontinuation of the study treatment (± 1 week). 
11 Quality of life questionnaires (EQ5D and EORTC-QLQ-C30 +LC13, Patient Global Impression of Change, and Patient Global Impression of Severity) are collected in Part 1 and Part 2 
and are intended to be collected on day of dosing, prior to dosing every 6 weeks, and prior to any other assessment procedures. In the event the patient permanently discontinues study 
treatment for reasons other than disease progression, QoL assessments should continue to take place every 6 weeks during the follow-up period until objective disease progression or 
commencement of new anti-neoplastic therapy. A ± 1-week window is permitted in order to sync assessment with clinic visit. The Patient Global Impression of Change is omitted at the 
screening assessment. 
12 Follow-up should occur every 1 month (± 2 weeks). 
13 Treatment Pause Modified Schedule: During treatment breaks, QoL assessments and radiological assessments should continue to follow the same frequency (every 6 weeks).  All 
remaining assessments only need to be completed when/if the patient comes in to clinic for a scan or QoL assessment during this break with the exception of safety monitoring, CBCs and 
serum chemistry collection.  Safety monitoring and labs should be collected at a reduced rate of a minimum of every 3 weeks since last clinic visit, or at a higher frequency based on 
investigator judgment.  If/when a patient restarts treatment, the cycle 2 and beyond schedule should be resumed. 
14 Within 14 days of C1D1. 
 


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8 
CLINICAL PROCEDURES AND ASSESSMENTS 
8.1 
Medical History 
A medical history will include all pertinent prior medical conditions, treatments for small cell 
lung cancer, surgeries or other medical procedures. Medical history should also include a 
history of tobacco use. 
8.2 
Adverse Event Assessment and Reporting 
Investigators should complete all routine and standard of care assessments to evaluate for AEs. 
This may include, but is not limited to, verbal reports from the patient and/or caregiver, physical 
examination and laboratory findings. Adverse events should be reported throughout the course 
of the study, including during the 30 day follow-up period (or until death or withdrawal of 
consent if they occur before the end of this period). 
8.3 
Physical Exam 
Physical examination will include a careful assessment of all body systems, including the skin; 
central and peripheral nervous system; eyes; ears, nose and throat; respiratory, musculoskeletal 
and cardiovascular systems; abdomen and extremities. Particular attention should be paid to 
areas of possible neoplastic involvement.  
8.4 
Vital Signs 
Vital signs should include height (screening only), weight, resting blood pressure, pulse, 
respiratory rate, and temperature. 
8.5 
Performance Status Assessment 
The Eastern Cooperative Oncology Group (ECOG) performance status will be obtained by the 
Investigator or his/her designee by questioning the patient about their functional capabilities. A 
description of the ECOG performance status criteria is summarized in Appendix II. 
8.6 
Quality of Life Assessments 
A quality of life assessment will be performed using the EQ-5D-5L and the 
EORTC-QLQ-C30 + LC13), to be collected via an electronic ePRO device. The EORTC 
QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients. Patient 
reported symptoms from EORTRC-QLQ are recorded on a 4-point scale with values ranging 
from 1 (no symptoms experienced at all) to 4 (symptomology experienced is very much). The 
EORTC QLQ-LC13 is a lung cancer specific module to be used in conjunction with the EORTC 
QLQ-C30. The LC13 covers typical symptoms of patients with lung cancer, such as cough, pain, 
dyspnea, sore mouth, peripheral neuropathy, hair loss (Koller, 2015) with 13 questions. The 
EORTC-QLQ-C30 + LC13 has a total of 43 questions. The EQ-5D-5L consists of the 
EQ-5D-5L descriptive system and the EQ visual analogue scale. The descriptive system 
comprises 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 extreme problems. 
Two additional single item patient-reported outcomes assessments, the PGI-S and the PGI-C, 
will be administered at each quality of life assessment. The PGI-C is not included in the 
screening assessment, since the baseline assessment is not applicable for this instrument. 
Patients in Parts 1 and 2 will be required to complete the QoL questionnaires at time points 
outlined in the Schedule of Assessments (at screening and every 6 weeks thereafter). On days 
that the patient is to receive study drug, assessments should be completed prior to study drug 
administration, and prior to any other assessment procedures. The first collection of quality of 
life assessments must be completed at screening. It is intended that questionnaires be completed 


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in clinic on days of dosing. A ± one-week window is allowed in order to assist synchronizing 
survey assessment with dosing. The sequence in which these questionnaires are completed 
should be as follows: the EORTC QLQ-C30 should be administered first, followed by the 
EORTC QLQ-LC13, the PGI-C and PGI-S, and the EQ-5D-5L in this order. The QoL 
questionnaires should be completed in a language that is understood by the patient. Only 
validated and approved translations can be used.  
8.7 
Electrocardiogram and Pharmacokinetic-Matched Holter Monitoring 
At screening, for Part 1 and 2, a single 12-lead ECG will be performed to include a description 
of the cardiac rate, rhythm, interval durations, and an overall impression, to determine 
eligibility. This will be assessed locally by the Investigator. 
Patients enrolled to Part 1 will undergo serial Holter monitoring ECG recordings and 
time-matched PK sampling. Holter monitoring comprises continuous ECG recording, and ECG 
extractions will be made via the vendor at the time points indicated within Table 7. ECG 
recordings will be time-matched with PK samples in order to assess any relationship between 
blood levels of irinotecan liposome injection and its metabolite SN-38 and possible QTcF 
interval changes, as shown in Table 5. Holter monitoring equipment will be provided, additional 
details regarding ECG collection should be followed in accordance with the central ECG 
manual. 
Based on the results of the Part 1 Holter data analysis, additional Holter data may be collected 
in Part 2 at the discretion of the Sponsor. 
Table 5: Part 1 PK and ECG Extraction Time Points 
Part 1 PK and ECG Extraction Time Points  
 
Cycle, 
Day 
Time point 
PK 
ECG 
(Holter monitoring, 
continuous ECG recording) 
ECG 
Recording 
Duration 
C1D1 
Pre-dose 
x 
x 
30 hours 
continuous 
C1D1 
End of irinotecan liposome injection 
infusion 
x 
x 
C1D1 
2 hours after end of infusion (±1 
hour) 
x 
x 
C1D2 
Approximately 24 hours after end of 
irinotecan liposome injection 
infusion 
x 
x 
C1D8 
Day of visit 
x 
x 
5 hours 
C1D15 
Pre-dose 
x 
x 
5 hours 
PK samples are collected in Part 1 and Part 2, however the PK matched ECG extractions are only 
performed during Part 1. 
C=cycle; D=day; ECG=electrocardiogram; PK=pharmacokinetic  
 
8.8 
Disease Evaluation 
Tumor assessments will be performed at screening and every 6 weeks (± 1 week) from C1D1 
using the RECIST guidelines Version 1.1 (Parts 1 and 2) and the RANO-BM criteria for CNS 
lesions (Part 2). All patients will have imaging of the brain at screening and at each restaging.  
The tumor assessment at screening are: 
• 
CT with contrast (chest/abdomen required and pelvis if clinically indicated) 
• 
Brain MRI with contrast. 


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Baseline tumor assessments performed per standard of care within 28 days of enrollment are 
acceptable as long they are consistent with protocol requirements, and imaging data is available 
to transmit for central review per IMI ICON specifications. 
The tumor assessment every 6 weeks (± 1 week) from C1D1 are: 
• 
CT with contrast (chest/abdomen required and pelvis if clinically indicated) 
• 
Brain MRI with contrast. 
For patients who are allergic to IV contract or cannot tolerate IV contrast due to impaired renal 
function or other issues, a regular CT or MRI is acceptable. Each follow-up tumor assessment 
should use the same assessment method as performed at screening, unless medically 
contraindicated. Patients who discontinue study treatment for reasons other than disease 
progression by RECIST (or RANO-BM for CNS lesions in Part 2) should continue to be 
followed on the same schedule until radiological documentation of progressive disease (based 
on local radiology review and/or investigator's assessment) or start of another treatment. The 
Sponsor will collect and store all tumor measurement images on all patients throughout the 
study; however, progressive disease will be determined by local radiology review and/or 
investigator assessment. A review of the scans will be performed by the Sponsor for an 
independent analysis of PFS and ORR. Details of BICR tumor assessment process and approach 
will be described in a separate imaging charter document.  
For Part 2 only, comparison of the rate of development/time to development of CNS 
progression and development of new CNS metastases (exploratory endpoint), tumor responses 
in the CNS will assessed using the response criteria developed by the Response Assessment in 
Neuro-oncology Brain Metastases (RANO-BM) working group (Lin 2015). See Appendix III 
for details of the RANO-BM response assessment. 
9 
LABORATORY PROCEDURES AND ASSESSMENTS 
9.1 
Complete Blood Count 
The CBC will include the following: hemoglobin, hematocrit, platelet count, RBC, WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and other cells). 
Local laboratory results may be used for enrollment and dosing decisions. 
9.2 
Serum Chemistry 
Serum chemistry will include electrolytes (sodium, potassium, chloride and bicarbonate), blood 
urea nitrogen (BUN), serum creatinine, glucose, bilirubin, AST, ALT, alkaline phosphatase, 
lactate dehydrogenase, uric acid, total protein, albumin, calcium, magnesium and phosphate. 
A chemistry sample must be sent to the central laboratory; local laboratory results may be used 
for enrollment and dosing decisions. 
9.3 
Pregnancy Test 
For women of childbearing potential, (refer to Section 4.2 Exclusion Criterion (2) for 
definition), pregnancy tests should be performed via serum β-HCG within 7 days of C1D1 in 
the Screening period. During the treatment period on D1 of every cycle and at the 30 day 
follow-up visit, a urine or serum β-HCG pregnancy test should be administered. At C1D1, the 
pregnancy test does not need to be repeated if already performed within 7 days of C1D1. Any 
positive urine pregnancy test must be confirmed via serum β-HCG.  
9.4 
UGT1A1*28  
A whole blood sample will be collected and assessed centrally within 28 days of C1D1 to test 
for UGT1A1*28 genotype from all patients. The result is not needed prior to the initial dose of 
irinotecan liposome injection or topotecan, but the result will be provided to the site. All patients 


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receiving irinotecan liposome injection will receive the same starting dose regardless of their 
UGT1A1*28 genotype. 
9.5 
Pharmacokinetic Sampling 
Plasma samples will be collected to determine the levels of irinotecan and SN-38. The PK time 
points are outlined in Table 6. PK samples will be collected during Parts 1 and 2 of the study. 
Table 6: Pharmacokinetic Sampling Plan  
Sample 
Timepoint 
Window 
 
Part 1: 
1 
Cycle 1 Day 1 (Pre-Dose): prior to irinotecan liposomal injection 
-24 hr 
2 
Cycle 1 Day 1 (Post-Dose): at the end of the irinotecan liposomal 
injection infusion. 
+15 min 
3 
Cycle 1 Day 1 (Post-Dose): at 2 hours after end of the irinotecan 
liposomal injection infusion. 
±1 hr 
4 
Cycle 1 Day 1 (Post-Dose): at 24 hours after end of the irinotecan 
liposomal injection infusion. 
±6 hr 
5 
Cycle 1 Day 8: at any time of day. 
±1 day 
6 
Cycle 1 Day 15 (Pre-Dose): prior to irinotecan liposomal injection 
infusion. 
-24 hr 
7 
Cycle 2 Day 22: at any time of day. 
±1 day 
8 
Early withdrawal visit: at any time of day. 
 
  
Part 2  
1 
Cycle 1 Day 1 (Pre-Dose): prior to irinotecan liposomal injection 
-24 hr 
2 
Cycle 1 Day 1 (Post-Dose): at the end of the irinotecan liposomal 
injection infusion. 
+15 min 
3 
Cycle 1 Day 1 (Post-Dose): at 2 hours after end of the irinotecan 
liposomal injection infusion. 
±1 hr 
4 
Cycle 1 Days 2 to 6 (optional sample*): anytime between 1 and 5 days 
after the start of irinotecan liposomal injection infusion. 
±3 days 
5 
Cycle 1 Day 8: at any time of day. 
±1 day 
6 
Cycle 1 Day 15 (Pre-Dose): prior to irinotecan liposomal injection 
infusion. 
-24 hr 
For Part 2 of the study, PK samples are only expected for patients enrolled to the irinotecan liposome injection arm. 
hr=hour; min=minutes 
*Optional sampling: to be taken if the patient visits or is at the clinic on these days 
Directions for processing and shipping the PK plasma samples can be found in the central 
laboratory flow chart and manual. Full details regarding the destruction processes for these 
samples are documented in the PK Sample Management Plan. 
Residual plasma samples used for irinotecan liposome injection and SN-38 analysis may also 
be used for exploratory analysis. This could include using leftover plasma samples for protein 
binding analysis, metabolite profiling or analysis of excipients. Plasma samples remaining from 
the analysis may be retained by the Sponsor for additional investigations (i.e. long-term 
stability, reproducibility and bioanalytical method cross-validation). 
9.6 
Biobanking 
Biobanking is optional and will only be collected for those patients who have agreed to it by 
signing the specific informed consent form for the exploratory part of the study. Archival tumor 
tissue samples will be collected at baseline (C1D1), if available. Blood and stool samples at 
proposed timepoints will be collected as indicated in schedule of assessments Section 7: 
• 
Plasma (5 mL, dry tube) 
• 
Blood for RNA (2.5 mL, Paxgene RNA tube) 


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• 
Blood for DNA (2.5 mL, Paxgene DNA tube) 
• 
Blood for cfDNA (10 mL, Streck tube) 
• 
Stool sample (outlined in laboratory manual). 
Instructions for collection, processing, handling and shipment of the samples for biobanking 
will be outlined in the laboratory manual. Full details regarding the destruction processes for 
these samples are documented in the Biobanking Sample Management Plan. 
Samples will be archived in a central biorepository designated by the Sponsor and according to 
local administration regulations and/or the EMA and will not carry personal identification (such 
as patient’s social security number or name). The samples will be destroyed no more than 
15 years after the end of the main study or at the patient’s request. 
Blood samples are biobanked for future analysis of additional circulating markers, including 
proteins, pharmacogenetic and pharmacogenomic biomarkers (including potential genetic 
research). 
Analysis from the biobank samples will be performed outside the scope of the main study and 
reported separately. Exploratory analysis techniques, including graphical representations, may 
be employed, including graphical representations, appropriate to examine relationships between 
the study endpoints and observed genotypes. 
Only those designated by the Sponsor will be allowed access to the samples. All information 
collected will be kept strictly confidential and all clinical information will be anonymous. This 
means that no personally identifiable information will be retained with the results of the 
exploratory analyses, so that no individual or collective results will be linked to the individual 
patient whose sample was taken in the study. No individual genetic results will be 
communicated to the Investigator or patient unless required by local regulation. The Sponsor 
will comply with all local regulations related to the establishment, management and application 
of a human blood samples biobank. 
10 
ADVERSE EVENT REPORTING 
10.1 
Definitions 
10.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily need to have a causal 
relationship with this treatment. An AE 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 of the underlying disease (e.g. progression of small cell lung 
cancer), for which the efficacy of the study drug is being evaluated will not be considered an 
AE in this study. 
10.1.2 
Serious Adverse Events 
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 
(Exception: hospitalization for elective treatment of a pre-existing condition that did not 
worsen during the study is not considered an AE. NOTE: Complications that occur 


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during hospitalization are AEs and if a complication prolongs hospitalization, then the 
event is serious). 
• 
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 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. 
In addition to the above criteria, the following is considered a medically important event and 
must be reported to the Sponsor under the SAE reporting rules in Section 10.3 within 24 hours 
of site awareness, irrespective of causality: 
• 
Thrombo-embolic events, NCI CTCAE Grade 1 to 5. 
While the term “severe” is often used to describe the intensity (severity) of an event, the event 
itself may be of relatively minor significance (such as a severe headache). This is not the same 
as “serious”, which is based on a patient/event outcome or action criteria usually associated 
with events that pose a risk to a patient’s life or functioning. 
Any additional AE that the Sponsor or Investigator considers serious should be immediately 
reported to the Sponsor and included in the corporate SAEs database system. This includes any 
suspected or confirmed coronavirus COVID-19 (SARS-CoV-2) infection (seriousness criteria 
should be “other medically significant” if no other seriousness criteria are present (e.g. 
hospitalisation)). 
10.2 
Assessing and Documenting Adverse Events 
Adverse event reporting will begin in conjunction with the signing of informed consent for the 
study. Investigators should complete all routine and standard of care assessments to evaluate 
for toxicity and symptoms of drug-induced AEs. This may include, but is not limited to, verbal 
reports from the patient and/or caregiver, physical examination and laboratory findings. 
All AEs, whether serious or not, will be described in the source documents and the AE page of 
the case report form. All new events, as well as those that worsen in intensity or frequency 
relative to screening, which occur after signing of informed consent and during the 30 day 
follow-up period, must be recorded. However, new AEs felt by the Investigator to be related to 
study treatment, must be reported any time the Investigator becomes aware of such an event, 
even if this occurrence is after the 30 day follow-up period. All AEs should be followed until 
resolution, until death or withdrawal of consent. 
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if they are 
medically relevant, e.g. symptomatic, requiring corrective treatment, leading to discontinuation 
and/or fulfilling a seriousness criterion. 
Information to be reported in the description of each AE 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 
• 
A determination of relatedness to the study drug 


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• 
Action taken: none; change in the study drug administration (e.g., temporary interruption 
in dosing); drug treatment required; non-drug treatment required; diagnostic or 
concomitant procedure performed; patient discontinued from the study treatment 
(complete Treatment Termination case report form) 
• 
Outcome: resolved without sequelae; resolved with sequelae; event ongoing; subject died 
(notify the Sponsor immediately, and complete the SAE page and the Subject Death 
page). 
10.3 
Reporting Serious Adverse Events 
Serious adverse event reporting will begin in conjunction with the date of informed consent. 
All fatal or life-threatening AEs must be immediately reported to the Sponsor or Contract 
Research Organizations (CRO’s) medical team by telephone or e-mail. Within 24 hours of the 
event, the SAE form must be emailed to 
 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. De-identified 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 study drug (irinotecan liposome injection or 
topotecan), even if asymptomatic or not fulfilling a seriousness criterion, the overdose is to be 
reported to the Sponsor immediately (within 24 hours) using the AE and SAE forms. 
All other SAEs and any medically important events (Section 10.1.2) must be reported to the 
Sponsor within 24 hours by phone or e-mail. Details are outlined in the study procedure 
manuals. The SAE form must also be emailed to
 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 SAE to all regulatory authorities with jurisdiction over 
ongoing trials with the study drug, to the EC and to all other investigators involved in clinical 
trials with the study drug. The Investigator is responsible for reporting all SAEs to the 
appropriate IRB/EC, if appropriate according to local requirements. 
10.4 
Determining the Severity and Relatedness of an Event 
10.4.1 
Grading the Severity of an Adverse Event 
Each AE will be graded according to the NCI CTCAE Version 5.0, 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; 
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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. 
10.4.2 
Relationship to Study Drug 
The investigator must attempt to determine if there exists reasonable possibility that an AE is 
related to the use of the study drug. This relationship should be described as related or non-
related. 
10.4.3 
Reporting and Follow-up of Pregnancy 
The Investigator must instruct all female patients to inform them immediately should they 
become pregnant during the study. The Investigator should counsel the patient, discuss 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. If the Investigator becomes aware of a 
pregnancy occurring in the partner of a male patient participating in the study, this should be 
reported to the Sponsor. Monitoring of the partner pregnancy should continue until conclusion 
of the pregnancy. 
11 
STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a SAP, which will be dated and completed prior to database lock. The 
SAP may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint and/or its analysis will also be reflected in a protocol amendment. 
11.1 
General Considerations 
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). 
The efficacy and safety of irinotecan liposome injection in Part 1 will be reported descriptively. 
11.2 
Statistical Hypothesis and Determination of Sample Size 
Part 2 
The primary endpoint is OS. The primary hypothesis will test whether OS is increased in 
patients treated with irinotecan liposome injection. 
A total of 450 patients will be randomized in a 1:1 ratio to the two treatment arms. The primary 
OS test will be performed when at least 350 OS events are observed across the two treatment 
arms to provide at least 87% power to detect a true hazard ratio of HR ≤0.714 (median OS: 
7.5 versus 10.5 months) using a stratified logrank test (stratified by region and platinum 
sensitivity) with overall 1-sided significance level of 0.025 (adjusted for interim analyses). 
Assuming enrollment over 24 months with a ramp-up to a maximum of 21 patients per month 
and lost-to-follow-up rate of 5% across both treatment arms, the timing of the primary analysis 
is expected to be at 37 months. 
An interim OS analysis for futility will be conducted when approximately 29% of the planned 
final number of OS events (i.e., approximately 100 of 350 OS events) has been observed in the 
ITT population. To control type I and type II errors, the planned interim analyses for OS will 
utilize an alpha and (non-binding) beta spending function approach with Hwang-Shih-Decani 
spending and γ parameter equal to -4.5 and -1 for each error type, respectively (Hwang, 1990). 
Non-binding for the futility indicates that the boundary will be constructed in such a way that 
it can be overruled if desired without inflating the type I or II error. Nominal alpha of 0.0001 
will be spent at the supplemental interim analysis requested by FDA. Since the boundary is 


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dependent on the number of OS events, the actual boundary used will be re-calculated, 
incorporating the spending function as defined, based on the number of actual OS events 
analyzed at the time of the analyses and to reflect the nominal α spent at the supplemental 
interim analysis. P-boundary will be used as the criteria for the formal statistical inference. 
The interim analysis specifications per the plan are provided in Table 7. 
Table 7: Type I (α) and Type II (β) Error Spending for the Planned OS Analyses 
 
 
Futility 
Efficacy 
Analysis 
D 
Zboundary 
pboundary 
Cum β 
spend 
HRcrit 
Zboundary 
pboundary 
Cum α 
spend 
HRcrit 
Interim 
100 
0.276 
0.609 
0.025 
1.057 
-3.181 
0.001 
0.001 
0.529 
Final 
350 
-1.967 
0.025 
0.13 
0.810 
-1.967 
0.025 
0.025 
0.810 
D = # of OS events at analysis. Zboundary is the critical test statistic value at which futility (< Z) or efficacy (> Z) would be 
concluded. pbounday is the critical one-sided p-value threshold for the comparison (>p for futility, <p for efficacy). HRcrit is 
the observed hazard ratio threshold (> HR for futility, < HR for efficacy).  
 
The DMC will be responsible for evaluating the futility OS analysis and making a 
recommendation about early termination due to observed study results. At the time of the 
interim analysis, ORR by BICR tumor assessments will be analyzed descriptively by the 
independent DMC for the first 200 patients randomized in Part 2 of the study (i.e. approximately 
100 patients from each arm). The independent DMC will notify the Sponsor if pre-specified 
criteria for ORR are met. A supplemental interim analysis is planned on data collected 24 weeks 
after the last patient has been randomized based on the ITT population to fulfill FDA 
recommendation. At this timepoint, OS and ORR (supported by duration of response (DOR)) 
will be summarized descriptively. Further detail on statistical analysis is provided in SAP. A 
Data Integrity Management Plan will also be created and finalized prior to the descriptive 
analysis of ORR at the time of the interim analysis to clearly describe the data handling 
approach and the data transfer and review pathway. 
Key secondary endpoints are PFS, ORR, and change from baseline in patient-reported 
symptoms (dyspnea and cough). 
Key secondary endpoints will be tested no more than once. To control the overall Type I error 
rate for the comparison between irinotecan liposome injection and topotecan for the primary 
and secondary endpoints, a hierarchical approach will be applied to the statistical testing of the 
secondary endpoints. The statistical inference for the first secondary endpoint of PFS (by BICR) 
will only be performed if the primary endpoint, OS, is statistically significant. The second 
secondary endpoint of ORR (by BICR) will only be tested if PFS is statistically significant. 
Similarly, the PRO endpoints will only be tested if ORR is statistically significant. Any 
parameter which is not statistically significant will be regarded as descriptive and exploratory. 
Further information on alpha control methods will be provided in the SAP. 
Where treatment comparisons are by stratified analysis, stratification factors will be region and 
platinum sensitivity with classification according to the randomization designation. 
Any additional data collected after primary and secondary analyses have been completed may 
be used in post-hoc analysis as deemed appropriate. 
11.3 
Analysis Populations 
Patients enrolled and treated with at least one dose of irinotecan liposome injection will 
comprise the Part 1 safety and efficacy populations. The safety and efficacy of these patients 
will be presented descriptively. 
Patients randomized in Part 2 will comprise the ITT population. This will be the population that 
is evaluated in comparison to evaluate the efficacy (OS, PFS, ORR) of the experimental arm. 


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In the ITT analyses of efficacy, each patient will be considered according to the randomized 
treatment assignment. Patients who received any dose of any study drug will define the Part 2 
safety population. 
Patient reported outcome (PRO) endpoints will be evaluated on the ITT. 
The PK population will include all irinotecan liposome injection treated patients which received 
at least one dose, and who had at least one plasma concentration and no major protocol 
deviations affecting PK variables. 
11.4 
Disposition, Demographics, and Baseline Characteristics 
Disposition of patients will be summarized, including those screened, randomized, treated, 
discontinued from treatment, and discontinued from study. Reasons for discontinuation will be 
tabulated. Demographic and baseline characteristics will be summarized. Medical history and 
prior medications will be tabulated. 
11.5 
Efficacy Analysis 
11.5.1 
Primary Efficacy Analysis (Part 2) 
Overall survival is defined as the number of months from randomization in Part 2 to the date of 
death. Patients without observed death at the time of the primary analysis will have OS censored 
according to the last recorded date alive. 
The primary analysis will be performed using a stratified log-rank test (stratified by region and 
platinum sensitivity) comparing the OS difference between two treatment arms with level of 
significance controlled at the one-sided 0.025 level. Kaplan-Meier methods will be used to 
estimate median OS (with 95% CI) and to display OS time graphically. A stratified Cox 
proportional hazards model will be used to estimate hazard ratio and its corresponding 95% CI. 
Sensitivity analyses for OS will be described in the SAP and will include subgroup analyses 
(according to levels of each stratification factor and other potential prognostic variables). 
11.5.2 
Key Secondary Analyses (Part 2) 
Key secondary endpoints are PFS, ORR, and change from baseline in patient-reported 
symptoms (dyspnea and cough). Key secondary endpoints will be tested no more than once. 
11.5.2.1 Progression-free Survival 
Progression-free survival is the time from randomization in Part 2 to the first documented 
objective disease progression (PD) using RECIST Version 1.1 (or RANO-BM criteria for CNS 
lesions) or death due to any cause, whichever occurs first. Determination of PFS will be based 
on BICR tumor assessment, with PFS based on investigator tumor assessments as a sensitivity 
analysis. If neither death nor progression is observed, data will be censored on the date of the 
last observed tumor assessment date. Patients without a valid tumor response evaluation at 
enrollment/randomization will be censored on the date of enrollment/randomization. Patients 
starting a new anti-cancer treatment prior to documented PD will be censored at the date of the 
last observed tumor assessment prior to start of the new treatment. Patients with documented 
PD or death after an unacceptable long interval (i.e., 2 or more missed or indeterminate 
scheduled assessments) will be censored at the time of the last observed non-PD tumor 
assessment date prior to progression or death. Details of data handling for censoring of PFS 
will be provided in the SAP. 
The difference in PFS between treatments will be evaluated using a stratified log-rank test 
(stratified by region and platinum sensitivity). Kaplan-Meier methods will be used to estimate 
median PFS (with 95% CI) and to display PFS time graphically. A stratified Cox proportional 
hazards model will be used to estimate the PFS hazard ratio and its corresponding 95% CI. 
Sensitivity analyses for PFS will be described in the SAP. 


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11.5.2.2 Objective Response 
Objective response rate is the proportion of patients who achieve partial response (PR) or 
complete response (CR) according to RECIST Version 1.1 guidelines (or RANO-BM criteria 
for CNS lesions in Part 2). An estimate of the ORR and its 95% CI will be calculated. The 
difference in ORR between treatment groups will be compared using Cochran-Mantel-Haenszel 
method, incorporating analysis stratification factors (region and platinum sensitivity). 
In addition to investigator assessment, a BICR review of the tumor assessment images will be 
performed for all patients included in the study, and more specifically at the time of: 
• 
the interim analysis for the descriptive analysis of ORR based on the first 200 patients 
randomized in both arms (i.e. approximately 100 patients from each arm), as well as for 
the patients included in Part 1 and treated with the selected dose for Part 2. 
• 
the supplemental interim analysis, for tumor images for all randomized patients collected 
24 weeks after last patient has been randomized  
A final formal test on secondary endpoint ORR will be based on BICR tumor assessment, with 
ORR based on investigator tumor assessments as a sensitivity analysis. 
11.5.2.3 Change From Baseline in Dyspnea and Cough Symptoms 
The efficacy of irinotecan liposome injection compared to topotecan on dyspnea and will be 
evaluated considering the response to treatment in terms of: 
• 
Change from baseline to Week 12 in patient’s perceived dyspnea, as measured by 
EORTC QLQ-C30/LC13  
• 
Change from baseline to Week 12 in patient’s perceived cough, as measured by EORTC 
QLQ-LC13  
Change from baseline defined as post-baseline value minus baseline value will be calculated 
for each assessment.  
Change from baseline at Week 12 in dyspnea/cough will be analysed using an ANCOVA model 
with covariates treatment group, stratification factors (region, platinum sensitivity, performance 
status, prior immunotherapy), and PRO score at baseline. Patients having missing baseline, 
Week 6, or Week 12 dyspnea/cough score will have their missing dyspnea score imputed under 
the Missing at Random (MAR) assumption using the multiple imputation (MI) methodology in 
the primary analysis, and under the missing not at random (MNAR) assumption in the 
sensitivity analysis. Detailed analysis methods for PRO endpoints will be discussed in the SAP. 
11.5.3 
Exploratory Objectives Analyses 
11.5.3.1 Time to treatment failure 
Time to treatment failure (TTF) is the time from randomization to the occurrence of 
discontinuation of treatment for any reason, including disease progression, treatment toxicity, 
and death. The treatment-failure date for patients who discontinue for reasons other than 
RECIST Version 1.1 (or RANO-BM criteria for CNS lesions in Part 2) progression will be the 
date of the last study drug administration. Patients who have not discontinued treatment prior 
to the data cut-off date will be censored at the date of last tumor assessment documenting no 
objective progression. TTF will be described by Kaplan-Meier methods and treatments will be 
compared using stratified log-rank test. 
11.5.3.2 EORTC-QLQ outcomes 
Analysis of the EORTC-QLQ-C30 questionnaires will be performed in accordance with the 
EORTC guidelines (Fayers, 2001). The subscales of the EORTC QLQ-C30 and the QLQ-LC13 
will be scored based on the EORTC scoring manual. Scores will be standardized such that 


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higher scores on the EORTC QLQ-C30 or the QLQ-LC13 will represent higher (“better”) levels 
of functioning and/or a higher (“worse”) level of symptoms. 
EORTC QLQ-C30 and QLQ-LC13 scale scores will be summarized by treatment group using 
descriptive statistics (mean, standard deviation, minimum, maximum and median) on ITT. An 
ANOVA model will be used to analyze the change in the EORTC QLQ-C30 and QLQ-LC13 
scale scores from baseline to post-baseline visits. 
For each QLQ-C30 and QLQ-LC13 subscale, the proportion of patients with improvement will 
be tabulated by treatment group and will be compared between treatment groups using a logistic 
regression model adjusting for the randomization stratification factors (region and platinum 
sensitivity). 
Additional EORTC QLQ analyses will be performed and details are provided in a standalone 
PRO SAP. 
11.5.3.3 Patient Global Impression of Change and Severity 
The PGI-C and PGI-S will be used as anchors in analyses designed to compute a responder 
definition of the EORTC QLQ scales. This responder definition will be used in analysis of the 
specified EORTC QLQ-C30 and QLQ-LC13 scales as secondary endpoints. 
11.5.3.4 EQ-5D-5L 
EQ-5D-5L visual analog scale (VAS) will be descriptively reported as a total score. Utility 
score and change from baseline over time will be reported. Mean change scores will be 
compared between treatment groups descriptively and may be explored via longitudinal 
modeling (i.e., covariate analysis and repeated measures modeling). 
11.5.3.5 Time to CNS Progression 
The time to CNS progression is defined as the time from randomization to the development of 
CNS progression as defined by the RANO-BM working group (Lin, 2015). Time to CNS 
progression (by BICR and by investigator assessment) will be described by Kaplan-Meier 
methods and treatments will be compared using stratified log-rank test. 
11.5.3.6 Biomarkers 
The biobanked samples may be used to identify prognostic markers, as well as predictive 
markers (i.e, other variants of drug metabolizing enzymes such as UGT1A1, p53 mutations) 
that may correlate with the PKs, efficacy and safety of irinotecan liposome injection. 
11.6 
Safety Analysis 
Safety analyses (AEs and laboratory analyses) will be performed using the safety population, 
defined as all patients receiving any study drug. Treatment assignment will be according to 
actual treatment received. Adverse events will be coded using MedDRA (Version 21.0 or later). 
Severity will be graded according to the NCI CTCAE Version 5.0. 
Treatment-emergent adverse events are defined as any AEs reported from the date of first study 
drug exposure to 30 days after the last date of study drug exposure. Frequency and percentages 
of patients will be summarized for: any grade TEAE, Grade 3 or higher TEAE, study-drug 
related TEAE, serious TEAE, TEAE leading to dose modification, TEAE leading to study drug 
discontinuation, death and TEAE leading to death. Adverse events will be summarized by 
system organ class and preferred term. All AE data will be listed by patient. Based on 
accumulated data a subgroup analysis of safety by UGT1A1*28 allele status may be performed. 
Laboratory data will be summarized according to parameter type. Where applicable, toxicity 
grading for laboratory safety parameters will be assigned based on NCI CTCAE Version 5.0 
criteria. 


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11.7 
Pharmacokinetic Analysis 
11.7.1 
Listings and Summary Statistics of Concentrations 
Individual plasma concentrations for total irinotecan and SN-38 will be listed and summarized 
by timepoint and dose level, for both Part 1 and for Part 2, using descriptive statistics for 
continuous variables (number of available observations, number of below the limit of 
quantification (BLQ), mean, SD, %CV, geometric mean and %CVgeomean, median, minimum, 
maximum). 
11.7.2 
Pharmacokinetic Data Analysis 
Pharmacokinetics of total irinotecan and SN-38 will be quantified from the concentrations from 
plasma samples using nonlinear mixed effect modeling. The population PK model previously 
developed on historical data will be applied to this SCLC study by reassessing previous 
covariates found in the previous model and additional factors specific to this study if required. 
A full description of this Population PK analysis of the concentration data will be captured 
separately in a data analysis plan, and results will be reported in a standalone report. 
11.7.3 
Pharmacokinetics/Pharmacodynamics Relationship 
Graphical exploration will be performed to investigate any relationship between PK and 
pharmacodynamic endpoints (efficacy, safety). If a trend is shown, PK/PD modelling will be 
performed, and this will be described in a separate Data Analysis Plan and reported in a 
standalone report. 
12 
STUDY ADMINISTRATION 
12.1 
Pre-Study Documentation 
Prior to initiating the trial, the Investigator will provide the Sponsor or designee required 
documents according to ICH GCP, and at a minimum: 
• 
A signed FDA Form 1572 or equivalent 
• 
A current (i.e. updated no more than 12 months prior) curriculum vitae for the Principal 
Investigator and each sub-investigator listed on the FDA Form 1572 or equivalent that is 
signed and dated. A copy of the current medical license for the Investigator and each 
sub-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) 
• 
The current IRB/EC membership list for the reviewing IRB/EC 
• 
A signed Investigator Protocol Agreement 
• 
A completed financial disclosure form for the Investigator and all sub-investigators 
• 
A current laboratory certification for the local reference laboratory and curriculum vitae 
of the laboratory director 
• 
A list of current laboratory normal values for the reference laboratory. 
12.2 
Source Documents 
The Investigator will maintain records separate from the case report forms in the form 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 


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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. Source data must 
be attributable, legible, contemporaneous, original, accurate and complete. All information 
obtained from source documents will be kept in strict confidentiality. Source data sent to the 
Sponsor or the Sponsor’s representative as supporting documentation for SAEs 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, the 
International Council on Harmonization guidance (ICH) 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, and all required local regulatory guidelines including applicable privacy laws. 
However, it is up to the Investigator to provide a final informed consent that may include 
additional elements required by the Investigator’s institution. Changes to the Sponsor’s sample 
informed consent should receive approval from the Sponsor or the Sponsor’s representative 
prior to use in the study. 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 patient who agrees to participate in the trial and who signs the informed consent form will 
be given a copy of the signed, dated and witnessed document. The provision of informed 
consent must be documented in the medical record. 
The ICF will contain a separate section that addresses the use of all data and remaining material 
after analysis from mandatory samples and extra samples for optional future research. These 
data and biosamples may only be used for scientific health-related research to find new ways 
to detect, treat, prevent or cure health problems. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the study 
and the storage period. A specific consent will be required to document a patient’s agreement 
to allow any data and remaining specimens to be used for future research. 
12.5 
Investigational Review Board and Independent 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 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC). The IRB or IEC 
should be duly constituted according to local regulatory requirements. Approval must be in the 
form of a letter signed by the Chairperson of the IRB/IEC or the Chairperson’s designee, must 
be on IRB/IEC stationary and must include the protocol by name and/or by designated number. 
If an investigator is a member of the IRB/IEC, 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/IEC of any SAE 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/IEC 
a final summary of the results of the trial at the conclusion of the trial. 


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This study has the option for patients to consent to the collection of samples for biobanking for 
future exploratory analysis, and storage for up to 15 years (where local regulations allow). A 
specific informed consent is required for the collection of these samples and will be explained 
after the patient has given written informed consent for the main study. Patients must receive 
an explanation that they are completely free to refuse to enter the exploratory part of the study 
and may withdraw from it at any time and for any reason up to 15 years after the end of the 
study and will still be allowed to take part in the main study. 
12.6 
Monitoring 
Overall study monitoring will be conducted through a combination of on-site visit and 
centralized monitoring. Details regarding the monitoring will be described in the monitoring 
plan. A clinical monitor will make regularly scheduled trips to the investigational site to review 
the progress of the trial, study data and site processes. At each visit, the monitor will review 
various aspects of the trial including, but not limited to: screening and enrollment logs; 
compliance with the protocol and study manual and with the principles of Good Clinical 
Practice; completion of case report forms; source data verification; study drug accountability 
and storage; facilities and staff. 
The actual frequency of monitoring trips will depend on the enrollment rate and performance 
at each site. The Investigator will allow the Sponsor, and/or its representatives or designees, 
access to all pertinent medical records, as required by national regulations, in order to allow for 
the verification of data gathered in the CRFs and for the review of the data collection process. 
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 on-site monitoring 
visits, the Sponsor and/or representatives will also be routinely reviewing data. Any queries 
identified through this review will be managed within the systems established for query 
resolution and tracking. Inquiries related to study conduct which require further information or 
action will be discussed within the study team for appropriate and documented escalation plans. 
It is expected that response to data clarification requests and other trial-related inquiries will 
occur throughout the course of the study through regular communication with the site monitor, 
the Sponsor or representatives, and review/entry of data into the electronic study database. 
At any time during the course of the study, 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 local regulations, such as the Health Insurance Portability and 
Accountability Act in the US and associated privacy regulations, a patient’s authorization to 
use personal identifiable health information may be required from 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 
Data Quality Assurance 
Electronic data capture will be utilised for collecting patient data. Each site is required to have 
a computer and internet connection available for site entry of clinical data. All entries in the 
eCRF will be done under the e-signature of the person performing the action. This e-signature 
consists of an individual and confidential username and password combination. It is declared 


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to be the legally binding equivalent of the hand-written signature. Only sponsor authorised users 
will get access to the eCRF as appropriate to their study responsibilities. Site users must have 
successfully undergone software application training prior to entering data into the eCRF. 
Data management will be conducted by a service provider under the responsibility of the 
Sponsor’s Data Management Department. All data management procedures will be completed 
in accordance with the Sponsor’s and the CRO’s Standard Operating Procedures. 
The Sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, 
and suitable queries are raised to resolve any missing or inconsistent data. The Investigator will 
receive their data, from the clinical study, in an electronic format (PDF files) which will be an 
exact copy of the eCRF, and will include the full audit trail for the study, for archiving purposes 
and future reference. 
Any queries generated during the data management process will be raised within the EDC 
system. It is the monitor’s responsibility to ensure that all queries are resolved by the relevant 
parties. 
The Sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the Sponsor’s Pharmacovigilance department (and vice versa). 
The coding of an AE, medical history and concomitant medication terms will be performed by 
the service provider. Concomitant medications will be coded using the World Health 
Organisation Drug Dictionary and AEs/medical history terms will be coded using MedDRA. 
12.8 
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 
information must be kept in a secure location with access limited to the study staff directly 
participating in the trial. 
12.9 
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 the local 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/or 
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 their IRB/EC and 
the Sponsor will immediately notify applicable regulatory authorities. 
12.10 
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 multi-centre 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 


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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. 
12.11 
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. 
12.12 
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 of irinotecan liposome 
injection in this indication 
• 
A request to discontinue the study by the FDA and/or local regulatory authorities 


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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 the IRB/IEC if the study is suspended or terminated.  
 


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13 
INVESTIGATOR 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 will identify study personnel conducting study 
specific procedures and appropriately document their training and/or delegated responsibilities. 
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 (GCP). 
 
 
_________________________________ 
 
 
_______________________ 
Signature of Investigator 
 
 
 
 
Date 
 
 
________________________________ 
 
 
 
 
 
Print Name of Investigator 
 
 
 
 
 
 
_______________________________ 
 
 
______________________ 
On behalf of the Sponsor 
 
 
 
 
Date 
 
 
 
 Oncology 
Global Drug Development, R&D 
IPSEN  
 
PPD


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14 
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of 5-fluorouracyl/leucovorin/irinotecan toxicity: Results of the PETACC-3 trial. Eur J Cancer 
2018 ;99:66-77. 
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. 
Topotecan injection for intravenous use U.S. Package Insert, 
Topotecan European Union summary of product characteristics, 
Ustaris F, MD, Saura C, Di Palma J et al. Effective management and prevention of 
neratinib-induced diarrhea. American journal of hematology/oncology. 2015;11(11):13-22. 
Van Cutsem E, Dirix L, Van Laethem JL, Van Belle S, Borner M, Gonzalez Baron M, et al. 
Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer 


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after 5-FU failure: results from a multinational, randomised phase II study. Br J Cancer. 2005 
Mar 28; 92(6):1055-62. 
Von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al: 
Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent 
small cell lung cancer. J Clin Oncol 1999; 17:658-667. 
Von Pawel J, Jotte R, Spigel DR, O’Brien MER, Socinski MA, Mezger J, et al. Randomized 
phase III trial of Amrubicin versus topotecan as second-line treatment for patients with small-
cell lung cancer. J. Clin. Oncol. 2014; 32(35):4012–4018. 
Wakuda K, Kenmotsu H, Naito T, Akamatsu H, Ono A, Shukuya T, Nakamura Y, Tsuya A, 
Murakami H, Takahashi T, Endo M, Nakajima T, Yamamoto N. Efficacy of rechallenge 
chemotherapy in patients with sensitive relapsed small cell lung cancer. Am J Clin Oncol. 2015 
Feb; 38(1):28-32.  
Zatloukal P, Cardenal F, Szczesna A, Gorbunova V, Moiseyenko V, Zhang X, Cisar L, Soria 
JC, Domine M, Thomas M. A multicenter international randomized phase III study comparing 
cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung 
cancer patients with extensive disease. Ann Oncol. 2010 Sep;21(9):1810-6.  


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15 
APPENDIX  
15.1 
Appendix I: Recommendations for Management of Chemotherapy Induced 
Diarrhea 
Proposed algorithm for the assessment and management of treatment-induced diarrhea is 
provided below in Table 8. These guidelines are adapted from those developed by an American 
Society of Clinical Oncology (ASCO) panel and ESMO Clinical Practice Guidelines for 
treating chemotherapy-induced diarrhea (Benson 2004, Ustaris 2015, Bossi 2018). Also 
Section 5.3 for management of dose modifications. 
Anti-diarrhea management should be initiated at the first episode of poorly formed or loose 
stools or the earliest onset of bowel movements that are more frequent than normal. 
Table 8 
Recommendations for Management of Chemotherapy Induced Diarrhea 
Dietetic 
Dietetic Measures (applicable for all grades of diarrhea) 
Stop all lactose-containing products 
Drink 8 to 10 large glasses of clear liquids per day 
Eat frequent small meals 
Recommend low-fat diet enriched with bananas, rice, apple sauce and toast i.e. BRAT diet 
Fluid Intake 
Approximately 2L should be maintained 
Ensure appropriate fluid and electrolyte replacement 
Pharmacological Treatment 
First Line Therapy: loperamide 
Clinical Presentation 
Intervention 
If receiving prophylaxis:  
Increase loperamide dose to a maximum of 16 mg/day. Continue until 
diarrhea free for 12 hours. If no improvement within 48 hours 
implement second-line therapy. 
If new-onset diarrhea (i.e. first loose 
stool): 
Take loperamide 4 mg with first bout of diarrhea followed by 2 mg 
every 4 hours or after every unformed stool (maximum 16 mg/day). 
Continue until diarrhea free for 12 hours. If no improvement within 48 
hours implement second-line therapy. 
With recovery to ≤Grade 1: 
Take loperamide 4 mg one dose with each subsequent cycle of 
irinotecan liposome injection administration. 
Second Line Therapy 
Grade 1 
If persistent diarrhea on loperamide: 
Add diphenoxylate, hydrochloride plus atropine suffate (Lotomil®) 
2.5 mg every 6-8 hours. 
Monitor for trend in decreasing WBC and/or neutropenia. 
Recommend G-CSF if decreasing WBC and/or neutropenia to avoid 
infectious/septic complications. See Section 5.4.1. 


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Grade 2  
If persistent diarrhea on loperamide: 
Add octreotide (short acting) 150 μg subcutaneously tid or after initial 
dose of short acting octreotide, if well tolerated, a single dose of 
octreotide LAR 20 mg intramuscularly. 
Monitor for trend in decreasing WBC and/or neutropenia. 
Recommend G-CSF if decreasing WBC and/or neutropenia to avoid 
infectious/septic complications. See Section 5.4.1. 
Consider stool cultures to exclude infectious causes (e.g. Clostridium 
difficile) prior to prophylactic antibiotics, especially if diarrhea is 
persistent beyond 24 hours or if there is a fever or Grade 3 or 4 
neutropenia 
Grade 3/4 
After intensive loperamide therapy:  
Titrate loperamide to keep diarrhea controlled (<4 stools/day). 
Octreotide (100 to 150 μg subcutaneously bid or 25 to 50 μg/hour 
intravenously if dehydration is severe, with dose escalation up to 500μg 
subcutaneously tid). 
Intravenous fluids as appropriate. 
Consider prophylactic antibiotics, especially if diarrhea is persistent 
beyond 24 hours or if there is a fever or Grade 3 or 4 neutropenia. 
Stool cultures to exclude infectious causes. 
Monitor for trend in decreasing WBC and/or neutropenia. 
Recommend G-CSF if decreasing WBC and/or neutropenia to avoid 
infectious/septic complications. See Section 5.4.1. 
Consider stool cultures to exclude infectious causes (e.g. Clostridium 
difficile) prior to prophylactic antibiotics, especially if diarrhea is 
persistent beyond 24 hours or if there is a fever or Grade 3 or 4 
neutropenia 
 


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15.2 
Appendix II: 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 selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; 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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15.3 
Appendix III: Response Criteria for CNS Metastases  
Summary of the response criteria for CNS metastases proposed by the Response Assessment in 
Neuro-Oncology Brain Metastases (RANO-BM) working group (Lin, 2015) 
 
Complete 
Response 
Partial Response 
Stable Disease 
Progressive 
Disease 
Target Lesions 
None 
≥30% decrease in 
sum longest 
distance relative to 
baseline 
<30% decrease 
relative to baseline 
but <20% increase in 
sum longest distance 
relative to nadir 
≥20% increase in 
sum longest 
diameter relative 
to nadira 
Non-target lesions 
None 
Stable or improved 
Stable or improved 
Unequivocal 
progressive 
diseasea 
New lesion(s)b 
None 
None 
None 
Presenta 
Corticosteroids 
None 
Stable or decreased Stable or decreased 
Not applicablec 
Clinical status 
Stable or 
improved 
Stable or improved 
Stable or improved 
Worsea 
Requirement for 
response 
All 
All 
All 
Anyc 
a Progression occurs when this criterion is met.  
b A new lesion is one that is not present on prior scans and is visible in minimum two projections. If a new 
lesion is equivocal, for example because of its small size, continued therapy can be considered, and follow-up 
assessment will clarify if the new lesion is new disease. If repeat scans confirm there is definitely a new 
lesion, progression should be declared using the date of the initial scan showing the new lesion. For 
immunotherapy-based approaches, new lesions alone do not define progression. 
c Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration. 


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15.4 
Appendix IV: Temporary Measures and Procedures Related to COVID-19 
Pandemic 
This appendix serves as notification of the temporary measures put in place for the conduct of 
the study during the COVID-19 pandemic and until such time as the situation resolves, at which 
point the protocol assessments will return to those specified in the current approved protocol 
effective at that time. The timing of when the pandemic is declared over may vary on a country 
by country basis as well as between sites in the same country, and as such the temporary 
measures may remain in place for differing periods of time per country/site. Investigators will 
determine the feasibility of starting or continuing study treatment on a patient by patient basis, 
depending on the ability to conduct safety monitoring and providing patients an adequate supply 
of study treatment, in accordance with local requirements. 
Any temporary measure will be reported as a protocol deviation related to COVID-19. 
This appendix was assembled using suggestions from the TransCelerate publication "Beyond 
COVID-19: Modernizing Clinical Trial Conduct" published by TransCelerate Biopharma Inc. 
2020, which was influenced by FDA and EMA guidance issued for conduct and management 
of clinical trials during the COVID-19 pandemic. 
Specific Guidance for Study Visits and Assessments 
Informed Consent (including Re-consent) 
As per guidelines issued by the FDA in the US and in line with guidance in other countries, the 
use of electronic signatures is authorised to obtain the patient’s informed consent. The Sponsor 
and IRB need to be notified, and approval obtained where applicable, of the use of electronic 
informed consent signature and the accepted electronic formats need to be clearly documented. 
This is not meant to replace the important discussion between the patient, Investigator and site 
staff. Such a discussion must still occur and be part of a screening visit (in-person, by 
telemedicine, or home health visit). A clear, documented process on how patients are contacted 
virtually to explain the study and close monitoring need to be in place. 
Dosing visits (Arm A and Arm B) 
Dosing visits may be delayed due to COVID-19 (for example temporary closure of the site, 
patient unable to travel etc). Dose delay rules should be followed per protocol (Section 6.2). In 
case of dosing visit delays outside of the protocol these should be discussed between the 
Investigator and the Sponsor. Screening visit and assessments (apart from informed consent as 
described above) must be performed on site. 
Physical Examinations and ECOG Performance Status: Assessment can be done via 
telemedicine (as per the rules below) and should be done according to local practice.  
Quality of Life Assessments:  
The QoL assessments are routinely captured while the patient is at the site, in real time. The 
site has an electronic tablet containing the questionnaires, in which the patient records his/her 
answers. As some patients are concerned about touching the device, sanitation practices that 
allows for thorough cleaning of the device have been implemented. In cases where study staff 
are not allowed on site or patients unable to attend their visit, interview mode is used to capture 
e-PRO and electronic clinical outcome assessment (e-COA). The site staff will call the patient, 
ask the questions as per the assessment in exactly the same order and wording (paraphrasing is 
not allowed apart from the VAS scales for the EQ-5D-5L. The clinician should define for the 
patient the upper and lower bounds (ie. 100 is the best you you have ever felt and 0 is the worst)) 
and directly enter the data into the ePRO system on behalf of the patient. Answers to questions 
must not be noted down first and then entered into the eCRF as this could impact validation of 


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the ePRO tool. Details of the verification of the patient and the site personnel conducting the 
assessment should be documented. 
The interview mode has been authorized by the vendor with specific guidance/rules provided 
to the sites to conduct these interviews. 
Disease Evaluation: CT/MRI Scans: This study assessment does not always coincide with a 
dosing day, though it might coincide if the patient has had no dosing delays (e.g. due to toxicity). 
In the case where the assessment does not coincide with a dosing visit, to reduce the risk 
associated with travelling (to a study site), imaging may be performed at a local imaging 
facility. The modality to be used for the imaging is to be documented and shared with the local 
imaging facility for consistency to ensure the same imaging modality is used. Documentation 
of the imaging facility is to be collected by the site and retained. Scanned images are to be 
shared with the site. The site is responsible for submitting scans to the central imaging vendor. 
The RECIST reading is to be done by the Investigator (as per Section 8.8). 
Sample Collection 
Haematology and Biochemistry: To reduce the risk associated with travel to the site if the 
subject comes in the day prior to dosing for haematology sampling, or to reduce the risk 
associated with time the subject spends at the study site, a local laboratory may be used to obtain 
and analyse the haematology samples. Results of haematology samples taken need to be shared 
with the investigational site and assessed prior to dosing as per protocol requirements. 
Documentation of the local laboratory (accreditation and reference ranges) are required to be 
collected and shared with the Sponsor. As the subject comes at the site for dosing, effort should 
be made to collect biochemistry samples for central laboratory assessment, as well as all other 
central laboratory samples. If this is not possible, local biochemistry samples are to be collected 
as described above. 
Pregnancy Test: Pregnancy testing is required on Day 1 of each cycle. To reduce the risk 
associated with travel to the site, if the patient comes in the day prior to dosing for pregnancy 
testing, or to reduce the risk associated with time the patient spends at the study site, a local 
laboratory, hospital or general medical practice may be used to obtain the pregnancy test. 
Results of the pregnancy test need to be shared with the investigational site and assessed prior 
to dosing as per protocol requirements. 
Concomitant Medications and Procedures: Details can be collected by site staff via 
telephone call as per the rules relating to use of telemedicine below.  
AE Reporting: Details can be collected by site staff via telephone call as per the rules relating 
to use of telemedicine below. 
Specific Rules Relating to use of Telemedicine  
The form of telemedicine used (phone call or use of a platform), the legal and privacy protection 
of the subject as well as details of the verification of the identity of the subject and site personnel 
conducting the assessment must be documented at site level and should be available for review 
by the monitor. 
Note that further information about specific measures adopted for the COVID-19 situation to 
cover temporary discontinuations and SAE reporting are found in Sections 6.2.1 and 10.1.2, 
respectively. 
 

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N o n Cli nical
1 2- N o v- 2 0 2 1 1 5: 3 3: 2 2 G M T + 0 0 0 0
Cli nical
1 2- N o v- 2 0 2 1 1 6: 0 4: 5 8 G M T + 0 0 0 0
Cli nical
2 3- N o v- 2 0 2 1 1 5: 1 7: 0 3 G M T + 0 0 0 0
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M M -3 9 8 -0 1 -0 3 -0 4  
R E SILI E N T: A R a n d o miz e d, O p e n L a b el P h as e 3 S tu d y of Iri n ot e c a n 
Li p os o m e I nj ecti o n ( O NI V Y D E  ® ) v ers us T o p ot ec a n i n P ati e nts wit h 
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V ersi o n N u m b er a n d D at e: Fi n al V 4 . 0 1 1 N O V 2 0 2 1  
 
 
 
 
 
 
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S T A TI S TI C AL A N AL Y SI S P L A N S I G N A T U R E P A G E  
St atistic al A n al ysis Pl a n V 4 . 0 ( D at e d 1 1 N O V 2 0 2 1 ) f or Pr ot oc ol M M -3 9 8 -0 1 -0 3 -0 4  v ersi o n 8 . 0. 
 
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U p o n r evi e w of t his d oc u m e nt, t h e u n d ersi g n e d a p pr o v es t his v ersi o n of t h e O ut p ut T e m pl at es , a ut h orizi n g t h at 
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M O DI FI C A TI O N H I S T O R Y 
 
 
U ni q u e 
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V ersi o n  
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1. 0  
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- 
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A d di n g s u m m ar y’s s plit b y pl ati n u m s e nsiti vit y 
a n d P K a n al ysis.  
I m pl e m e nti n g u p d at es fr o m pr ot oc ol 
a m e n d m e nts 4, 5, 6 a n d 7.  
2. 1  
1 2 M A R 2 0 2 1  
 
I ncl u d e d s e nsiti vit y s u b gr o u p a n al ysis f or 
ori gi n al pl ati n u m s e nsiti vit y 
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4. 0  
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U p d at e d d et ails of t h e O S f utilit y a n al ysis t o 
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T A BL E O F C O N T E N T S  
1.  
LI S T O F A B B R E VI A TI O N S  ....................................................................................................... 1 2  
2.  
I N T R O D U C TI O N ......................................................................................................................... 1 5  
3.  
S T U D Y O BJ E C TI V E S  .................................................................................................................. 1 5  
3. 1.  
P art 1 O bj ecti v es  ........................................................................................................................................1 5  
3. 1. 1.  
Pri m ar y O bj ecti v es  ................................................................................................................................... 1 5  
3. 1. 2.  
S ec o n d ar y O bj ecti v es  ............................................................................................................................... 1 5  
3. 1. 3.  
Ex pl or at or y O bj ecti v es  ............................................................................................................................. 1 5  
3. 2.  
P art 2 O bj ecti v es a n d Esti m a n ds  ................................................................................................................1 6  
3. 2. 1.  
Pri m ar y O bj ecti v es  ................................................................................................................................... 1 6  
3. 2. 2.  
S ec o n d ar y O bj ecti v es  ............................................................................................................................... 1 6  
3. 2. 3.  
Ex pl or at or y O bj ecti v es  ............................................................................................................................. 1 6  
3. 2. 4.  
Esti m a n ds  ................................................................................................................................................. 1 7  
4.  
S T U D Y D E SI G N  ........................................................................................................................... 2 0  
4. 1.  
G e n er al D escri pti o n  ...................................................................................................................................2 0  
4. 2.  
Sc h e d ul e of E v e nts  .....................................................................................................................................2 2  
4. 3.  
C h a n g es t o A n al ysis fr o m Pr ot oc ol .............................................................................................................2 2  
5.  
P L A N N E D A N A L Y S E S  ................................................................................................................ 2 2  
5. 1.  
D at a M o nit ori n g C o m mitt e e ( D M C)  ...........................................................................................................2 2  
5. 2.  
I nt eri m A n al ysis .........................................................................................................................................2 3  
5. 2. 1.  
O S F utilit y A n al ysis  ................................................................................................................................... 2 3  
5. 2. 2.  
O R R A n al ysis  ............................................................................................................................................. 2 3  
5. 3.  
S u p pl e m e n t al I nt eri m A n al ysis ..................................................................................................................2 4  
5. 4.  
Pri m ar y A n al ysis  ........................................................................................................................................2 4  
6.  
A N A L Y SI S S E T S  ........................................................................................................................... 2 5  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 8  of 7 5  
 
6. 1.  
All P ati e nts E nr oll e d P o p ul ati o n  ................................................................................................................2 5  
6. 2.  
P art 1 S af et y P o p ul ati o n  ............................................................................................................................2 5  
6. 3.  
P art 1 P K P o p ul ati o n  ..................................................................................................................................2 5  
6. 4.  
P art 2 S af et y P o p ul ati o n  ............................................................................................................................2 5  
6. 5.  
P art 2 I nt e nt -t o-Tr e at P o p ul ati o n (I T T)  ......................................................................................................2 5  
6. 6.  
P art 2 P er Pr ot oc ol P o p ul ati o n ( P P)  ...........................................................................................................2 5  
6. 7.  
P art 2 P K P o p ul ati o n  ..................................................................................................................................2 6  
7.  
G E N E R A L C O N SI D E R A TI O N S  ................................................................................................. 2 6  
7. 1.  
R ef er e nc e St art D at e a n d St u d y D a y  ..........................................................................................................2 6  
7. 2.  
B as eli n e  .....................................................................................................................................................2 7  
7. 3.  
R et ests, U nsc h e d ul e d Visits a n d E arl y T er mi n ati o n D at a  ...........................................................................2 7  
7. 4.  
Wi n d o wi n g C o n v e nti o ns  ............................................................................................................................2 7  
7. 5.  
St atistic al T ests  ..........................................................................................................................................2 8  
7. 6.  
C o m m o n C alc ul ati o ns  ................................................................................................................................2 8  
7. 7.  
S oft w ar e V ersi o n  .......................................................................................................................................2 8  
8.  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................................... 2 8  
8. 1.  
A dj ust m e nts f or C o v ari at es a n d F act ors t o b e I ncl u d e d i n A n al ys es  ..........................................................2 8  
8. 2.  
M ultic e nt er St u di es  ...................................................................................................................................2 8  
8. 3.  
Missi n g d at a  ..............................................................................................................................................2 9  
8. 4.  
M ulti pl e C o m p aris o ns/ M ulti plicit y  ...........................................................................................................2 9  
8. 5.  
E x a mi n ati o n of S u b gr o u ps  .........................................................................................................................3 0  
9.  
O U T P U T P R E S E N T A TI O N S  ..................................................................................................... 3 1  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 9  of 7 5  
 
1 0.  
DI S P O SI TI O N A N D WI T H D R A W A L S  .................................................................................... 3 1  
1 1 . 
P R O T O C O L D E VI A TI O N S ......................................................................................................... 3 1  
1 2.  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E R I S TI C S ...................................... 3 1  
1 2. 1.  
D eri v ati o ns  ............................................................................................................................................3 3  
1 3.  
S U R GI C A L A N D  M E DI C A L HI S T O R Y  .................................................................................... 3 3  
1 4.  
C O N C O MI T A N T P R O C E D U R E S  .............................................................................................. 3 4  
1 5.  
C O N C O MI T A N T R A DI O T H E R A P Y  ......................................................................................... 3 4  
1 6.  
P RI O R A N D C O N C O MI T A N T M E DI C A TI O N S  ..................................................................... 3 4  
1 7.  
E X T E N T O F DI S E A S E A T  B A S E LI N E  ..................................................................................... 3 5  
1 8.  
S T U D Y M E DI C A TI O N E X P O S U R E  .......................................................................................... 3 5  
1 9.  
E F FI C A C Y O U T C O M E S  .............................................................................................................. 3 6  
1 9. 1.  
Pri m ar y Effic ac y  .....................................................................................................................................3 6  
1 9. 1. 1.  
Pri m ar y Effic ac y V ari a bl e & D eri v ati o n  ..................................................................................................... 3 6  
1 9. 1. 2.  
Pri m ar y A n al ysis of Pri m ar y Effic ac y V ari a bl e  .......................................................................................... 3 7  
1 9. 1. 3.  
S e nsiti vit y A n al ysis of Pri m ar y Effic ac y V ari a bl e  ...................................................................................... 3 7  
1 9. 1. 4.  
A n al ys es of S u b gr o u ps  ............................................................................................................................. 3 7  
1 9. 2.  
S ec o n d ar y Effic ac y  .................................................................................................................................3 7  
1 9. 2. 1.  
S ec o n d ar y Effic ac y V ari a bl es & D eri v ati o ns  ............................................................................................. 3 8  
1 9. 2. 1. 1.  
Pr o gr essi o n -fr e e s ur vi v al .................................................................................................................. 3 8  
1 9. 2. 1. 2.  
O bj ecti v e R es p o ns e R at e ( O R R)  ....................................................................................................... 3 9  
1 9. 2. 1. 3.  
O v er all S ur vi v al P art 1  ...................................................................................................................... 4 0  
1 9. 2. 1. 4.  
P ati e nts wit h S y m pt o m of c o u g h a n d d ys p n e a  ................................................................................ 4 0  
1 9. 2. 2.  
A n al ysis of S ec o n d ar y Effic ac y V ari a bl es  .................................................................................................. 4 1  
1 9. 2. 2. 1.  
A n al ysis of Pr o gr essi o n Fr e e S ur vi v al  ............................................................................................... 4 1  
1 9. 2. 2. 2.  
A n al ysis of O bj ecti v e R es p o ns e R at e  ................................................................................................ 4 1  
1 9. 2. 2. 3.  
O v er all S ur vi v al f or P art 1  ................................................................................................................. 4 1  
1 9. 2. 2. 4.  
S u m m ar y of T u m or R es p o ns e  .......................................................................................................... 4 2  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 0  of 7 5  
 
1 9. 2. 2. 5.  
P ati e nts wit h S y m pt o m of C o u g h a n d D ys p n e a  ............................................................................... 4 2  
1 9. 3.  
E x pl or at or y Effic ac y  ...............................................................................................................................4 6  
1 9. 3. 1 . 
Ex pl or at or y Effic ac y V ari a bl es & D eri v ati o ns  ........................................................................................... 4 6  
1 9. 3. 1. 1.  
Q Tc F f oll o wi n g tr e at m e nt wit h iri n ot ec a n li p os o m e i nj ecti o n  ........................................................ 4 6  
1 9. 3. 1. 2.  
Ti m e t o Tr e at m e nt F ail ur e ( T T F)  ...................................................................................................... 4 6  
1 9. 3. 1. 3.  
E O R T C -QL Q -C 3 0 a n d L C 1 3  ................................................................................................................ 4 6  
1 9. 3. 1. 4.  
P ati e nt Gl o b al I m pr essi o n of C h a n g e ( P GI -C) a n d S ev erit y ( P GI -S)  .................................................. 4 7  
1 9. 3. 1. 5.  
E Q -5 D -5L  .......................................................................................................................................... 4 8  
1 9. 3. 1. 6.  
Ti m e t o C N S pr o gr essi o n ( P art 2)  ..................................................................................................... 4 9  
1 9. 3. 2.  
A n al ysis of Ex pl or at or y Effic ac y V ari a bl es  ................................................................................................ 4 9  
1 9. 3. 2. 1.  
Q Tc F a n al ysis ( P art 1 o nl y)  ............................................................................................................... 4 9  
1 9. 3. 2. 2.  
Ti m e t o Tr e at m e nt F ail ur e ( T T F)  ...................................................................................................... 4 9  
1 9. 3. 2. 3.  
E O R T C -QL Q -C 3 0 a n d L C 1 3  ................................................................................................................ 5 0  
1 9. 3. 2. 4.  
P ati e nt Gl o b al I m pr essi o n of C h a n g e ( P GI -C) a n d S e v erit y  ( P GI-S)  .................................................. 5 0  
1 9. 3. 2. 5.  
E Q -5 D -5L  .......................................................................................................................................... 5 0  
1 9. 3. 2. 6.  
Ti m e t o C N S pr o gr essi o n  .................................................................................................................. 5 0  
2 0.  
S A F E T Y O U T C O M E S  .................................................................................................................. 5 0  
2 0. 1.  
A d v ers e E v e nts  ......................................................................................................................................5 1  
2 0. 1. 1.  
All T E A Es  ................................................................................................................................................... 5 1  
2 0. 1. 2.  
All T E A Es B y M axi m u m C T C A E Gr a d e  ....................................................................................................... 5 1  
2 0. 1. 3.  
All T E A Es of Gr a d e 3 or m or e  ................................................................................................................... 5 1  
2 0. 1. 4.  
All R el at e d T E A Es  ...................................................................................................................................... 5 2  
2 0. 1. 5.  
All S eri o us T E A Es  ...................................................................................................................................... 5 2  
2 0. 1. 6.  
All S eri o us R el at e d T E A Es  ......................................................................................................................... 5 2  
2 0. 1. 7.  
T E A Es L e a di n g t o D os e A dj ust m e nt  ......................................................................................................... 5 2  
2 0. 1. 8.  
T E A Es L e a di n g t o Tr e at m e nt Disc o nti n u ati o n  .......................................................................................... 5 2  
2 0. 1. 9.  
T E A Es L e a di n g t o D e at h ............................................................................................................................ 5 3  
2 0. 1. 1 0.  
I nf usi o n R el at e d T E A Es ......................................................................................................................... 5 3  
2 0 . 1. 1 1. 
D os e Li miti n g T oxiciti es ( DL Ts) A Es  ...................................................................................................... 5 3  
2 0. 1. 1 2.  
R el at e d T E A Es Gr a d e 3 or Hi g h er b y Pl ati n u m S e nsiti vit y  .................................................................... 5 3  
2 0. 1. 1 3.  
S u b gr o u ps of A d v ers e E v e nts  ............................................................................................................... 5 3  
2 0. 2.  
D e at hs ....................................................................................................................................................5 4  
2 0. 3.  
L a b or at or y E v al u ati o ns  ..........................................................................................................................5 4  
2 0. 4.  
E C G E v al u ati o ns  .....................................................................................................................................5 4  
2 0. 4. 1.  
E C G M ar k e dl y A b n or m al Crit eri a  ............................................................................................................. 5 5  
2 0. 5.  
Vit al Si g ns  ..............................................................................................................................................5 5  
2 0. 5. 1.  
Vit al Si g ns M ar k e dl y A b n or m al Crit eri a  ................................................................................................... 5 6  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 1  of 7 5  
 
2 0. 6.  
P h ysic al E x a mi n ati o n  .............................................................................................................................5 7  
2 0. 7.  
U G T 1 A 1 * 2 8 a n d Ot h er G e n ot y p es  .........................................................................................................5 7  
2 0. 8.  
P h ar m ac o ki n etics  ...................................................................................................................................5 7  
2 0. 8. 1.  
Listi n gs a n d S u m m ar y St atistics of C o nc e ntr ati o ns .................................................................................. 5 7  
2 0. 8. 2.  
P h ar m ac o ki n etic D at a A n al ysis  ................................................................................................................ 5 8  
2 0. 8. 3.  
P h ar m ac o ki n etics / P h ar m ac o d y n a mics R el ati o ns hi p  ............................................................................. 5 8  
2 1.  
R E F E R E N C E S  ............................................................................................................................... 5 9  
A P P E N DI X 1.  R E P O R TI N G C O N V E N TI O N S  .................................................................................... 6 0  
A P P E N DI X 2.  P A R TI A L D A T E C O N V E N T I O N S .............................................................................. 6 1  
A P P E N DI X 3.  C T C A E G R A DI N G F O R N U M E RI C L A B V A L U E S  .................................................. 6 5  
A P P E N DI X 4: E O R T C Q L Q -C 3 0  ......................................................................................................... 6 9  
A P P E N DI X 5: E O R T C Q L Q -L C 1 3  ....................................................................................................... 7 3  
A P P E N D I X 6: C O N FI R M E D B E S T O V E R A L L R E S P O N S E  ............................................................ 7 5  
 
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 2  of 7 5  
 
1.  LI S T O F A B B R E VI A TI O N S  
 
A b br e vi ati o n  
D efi niti o n  
A E  
A d v ers e E v e nt  
AL T  
Al a ni n e a mi n otr a nsf er as e  
A N C O V A  
A n al ysis of C o v ari a nc e  
A S T  
As p art at e a mi n otr a nsf er as e  
BI C R  
Bli n d e d I n d e p e n d e nt C e ntr al R evi e w  
BL Q  
B el o w Li mit of Q u a ntific ati o n  
B O R  
B est O v er all R es p o ns e  
B U N  
Bl o o d ur e a nitr o g e n  
CI  
C o nfi d e nc e I nt er v al  
C N S  
C e ntr al N er v o us S yst e m  
C R  
C o m pl et e R es p o ns e  
C R F  
C as e R e p ort F or m  
C T C A E  
C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts  
C V  
C o effici e nt of V ari ati o n  
D B P  
Di ast olic Bl o o d Pr ess ur e  
D C R  
Dis e as e C o ntr ol R at e  
DL T  
D os e Li miti n g T oxicit y  
D M C  
D at a M o nit ori n g C o m mitt e e  
D O R  
D ur ati o n of R es p o ns e  
E C G  
El ectr oc ar di o gr a m  
E C O G  
E ast er n C o o p er ati v e O nc ol o g y Gr o u p  
E O R T C  
E ur o p e a n Or g a niz ati o n f or R es e arc h a n d Tr e at m e nt of C a nc er  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 3  of 7 5  
 
E O R T C -QL Q -C 3 0  
E O R T C q u alit y -of -lif e c or e 3 0 q u esti o n n air e 
E O R T C -QL Q -L C 1 3 
E O R T C q u alit y -of -lif e q u esti o n n air e l u n g c a nc er s u p pl e m e nt 
E Q -5 D -5L  
E ur o Q oL 5 di m e nsi o n h e alt h st at us q u esti o n n air e ( 5 l ev el)  
H R  
H az ar d R ati o  
I T T 
I nt e nt-t o-Tr e at  
I V 
I ntr a v e n o us 
I W R S 
I nt er acti v e W e b R es p o ns e S yst e m 
L S 
L e ast S q u ar e 
M A R  
Missi n g At R a n d o m  
M C M C  
M ar k o v C h ai n M o nt e C arl o  
M e d D R A  
M e dic al Dicti o n ar y f or R e g ul at or y Acti viti es  
MI  
M ulti pl e I m p ut ati o n  
M N A R  
Missi n g N ot At R a n d o m  
N CI  
N ati o n al C a nc er I nstit ut e  
O R R  
O bj ecti v e R es p o ns e R at e  
O S  
O v er all S ur vi v al  
P D  
Pr o gr essi v e dis e as e or dis e as e pr o gr e ssi o n 
P F S  
Pr o gr essi o n Fr e e S ur vi v al  
P GI -C  
P ati e nt Gl o b al I m pr essi o n of C h a n g e  
P GI -S  
P ati e nt Gl o b al I m pr essi o n of S ev erit y  
P K  
P h ar m ac o ki n etics  
P R  
P arti al R es p o ns e  
P R O  
P ati e nt R e p ort e d O utc o m e  
P T  
Pr ef err e d T er m  
Q oL  
Q u alit y of Lif e  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 4  of 7 5  
 
Q Tc F  
Q T i nt er v al, Fri d erici a c orr ecti o n  
R A N O  
R es p o ns e Ass ess m e nt i n N e ur o -O nc ol o g y  
R B C  
R e d Bl o o d C ell  
R E CI S T  
R es p o ns e E v al u ati o n Crit eri a i n S oli d T u m ors  
R S  
R a w Sc or e  
S B P  
S yst olic Bl o o d Pr ess ur e  
S A E  
S eri o us A d v ers e E v e nt  
S A P  
St atistic al A n al ysis Pl a n  
S CL C  
S m all C ell L u n g C a nc er  
S D  
St a bl e Dis e as e  
S O C  
S yst e m Or g a n Cl ass  
T E A E  
Tr e at m e nt E m er g e nt A d v ers e E v e nt  
T T F  
Ti m e t o Tr e at m e nt F ail ur e  
U G T 1 A 1  
Uri di n e di p h os p h at e Gl uc ur o n osyl Tr a nsf er as e 1 A 1  
U G T 1 A 1 * 2 8  
U G T 1 A 1 p h ar m ac o g e n etic v ari a nt * 2 8  
UL N  
U p p er Li mit of N or m al  
W B C  
W hit e Bl o o d C ell  
 
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 5  of 7 5  
 
2.  IN T R O D U C TI O N  
T his d oc u m e nt d escri b es t h e r ul es a n d c o n v e nti o ns t o b e us e d i n t h e pr es e nt ati o n a n d a n al ysis of effic ac y a n d 
s af et y d at a f or Pr ot oc ol M M -3 9 8 -0 1 -0 3 -0 4.   It d escri b es t h e d at a t o b e s u m m ariz e d a n d a n al yz e d, i ncl u di n g 
s p ecifics of t h e st atistic al a n al ys es t o b e p erf or m e d.  T his a n al ysis pl a n d o es n ot c o v er P K a n d Bi o m ar k er a n al ys es 
w hic h will b e d escri b e d i n a s e p ar at e pl a n.   T h e P ati e nt R e p ort e d O utc o m es ( P R O) will als o b e c o v er e d i n a 
s e p ar at e pl a n pr e p ar e d b y t h e R e al-W orl d A n al ytics a n d S ol uti o ns gr o u p.  
T his st atistic al a n al ysis pl a n ( S A P) is b as e d o n pr ot oc ol v ersi o n 8 . 0 d at e d 0 7 O C T 2 0 2 1 . 
3.  S T U D Y O BJ E C TI V E S  
T his st u d y will b e c o n d uct e d i n t w o p arts:  a n o p e n -l a b el, si n gl e-ar m, s af et y r u n -i n ( P art 1) t o c o nfir m t h e P art 2 
d os e of iri n ot ec a n li p os o m e i nj ecti o n, f oll o w e d b y  a r a n d o miz e d, o p e n -l a b el c o m p aris o n of iri n ot ec a n li p os o m e 
i nj ecti o n a n d t o p ot ec a n i n p ati e nts wit h S m all C ell L u n g C a nc er  (S CL C ). 
3. 1.  P A R T 1  O BJ E C TI V E S  
3. 1. 1.  
P RI M A R Y O BJ E C TI V E S  
T h e pri m ar y o bj ecti v es of P art 1 ar e:  
•  
D escri b e t h e s af et y a n d t ol er a bilit y of iri n ot ec a n li p os o m e i nj ecti o n m o n ot h er a p y a d mi nist er e d ev er y 2 
w e e ks  
•  
T o d et er mi n e t h e iri n ot ec a n li p os o m e i nj ecti o n m o n ot h er a p y d os e ( 8 5 m g/ m 2 or 7 0 m g/ m 2 
a d mi nist er e d e v er y 2 w e e ks) f or P art 2 of t his st u d y.  
3. 1. 2.  
S E C O N D A R Y O BJ E C TI V E S  
T h e s ec o n d ar y o bj ecti v es of P art 1 ar e t o ass ess t h e pr eli mi n ar y effic ac y of iri n ot ec a n li p os o m e i nj ecti o n ( at 
eit h er t h e 8 5 m g/ m 2 d os e l e v el or t h e 7 0 m g/ m 2 d os e l ev el) as d et er mi n e d b y  
•  
O bj ecti v e r es p o ns e r at e ( O R R)  
•  
Pr o gr essi o n fr e e s ur vi v al ( P F S)  
•  
O v er all s ur vi v al ( O S)  
3. 1. 3.  
E X PL O R A T O R Y O BJ E C TI V E S  
•  
T o d escri b e Q Tc F f oll o wi n g tr e at m e nt wit h iri n ot ec a n li p os o m e i nj ecti o n  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 6  of 7 5  
 
•  
T o ex pl or e t h e bi o m ar k ers ass oci at e d wit h t oxicit y a n d effic ac y  f oll o wi n g tr e at m e nt wit h iri n ot ec a n 
li p os o m e i nj ecti o n i n t his p ati e nt p o p ul ati o n 
•  
T o d escri b e t h e ass oci ati o n b et w e e n U G T 1 A 1 * 2 8 a n d ot h er U G T 1 A 1 g e n ot y p es, S N -3 8 c o nc e ntr ati o n 
a n d s af et y  
•  
T o e v al u at e t h e p h ar m ac o ki n etics a n d t h e r el ati o ns hi p b et w e e n p h ar m a c o ki n etic ex p os ur e a n d effic ac y 
a n d s af et y f oll o wi n g iri n ot ec a n li p os o m e i nj ecti o n i n t his p ati e nt p o p ul ati o n  
•  
T o ex pl or e p ati e nt -r e p ort e d o utc o m es ( P R Os) b et w e e n ar ms usi n g E ur o p e a n Or g a niz ati o n f or R es e arc h 
a n d Tr e at m e nt of C a nc er Q u alit y of Lif e Q u esti o n n air e C or e 3 0 ( E O R T C -QL Q -C 3 0) a n d E ur o p e a n 
Or g a niz ati o n f or R es e arc h a n d Tr e at m e nt of C a nc er Q u alit y of Lif e Q u esti o n n air e L u n g C a nc er 1 3 
( E O R T C-QL Q -L C 1 3), P ati e nt Gl o b al I m pr essi o n of S e v erit y ( P GI -S), P ati e nt Gl o b al I m pr essi o n of C h a n g e 
( P GI-C), a n d E ur o Q oL 5 di m e nsi o n s h e alt h st at us q u esti o n n air e ( 5 l e v el) ( E Q -5 D -5L)  
3. 2.  P A R T 2  O BJ E C TI V E S A N D E S TI M A N D S  
3. 2. 1.  
P RI M A R Y O BJ E C TI V E S  
T h e pri m ar y o bj ecti v e of P art 2 is t o c o m p ar e o v er all s ur vi v al f oll o wi n g tr e at m e nt wit h iri n ot ec a n li p os o m e 
i nj ecti o n wit h o v er all s ur vi v al f oll o wi n g tr e at m e nt wit h I V t o p ot ec a n. 
3. 2. 2.  
S E C O N D A R Y  O BJ E C TI V E S  
T h e s ec o n d ar y o bj ecti v es of P art 2 ar e t o c o m p ar e t h e f oll o wi n g b et w e e n t h e tr e at m e nt ar ms:  
•  
Pr o gr essi o n fr e e s ur vi v al ( P F S)  
•  
O bj ecti v e R es p o ns e  r at e ( O R R) 
•  
P ati e nt R e p ort e d O utc o m es ( P R O)  
•  
S af et y pr ofil e  
3. 2. 3.  
E X PL O R A T O R Y O BJ E C TI V E S  
•  
T o ex pl or e t h e bi o m ar k ers ass oci at e d wit h t oxicit y a n d effic ac y f oll o wi n g tr e at m e nt wit h iri n ot ec a n 
li p os o m e i nj ecti o n i n t his p ati e nt p o p ul ati o n 
•  
T o d escri b e t h e ass oci ati o n b et w e e n U G T 1 A 1 * 2 8 a n d ot h er U G T 1 A 1 g e n ot y p es, S N -3 8  c o nc e ntr ati o n 
(iri n ot ec a n li p os o m e i nj ecti o n tr e at e d p ati e nts o nl y) a n d s af et y 
•  
T o e v al u at e t h e p h ar m ac o ki n etics a n d t h e r el ati o ns hi p b et w e e n p h ar m ac o ki n etic ex p os ur e a n d effic ac y 
a n d s af et y f oll o wi n g iri n ot ec a n li p os o m e i nj ecti o n i n t his p ati e nt p o p ul ati o n  
•  
T o c o m p ar e t h e r at e of d e v el o p m e nt/ti m e t o d ev el o p m e nt of c e ntr al n er v o us s yst e m ( C N S) pr o gr essi o n 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 7  of 7 5  
 
a n d d ev el o p m e nt of n e w C N S m et ast as es  b et w e e n tr e at m e nt ar ms  
•  
T o c o m p ar e ti m e t o tr e at m e nt f ail ur e ( T T F) b et w e e n tr e at m e nt ar ms  
•  
T o ass ess t h e pr o p orti o n of p ati e nts wit h i m pr o v e m e nt i n s y m pt o ms as m e as ur e d b y E O R T C QL Q -
C 3 0/L C 1 3 d ys p n e a sc al e  
•  
T o ass ess t h e pr o p orti o n of p ati e nts wit h i m pr o v e m e nt i n s y m pt o ms as m e as ur e d b y t h e E O R T C QL Q -
L C 1 3 c o u g h sc al e 
•  
T o c o m p ar e t h e eff ect of iri n ot ec a n li p os o m e i nj ecti o n v er s es t o p ot ec a n o n s y m pt o ms ( ot h er t h a n 
d ys p n e a a n d c o u g h), f u ncti o ni n g a n d gl o b al h e alt h st at us as m e as ur e d b y E O R T C -QL Q -C 3 0, E O R T C QL Q -
L C 1 3 a n d E Q-5 D -5L  
3. 2. 4.  
E S TI M A N D S 
T h e pri m ar y a n d s ec o n d ar y effic ac y esti m a n ds f or p art 2 ar e d escri b e d i n t h e f oll o wi n g t a bl e.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 8  of 7 5  
 
T a bl e 1:  E sti m a n d s  
Esti m a n d  
Attri b utes  
Tre at me nt  
P o p ul ati o n  
V ari a ble ( or 
e n d p oi nt)  
I nterc urre nt e ve nts (I C Es) 
P o p ul ati o n le v el s u m m ar y  
Descri pti o n  
H a n dli n g str ate g y  
Pri mar y  
Ra n d o mize d 
iri n oteca n 
li p os o me 
i nj ecti o n or I V 
t o p oteca n 
P atie nts wit h S C L C 
w h o ha ve pr o gresse d 
o n or after plati n u m -
base d first -li ne 
t hera p y as s pecifie d 
i n t he i ncl usi o n a n d 
e xcl usi o n criteria 
( Pr ot oc ol Secti o n 4. 1 
a n d Secti o n 4 . 2), 
res pecti vel y 
O verall 
s ur vi val, 
defi ne d as t he 
ti me fr o m 
ra n d o mizati o n 
date t o t he date 
of deat h  
1. Wit h dra wal 
fr o m st u d y a n d 
l ost t o f oll o w u p 
2. Start of ne w 
a ntica ncer 
treat me nt 
3. P er ma ne ntl y 
disc o nti n uat i o n 
fr o m st u d y 
treat me nt d ue t o 
a n y reas o ns  
1. W hile ali ve strate g y  
: P atie nts wit h I C E 1 
will b e ce ns ore d at 
t heir last k n o w n ali ve 
date.  
2. Treat me nt p olic y 
strate g y: I C E 2 a n d 3 
will n ot affect t he 
assess me nt of O S.  
Me dia n O S calc ulate d wit h 
Ka pla n -Mei er ( K M) 
esti mat or f or eac h treat me nt 
gr o u p. T he differe nce i n O S 
bet wee n treat me nt gr o u ps 
will b e teste d usi n g a 
stratifie d l o g-ra n k test. T he 
hazar d rati o  ( H R) will be 
esti mate d i n a  stratifie d C o x 
pr o p orti o nal hazar ds m o del.   
Sec o n dar y  
As descri be d f or 
t he pri mar y 
esti ma n d 
a nal ysis  
As descri be d f or t he 
pri mar y esti ma n d 
a nal ysis  
Pr o gressi o n 
free s ur vi val, 
defi ne d as ti me 
fr o m 
ra n d o mizati o n 
t o first 
d oc u me nte d 
o bj ecti ve 
disease 
pr o gressi o n 
( P D) or deat h . 
1. Start of ne w 
a ntica ncer 
treat me nt 
2. P er ma ne ntl y 
disc o nti n uati o n 
fr o m st u d y 
treat me nt d ue t o 
a n y reas o ns  
3. T w o a n d m ore 
c o nsec uti vel y 
missi n g 
sc he d ule d t u m or 
assess me nts  
1. H y p ot hetical 
strate g y 
: P atie nts wit h I C E 1, 2 
a n d 3 will be ce ns ore d 
at last t u m or 
assess me nt 
d oc u me nti n g n o P D or 
deat h pri or t o I C Es  
Me dia n P F S calc ulate d wit h 
Ka pla n -Meier ( K M) 
esti mat or f or eac h treat me nt 
gr o u p. T he differe nce i n P F S 
bet wee n treat me nt gr o u ps 
will b e teste d usi n g a 
stratifie d l o g-ra n k test. T he 
hazar d rati o  ( H R) will be 
esti mate d i n a  stratifie d C o x 
pr o p orti o nal hazar ds m o del.  
Sec o n dar y  
As descri be d f or 
t he pri mar y 
esti ma n d 
a nal ysis  
As descri be d f or t he 
pri mar y esti ma n d 
a nal ysis  
O bj ecti ve 
Res p o nse Rate, 
defi ne d as 
pr o p orti o n of 
1. P er ma ne ntl y 
disc o nti n uati o n 
fr o m st u d y 
treat me nt d ue t o 
1. C o m p osite strate g y: 
P atie nts wit h B O R as 
N ot E val ua ble ( N E) 
a n d I C E 1 pri or t o 
T he  differe nce i n O R R 
bet wee n treat me nt gr o u ps 
will b e c o m pare d usi n g 
C oc hra n -Ma ntel -Hae nszel 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 1 9  of 7 5  
 
patie nts wit h a 
Best O verall 
Res p o nse 
( B O R) [ 1] 
c haracterize d 
as eit her a 
C o m plete 
Res p o nse ( C R) 
or P artial 
Res p o nse ( P R)  
a n y reas o ns  
 
disease pr o gressi o n or 
deat h will be treate d as 
n o n -res p o n der. 
met h o d, i nc or p orati n g 
a nal ysis stratificati o n fact ors 
(re gi o n a n d plati n u m 
se nsiti vit y) 
Sec o n dar y  
As descri be d f or 
t he pri mar y 
esti ma n d 
a nal ysis  
As descri be d f or t h e 
pri mar y esti ma n d 
a nal ysis  
C ha n ge fr o m 
Baseli ne t o 
Wee k 1 2 i n 
E O R T C -
C 3 0/ L C 1 3 
d ys p nea, 
re gar dless of 
pre mat ure 
st u d y treat me nt 
disc o nti n uati o n  
1. P er ma ne ntl y 
disc o nti n uati o n 
fr o m st u d y 
treat me nt pri or t o 
Wee k 1 2 visit 
d ue t o a n y 
reas o ns 
2. Start of ne w 
a ntica ncer 
treat me nt 
3. Deat h  
1. Treat me nt p olic y 
strate g y: A n y val ues 
p ost -treat me nt 
disc o nti n uati o n ( u ntil 
start ne w a ntica ncer 
treat me nt or deat h) 
will b e c ollecte d a n d 
i ncl u de d i n t he 
a nal ysis.  
2. H y p ot hetical 
strate g y: A n y val ues 
after I C E 2 a n d 3 will 
b e c o nsi dere d missi n g.  
T he differe nce of C ha n ge 
fr o m Baseli ne t o W ee k 1 2 i n 
E O R T C -C 3 0/ L C 1 3 d ys p nea 
sc ore bet wee n treat me nt 
gr o u ps will be teste d usi n g 
a n A N C O V A m o del. 
Missi n g val ues will be 
i m p ute d usi n g m ulti ple 
i m p utati o ns u n der a M A R 
ass u m pti o n.  
 
Sec o n dar y  
As descri be d f or 
t he pri mar y 
esti ma n d 
a nal ysis  
As descri be d f or t he 
pri mar y esti ma n d 
a nal ysis  
C ha n ge fr o m 
Baseli ne t o 
Wee k 1 2 i n 
E O R T C -L C 1 3 
c o u g h, 
re gar dless of 
pre mat ure 
st u d y treat me nt 
disc o nti n uati o n  
Sa me as d ys p nea  
Sa me as d ys p nea  
T he differe nce of C ha n ge 
fr o m Baseli ne t o W ee k 1 2 i n 
E O R T C -L C 1 3 c o u g h sc ore 
bet wee n treat me nt gr o u ps 
will b e teste d usi n g a n 
A N C O V A m o del. Missi n g 
val ues will be i m p ute d usi n g 
m ulti ple i m p utati o ns u n der a 
M A R ass u m pti o n.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 0  of 7 5  
 
4.  S T U D Y D E SI G N  
4. 1.  G E N E R AL D E S C RI P TI O N  
T his st u d y will b e c o n d uct e d i n t w o p arts: a n o p e n -l a b el, si n gl e-ar m, s af et y r u n -i n p eri o d ( P art 1) f oll o w e d b y a 
r a n d o miz e d p eri o d ( P art 2) ass essi n g iri n ot ec a n li p os o m e i nj ecti o n v ers us i ntr a v e n o us (I V) t o p ot ec a n i n p ati e nts 
wit h S CL C w h o h a v e pr o gr ess e d o n or aft er pl ati n u m -b as e d first li n e t h er a p y.  
P art 1  is a n o p e n-l a b el, si n gl e-ar m, s af et y r u n -i n e v al u ati o n of iri n ot ec a n li p os o m e i nj ecti o n a d mi nist er e d e v er y 2 
w e e ks, i nt e n d e d t o c o nfir m t h e a ntici p at e d P art 2 r e gi m e n ( 8 5 m g/ m 2), b as e d o n s af et y a n d pr eli mi n ar y effic ac y.  
A c o nti n g e nc y h as b e e n i ncl u d e d f or ev al u ati o n of iri n ot ec a n li p os o m e i nj ecti o n at a d os e l e v el of 7 0 m g/ m 2, 
s h o ul d t h e hi g h er d os e l e v el of 8 5 m g/ m 2 r es ult i n u n acc e pt a bl e t oxicit y.  At eit h er d os e l ev el of iri n ot ec a n 
li p os o m e i nj ecti o n, u p t o 2 4 p ati e nts will b e e nr oll e d.  T h e s af et y ass ess m e nt a n d t h e c orr es p o n di n g ex p a nsi o n 
will b e c o n d uct e d acc or di n g t o a “ 6 + 6” d esi g n f oll o w e d b y e nr ol m e nt of a n a d diti o n al 1 2 p ati e nts ( as d escri b e d 
b el o w).  P ati e nts will i niti all y b e tr e at e d wit h iri n ot ec a n li p os o m e i nj ecti o n 8 5 m g/ m 2 e v er y 2 w e eks .  D os e 
li miti n g t oxiciti es ( DL Ts) will b e e v al u at e d f or t h e first 1 2 p ati e nts tr e at e d, d uri n g t h e first 2 8 d a ys of tr e at m e nt 
( or u p t o 1 4 d a ys aft er t h e s ec o n d d os e of st u d y tr e at m e nt if t h er e is a tr e at m e nt d el a y d u e t o n o n-DL T r el at e d 
r e as o ns). 
•  
A m o n g t h e first 6 p ati e nts r ec ei vi n g iri n ot ec a n li p os o m e i nj ecti o n 8 5 m g/ m 2, (i. e. 8 5 m g/ m2 c o h ort) if ≤2 
p ati e nts ex p eri e nc e a DL T, a n ot h er 6 p ati e nts will b e e nr oll e d.  Ot h er wis e, e nr oll m e nt i nt o t h e 7 0 
m g/ m 2 c o h ort will b e i niti at e d.  
•  
A m o n g t h e first 1 2 p ati e nts r ec ei vi n g iri n ot ec a n li p os o m e i nj ecti o n 8 5 m g/ m 2, if ≤ 2 p ati e nts ex p eri e nc e 
a DL T, t his c o h ort wi ll b e ex p a n d e d b y 1 2 a d diti o n al p ati e nts.  Ot h er wis e, t h e e nr oll m e nt of t h e 8 5 
m g/ m 2 c o h ort will b e st o p p e d a n d t h e e nr oll m e nt of t h e 7 0 m g/ m 2 c o h ort will b e i niti at e d.  
T h e s a m e d esi g n will b e f oll o w e d f or t h e 7 0 m g/ m 2 c o h ort. 
 
P art 2  will b e r a n d o miz e d a n d ass ess t h e effic ac y of iri n ot ec a n li p os o m e i nj ecti o n v ers us I V t o p ot ec a n.   
A p pr oxi m at el y 4 5 0 eli gi bl e p ati e nts will b e r a n d o miz e d i n a 1: 1 r ati o b et w e e n t h e ex p eri m e nt al ar m ( Ar m A: 
b as e d o n t h e fi n di n gs of P art 1 ( 8 5 m g/ m 2 or 7 0 m g/ m 2 of iri n ot ec a n li p o s o m e i nj ecti o n)) a n d t h e c o ntr ol ar m 
( Ar m B: I V t o p ot ec a n).  P ati e nts will b e r a n d o miz e d t o t h e tr e at m e nt ar ms usi n g t h e I nt er acti v e W e b R es p o ns e 
S yst e m (I W R S) at a c e ntr al l oc ati o n.  R a n d o miz ati o n will b e str atifi e d, b as e d o n t h e f oll o wi n g f act ors:   
•  
R e gi o n ( N ort h A m eric a vs Asi a vs Ot h er)  
•  
Pl ati n u m s e nsiti vit y (s e nsiti v e vs r esist a nt).  Pr o gr essi o n wit hi n 9 0 d a ys fr o m t h e c o m pl eti o n of first -li n e 
pl ati n u m t h er a p y is c o nsi d er e d “ pl ati n u m r esist a nt” a n d t h e ot h ers “ pl ati n u m s e nsiti v e”.  
•  
P erf or m a nc e st at us ( E C O G 0 vs 1)  
•  
Pri or i m m u n ot h er a p y ( y es vs n o)  
O nl y r e gi o n ( N ort h A m eric a vs Asi a vs Ot h er) a n d pl ati n u m s e nsiti vit y (s e nsiti v e vs r esist a nt) will b e us e d f or t h e 
C CI


Statistical Analysis Plan
IPSEN Bioscience, Inc
PROTOCOL MM-398-01-03-04
Page 21 of 75
stratified efficacy analysis.
Tumor responses will be measured and recorded every 6 weeks (+/- 1 week), using the RECIST guideline (V1.1) 
(Parts 1 and 2) and Response Assessment in Neuro-Oncology (RANO) criteria for central nervous system (CNS 
lesions) in Part 2.  Patients who discontinue study treatment, for reasons other than disease progression, should 
continue to be followed-up until radiological documentation of progressive disease with the same schedule of 
tumor assessments (every 6 weeks ± 1 week) until radiological documentation of progressive disease or until the 
start of new anti-neoplastic therapy. All patients will be followed at least monthly for survival status until death, 
loss to follow-up or study closure, whichever comes first.
A quality of life assessment will be performed using the EORTC-QLQ-C30, EORTC-QLQ-LC13, PGI-C, PRI-S and EQ-
5D-5L (Part 2 only) questionnaires.  All patients reported outcome will be administered at baseline and prior to 
dosing at 6 week intervals following start of treatment, at treatment discontinuation and at the 30-day follow-up 
visit.  Adverse events (AEs) will be evaluated according to the National Cancer Institute’s (NCI) Common 
Terminology Criteria for Adverse Events version 5.0 (CTCAE Version 5.0).  For summary of AEs, events will be 
coded using the latest Medical Dictionary for Regulatory Activities (MedDRA) dictionary version at the start of 
the study.
Each part will consist of three stages: screening stage, treatment/active follow-up stage and long-term follow-up 
stage.  Once consented, patients will enter a screening stage.  Upon first dose of study treatment in Part 1 or 
randomization (Part 2), patients will enter the treatment/active follow-up stage.  Once a decision is made to 
permanently discontinue the patient from study treatment, a 30-day follow-up visit will occur and the patient 
will enter the long-term follow-up stage. It is intended that all patients in Part 1 and Part 2 will be treated until 
progressive disease or unacceptable toxicity.  After permanent discontinuation of study treatment, patients will 
return to the study site for a 30-day follow up visit.  
Figure 1:
Study Scheme
Note: ONIVYDE is also known as irinotecan liposome injection, liposomal irinotecan or nal-IRI
CCI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 2  of 7 5  
 
4. 2.  S C H E D UL E O F E V E N T S  
Sc h e d ul e of e v e nts c a n b e f o u n d i n S ecti o n 7. 1 a n d 7. 2 of t h e pr ot oc ol.  
4. 3.  C H A N G E S T O A N AL Y SI S F R O M P R O T O C OL  
N o c h a n g es t o a n al ysis fr o m pr ot oc ol.  
5.  P L A N N E D A N AL Y S E S  
T h e f oll o wi n g a n al ys es will b e p erf or m e d f or t his st u d y:  
 
P art 1:  
•  
Fi n al A n al ysis : aft er t h e l ast p ati e nt  of P art 1 fi nis h e d t h eir f oll o w-u p visit a n d t h e d at a b as e  w as cl e a n e d 
a n d g ot l oc ke d . 
P art 2:  
A n al ys es f or D at a M o nit ori n g C o m mitt e e ( D M C) m e eti n gs .   
•  
T h e first D M C will occ ur aft er t h e 3 0 t h p ati e nt is r a n d o miz e d a n d tr e at e d f or at l e ast o n e c ycl e or 
p er m a n e ntl y dis c o nti n u es st u d y dr u g, w hic h e v er occ urs first.  
I nt eri m A n al ysis:   
•  
A n I nt eri m A n al ysis f or O S f utilit y is pl a n n e d at a p pr oxi m at el y t h e 2 9 % i nf or m ati o n ti m e, aft er at l e ast 
1 0 0 O S e v e nts h a v e occ urr e d . 
•  
A s u p pl e m e nt ar y i nt eri m a n al ysis is pl a n n e d o n d at a c ollect e d 2 4 w e eks aft er t h e l ast p ati e nt h as b e e n 
r a n d o miz e d b as e d o n t h e I T T P o p ul ati o n. 
Pri m ar y  A n al ysis is pl a n n e d w h e n at l e ast 3 5 0 O S ev e nts h a v e occ urr e d i n p art 2 . 
5. 1.  D A T A M O NI T O RI N G C O M MI T T E E ( D M C)  
A n i n d e p e n d e nt D M C will b e est a blis h e d t o m o nit o r d at a i n P art 2 of t h e st u d y t o e v al u at e t h e pl a n n e d i nt eri m 
a n al ys es a n d t o m a k e r ec o m m e n d ati o n t o t h e s p o ns or b as e d o n t h e r es ults of t h e i nt eri m a n al ys es o v er 
c o nti n u ati o n or st o p p a g e of t h e st u d y. At t h e ti m e of t h e i nt eri m a n al ysis f or t h e O S f utilit y a n al ysis, O R R b y 
bli n d e d i n d e p e n d e nt c e ntr al r e vi e w ( BI C R) t u m or ass ess m e nts will b e a n al yz e d d escri pti v el y. T h e i n d e p e n d e nt 
D M C will n otif y t h e s p o ns or if pr e -s p ecifi e d crit eri a f or O R R ar e m et, as d et ail e d i n t h e D M C c h art er . All t h e 
crit eri a will b e pr e -s p ecifi e d i n t h e D M C c h art er d oc u m e nts.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 3  of 7 5  
 
5. 2.  IN T E RI M A N AL Y SI S  
A n i nt eri m O S a n al ysis f or f utilit y  will b e c o n d uct e d w h e n a p pr oxi m at el y  2 9 % of t h e pl a n n e d fi n al n u m b er of O S 
ev e nts (i. e., 1 0 0 of 3 5 0 O S e v e nts) h as b e e n o bs er v e d i n t h e  P art 2  i nt e nt-t o-tr e at (P 2 I T T) p o p ul ati o n. At t h e ti m e 
of t h e i nt eri m a n al ysis f or t h e O S f utilit y a n al ysis, O R R b y bli n d e d i n d e p e n d e nt c e ntr al r e vi e w ( BI C R) t u m or 
ass ess m e nts will b e a n al yz e d d escri pti v el y i n t h e first 2 0 0 r a n d o miz e d p ati e nts i n p art 2  (i. e. first 1 0 0 p ati e nts 
fr o m e ac h ar m).  
5. 2. 1.  
O S  F U TILI T Y A N AL Y SI S  
T o  c o ntr ol t y p e I a n d t y p e II err ors, t h e pl a n n e d i nt eri m a n al ys es f or O S will utiliz e a n al p h a a n d ( n o n -bi n di n g) 
b et a s p e n di n g f u ncti o n a p pr o ac h wit h H w a n g -S hi h -D ec a ni s p e n di n g a n d γ  p ar a m et er e q u al to  -4. 5 a n d -1 f or 
e ac h err or t y p e, r es p ecti v el y ( H w a n g, 1 9 9 0 ).  N o n-bi n di n g f or t h e f utilit y i n dic at es t h at t h e b o u n d ar y will b e 
c o nstr uct e d i n s uc h a w a y t h at it c a n b e o v err ul e d if d esir e d wit h o ut i nfl ati n g t h e t y p e I or II err or.   N o mi n al al p h a 
of 0. 0 0 0 1 will b e s p e nt at t h e s u p pl e m e nt al i nt eri m a n al ysis r e q u est e d b y F D A. Si nc e t h e b o u n d ar y is d e p e n d e nt 
o n t h e n u m b er of O S e v e nts , at t h e ti m e of fi n al a n al ysis, t h e act u al b o u n d ar y us e d will b e r e-c alc ul at e d, 
i nc or p or ati n g t h e s p e ndi n g f u ncti o n as d efi n e d, b as e d o n t h e n u m b er of act u al O S e v e nts a n d t o r efl ect t h e 
n o mi n al al p h a s p e nt at t h e s u p pl e m e nt al i nt eri m a n al ysis.   T h e P b o u n d ar y will b e us e d as t h e crit eri a f or t h e f or m al 
st atistic al i nf er e nc e. 
T h e i nt eri m a n d pri m ar y  a n al ysis s p ecific ati o ns p er t h e pl a n ar e pr o vi d e d i n t h e t a bl e b el o w:  
 
T a bl e 2:  T y p e I ( α) a n d T y p e II ( β) Err or S p e n di n g f or t h e Pl a n n e d O S A n al y s e s  
 
 
F utilit y  
Efficac y  
A n al ysis  
D  
Z b o u n d ar y  
p b o u n d ar y  
β s pe n d  H R crit 
Z b o u n d ar y  p b o u n d ar y  α s pe n d  
H R crit 
I nteri m 
a nal ysis 
1 0 0  -0. 2 7 6  
0. 6 0 9  
0. 0 2 5  
1. 0 5 7  
-3. 1 8 1  
0. 0 0 1  
0. 0 0 1  
0. 5 2 9  
P ri mar y 
3 5 0  1. 9 7 6  
0. 0 2 5  
0. 1 3  
0. 8 1 0  
-1. 9 6 7  
0. 0 2 5  
0. 0 2 5  
0. 8 1 0  
D = # of O S e v e nts at a n al ysis. Z b o u n d ar y is t h e critic al t est st atistic v al u e at w hic h f utilit y ( < Z) or effic ac y ( > Z) w o ul d 
b e c o ncl u d e d.  P b o u n d ar y is t h e critic al o n e-si d e d p-v al u e t hr es h ol d f or t h e c o m p aris o n ( > p f o r f utilit y, < p f or 
effic ac y). H R crit is t h e o bs er v e d h az ar d r ati o t hr es h ol d ( > H R f or f utilit y, < H R f or effic ac y). 
T h e r es ults of t h e i nt eri m a n al ys e s will b e b as ed o n t h e u n bli n d e d tr e at m e nt gr o u ps ( o p e n -l a b el st u d y).  T h e list 
of o ut p uts pr o vi d e d wit h t h e f ull s et of o ut p ut t e m pl at es ( pl a n n e d f or t h e pri m ar y  a n al ysis) will hi g hli g ht w hic h of 
t h es e o ut p uts will als o b e pr o vi d e d f or t h e i nt eri m a n al ysis.  D eri v ati o n s a n d d efi niti o ns f or t h e i nt eri m a n al ysis 
will b e b as e d o n t h os e r e q uir e d f or t h e pri m ar y  a n al ysis c o nt ai n e d i n t his a n al ysis pl a n, u nl ess d e vi ati o ns ar e 
st at e d wit hi n t h e t ext. 
5. 2. 2.  
O R R  A N AL Y SI S  
O R R b y bli n d e d i n d e p e n d e nt c e ntr al r e vi e w ( BI C R) t u m or ass ess m e nts will b e a n al yz e d d escri pti v el y i n t h e first 
2 0 0 r a n d o miz e d p ati e nts i n p art 2  (i. e. first 1 0 0 p ati e nts fr o m e ac h ar m). A n esti m at e of t h e O R R a n d its 9 5 % CI 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 4  of 7 5  
 
will b e c alc ul at e d f or e ac h tr e a t m e nt ar m. A n esti m at e of D ur ati o n of R es p o ns e ( D O R ) wit h 9 5 % CI will b e 
r e p ort e d f or e ac h ar m t o s u p p ort t h e O R R a n al ysis. Ti m e t o o bj ecti v e r es p o ns e wit h 9 5 % CI will als o b e r e p ort e d 
f or e ac h ar m. T h e i n d e p e n d e nt D M C will r e vi e w t h e effic ac y a n d s af et y d at a a n d n otif y t h e s p o ns or if t h e crit eri a 
f or O R R ar e m et. All t h e crit eri a will b e pr e-s p ecifi e d i n t h e D M C c h art er d oc u m e nts.  
S e nsiti vit y a n al ysis will b e p erf or m e d f or O R R b y BI C R acc or di n g t o R E CI S T v 1. 1 g ui d eli n e ( E. A. Eis e n h a u er a 2 0 0 9) 
a n d R A N O -B M crit eri a f or C N S l esi o ns i n t h e p er pr ot oc ol p o p ul ati o n ( P P) f or e ac h tr e at m e nt ar m. 
S u p pl e m e nt ar y a n al ysis f or O R R usi n g BI C R ass ess m e nts will als o b e p erf or m e d by  c o m bi ni n g p ati e nts at t h e 
7 0 m g / m2 d os e l ev el i n p art 1 wit h p art 2 Iri n ot ec a n p ati e nts. A n o t h er s u p pl e m e nt ar y a n al ysis will b e d o n e f or 
O R R usi n g t h e i n v esti g at or ass ess m e nt r es p o ns e d at a  i n t h e first 1 0 0 p art 2 p ati e nts r a n d o miz e d i nt o Iri n ot ec a n 
li p os o m e i nj ecti o n ar m a n d als o i n t his p ati e nt c o h ort c o m bi n e d wit h p ati e nts at 7 0 m g/ m2 d os e l ev el  i n p art 1. 
A n a d diti o n al s e nsiti vit y a n al ysis will b e p erf or m e d f or c o nfir m e d r es p o ns e f or e ac h tr e at m e nt ar m b y BI C R. B est 
o v er all r es p o ns e n e e ds t o b e d eri v e d b as e d o n c o nfir m e d c o ns ec uti v e C R a n d/ or P R p er t h e BI R C’s ass ess m e nt at 
l e ast 4 w e e ks l at er wit h t h e crit eri a listi n g i n t a bl e 3 of R E CI S T v 1. 1 ( E. A. Eis e n h a u er a 2 0 0 9) i n A p p e n dix 6. 
A n ot h er s e nsiti vit y a n al ysis will b e p erf or m e d f or c o nfir m e d r es p o ns e b y t h e i n v esti g at or b as e d o n c o nfir m e d 
c o ns ec uti v e C R a n d/ or P R usi n g t h e s a m e i m a gi n g t ec h ni q u e  at l e a st 4 w e eks l at er.  
S af et y A n al ysis f or I nt eri m A n al ysis  
T h e s af et y a n al ysis will b e p erf or m e d as p er s ecti o n 2 0  o n t h e  first 2 0 0 p ati e nts i n t h e s af et y p o p ul a ti o n a n d als o 
i n t h e s af et y p o p ul ati o n f or all p art 2 p ati e nts e nr oll e d b y t h e d at a c ut-off d at e f or t his i nt eri m a n al ysis . 
S u b gr o u p a n al ysis f or O R R  
S u b gr o u p a n al ysis o utli n e d i n s ecti o n 8. 5 will b e p erf or m e d f or t his i nt eri m a n al ysis f or O R R b y BI C R a n d 
i n v esti g at or ass ess m e nt f or t h e first 1 0 0 p ati e nts e nr oll e d i n e ac h tr e at m e nt ar m i n p art 2. 
5. 3.  S U P PL E M E N T AL IN T E RI M A N AL Y SI S  
A s u p pl e m e nt al i nt eri m a n al ysis will b e c o n d uct e d o n d at a c oll ect e d 2 4 w e eks aft er t h e l ast p ati e nt h as b e e n 
r a n d o miz e d b as e d o n t h e I T T p o p ul ati o n . All a n al ysis t h at occ urr e d f or t h e i nt eri m O S a n al ysis, p er s ecti o n 5. 2. 2 , 
will b e d o n e f or t h e s u p pl e m e nt al i nt eri m a n al ysis b ut o n all t h e p art 2 r a n d o miz e d p ati e nts r at h er t h a n t h e first 
2 0 0 r a n d o miz e d p ati e nts.  
N o mi n al al p h a of 0. 0 0 0 1 will b e s p e nt  f or t h e d escri pti v e O S a n al ysis at t his I A . 
5. 4.  P RI M A R Y  A N AL Y SI S  
All pl a n n e d a n al ys es i d e ntifi e d i n t his S A P will b e p erf or m e d b y I Q VI A Bi ost atistics f oll o wi n g S p o ns or 
A ut h oriz ati o n of t his St atistic al A n al ysis Pl a n, D at a b as e L oc k, S p o ns or A ut h oriz ati o n of A n al ysis S ets.  T h e pri m ar y 
a n al ysis is pl a n n e d w h e n at l e ast 3 5 0 O S ev e nts h a v e occ urr e d i n P art 2.  
A n al ysis of ex pl or at or y bi o m ar k er e n d p oi nt a n d P K a n al ysis will b e p erf or m e d a n d r e p ort e d s e p ar at el y.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 5  of 7 5  
 
6.  A N AL Y SI S S E T S  
A gr e e m e nt a n d a ut h oriz ati o n of p ati e nt s i ncl u d e d/ excl u d e d fr o m e ac h a n al ysis s et will b e c o n d uct e d pri or t o t h e 
d at a b as e l oc k .  
6. 1.  A LL P A TI E N T S E N R OLL E D P O P UL A TI O N  
T h e all p ati e nt s e nr oll e d ( E N R) s et will c o nt ai n all p ati e nt s w h o pr o vi d e i nf or m e d c o ns e nt f or t his st u d y.  
6. 2.  P A R T 1  S A F E T Y P O P UL A TI O N  
P ati e nts e nr oll e d a n d tr e at e d wit h at l e ast o n e d os e of iri n ot ec a n li p os o m e i nj ecti o n will c o m pris e t h e P art 1 
S af et y P o p ul ati o n.  
6. 3.  P A R T 1  P K  P O P UL A TI O N  
All iri n ot ec a n li p os o m e i nj ecti o n tr e at e d P art 1 p ati e nts w h o r ec ei v e d at l e ast o n e d os e a n d h a d at l e ast o n e 
pl as m a c o nc e ntr ati o n will c o m pris e t h e P art 1 P K P o p ul ati o n.  
6. 4.  P A R T 2  S A F E T Y P O P UL A TI O N  
P ati e nts r a n d o miz e d  a n d tr e at e d wit h at l e ast o n e d os e of  st u d y m e dic ati o n will c o m pris e t h e P art 2 S af et y 
P o p ul ati o n.   P ati e nts will b e a n al yz e d acc or di n g t o t h e st u d y m e dic ati o n r ec ei v e d.  
6. 5.  P A R T 2  IN T E N T -T O -T R E A T P O P UL A TI O N (I T T) 
P ati e nts r a n d o miz e d i n P art 2  will c o m pris e t h e  I nt e nt-t o-Tr e at  P o p ul ati o n.  P ati e nts will b e a n al yz e d acc or di n g 
t o t h e st u d y m e dic ati o n pl a n n e d. 
6. 6.  P A R T 2  P E R P R O T O C OL P O P UL A TI O N ( P P) 
P ati e nts fr o m t h e P art 2 I nt e nt -t o-Tr e at P o p ul ati o n wit h o ut a n y m aj or pr ot oc ol d evi ati o ns  f oll o wi n g m a n u al 
m e dic al  r evi e w will c o m pris e t h e P er Pr ot oc ol  P o p ul ati o n. Pri or t o  e ac h  d at a b as e l oc k a d at a r evi e w m e eti n g will 
b e h el d i n or d er t o fi n aliz e t h e P P p o p ul ati o n . M or e i nf or m ati o n will b e d oc u m e nt e d i n t h e pr ot oc ol d evi ati o n 
pl a n .  
Pr ot oc ol d evi ati o ns ar e c oll ect e d t hr o u g h C T M S syst e m, c ritic al a n d m aj or pr ot oc ol vi ol ati o n t h at c o ul d excl u d e a 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 6  of 7 5  
 
p ati e nt fr o m t h e p o p ul ati o n ar e, b ut n ot li mit e d t o t h e f oll o wi n g:  
- 
P ati e nts w h o di d n ot s atisfy i ncl usi o n a n d excl usi o n crit eri a  
- 
P ati e nts r ec ei v e d i nc orr ect tr e at m e nt ar m  
- 
Scr e e ni n g t u m or sc a n a n d R E CI S T 1. 1 ass ess m e nt w as n ot p erf or m e d.  
- 
P ost b as eli n e t u m or sc a n a n d R E CI S T 1. 1 ass ess m e nt w as n ot p erf or m e d.  
6. 7.  P A R T 2  P K  P O P UL A TI O N  
All iri n ot ec a n li p os o m e i nj ecti o n tr e at e d P art 2 p ati e nts w h o r ec ei v e d at l e ast o n e d os e a n d h a d at l e ast o n e 
pl as m a c o nc e ntr ati o n a n d n o m aj or pr ot oc ol d evi ati o ns aff ecti n g P K v ari a bl es will c o m pris e t h e P art 2 P K 
P o p ul ati o n.  
7.  G E N E R AL C O N SI D E R A TI O N S  
7. 1.  R E F E R E N C E S T A R T D A T E A N D S T U D Y D A Y  
St u d y D a y will b e c alc ul at e d fr o m t h e r ef er e nc e st art d at e  a n d will b e us e d t o s h o w st art/ st o p d a y of 
ass ess m e nts a n d e v e nts.  
T h e f oll o wi n g r ef er e nc e d at es will b e us e d i n t his st u d y:  
1)  I nf or m e d c o ns e nt d at e f or b ac k gr o u n d d at a 
2)  First d os e d at e f or s af et y a n al ysis a n d P art 1 effic ac y.  T h e first d os e of st u d y m e dic ati o n is t a k e n fr o m 
t h e ex p os ur e p a g e  of t h e C R F wit h t h e st art d at e a n d ti m e of i nf usi o n, ( d a y 1 is t h e d a y of t h e first d os e 
of st u d y m e dic ati o n) . F or t u m or ass ess m e nts i n P art 2 t h e first d os e d at e is als o us e d. 
3)  R a n d o miz ati o n d at e f or P art 2 effic ac y  a n al ysis  
 
•  
If t h e d at e of t h e e v e nt is o n or aft er t h e r ef er e nc e d at e t h e n:  
St u d y D a y = ( d at e of e v e nt –  r ef er e nc e d at e) + 1. 
 
•  
If t h e d at e of t h e e v e nt is pri or t o t h e r efer e nc e d at e t h e n:  
St u d y D a y = ( d at e of e v e nt –  r ef er e nc e d at e). 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 7  of 7 5  
 
7. 2.  B A S ELI N E  
U nl ess ot h er wis e s p ecifi e d, b as eli n e is d efi n e d as t h e l ast n o n -missi n g m e as ur e m e nt t a k e n pri or t o r ef er e nc e 
st art d at e (i ncl u di n g u nsc h e d ul e d ass ess m e nts). F or t h e P R O e n d p oi nts, b a s eli n e is d efi n e d as t h e l ast o bs er v e d 
m e as ur e m e nt pri or t o t h e first dr u g a d mi nistr ati o n.  I n t h e c as e w h er e t h e l ast n o n-missi n g m e as ur e m e nt a n d t h e 
r ef er e nc e st art d at e c oi nci d e, t h at m e as ur e m e nt will b e c o nsi d er e d pr e -b as eli n e , b ut Ad v ers e E v e nts ( A Es) a n d 
m e dic ati o ns c o m m e nci n g o n t h e r ef er e nc e st art d at e will b e c o nsi d er e d p ost-b as eli n e . 
7. 3.  R E T E S T S , U N S C H E D UL E D V I SI T S A N D E A RL Y T E R MI N A TI O N D A T A  
I n g e n er al, f or b y-visit s u m m ari es, d at a r ec or d e d at t h e n o mi n al visit will b e pr es e nt e d. U nsc h e d ul e d 
m e as ur e m e n ts will n ot b e i ncl u d e d i n b y-visit s u m m a ri es b ut will b e us e d f or t h e l a b or at or y s hift t a bl es .  
E arl y t er mi n ati o n d at a will b e m a p p e d t o t h e n ext a v ail a bl e visit n u m b er f or b y -visit s u m m ari es.  
Listi n gs will i ncl u d e sc h e d ul e d, u nsc h e d ul e d, r et est a n d e arl y  disc o nti n u ati o n d at a.  
7. 4.  W I N D O WI N G C O N V E N TI O N S  
F or s u m m ari es of P R O d at a, ass ess m e nts will b e assi g n e d t o c alc ul at e d visit wi n d o ws.  T h e ti m e wi n d o ws will b e 
ex h a usti v e s o t h at d at a r ec or d e d at a n y ti m e p oi nt h a v e t h e p ot e nti al t o b e s u m m ariz e d.  I ncl usi o n wit hi n t h e 
visit wi n d o w will b e b as e d o n t h e act u al d at e a n d n ot t h e i nt e n d e d d at e of t h e visit.  T h e wi n d o w f or t h e visits 
f oll o wi n g b as eli n e will b e c o nstr uct e d i n s uc h a w a y t h at t h e u p p er li mit of t h e i nt er v al f alls h alf w a y b et w e e n t h e 
t w o visits.  T h e crit eri a t h at will b e us e d t o d efi n e t h e P R O ass ess m e nt visit ar e dis pl a y e d i n t h e t a bl e b el o w.  
 
T a bl e 3:  Vi sit Wi n d o wi n g  
Vi sit  
Wi n d o w  
B as eli n e  
St u d y d a y  aft er First D os e D at e  ≤1  
W e e k 6  
1 < St u d y d a y  aft er First D os e D at e  ≤ 6 4  
W e e k 1 2  
6 4  < St u d y d a y  aft er First D os e D at e  ≤ 1 0 6  
W e e k 1 8  
1 0 6  < St u d y d a y  aft er First D os e D at e  ≤ 1 4 8  
W e e k 2 4  
1 4 8  < St u d y d a y  aft er First D os e D at e  ≤ 1 9 0  
W e e k 3 0  
1 9 0  < St u d y d a y  aft er First D os e D at e  ≤ 2 3 2  
If t h er e is m or e t h a n o n e v al u e p er p ati e nt wit hi n a n ass ess m e nt wi n d o w t h e n t h e cl os est t o t h e pl a n n e d st u d y 
d a y v al u e s h o ul d b e s u m m ariz e d, or t h e e arli er i n t h e e v e nt t h e v al u es ar e e q ui dist a nt fr o m t h e pl a n n e d st u d y 
d a y.  T h e v al u e at a gi v e n ti m e p oi n t will b e missi n g if n o ass ess m e nt w as r e p ort e d wit hi n t h e s p ecifi e d 
ass ess m e nt wi n d o w ar o u n d t h e pl a n n e d st u d y d a y.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 8  of 7 5  
 
7. 5.  S T A TI S TI C AL T E S T S  
P art 1  of t h e st u d y will ass ess t h e s af et y a n d t ol er a bilit y of iri n ot ec a n li p os o m e i nj ecti o n m o n ot h er a p y.  N o 
f or m al i nf er e nti al a n al ys es will d et er mi n e s af et y a n d t ol er a bilit y. 
P art 2  of t h e st u d y, t h e r a n d o miz e d o p e n -l a b el p orti o n of t h e st u d y, w h er e th e pri m ar y h y p ot h esis is t o t est 
w h et h er O S is i ncr e as e d i n p ati e nts tr e at e d wit h iri n ot ec a n li p os o m e i nj ecti o n.  C o m p aris o n s b et w e e n t h e t w o 
tr e at m e nt gr o u ps will b e d o n e at a l ev el of si g nific a nc e c o ntr oll e d at t h e o n e-si d e d 0. 0 2 5 l e v el.  T h e s ec o n d ar y 
e n d p oi nts will als o b e t est e d at t h e o n e -si d e d 0. 0 2 5 l e v el  
Ot h er c o m p aris o ns will b e d o n e at t h e si g nific a nc e l e v el of  ( 5 %); c o nfi d e nc e i nt er v als will b e 9 5 % a n d  all t ests will 
b e t w o -si d e d. 
7. 6.  C O M M O N C AL C UL A TI O N S  
F or q u a ntit ati v e m e as ur e m e nts, c h a n g e fr o m b as eli n e will b e c alc ul at e d as:  
•  
T est V al u e at Visit X –  B as eli n e V al u e  
T h e p erc e nt c h a n g e fr o m b as eli n e will b e c alc ul at e d as: 
•  
( T est V al u e at Visit X –  B as eli n e V al u e)/ B as eli n e V al u e  
7. 7.  S O F T W A R E V E R SI O N  
All a n al ys es will b e c o n d uct e d usi n g S A S v ersi o n 9. 4 .  
8.  S T A TI S TI C AL C O N SI D E R A TI O N S  
8. 1.  A DJ U S T M E N T S F O R C O V A RI A T E S  A N D F A C T O R S T O B E IN CL U D E D I N A N AL Y S E S  
T h e f oll o wi n g c o v ari at es a n d f act ors ar e us e d as str at a i n t h e a n al ys es. 
•  
R e gi o n: N ort h A m eric a, Asi a, Ot h er  
•  
Pl ati n u m S e nsiti vit y: S e nsiti v e, R esist a nt  
8. 2.  M UL TI C E N T E R S T U DI E S  
T his st u d y will b e c o n d uct e d b y m ulti pl e i n v esti g at ors at m ulti pl e c e nt ers i nt er n ati o n all y , ar o u n d 1 3 7 sit es will 
p artici p at e .  R a n d o miz ati o n t o tr e at m e nt ar ms is str atifi e d b y f act ors i ncl u di n g r e gi o n.   
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 2 9  of 7 5  
 
W h e n s p ecifi e d, st atistic al a n al ysis will b e a dj ust e d f or g e o gr a p hic r e gi o n.   
8. 3.  M I S SI N G D A T A 
Missi n g s af et y d at a will n ot b e i m p ut e d.  
Missi n g effic ac y d at a will b e h a n dl e d as d escri b e d i n  s ecti o n 1 9  of t his a n al ysis pl a n.  
8. 4.  M UL TI PL E C O M P A RI S O N S /  M UL TI PLI CI T Y  
K ey s ec o n d ar y e n d p oi nts i n P art 2, w hic h ar e: P F S, O R R, P R O e n d p oi nts (i ncl u di n g c h a n g e fr o m b as eli n e f or 
d ys p n e a a n d c h a n g e fr o m b as eli n e f or c o u g h ). 
K ey s ec o n d ar y e n d p oi nts will b e t est e d n o m or e t h a n o nc e. T o c o ntr ol t h e o v er all Ty p e I err or r at e f or t h e 
c o m p aris o n b et w e e n iri n ot ec a n li p os o m e i nj ecti o n a n d t o p ot ec a n f or t h e pri m ar y a n d s ec o n d ar y e n d p oi nts, a 
hi er arc hic al a p pr o ac h will b e a p pli e d t o t h e st atistic al t esti n g of t h e s ec o n d ar y e n d p oi nts. T h e st atistic al 
i nf er e nc e f or t h e first s ec o n d ar y e n d p oi nt of P F S will o nl y b e p erf or m e d if t h e pri m ar y e n d p oi nt ( O S), is 
st atistic all y si g nific a nt. T h e s ec o n d s ec o n d ar y e n d p oi nt of O R R will o nl y b e t est e d if P F S is st atistic all y si g nific a nt. 
Si mil arl y, t h e P R O e n d p oi nts will o nl y b e t est e d if O R R is st atistic all y si g nific a nt. A n y p ar a m et er w hic h is n ot 
st atistic all y si g nific a nt will b e r e g ar d e d as d escri pti v e a n d ex pl or at or y. 
W h er e tr e at m e nt c o m p aris o ns ar e b y str atifi e d a n al ysis, str atific ati o n f act ors will b e r e gi o n a n d pl ati n u m 
s e nsiti vit y wit h cl assific ati o n acc or di n g t o t h e r a n d o miz ati o n d esi g n ati o n.  
If all O S, P F S a n d O R R ar e f o u n d si g nific a nt, t h e n t h e d ys p n e a a n d c o u g h s y m pt o ms will b e t est e d usi n g t h e 
B e nj a mi ni -H oc h b er g c orr ecti o n ( B e nj a mi ni & H oc h b er g, 1 9 9 5) f or a o n e -si d e d α l e v el t esti n g of t w o pl a n n e d 
c o m p aris o ns (t w o sy m pt o ms fr o m t h e E O R T C-QL Q , d ys p n e a a n d c o u g h ).  A dj ust e d p-v al u es will b e r e p ort e d, 
usi n g S A S P R O C M UL T T E S T wit h F D R o pti o n or e q ui v al e nt al g orit h m.  A n y p ar a m et er w hic h is n ot st atistic all y 
si g nific a nt will b e r e g ar d e d as d escri pti v e a n d ex pl or at or y.  
T h e B e nj a mi ni & H oc h b er g pr oc e d ur e will b e a p pli e d t o c o ntr ol f or m ulti plicit y of t h e st atistic al t ests.  T h e d et ails 
of t h e pr oc e d ur e ar e as f oll o ws:  
•  
P -v al u es of t h e 2  t ests will b e s ort e d i n asc e n di n g or d er: 
o  
L et p 1, p2 b e t h e r a w p -v al u es o bt ai n e d w h e n t esti n g t h e 2  c o m p aris o ns r el at e d t o  t h e t w o 
E O R T C -QL Q sy m pt o ms  
o  
L et p ( 1)< p ( 2) b e t h e c orr es p o n di n g or d er e d p -v al u es.  T h e F D R -a dj ust e d p -v al u es 𝑝(i) ar e o bt ai n e d 
as f oll o ws w h er e m = 2  i n o ur p artic ul ar t esti n g sc h e m e: 
 
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 0  of 7 5  
 
o  
Usi n g P R O C M UL T T E S T wit h o pti o n F D R i n S A S t h e a dj ust e d p -v al u es will b e o bt ai n e d.  T h es e 
a dj ust e d p -v al u es will t h e n b e c o m p ar e d t o t h e l e v el of t y p e -1 err or us e d f or t esti n g O S  as 
d efi n e d b y t h e al p h a -s p e n di n g f u ncti o n. 
8. 5.  E X A MI N A TI O N O F S U B G R O U P S  
S u b gr o u p a n al ys es will b e c o n d uct e d as st at e d i n t h e s u b gr o u p a n al ysis s ecti o ns  f or P art 2 o nl y. It s h o ul d b e 
n ot e d t h at t h e st u d y w as n ot d esi g n e d t o d et ect tr e at m e nt diff er e nc es wit h hi g h st atistic al p o w er wit hi n 
s u b gr o u ps R es ults will b e pr es e nt e d if all t h e s u b c at e g ori es will b e e q u al t o or m or e t h a n 5 p ati e nts . 
T h e f oll o wi n g s u b gr o u ps will  b e ass ess e d a n d  d escri b e d wit hi n t h e s u b gr o u p  a n al ysis s ecti o ns : 
o  
G e n d er:  
 
F e m al e  
 
M al e  
o  
A g e ( y e ars):  
 
< 6 5  
 
≥6 5  
o  
R ac e i n 2 c at e g ori es:  
 
Bl ac k/ Afric a n A m eric a n  
 
All ot h er r ac es c o m bi n e d ( A m eric a n I n di a n/ Al ask a N ati v e, Asi a n, N ati v e H a w aii a n/ Ot h er 
P acific Isl a n d ers, or W hit e)  
o  
R e gi o n:  
 
N ort h A m eric a  
 
Asi a  
 
Ot h er  
o  
C orr ect e d Pl ati n u m S e nsiti vit y  
 
S e nsiti v e  
 
R esist a nt  
o  
Br ai n m et ast as es dis e as e at b as eli n e  
 
Y es  
 
N o  
o  
Pri or i m m u n ot h er a p y  
 
Y es  
 
N o  
T h e f oll o wi n g s u b gr o u p will als o b e ass ess e d as a s e nsiti vit y a n al ysis : 
o  
Ori gi n al Pl ati n u m S e nsiti vit y :  
 
S e nsiti v e  
 
R esist a nt  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 1  of 7 5  
 
9.  O U T P U T P R E S E N T A TI O N S  
A p p e n dix 1 s h o ws c o n v e nti o ns f or pr es e nt ati o n of d at a i n o ut p uts.  
T h e t e m pl at es pr o vi d e d wit h t his S A P d escri be t h e pr es e nt ati o ns f or t his st u d y a n d t h er ef or e t h e f or m at a n d 
c o nt e nt of t h e s u m m ar y t a bl es, fi g ur es a n d listi n gs t o b e p r o vi d e d b y I Q VI A Bi ost atistics.  
1 0.  D I S P O SI TI O N A N D W I T H D R A W AL S 
All p ati e nt s w h o pr o vi d e i nf or m e d c o ns e nt will b e acc o u nt e d f or i n t his s t u d y.  
F or P art 1 a n d P art 2 of t h e st u d y, t h e n u m b er a n d p erc e nt a g e  of p ati e nt s scr e e n e d, r a n d o miz e d ( P art 2 o nl y), 
tr e at e d a n d w h o disc o nti n u e d fr o m st u d y a n d tr e at m e nt, as w ell as t h eir r e as o ns f or disc o nti n u ati o n will b e 
s u m m ariz e d b y p art a n d by tr e at m e nt gr o u p. T h e n u m b er of p ati e nts  i n l o n g t er m f oll o w-u p will als o b e i ncl u d e d.  
P ati e nts w h o disc o nti n u e d st u d y or tr e at m e nt d u e t o C O VI D -1 9 will als o b e s u m m ariz e d.  
P ati e nt  dis p ositi o n a n d wit h dr a w als will b e pr es e nt e d f or t h e all p ati e nt  e nr oll e d  set.  
1 1.  P R O T O C OL D E VI A TI O N S  
All i nst a nc es of d e vi ati o ns fr o m t h e pr ot oc ol will b e d oc u m e nt e d i n t h e Cli nic al Tri al M a n a g e m e nt S yst e m ( C T M S) 
l o g w hic h will i ncl u d e a n y pr o gr a m m a bl e d evi ati o ns . A d e vi ati o n occ urs w h e n a n i n v esti g at or sit e, or st u d y 
p ati e nt , d o es n ot a d h er e t o pr ot oc ol sti p ul at e d r e q uir e m e nts. D e vi ati o ns will b e ass ess e d a n d c at e g oriz e d as 
eit h er M aj or or Mi n or. T h e Pr ot oc ol D evi ati o n l o g m ust b e a p pr o v e d b y I ps e n pri or t o d at a b as e l oc k.  
B ot h M aj or a n d Mi n or pr ot oc ol d evi ati o ns i n t h e C T M S l o g f or p ati e nts  i n t h e s af et y p o p ul ati o n will b e 
s u m m ariz e d, f or p art 1 a n d p art 2 s e p ar at el y, dis pl a yi n g t h e n u m b er a n d p erc e nt a g e of p ati e nts  wit h a n y 
pr ot oc ol d evi ati o n as w ell as t h e c at e g ori es f or t h e d e vi ati o ns. All d evi ati o ns r es ulti n g i n s u bj ects excl u d e d fr o m 
t h e P P p o p ul ati o n will als o b e s u m m ariz e d s e p ar at el y. 
All pr ot oc ol d evi ati o ns will b e list e d.  A s e p ar at e listi n g will b e pr e p ar e d f or p ati e nts wit h pr ot oc ol d evi ati o ns 
r el at e d t o t h e C O VI D-1 9 p a n d e mic.  A s e p ar at e listi n g will als o b e pr e p ar e d f or C O VI D -1 9 r el at e d st u d y disr u pti o n 
b y s u bj ect a n d b y i n v esti g ati o n al sit e as r ec or d e d i n t h e C R F.    
1 2.  D E M O G R A P HI C A N D O T H E R  B A S ELI N E C H A R A C T E RI S TI C S  
D e m o gr a p hic d at a a n d b as eli n e c h ar act eristics will b e pr es e nt e d f or t h e S af et y P art 1 a n d t h e I nt e nt-t o-Tr e at  f or 
t h e P art 2  of t h e st u d y s e p ar at el y.   T h e diff er e nt s u b gr o u p v ari a bl es will b e s u m m ariz e d f or P art 2 wit hi n t h e 
s a m e t a bl e. 
N o st atistic al t esti n g will b e c arr i e d o ut f or d e m o gr a p hic or b as eli n e c h ar act eristics.  
T h e f oll o wi n g d e m o gr a p hic a n d ot h er b as eli n e c h ar act eristics will b e r e p ort e d f or t his st u d y:  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 2  of 7 5  
 
D e m o gr a p hics : 
o  
A g e ( y e ars) - c alc ul at e d r el ati v e t o d at e of c o ns e nt  
o  
S ex  
o  
R ac e ( A m eric a n I n di a n or Al ask a N ati v e, Asi a n, Bl ac k or Afric a n A m erica n, N ati v e H a w aii a n o r Ot h er 
P acific Isl a n d ers, W hit e, Ot h er , N ot R e p ort e d) 
o  
Et h nicit y  ( His p a nic or L ati no, N ot His p a nic or L ati n o, N ot R e p ort e d/ U n k n o w n)  
o  
W ei g ht ( k g)  at scr e e ni n g  
o  
H ei g ht (c m)  
o  
B MI ( k g/ m 2) 
o  
B as eli n e E C O G st at us  
o  
R e gi o n  
o  
U G T 1 A 1 * 2 8 all el e st at us ( h o m oz y g o us T A 7/ 7 –  Y es  or N o)  
Dis e as e Hist or y:  
o  
Ti m e si nc e di a g n osis  ( w e e ks) 
o  
Ti m e si nc e m ost r ec e nt pr o gr essi o n d at e ( w e eks) 
o  
Dis e as e St a g e at Di a g n osis (li mit e d, ext e nsi v e)  
o  
Pl ati n u m S e nsiti vit y (s e nsiti v e, r esist a nt)  
o  
Pri or I m m u n ot h er a p y ( y es, n o)  
o  
Pri or C h e m ot h er a p y ( y es, n o)  
o  
S y m pt o m atic fr o m S m all C ell L u n g C a nc er ( d ys p n e a, c o u g h, f ati g u e, p ai n, w ei g ht  l ost i n t h e l ast 6 0 
d a ys, ot h er, n o)  
o  
Dis e as e st at us (l oc all y a d v a nc e d, m et ast atic)  
o  
Dis e as e Sit e p er Or g a n ( p ati e nts m a y h a v e m or e t h a n o n e)  
P ati e nt Hist or y  
o  
Pri or M e dic al C o n diti o n  ( y es, n o) 
o  
P ast S ur gic al Pr oc e d ur e ( y es, n o)  
o  
P ast R a di ot h er a p y f or S m all C ell L u n g C a nc er ( y es, n o)  
o  
P ast C a nc er Tr e at m e nt R e gi m e ns f or S m all C ell L u n g C a nc er ( y es, n o)  
o  
T o b acc o us e ( n ev er, c urr e nt, f or m er)  
o  
Ti m e si nc e st art of t o b acc o us e  ( m o nt hs) 
o  
Ti m e si nc e st o p of t o b acc o us e ( m o nt hs) 
o  
D ur ati o n of t o b acc o us e ( m o nt hs) 
 
T h e f oll o wi n g p ati e nt c h ar act eristics will b e s u m m ariz e d b y pl ati n u m s e nsiti vit y ( pl ati n u m s e nsiti v e a n d pl ati n u m 
r esist a nt) i n all p art 2 p ati e nts  f or e ac h tr e at m e nt gr o u p. 
o  
A g e ( y e a rs) - c alc ul at e d r el ati v e t o d at e of c o ns e nt  
o  
S ex  
o  
R ac e ( A m eric a n I n di a n or Al ask a N ati v e, Asi a n, Bl ac k or Afric a n A m eric a n, N ati v e H a w aii a n or Ot h er 
P acific Isl a n d ers, W hit e, Ot h er, N ot R e p ort e d)  
o  
Dis e as e st at us (l oc all y a d v a nc e d, m et ast atic)  
o  
E C O G ( 0, 1)  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 3  of 7 5  
 
o  
O n Tr e at m e nt at c ut -off ( Y, N)  
1 2. 1.  D E RI V A TI O N S  
o  
B MI ( k g/ m 2) = w ei g ht ( k g)/ h ei g ht ( m)2 
o  
Ti m e si nc e di a g n osis  ( w e e ks) = ( (d at e of i nf or m e d c o ns e nt –  i niti al di a g n osis d at e) + 1)/ 7 
o  
Ti m e si nc e m ost r ec e nt pr o gr essi o n d at e  ( w e eks) = ( (d a t e of i nf or m e d c o ns e nt –  d at e o f r ec e nt 
pr o gr essi o n) + 1 )/ 7 
o  
Ti m e si nc e st art of t o b acc o us e  ( m o nt hs) = ( (i nf orm e d c o ns e nt d at e - t o b acc o st art d at e) + 
1 )/ 3 0. 4 3 75  
o  
Ti m e si nc e st o p of t o b acc o us e  ( m o nt hs) =  
 
if st o p d at e is pri or t o c o ns e nt d at e t h e n = ((i nf or m e d c o ns e nt d at e –  t o b acc o st o p d at e) + 
1 )/ 3 0. 4 3 75  
 
if st o p d at e is aft er c o ns e nt d at e t h e n = (t o b acc o st o p d at e –  i nf or m e d c o ns e nt 
d at e )/ 3 0. 4 3 75  
o  
D ur ati o n of t o b acc o us e  ( m o nt hs) = ( (t o b acc o st o p d at e –  t o b acc o st art d at e) + 1)/ 3 0. 4 3 75  
I m p ut ati o n f or p arti al t o b acc o us e d at es a n d r ec e nt pr o gr essi o n is d escri b e d i n Err or! R ef er e nc e s o urc e n ot 
f o u n d.. 
1 3.  S U R GI C AL A N D M E DI C AL H I S T O R Y 
S ur gic al a n d M e dic al Hist or y  i nf or m ati o n will b e pr es e nt e d f or t h e S af et y P o p ul ati o n  f or P art 1 a n d P art 2 
s e p ar at el y.  
o  
Pri or M e dic al C o n diti o n will b e c o d e d usi n g  t h e m ost c urr e nt M e d D R A dicti o n ar y. 
 
D at a c a pt ur e d o n t h e P erti n e nt Pri or M e dic al C o n diti o n s p a g e of t h e C R F will b e pr es e nt e d 
b y S O C ( S yst e m Or g a n Cl ass) a n d P T ( Pr ef err e d T er m).  
 
A s e p ar at e s u m m ar y will b e pr o vi d e d o n t h e c a nc er r el at e d pri or m e dic ati o n c o n diti o ns.  
 
A b y p ati e nt listi n g will als o b e pr o vi d e d.  
o  
P ast S ur g eri es a n d M e dic al or S ur gic al Pr oc e d ur es  will b e c o d e d usi n g t h e m ost c urr e nt M e d D R A 
dicti o n ar y . 
 
D at a c a pt ur e d o n t h e P ast S ur g eri es  a n d M e dic al or S ur gic al Pr oc e d ur es  p a g e o f t h e C R F 
will b e pr es e nt e d b y S O C ( S yst e m Or g a n Cl ass) a n d P T ( Pr ef err e d T er m).   
 
A b y p ati e nt listi n g will als o b e pr o vi d e d.  
 
o  
P ast R a di ot h er a p y  
 
T h e n u m b er of sit es of r a di ot h er a p y, t h e t ot al d os e r ec ei v e d, ti m e si nc e l ast r a di ot h er a p y  
( d eri v e d as t h e d at e of first d os e of st u d y dr u g  –  e n d d at e of l ast r a di ot h er a p y) , tr e at m e nt 
i nt e nt ( a dj u v a nt, n e o-a dj u v a nt, p alli ati v e,  c ur ati v e) a n d b est r es p o ns e will b e s u m m ariz e d 
d escri pti v el y  
 
A b y p ati e nt listi n g will als o b e pr o vi d e d . 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 4  of 7 5  
 
o  
Pr e vi o us S m all C ell L u n g C a nc er Tr e at m e nt R e gi m e ns  
 
C a nc er t h er a p y a g e nts ca pt ur e d o n t h e Pr evi o us S m all C ell L u n g C a nc er Tr e at m e nt 
R e gi m e ns  p a g e of t h e C R F will b e pr es e nt e d b y  r e gi m e n n a m e. 
 
A b y p ati e nt listi n g will als o b e pr o vi d e d.  
1 4.  C O N C O MI T A N T P R O C E D U R E S  
C o nc o mit a nt Pr oc e d ur es  will b e pr es e nt e d f or t h e S af et y P o p ul ati o n P art 1 a n d P art 2 . 
o  
C o nc o mit a nt Pr oc e d ur es  will b e c o d e d usi n g  t h e m ost c urr e nt M e d D R A dicti o n ar y .  
 
C o nc o mit a nt Pr oc e d ur es  ar e t h os e w hic h st art e d pri or t o or at Scr e e ni n g a n d ar e o n g oi n g 
at t h e d at e of Scr e e ni n g.  
 
D at a c a pt ur e d o n t h e C o nc o mit a nt Pr oc e d ur es  p a g e of t h e C R F will b e pr es e nt e d b y S O C 
( S yst e m Or g a n Cl ass) a n d P T ( Pr ef erre d T er m).  
 
C o nc o mit a nt Pr oc e d ur es will b e pr es e nt e d i n a b y p ati e nt  listi n g.  
 
1 5.  C O N C O MI T A N T R A DI O T H E R A P Y  
C o nc o mit a nt R a di ot h er a p y will b e pr es e nt e d f or t h e S af et y P o p ul ati o n P art 1 a n d P art 2 . 
o  
T h e n u m b er of sit es of r a di ot h er a p y, t h e t ot al d os e r ec ei v e d, t h e  tr e at m e nt i n dic ati o n a n d t h e b est 
r es p o ns e aft er c o nc o mit a nt r a di ot h er a p y will b e s u m m ariz e d i n a t a bl e. 
 
C o nc o mit a nt R a di ot h er a p y  ar e  t h os e w hic h st art e d pri or t o or at Scr e e ni n g a n d ar e 
o n g oi n g at t h e d at e of Scr e e ni n g.  
 
C o nc o mit a nt R a di ot h er a p y  will b e pr es e nt e d i n a b y p ati e nt  listi n g.  
1 6.  P RI O R A N D C O N C O MI T A N T M E DI C A TI O N S  
M e dic ati o ns will b e pr es e nt e d f or t h e S af et y P o p ul ati o n P art 1 a n d P art 2  a n d c o d e d usi n g  t h e m ost c urr e nt 
W H O dr u g dicti o n ar y.  
S e e A p p e n dix 2 f or h a n dli n g of p arti al d at es f or m e dic ati o ns, i n t h e c as e w h er e it is n ot p ossi bl e t o d efi n e a 
m e dic ati o n as pri or, c o nc o mit a nt, or p ost tr e at m e nt, t h e m e dic ati o n will b e cl assifi e d b y t h e w orst c as e; i. e. 
c o nc o mit a nt.  
o  
‘ Pri or’ m e dic ati o ns ar e m e dic ati o ns w hic h st art e d a n d st o p p e d pri or t o t h e first d os e of st u d y 
m e dic ati o n.  
o  
‘ C o nc o mit a nt’ m e dic ati o ns ar e m e dic ati o ns w hic h:  
 
st art e d pri or t o, o n or aft er t h e first d os e of st u d y m e dic ati o n a n d st art e d n o l at er t h a n  
t h e l ast d os e of st u d y dr u g t ak e n,  
 
A N D e n d e d o n or aft er t h e d at e of first d os e of st u d y m e dic ati o n or w er e o n g oi n g at t h e 
e n d of t h e st u d y.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 5  of 7 5  
 
o  
‘ P ost’ m e dic ati o ns ar e m e dic ati o ns w hic h st art e d aft er  t h e l ast d os e of st u d y m e dic ati o n. 
T h e n u m b er a n d p erc e nt a g e  of p ati e nts t a ki n g m e dic ati o ns will b e s u m m ariz e d b y tr e at m e nt gr o u p f or t h e pri or 
a n d c o nc o mit a nt m e dic ati o ns  usi n g  dr u g cl ass ( A T C l e v el 2, i. e. t h er a p e utic gr o u p) a n d pr ef err e d t er m.  
M e dic ati o ns will b e s ort e d al p h a b etic all y b y dr u g cl ass a n d b y pr ef err e d t er m wit hi n dr u g cl ass.  If a p ati e nt h as 
m or e t h a n o n e q u alifyi n g r ec o r d f or a m e dic ati o n, t h e p ati e nt will b e c o u nt e d o nl y o nc e. 
P ost tr e at m e nt will b e i ncl u d e d i n listi n gs.  P ost -tr e at m e nt a nti-c a nc er pr oc e d ur es will b e m o nit or e d, fl a g g e d a n d 
list e d. 
1 7.  E X T E N T O F D I S E A S E A T B A S ELI N E  
N u m b er of p ati e nts wit h t ar g et l esi o ns o nl y , n o n-t ar g et l esi o ns o nl y, a n d b ot h t ar g et a n d n o n-t ar g et l esi o ns will 
b e s u m m ariz e d.  I n di vi d u al dis e as e sit e f or t ar g et or n o n -t ar g et l esi o ns will b e s u m m ariz e d. 
1 8.  S T U D Y M E DI C A TI O N E X P O S U R E  
F or P art 1 a n d P art 2 t h e f oll o wi n g will b e s u m m ariz e d  b as e d o n t h e S af et y P o p ul ati o n . 
T h e ext e nt of ex p os ur e will b e s u m m ariz e d f or Iri n ot ec a n li p os o m e a n d T o p ot ec a n (f or P art 2 o nl y) as f oll o ws:  
•  
N u m b er a n d p erc e nt a g e of p ati e nts b e gi n ni n g 1, 2, 3 , 4, 5, 6,…,  > x  c ycl es 
•  
N u m b er of c ycl es st art e d as a c o nti n u o us v ari a bl e  
•  
T ot al Act u al D os e r ec ei v e d d efi n e d as act u al d os e ( m g) , s u m m e d acr oss all a d mi nistr ati o ns 
•  
T ot al pl a n n e d d os e is d efi n e d as t h e c u m ul ati v e pl a n n e d d os e i n e ac h c ycl e (r e g ar dl ess of d os e s ki p p e d 
or tr e at m e nt disc o nti n u ati o n). If a p ati e nt disc o n ti n u es t h e tr e at m e nt mi d c ycl e t h e pl a n n e d d os e i n 
f oll o wi n g d osi n g visits i n t h at c ycl e will b e i m p ut e d wit h t h e l ast a v ail a bl e v al u e wit hi n t h e c ycl e.  
•  
R el ati v e Act u al D os e = [ T ot al act u al d os e ( m g) di vi d e d b y T ot al i nt e n d e d d os e ( m g)] X 1 0 0, w h er e t ot al 
i nt e n d e d d os e is d efi n e d as t h e pl a n n e d d os e as pr escri b e d w hic h is s u m m e d fr o m first t o l ast i nt a k e 
d at e irr es p ecti v e of miss e d , i nt err u pte d , or u n pl a n n e d r e d uce d d os es .  U p t o t hr e e d os e r e d ucti o ns of 
iri n ot ec a n li p os o m e i nj ecti o n or u p t o t w o d os e r e d ucti o ns of t o p ot ec a n p er p ati e nt ar e p er mitt e d d u e 
t o t oxiciti es a n d will b e c o nsi d er e d i n t h e pl a n n e d d os e. 
•  
T ot al Ex p os ur e ( w e e ks) d eri v e d as (l ast d os e d at e –  first d os e d at e +1 4 )/ 7 f or p ati e nts i n t h e Iri n ot ec a n 
ar m or (l ast d os e d at e –  first d os e d at e + 2 1)/ 7 f or p ati e nts i n t h e T o p ot ec a n ar m.  
•  
R el ati v e t ot al d os e i nt e nsit y ( % ) will b e s u m m ariz e d as act u al t ot al  d os e i nt e nsit y  di vi d e d b y  pl a n n e d  
t ot al d os e i nt e nsit y * 1 0 0 .   
o  
T h e act u al t ot al  d os e int e nsit y ( m g/ m 2/ w e ek) = (c u m ul ati v e act u al d os e i n m g/ m 2) / (tr e at m e nt 
d ur ati o n), w h er e t h e tr e at m e nt d ur ati o n is d eri v e d as (l ast d os e d at e –  first d os e d at e +1 4 )/ 7 
f or p ati e nts i n t h e Iri n ot ec a n ar m or (l ast d os e d at e –  first d os e d at e + 2 1)/ 7 f or p ati e nts i n t h e 
T o p ot ec a n ar m.    
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 6  of 7 5  
 
o  
T h e  pl a n n e d t ot al dos e int e n sit y ( m g/ m 2/ w e ek) = (c u m ul ati v e pl a n n e d d os e i n m g/ m 2) / 
(tr e at m e nt d ur ati o n), a n d tr e at m e nt d ur ati o n ( w e eks) = 6 w e eks * t h e n u m b er of c ycl es t h at a 
p ati e nt r ec ei v es a d os e at . If a p ati e nt disc o nti n u es t h e tr e at m e nt mi d c ycl e  t h e n t h e pl a n n e d 
d os e a n d t h e B S A i n f oll o wi n g d osi n g visits  i n t h at c ycl e will b e i m p ut e d wit h t h e l ast a v ail a bl e 
v al u e wit hi n t h e c ycl e.  
Tr e at m e nt d el a ys a n d d os e m o dific ati o n  
D efi niti o ns:  
A d os e r e d ucti o n is d efi n e d f or Iri n ot ec a n Li p os o m e, as a n act u al d os e t h at is r e d uc e d d u e t o  h e m at ol o gic al 
t oxiciti es s uc h as n e utr o p e ni a, l e u k o p e ni a, or t hr o m b oc yt o p e ni a Gr a d e 3 or 4 N e utr o p e nic f e v er a n d all 
n o n h e m at ol o gic al t oxiciti es ( exc e pt ast h e ni a a n d a n or exi a), Gr a d e 3 or 4.  U p t o t hr e e d os e r e d ucti o ns ar e 
all o w e d.  D os e r e d ucti o n of t o p ot ec a n is all o w e d at i n v esti g at or discr eti o n as cli nic all y i n dic at e d aft er t h e i niti al 
f ull st arti n g d os e of 1. 5 m g/ m 2, u p t o t w o d os e r e d ucti o ns i n t o p ot ec a n ar e  all o w e d.   D os e r e d ucti o ns a r e 
r ec or d e d i n t h e C R F b y t h e i n v esti g at or.  
A d os e d el a y e d/i nt err u pt e d/ wit h dr a w n will b e d oc u m e nt e d b y t h e i n v esti g at or a n d r ec or d e d i n t h e C R F.  
F or P art 1 a n d P art 2 of t h e st u d y, t h e fr e q u e nc y a n d p erc e nt a g e of t h e f oll o wi n g will b e s u m m ariz e d : 
•  
P ati e nts wit h at l e ast o n e d os e r e d ucti o n o v er all a n d b y c ycl e  
•  
P ati e nts wi t h at l e ast o n e d os e r e d ucti o n d u e t o a n a d v ers e e v e nt 
•  
T ot al n u m b er of d os e r e d ucti o ns p er p ati e nt  
•  
N u m b er of d os e r e d ucti o ns  o v er all a n d b y c ycl e  
•  
P ati e nts wit h d os e d el a y e d, i nt err u pt e d a n d wit h dr a w n o v er all a n d b y c ycl e.  
1 9.  E F FI C A C Y O U T C O M E S  
1 9. 1.  P RI M A R Y E F FI C A C Y  
T his s ecti o n o nl y c o v ers P art 2 pri m ar y effic ac y, as f or P art 1 t h e pri m ar y o bj ecti v e is S af et y.  
1 9. 1. 1.  
P RI M A R Y E F FI C A C Y V A RI A BL E &  D E RI V A TI O N  
O S is d efi n e d as t h e ti m e fr o m r a n d o miz ati o n d at e t o t h e d at e of d e at h fr o m a n y c a us e. I n t h e a bs e nc e of 
c o nfir m ati o n of d e at h, s ur vi v al ti m e will b e c e ns or e d at t h e l ast d at e t h e p ati e nt is k n o w n t o b e ali v e.  T h e d at e 
l ast k n o w n t o b e ali v e will b e t a k e n fr o m t h e Ov er all S urviv al  C R F f or m, b ut c h ec ks w ill als o b e m a d e of 
l a b or at or y s a m pl e d at es, a d v ers e e v e nt st art a n d st o p d at es, c o nc o mit a nt m e dic ati o n st art a n d st o p d at es, as 
w ell as n or m al visit/f oll o w -u p d at es i n or d er t o o bt ai n t h e l ast r ec or d e d d at e t h at a p ati e nt w as k n o w n t o b e still 
ali v e.  P at i e nts wit h n o p ost-r a n d o miz ati o n i nf or m ati o n will b e c e ns or e d o n t h e d at e of r a n d o miz ati o n.  O S 
c alc ul ati o ns ( m o nt hs) will b e t h e f oll o wi n g:  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 7  of 7 5  
 
 
[ D e at h/ C e ns ori n g D at e –  R a n d o miz ati o n  D at e + 1]/ 3 0. 4 3 7 5  
1 9. 1. 2.  
P RI M A R Y A N AL Y SI S O F P RI M A R Y E F FI C A C Y V A RI A BL E  
T h e n ull h y p ot h esis is t h at t h e O S is t h e s a m e f or t h e t w o tr e at m e nts.  T h e alt er n ati v e h y p ot h esis is t h at 
Iri n ot ec a n Li p os o m e I nj ecti o n ( O NI V Y D E ®)  h as a l o n g er O S c o m p ar e d t o T o p ot ec a n I V.  
T h e pri m ar y effic ac y a n al ysis will b e p erf or m e d f or t h e P art 2 I n t e nt-t o-Tr e a t P o p ul ati o n. 
T h e pri m ar y a n al ysis will b e p erf or m e d usi n g a str atifi e d l o g -r a n k t est (str atifi e d b y r e gi o n ( N ort h A m eric a vs. Asi a 
vs. Ot h er)  a n d pl ati n u m s e nsiti vit y  (s e nsiti v e vs. r esist a nt) c o m p ari n g t h e O S b et w e e n t w o tr e at m e nt gr o u ps  wit h 
l ev el of sig nific a nc e c o ntr oll e d at t h e o n e -si d e d 0. 0 2 5 l e v el.  K a pl a n-M ei er m et h o ds will b e us e d t o esti m at e 
m e di a n O S ( wit h 9 5 % c o nfi d e nc e i nt er v als) a n d t o dis pl a y O S ti m e gr a p hic all y.  A str atifi e d  C ox pr o p orti o n al 
h az ar ds m o d el, (str atifi e d b y r e gi o n a n d pl ati n u m s e nsiti vit y ) will b e us e d t o esti m at e t h e tr e at m e nt h az ar d r ati o 
a n d its c orr es p o n di n g 9 5 % c o nfi d e nc e i nt er v al.   
T h e t a b ul ar s u m m ar y f or O S will pr es e nt t h e fr e q u e nc y distri b uti o n of O S st at us ( di e d or c e ns or e d), fr e q u e nc y 
distri b uti o n of t h e r e as o ns f or c e ns ori n g at t h e ti m e of t h e d at a c ut-off  ( ali v e, wit h dr a w n fr o m st u d y, l ost t o 
f oll o w-u p), K a pl a n -M ei er esti m at es of m e di a n s ur vi v al t i m e, q u artil es a n d  K a pl a n -M ei er esti m at es of O S r at e f or 
m o nt hs 3, 6, 9 , 1 2  or m or e . 
A fi g ur e dis pl a yi n g t h e K a pl a n -M ei er s ur vi v al c ur v es f or e ac h tr e at m e nt will b e pr es e nt e d.  
1 9. 1. 3.  
S E N SI TI VI T Y A N AL Y SI S O F P RI M A R Y E F FI C A C Y V A RI A BL E  
N o s e nsiti vit y a n al ysis pl a n n e d.  
1 9. 1. 4.  
A N AL Y S E S O F S U B G R O U P S  
T o ass ess t h e r o b ust n ess of r es ults, s u b gr o u p a n al ys es of o v er all s ur vi v al will b e p erf or m e d t o ex a mi n e 
diff er e nc es i n t h e eff ects of tr e at m e nt i n d iff er e nt s e g m e nts of t h e st u d y po p ul ati o n.  T h e f act ors ex pl or e d will 
i ncl u d e t h os e i d e ntifi e d i n S ecti o n 8. 5 . 
A s e p ar at e C ox r e gr essi o n a n al ysis o n o v er all s ur vi v al will b e c o n d uct e d f or e ac h f act or usi n g a m o d el c o nt ai ni n g 
tr e at m e nt gr o u p, t h e f act or, a n d t h e tr e at m e nt gr o u p-b y -f act or i nt er acti o n.  F or c at e g oric al f act ors, t h e h az ar d 
r ati o will b e esti m at e d wit hin e ac h s u b gr o u p fr o m t h e m o d el ( e. g., s e p ar at el y f or m al es a n d f e m al es i n t h e 
ass ess m e nt of s ex) a n d a t est of h o m o g e n eit y will b e c o n d uct e d (t h e t est of t h e tr e at m e nt gr o u p -b y -f act or 
i nt er acti o n) t o ass ess t h e c o nsist e nc y of t h e tr e at m e nt gr o u p eff ect a m on g s u b gr o u ps.   
K a pl a n -M ei er pl ots o f esti m at e d s ur vi v al f u ncti o n will b e cr e at e d f or e ac h c o m bi n ati o n of tr e at m e nt ar m a n d 
s u b gr o u p.  F or e ac h p air wis e tr e at m e nt ar m c o m p aris o n, a s u m m ar y of t h e s u b gr o u p a n al ys es will b e pr es e nt e d 
i n f or est pl ots, s h o wi n g h az ar d r ati o  esti m at es a n d u n a dj ust e d 9 5 % CI s f or e ac h s u b gr o u p.  T h es e a n al ys es will b e 
p erf or m e d o n t h e  P art 2 I nt e nt -t o-Tr e at  p o p ul ati o n.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 8  of 7 5  
 
1 9. 2.  S E C O N D A R Y E F FI C A C Y 
T h e s ec o n d ar y effic ac y a n a l ys es will b e p erf or m e d o n t h e S af et y P o p ul ati o n f or P art 1 p ati e nt s a n d o n t h e I nt e nt -
t o-Tr e at P o p ul ati o n f or P art 2 p ati e nt s.  F or  P art 1 p ati e nt s, o nl y d escri pti v e st atistics will b e pr o vi d e d.  
1 9. 2. 1.  
S E C O N D A R Y E F FI C A C Y V A RI A BL E S &  D E RI V A TI O N S  
1 9. 2. 1. 1.  
Pr o gr essi o n -fr e e s urviv al  
T h e d et er mi n ati o n of P F S will b e b as e d o n BI C R t u m or ass ess m e nt  usi n g  R E CI S T v ersi o n 1. 1 , wit h P F S b as e d o n 
i n v esti g at or t u m or ass ess m e nts as a s e nsiti vit y a n al ysis.  N o s e p ar at e pr o gr a m mi n g b as e d o n R E CI S T f or  t h e 
r es p o ns es will b e p erf or m e d.  All P F S c alc ul ati o ns ( m o nt hs) will b e t h e f oll o wi n g: 
[ Pr o gr essi o n/ D e at h/ C e ns ori n g D at e –  R a n d o miz ati o n D at e + 1]/( 3 0. 4 3 7 5)  
F or P art 1  t h e pr o gr essi o n-fr e e s ur vi v al ti m e is t h e ti m e fr o m first d os e of st u d y dr u g t o t h e first d oc u m e nt e d 
o bj ecti v e dis e as e pr o gr essi o n ( P D) usi n g R E CI S T V ersi o n 1. 1 or d e at h d u e t o a n y c a us e, w hic h e v er occ urs first.  
F or P art 2  th e pr o gr essi o n -fr e e s ur vi v al is t h e ti m e fr o m r a n d o miz ati o n i n P art 2 t o t h e first d oc u m e nt e d 
o bj ecti v e dis e as e pr o gr essi o n ( P D) usi n g R E CI S T V ersi o n 1. 1  ( or R A N O-B M crit eri a f or C N S l esi o ns)  or d e at h d u e 
t o a n y c a us e, w hic h e v er occ urs first.  D et er mi n ati o n of P F S will b e p er l oc al r a di ol o g y r e vi e w a n d/ or i n v esti g at or 
ass ess m e nt.     
C e ns ors hi p:  I n g e n er al, p ati e nts ar e c e ns or e d at t h e d at e of t h e l ast o bj ecti v e dis e as e ass ess m e nt t h at v erifi e d 
l ac k of dis e as e pr o gr essi o n if t h ey ar e l ast k n o w n t o b e  ali v e, o n -tr e at m e nt or wit hi n 30 d a ys f oll o wi n g tr e at m e nt 
disc o nti n u ati o n a n d pr o gr essi o n -fr e e. C e ns ori n g is ex plicitl y d escri b e d b el o w a n d i n t a bl e 4 . 
•  
P ati e nts wit h i n a d e q u at e/i nc o m pl et e  b as eli n e dis e as e ass ess m e nt will b e c e ns or e d at t h e d at e of 
r a n d o miz ati o n. 
•  
P ati e nts n ot r e ass ess e d aft er r a n d o miz ati o n will b e c e ns or e d at t h e d at e of r a n d o miz ati o n u nl ess d e at h 
occ urr e d wit hi n t h e ti m e wi n d o w f or t h e first t w o ass ess m e nt visits, pr o vi d e d  t h e p ati ent is still o n -
st u d y tr e at m e nt or < = 30 d a ys aft er st u d y tr e at m e nt disc o nti n u ati o n 
•  
P ati e nts wit h at l e ast o n e o n -st u d y dis e as e ass ess m e nt w h o disc o nti n u e tr e at m e nt wit h o ut d oc u m e nt e d 
dis e as e pr o gr essi o n or d e at h ar e c e ns or e d at t h e d at e of t h e l a st o bj ecti v e dis e as e ass ess m e nt 
d oc u m e nti n g n o pr o gr essi o n.  
T h er e ar e t w o exc e pti o ns.  
•  
If o bj ecti v e pr o gr essi o n or d e at h is d oc u m e nt e d < = 30 d a ys aft er st u d y tr e at m e nt disc o nti n u ati o n t h e n 
pr o gr essi o n or d e at h is a n e v e nt  
•  
If a n e w a nti-c a nc er tr e at m e nt is st art e d pri or t o o bj ecti v e pr o gr essi o n a n d < = 6 0 d a ys aft er st u d y 
tr e at m e nt disc o nti n u ati o n, t h e n c e ns ors hi p is at t h e d at e of t h e l ast o bj ecti v e dis e as e ass ess m e nt t h at 
v erifi e d l ac k of dis e as e pr o gr essi o n pri or t o t h e n e w tr e at m e nt  
P ati e nts wit h d oc u m e nt ati o n of pr o gr essi o n or d e at h aft er a n u n acc e pt a bl e l o n g i nt er v al (i. e. 2 or m or e miss e d 
or i n d et er mi n at e/ n ot e v al u a bl e ass ess m e nts) si nc e t h e l ast t u m or ass ess m e nt will b e c e ns or e d at t h e ti m e of l ast 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 3 9  of 7 5  
 
o bj ecti v e ass ess m e nt pri or t o t h e miss e d/i n d et er mi n at e/ n ot ev al u a bl e ass ess m e nts.  
 
T a bl e 4 :  E v al u ati o n of D o c u m e nt e d Di s e a s e Pr o gr e s si o n a n d C e n s ori n g  
Sit u ati o n  
D at e of  
O ut c o m e  
I n a d e q u at e b a s eli n e t u m or a s s e s s m e nt 
R a n d o mi z ati o n  
 
 
C e n s or e d  
 
N o p o st -b a s eli n e a s s e s s m e nt pri or t o fir st 
s c h e d ul e d a s s e s s m e nt  
C e n s or e d  
 
D e at h or d o c u m e nt e d P D aft er ≥ 2 
c o n s e c uti v el y mi s s e d a n d/ or n ot e v al u a bl e 
s c h e d ul e d t u m or a s s e s s m e nt s  
L a st t u m or a s s e s s m e nt d o c u m e nti n g 
n o P D ( pri or t o t h e mi s s e d/ n ot 
e v al u a bl e a s s e s s m e nt s)  
C e n s or e d  
N e w a nti c a n c er tr e at m e nt pri or t o P D or d e at h  
L a st t u m or a s s e s s m e nt d o c u m e nti n g 
n o P D pri or t o n e w a nti c a n c er 
tr e at m e nt 
C e n s or e d  
St u d y tr e at m e nt di s c o nti n u ati o n d u e t o t o xi cit y, 
u n d o c u m e nt e d pr o gr e s si o n, or ot h er r e a s o n 
a n d n o d o c u m e nt e d P D  or d e at h  pri or t o 
tr e at m e nt di s c o nti n u ati o n 
L a st t u m or a s s e s s m e nt d o c u m e nti n g 
n o P D pri or t o st u d y di s c o nti n u ati o n  
C e n s or e d  
Ali v e, o n -tr e at m e nt, a n d n o d o c u m e nt e d P D 
L a st t u m or a s s e s s m e nt d o c u m e nti n g 
n o P D  
C e n s or e d  
D o c u m e nt e d di s e a s e pr o gr e s si o n wit hi n 2 
c o n s e c uti v e s c h e d ul e d t u m or a s s e s s m e nt s of 
b a s eli n e or t h e l a st n o n -P D t u m or a s s e s s m e nt  
Fir st t u m or a s s e s s m e nt d o c u m e nti n g 
P D  
Pr o gr e s si o n  
( E v e nt) 
D e a t h wit h o ut d o c u m e nt e d P D a n d wit hi n 2 
c o n s e c uti v e s c h e d ul e d t u m or a s s e s s m e nt s of 
b a s eli n e or t h e l a st n o n -P D t u m or a s s e s s m e nt  
D e at h  
D e at h ( E v e nt)  
N ot e:  T u m or  ass ess m e nts ar e pl a n n e d e v er y 6  w e eks, wit h a wi n d o w of +/ -7  d a ys f or e ac h ass ess m e nt.  T h us, a 
p ati e nt will b e c o nsi d er e d t o h a v e miss e d ≥2 c o ns ec uti v e ass ess m e nts if t h e ti m e b et w e e n t w o e v al u a bl e 
ass ess m e nts is >  1 4 w e e ks ( 9 8  d a ys).  F oll o w -u p sc a ns c a n b e p erf or m e d u p t o 4 w e eks fr o m l ast d os e d at e 
acc or di n g t o t h e pr ot oc ol.  
1 9. 2. 1. 2.  
O bj ectiv e R es p o ns e  R at e ( O R R)  
B est O v er all R es p o ns e ( B O R) is r ec or d e d fr o m r a n d o miz ati o n f or P art 2 or d at e of first  tr e at m e nt d os e f or P art 1 
u ntil d oc u m e nt e d dis e as e pr o gr essi o n or d e at h.  O R R is d efi n e d as t h e pr o p orti o n of p ati e nts wit h a B O R 
c h ar act eriz e d as eit h er a C o m pl et e R es p o ns e ( C R) or P arti al R es p o ns e ( P R) as d efi n e d  acc or di n g t o R E CI S T V 1. 1 
g ui d eli n e  i n P art 2 r el ati v e t o t h e t ot al n u m b er of p ati e nts i n t h e I T T p o p ul ati o n. P er R E CI S T V 1. 1 g ui d eli n es, 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 0  of 7 5  
 
p ati e nts wit h d oc u m e nt e d P R or C R will n ot n e e d c o nfir m at or y t u m or ass ess m e nts t o d oc u m e nt t u m or r es p o ns e.  
P ati e nts w it h o ut b as eli n e or p ost-b as eli n e t u m or ass ess m e nts will b e c o nsi d er e d n o n -ev al u a bl e f or t his a n al ysis.   
P ati e nts wit h a B O R of C R or P R will b e c o nsi d er e d a r es p o n d er f or t h e O R R a n al ysis, w hil e p ati e nts wit h a B O R of 
S D, P D, N ot E v al u a bl e or N ot D o n e will  b e c o nsi d er e d a n o n -r es p o n d er. 
T h e O R R will b e d et er mi n e d f or t h e P art 1 a n d t h e P art 2.   F or P art 2  all p ati e nts will b e r e p ort e d usi n g t h e R E CI S T 
1. 1 crit eri a f or  t h e O R R. F or p ati e nts w h o h a v e C N S dis e as e at b as eli n e t h e R A N O crit eri a will b e us e d f or t h e C N S 
l esi o ns.  
T h e d et er mi n ati o n of O R R i n p art 2 will b e b as e d o n BI C R t u m or ass ess m e nt usi n g R E CI S T v ersi o n 1. 1, wit h O R R 
b as e d o n i n v esti g at or t u m or ass ess m e nts as a s e nsiti vit y a n al ysis.  
T h e d ur ati o n of o bj ecti v e r es p o ns e will als o b e s u m m ariz e d.  It is d efi n e d as f oll o ws:  D ur ati o n ( w e eks) = ((D at e of 
P D/ d e at h /c e ns ori n g) mi n us d at e of O R  ( C R or P R w hic h e v er occ urs first)) + 1)/ 7.  If pr o gr essi o n or d e at h h as n ot 
b e e n d oc u m e nt e d, a p ati e nt’s d ur ati o n of O R  will b e c e ns or e d at t h e d at e of t h e l ast v ali d t u m or ass ess m e nt.  
P ati e nts wit h a n e w a nti -c a nc er t h er a p y aft er t h e first r es p o ns e b ut pri or t o d oc u m e nt e d P D or d e at h will b e 
c e ns or e d at t h e l ast t u m or ass ess m e nt pri or t o n e w a nti -c a nc er t h er a p y. 
T h e ti m e t o o bj ecti v e r es p o ns e will als o b e s u m m ariz e d.  T his is t h e ti m e fr o m r a n d o miz ati o n t o t h e first 
o bj ecti v e t u m or r es p o ns e o bs er v e d f or p ati e nt w h o ac hi e v e d a C R or P R a n d is d efi n e d as f oll o ws:  Ti m e t o O R  
( w e eks) = (( D at e of O R/c e ns ori n g ) mi n us d at e of r a nd o miz ati o n + 1)/ 7.  If o bj ecti v e r es p o ns e h as n ot occ urr e d , a 
p ati e nt’s ti m e t o O R will b e c e ns or e d at t h e d at e of t h e l ast v ali d t u m or ass ess m e nt.  P ati e nts wit h a n e w a nti -
c a nc er t h er a p y pri or t o O R will b e c e ns or e d at t h e l ast t u m or ass ess m e nt pri or t o n e w  a nti -c a nc er t h er a p y.  
1 9. 2. 1. 3.  
O v er all S ur viv al P art 1  
T h e O S f or t h e P art 1 w hic h is d efi n e d as t h e ti m e fr o m first d os e of st u d y dr u g t o t h e d at e of d e at h fr o m a n y 
c a us e.  I n t h e a bs e nc e or c o nfir m ati o n of d e at h, s ur vi v al ti m e will b e c e ns or e d at t h e l ast d at e t h e p ati e nt is 
k n o w n t o b e ali v e.  T h e d at e l ast k n o w n ali v e will b e t a k e n fr o m t h e Ov er all S urviv al  C R F f or m, b ut c h ec ks will 
als o b e m a d e of l a b or at or y s a m pl e d at es, a d v ers e e v e nt st art a n d st o p d at es, c o nc o mit a nt m e dic ati o n st art a n d 
st o p d at es, as w ell as n or m al visit/f oll o w -u p d at es i n or d er t o o bt ai n t h e l ast r ec or d e d d at e t h at a p ati e nt w as 
k n o w n t o b e still ali v e.  P ati e nts wit h n o p ost -first d os e of st u d y dr u g i nf or m ati o n will b e c e ns or e d o n t h e d at e of 
first d os e of st u d y dr u g.  O S c alc ul ati o ns ( m o nt hs) will b e t h e f oll o wi n g: 
 
 
[ D e at h/ C e ns or D at e –  First St u d y Dr u g D os e  D at e + 1]/ 3 0. 4 3 7 5  
1 9. 2. 1. 4.  
P ati e nts wit h S y m pt o m of c o u g h a n d d ys p n e a  
T h e E O R T C QL Q -L u n g C a nc er 1 3 (L C 1 3) is a 1 3 -it e m, l u n g c a nc er-s p ecific m o d ul e t o b e us e d i n c o nj u ncti o n wit h 
t h e E O R T C QL Q -C 3 0.  T h e L C 1 3 c o v ers t y pic al l u n g c a nc er -ass oci at e d s y m pt o ms s uc h as c o u g h a n d dys p n e a .  
Sc or e will r a n g e fr o m 0 t o 1 0 0 o nc e tr a nsf or m e d.  A hi g h sc or e r e pr es e nts a hi g h l e v el of 
sy m pt o m at ol o g y/ pr o bl e ms.  T h e i nstr u m e nt a n d sc ori n g al g orit h m  f or E O R TC QL Q C 3 0  c a n b e f o u n d i n a p p e n dix 
4 a n d f or E O R T C QL Q L C 1 3 c a n b e f o u n d i n a p p e n dix 5.  
T h e c h a n g e fr o m b as eli n e t o w e e k 1 2 i n E O R T C  QL Q -C 3 0/L C 1 3 d ys p n e a a n d  i n E O R T C-QL Q -L C 1 3 c o u g h will b e 
c o m p ut e d. 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 1  of 7 5  
 
1 9. 2. 2.  
A N AL Y SI S O F S E C O N D A R Y E F FI C A C Y V A RI A BL E S  
1 9. 2. 2. 1.  
A n al ysis of Pr o gr essi o n Fr e e S ur viv al  
F or P arts 1 a n d P art 2 K a pl a n -M ei er m et h o ds will b e us e d t o esti m at e m e di a n  a n d q u artil es P F S ( wit h 9 5 % 
c o nfi d e nc e i nt er v als) a n d esti m at es of P F S at 3, 6, 9 a n d 1 2 m o nt hs a n d t o dis pl a y P F S ti m e gr a p hic all y.  
T h e t a b ul ar s u m m ar y f or P F S will pr es e nt t h e fr e q u e nc y distri b uti o n of P F S st at us ( e v e nt or c e ns or e d) a n d t h e 
fr e q u e nc y distri b uti o n of t h e r e as o ns f or c e ns ori n g at t h e ti m e of t h e d at a c ut-off.  
F or P art 2 t h e diff er e nc e i n P F S b et w e e n tr e at m e nts will b e ev al u at e d usi n g a str atifi e d l o g -r a n k t est (str atifi e d b y 
r e gi o n ( N ort h A m eric a vs. Asi a vs. Ot h er) a n d c orr ect e d pl ati n u m s e nsiti vit y  (s e nsiti v e vs. r esist a nt)).  A str atifi e d 
C ox pr o p orti o n al h az ar ds m o d el will b e us e d t o esti m at e t h e P F S h az ar d r ati o a n d its c orr es p o n di n g 9 5 % 
c o nfi d e nc e i nt er v al. T h e C ox pr o p orti o n al h az ar d m o d el will i ncl u d e t h e r a n d o miz ati o n str atific ati o n f act ors  
(r e gi o n a n d pl ati n u m s e nsiti vit y).   
F or t h e P art 2, t h e f oll o wi n g s e nsiti vit y a n al ysis will b e p erf or m e d:  
•  
E arl y disc o nti n u ati o n s e nsiti vit y a n al ysis:  P ati e nts wit h o ut d oc u m e nt e d P D w h o h a d s u bs e q u e nt 
t h er a p y or w er e disc o nti n u e d fr o m tr e at m e nt d u e t o n o n-pr o gr essi o n r e as o ns ar e c o nsi d er e d as P D at 
t h e ti m e of t h es e ev e nts 
•  
Missi n g d at a s e nsiti vit y a n al ysis:  d at e of P D is b ac k d at e d t o t h e ex p ect e d d at e of t h e first miss e d t u m or 
ass ess m e nt if o n e or m or e t u m or ass ess m e nts w er e missi n g i m m e di at el y pr ec e di n g P D  
1 9. 2. 2. 2.  
A n al ysis of O bj ectiv e  R es p o ns e  R at e  
A n esti m at e of t h e O R R  a n d its 9 5 % CI will b e c alc ul at e d.  T h e diff er e nc e i n O R R b et w e e n tr e at m e nt gr o u ps will 
b e c o m p ar e d usi n g C oc hr a n -M a nt el -H a e nsz el m et h o d, i nc or p or ati n g a n al ysis str atific ati o n f act ors (r e gi o n a n d 
pl ati n u m s e nsiti vit y) . 
A n al ys es will b e pr o vi d e d f or P art 1 a n d P art 2.   F or P art 1, n o tr e at m e nt c o m p aris o ns will b e d o n e, o nl y 
d escri pti v e s u m m ari es will b e pr es e nt e d.  
T h e d ur ati o n of o bj ecti v e r es p o ns e will als o b e c o m p ar e d usi n g a l o g -r a n k t est str atifi e d b y r e gi o n a n d pl ati n u m 
s e nsiti vit y. 
1 9. 2. 2. 3.  
O v er all S ur viv al f or P art 1  
T h e P art 1 O S a n al ysis will b e b as e d o n t h e P art 1 S af et y P o p ul ati o n .  K a pl a n-M ei er m et h o ds will b e us e d t o 
esti m at e m e di a n O S ( wit h 9 5 % c o nfi d e nc e i nt er v als) a n d t o dis pl a y O S ti m e gr a p hic all y.     
T h e t a b ul ar s u m m ar y f or O S will pr es e nt t h e fr e q u e nc y distri b uti o n of O S st at us ( di e d or c e ns or e d), fr e q u e nc y 
distri b uti o n of t h e r e as o ns f or c e ns ori n g at t h e ti m e of t h e d at a c ut ( ali v e, wit h dr a w n fr o m st u d y, l ost t o f oll o w -
u p), K a pl a n -M ei er es ti m at es of m e di a n s ur vi v al ti m e a n d K a pl a n -M ei er esti m at es of O S r at e f or m o nt hs 3, 6, 9 , 
1 2.  
A fi g ur e dis pl a yi n g t h e K a pl a n -M ei er s ur vi v al c ur v es will b e pr es e nt e d.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 2  of 7 5  
 
1 9. 2. 2. 4.  
S u m m ary of T u m or R es p o ns e  
T h e f oll o wi n g t u m or r es p o ns e c at e g ori es will b e s u m m ariz e d b y pl ati n u m s e nsiti vit y ( pl ati n u m s e nsiti v e a n d 
pl ati n u m r esist a nt) f or all p ati e nts  i n p art 2 s plit b y tr e at m e nt gr o u p. T um or r es p o ns e acc or di n g t o R E CI S T 1. 1 
a n d R A N O crit eri a will b e s u m m ariz e d s e p ar at el y f or b ot h t h e I n v esti g at or r es p o ns e i n t h e C R F a n d t h e 
i n d e p e n d e nt r evi e w er r es p o ns e. 
o  
B est O v er all R es p o ns e ( B O R) ( C R, P R, S D, P D, N E)  
o  
O R R ( Y es, N o)  
o  
Dis e as e C o ntr ol R at e ( D C R) ( Y es, N o) w h er e D C R is d efi n e d as pr o p orti o n of p ati e nts  wit h C R, P R or 
S D f or at l e ast 1 2 w e e ks  
o  
D ur ati o n of r es p o ns e  
1 9. 2. 2. 5.  
P ati e nts wit h S y m pt o m of C o u g h a n d Dys p n e a  
A t a bl e wit h d escri pti v e st atistics f or t h e c h a n g e fr o m b as eli n e i n d ys p n e a a n d c o u g h a n d c orr es p o n di n g 9 5 % 
c o nfi d e nc e i nt er v als ( CI), will b e pr es e nt e d b y tr e at m e nt gr o u p f or e ac h p ost -b as eli n e ass ess m e nt.  
C h a n g e fr o m b as eli n e t o W e e k 1 2 i n t h e p ati e nt’s p erc ei v e d d ys p n e a a n d c o u g h sc or es will b e a n al ys e d b y m e a ns 
of m ulti pl e i m p ut ati o n u n d er t h e missi n g at r a n d o m ( M A R) ass u m pti o n i n t h e pri m ar y a n al ysis a n d b y m e a ns of 
p att er n -mixt ur e m o d el u n d er t h e missi n g n ot at r a n d o m ( M N A R) ass u m pti o n i n t h e s e nsiti vit y a n al ysis.  
M ulti pl e I m p ut ati o n ( MI)  
T h e a n al ysis will i ncl u d e o bs er v e d v al u es w hil e a d h e ri n g t o t h e i niti al r a n d o miz e d tr e at m e nt as w ell as 
o bs er v ati o ns aft er disc o nti n u ati o n of t h e r a n d o miz e d tr e at m e nt.  
It is ac k n o wl e d g e d t h at p ati e nts will disc o nti n u e tr e at m e nt at diff er e nt ti m e p oi nts d uri n g t h e st u d y a n d t h at t his 
is a n i m p ort a nt ti m e with r e g ar ds t o P R O d at a c oll ecti o n. I n or d er t o i ncl u d e t h e 3 0 d a ys s af et y f oll o w -u p visits i n 
t h e a n al ysis, a n a n al ysis visit v ari a bl e will b e d eri v e d f or e ac h p ati e nt a n d ass ess m e nt, s o t h at t h e 3 0 d a ys s af et y 
f oll o w-u p visits will b e r e -m a p p e d a n d will b e  assi g n e d a s e q u e nti al n u m b er.  
P ati e nts h a vi n g missi n g b as eli n e, W e e k 6, or W e ek 1 2 sc or es will h a v e t h eir missi n g sc or e i m p ut e d u n d er t h e 
M A R ass u m pti o n usi n g t h e MI m et h o d ol o g y as f oll o ws.  
W e disti n g uis h b et w e e n m o n ot o n e a n d n o n -m o n ot o n e missi n g v al u es. N o n -m o n ot o n e missi n g v al u es ar e v al u es 
missi n g i nt er mitt e ntl y, w h er e a p ati e nt m a y miss s o m e P R O ass ess m e nts b ut h as P R O ass ess m e nts f or t h e s a m e 
sc or e l at er o n. M o n ot o n e missi n g v al u es ar e s uc h t h at o nc e a v al u e is missi n g f or a gi v e n sc or e, n o s u bs e q u e nt  
v al u es f or t his sc or e ar e a v ail a bl e. A n y gi v e n p ati e nt m a y h a v e a c o m bi n ati o n of n o n -m o n ot o n e a n d m o n ot o n e 
missi n g v al u es.  
T h e i m p ut ati o n will b e p erf or m e d usi n g t h e f oll o wi n g s e q u e nc e:  
St e p 1 : N o n-m o n ot o n e missi n g d at a will b e i m p ut e d first. N o n -m o n ot o n e missi n g v al u es ar e ass u m e d t o b e M A R 
a n d will b e m ulti pl y -i m p ut e d usi n g a M ar k o v C h ai n M o nt e C arl o ( M C M C) m et h o d of Pr oc MI i n S A S. T h e 
i m p ut ati o n m o d el will i ncl u d e t h e tr e at m e nt gr o u p, str atific ati o n f act ors (r e gi o n, pl ati n u m s e nsiti vit y), P R O sc or e 
at  b as eli n e a n d at all ot h er ti m e p oi nts ( e. g., W e ek 6 a n d W e e k 1 2), a g e, s ex, pri or c h e m ot h er a p y, a n d dis e as e 
st at us (l oc all y a d v a nc e d vs. m et ast atic).  
St e p 2 : T h e i m p ut ati o n of b as eli n e d at a. T h e i m p ut ati o n will b e d o n e usi n g a pr e dicti v e m e a n m atc hi n g m ulti pl e 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 3  of 7 5  
 
i m p ut ati o n m o d el a n d a m et h o d of F ull y C o n diti o n al S p ecific ati o n as i m pl e m e nt e d i n t h e S A S Pr oc e d ur e MI ( F C S 
st at e m e nt). T h e i m p ut ati o n m o d el will i ncl u d e t h e tr e at m e nt gr o u p, str atific ati o n f act ors (r e gi o n, pl ati n u m 
s e nsiti vit y, p erf or m a nc e st at us, pri or i m m u n ot h er a p y), P R O sc or e at b as eli n e, a g e, s ex, pri or c h e m ot h er a p y, a n d 
dis e as e st at us (l oc all y a d v a nc e d vs. m et ast atic).  
St e p 3 : T h e i m p ut ati o n of m o n ot o n e missi n g d at a. T h e i m p ut ati o n will b e d o n e o nl y o n e ti m e-p oi nt at a ti m e, i n 
c hr o n ol o gic al or der, usi n g a pr e dicti v e m e a n m atc hi n g m ulti pl e i m p ut ati o n m o d el. T h e i m p ut ati o n m o d el will 
i ncl u d e t h e tr e at m e nt gr o u p, str atific ati o n f act ors (r e gi o n, pl ati n u m s e nsiti vit y, p erf or m a nc e st at us, pri or 
i m m u n ot h er a p y), P R O sc or e at b as eli n e, t h e P R O sc or e at th e c orr es p o n di n g ti m e p oi nt, a g e, s ex, pri or 
c h e m ot h er a p y, a n d dis e as e st at us (l oc all y a d v a nc e d vs. m et ast atic).  
T h e n u m b er of cl os est o bs er v ati o ns us e d t o s a m pl e a n i m p ut e d v al u e b y t h e pr e dicti v e m e a n m atc hi n g m et h o d 
will b e 5 ( S A S d ef a ult s etti n g). O n e h u n dr e d ( 1 0 0) m ulti pl y -i m p ut e d d at as ets will b e g e n er at e d. T h e r a n d o m s e e d 
us e d i n t h e P R O C MI pr oc e d ur e will b e 1 2 3 4 5.  
E ac h i m p ut e d d at as et will b e a n al ys e d usi n g a n A n al ysis of C o v ari a nc e ( A N C O V A ) m o d el ( n ot r e p e at e d m e as ur es, 
a n d wit h n o r a n d o m eff ects)  wit h t h e f oll o wi n g c o v ari at es usi n g t h e S A S Pr oc Mix e d pr oc e d ur e: tr e at m e nt gr o u p, 
str atific ati o n f act ors (r e gi o n, pl ati n u m s e nsiti vit y), a n d P R O sc or e at b as eli n e.  
T h e r es ults fr o m m ulti pl e i m p ut e d d at as ets will b e c o m bi n e d usi n g R u bi n’s r ul e as i m pl e m e n t e d i n t h e S A S 
Pr oc e d ur e MI A N AL Y Z E.  
T h e s a m e m o d el will b e c o nsi d er e d f or d ys p n e a a n d c o u g h.  
 
S e nsiti vit y A n al ysis ( P att er n Mixt ur e M o d el ( P M M) ) 
A s e nsiti vit y a n al ysis will b e p erf or m e d b y m e a ns of p att er n -mixt ur e m o d el b y r e as o ns of disc o nti n u ati o n usi n g 
m ulti pl e i m p ut ati o n as d escri b e d b y O’ K ell y a n d R atitc h .  
Si mil ar t o t h e pri m ar y a n al ysis, n o n -m o n ot o n e missi n g d at a will b e i m p ut e d first, f oll o w e d b y t h e i m p ut ati o n of 
b as eli n e a n d t h e n m o n ot o n e missi n g d at a. Si mil ar i m p ut ati o n m o d els as d escri b e d a b o v e will b e c o nsi d er e d f or 
t h e n o n-m o n ot o n e missi n g d at a a n d b as eli n e missi n g d at a.  
T o i m p ut e m o n ot o n e missi n g v al u es, w e d efi n e p att er ns d e p e n di n g o n r e as o n a n d ti mi n g of missi n g n ess as 
f oll o ws: 
•  
P att er n 1: missi n g v al u es b ef or e or at  W e ek 1 2 aft er st u d y tr e at m e nt disc o nti n u ati o n d u e t o a d v ers e 
ev e nts ( A Es) or pr o gr essi o n b ut pri or t o d e at h;  
•  
P att er n 2: missi n g v al u es b ef or e or at W e ek 1 2 wit h missi n g n ess t h at d o es n ot s atisfy c o n diti o ns of 
P att er n 1.  
T h e f oll o wi n g ass u m pti o ns will b e m a d e f or t h e missi n g d at a i n e ac h p att er n:  
F or p att er n 1, i m p ut ati o ns will b e p erf or m e d f or b ot h tr e at m e nt ar ms usi n g a r ef er e nc e -gr o u p a p pr o ac h, w h er e 
t h e r ef er e nc e gr o u p is d efi n e d as p ati e nts  fr o m t h e s a m e tr e at m e nt gr o u p w h o disc o nti n u e d tr e at m e nt b ut ha v e 
p ost -disc o nti n u ati o n d at a c orr es p o n di n g t o W e ek 1 2.  
F or p att er n 2, d at a will b e ass u m e d t o b e M A R i n b ot h tr e at m e nt ar ms.  
O n e h u n dr e d ( 1 0 0) m ulti pl y -i m p ut e d d at as ets will b e g e n er at e d. T h e r a n d o m s e e d us e d i n t h e P R O C MI 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 4  of 7 5  
 
pr oc e d ur e will b e 1 2 3 4 5.  
E ac h i m p ut e d d at as et will b e a n al ys e d usi n g a n A N C O V A m o d el ( n ot r e p e at e d m e as ur es, a n d wit h n o r a n d o m 
eff ects) wit h t h e f oll o wi n g c o v ari at es usi n g t h e S A S Mix e d pr oc e d ur e: tr e at m e nt gr o u p, str atific ati o n f act ors 
(r e gi o n, pl ati n u m s e nsiti vit y), a n d P R O sc or e at b as eli n e.  
T h e r es ults fr o m m ulti pl e i m p ut e d d at as ets will b e c o m bi n e d usi n g R u bi n’s r ul e as i m pl e m e nt e d i n t h e S A S 
Pr oc e d ur e MI A N AL Y Z E.  
T h e tr e at m e nt diff er e nc es will b e esti m at e d fr o m t h e fi n al m o d el wit h L S -m e a ns diff er e nc es. T h e L S m e a n 
tr e at m e nt diff ere nc e, 9 5 % CI, a n d p -v al u e will b e pr es e nt e d.  
T h e a b o v e a n al ysis will b e p erf or m e d o nl y if s uffici e nt n u m b ers of p ati e nts h a v e P R O o utc o m es c oll ect e d aft er 
st u d y dr u g disc o nti n u ati o n. If t his is n ot t h e c as e, t h e P M M usi n g s e q u e nti al m o d elli n g wit h m ulti pl e  i m p ut ati o n 
a n d d elt a -a dj ust m e nt ( d escri b e d b el o w) will b e p erf or m e d.  
A d elt a -a dj ust m e nt a n al ysis ass u m es t h at p ati e nts w h o disc o nti n u e d t h e st u d y h a d o utc o m es t h at w er e w ors e 
t h a n ot h er wis e si mil ar p ati e nts t h at r e m ai n e d i n t h e st u d y. 
T h e diff er e nc e ( a dj u st m e nt) i n o utc o m es b et w e e n dr o p o uts a n d t h os e w h o r e m ai n will b e i m pl e m e nt e d as a 
s hift i n l oc ati o n (t h at is, a s hift i n m e a n of a p ati e nt’s i m p ut e d P R O sc or e).  
T o i m p ut e m o n ot o n e missi n g v al u es, w e d efi n e p att er ns d e p e n di n g o n r e as o n a n d ti mi n g of missi n g n ess as 
f oll o ws: 
•  
P att er n 1: missi n g v al u es b ef or e or at W e ek 1 2 aft er st u d y tr e at m e nt disc o nti n u ati o n d u e t o a d v ers e 
ev e nts ( A Es) b ut pri or t o pr o gr essi o n/ d e at h;  
•  
P att er n 2: missi n g v al u es b ef or e or at W e ek 1 2 aft er pr o gr essi o n b ut pri or t o d e at h;  
•  
P att er n 3: missi n g v al u es b ef or e or at W e ek 1 2 wit h missi n g n ess t h at d o es n ot s atisfy c o n diti o ns of 
P att er ns 1 t o 2.  
T h e f oll o wi n g ass u m pti o ns will b e m a d e f or t h e missi n g d at a i n e ac h p att er n:  
F or p att er n 1, a cli nic all y pl a usi bl e ass u m pti o n is t h at t oxicit y will  pr o d uc e s o m e eff ects o n p ati e nts’ P R Os. 
T h er ef or e, it is ass u m e d t h at p ati e nts w h o disc o nti n u e t h e st u d y tr e at m e nt d u e t o A Es at a gi v e n ti m e p oi nt 
w o ul d, o n a v er a g e, h a v e t h eir u n o bs er v e d sc or e ri g ht aft er a n A E t h at l e d t o tr e at m e nt disc o nti n u ati o n w ors e  b y 
s o m e a m o u nt δ c o m p ar e d t o t h e o bs er v e d sc or es of p ati e nts at t h at ti m e p oi nt. T his ass u m pti o n a p pli es t o b ot h 
tr e at m e nt ar ms. 
F or p att er n 2, a c o ns er v ati v e ass u m pti o n is t h at P R O sc or es will d et eri or at e c o nti n u o usl y aft er dis e as e 
pr o gr essi o n. It will b e  ass u m e d t h at u n o bs er v e d sc or es aft er dis e as e pr o gr essi o n w o ul d b e w ors e b y s o m e 
a m o u nt δ at e ac h visit aft er pr o gr essi o n c o m p ar e d t o p ati e nts wit h a v ail a bl e d at a ( a n d n o pr o gr essi o n). T his 
ass u m pti o n will b e a p pli e d t o b ot h tr e at m e nt ar ms.  
F or p att er n 3,  d at a will b e ass u m e d t o b e M A R i n b ot h tr e at m e nt ar ms.  
T h e i m p ut ati o n of m o n ot o n e missi n g d at a will b e d o n e s e q u e nti all y f or e ac h sc h e d ul e d P R O ass ess m e nt visit, 
k = k 1, …, K ( w h er e k 1 c orr es p o n ds t o t h e first visit u p t o W e ek 1 2 wit h a n y m o n ot o n e missi n g d at a, a n d K 
c orr es p o n ds t o W e e k 1 2) as f oll o ws:  
1.  I m p ut e all m o n ot o n e missi n g v al u es at visit k usi n g a n M A R-b as e d m ulti pl e i m p ut ati o n pr e dicti v e m e a n 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 5  of 7 5  
 
m atc hi n g m o d el i ncl u di n g t h e eff ects f or b as eli n e c o v ari at es as list e d f or t h e i m p ut ati o n m o d el of n o n -
m o n ot o n e missi n g d at a a b o v e a n d P R O v al u es at e ac h sc h e d ul e ass ess m e nt ti m e p oi nt u p t o ( k -1). T h e 
i m p ut ati o n m o d el will b e esti m at e d fr o m all st u d y p ati e nts wit h a v ail a bl e d at a at visit k, r e g ar dl ess of 
tr e at m e nt disc o nti n u ati o n, i ncl u di n g t h os e i m p ut e d i n st e p ( a) a b o v e. 
2.  A dj ust t h e m o n ot o n e i m p ut e d v al u es at visit k b y a m o u nt δ i n t h e dir ecti o n of sc or e w ors e ni n g f or t h e 
f oll o wi n g c as es:  
•  
F or p att er n 1, f or p ati e nts f or w h o m visit k is t h e first sc h e d ul e d P R O ass ess m e nt ti m e p oi nt aft er 
st u d y tr e at m e nt disc o nti n u ati o n.  
•  
All v al u es i n p att er n 2, t h at is all m o n ot o n e i m p ut e d v al u es w h er e visit k is aft er p ati e nt’s dis e as e 
pr o gr essi o n.  
T h e δ a dj ust m e nt will b e p erf or m e d f or b ot h tr e at m e nt ar ms. T h e a dj ust m e nt will b e i m pl e m e nt e d usi n g M N A R 
st at e m e nt i n Pr oc MI, usi n g ti m e p oi nt-s p ecific fl a gs t o d esi g n at e v al u es r e q uiri n g δ a dj ust m e nt.  
T h e a b o v e st e ps ( a) -( b) ar e p erf or m e d f or e ac h visit k, b ef or e pr oc e e di n g wit h t h e i m p ut ati o ns of t h e n ext visit 
( k + 1). 
F or p att er n 1, t his i m p ut ati o n str at e g y m atc h es t h e si n gl e e v e nt of t oxicit y l e a di n g t o t h e st u d y tr e at m e nt 
disc o nti n u ati o n wit h a si n gl e w ors e ni n g ( δ a dj ust m e nt) i n t h e P R Os ri g ht aft er t h e st u d y  tr e at m e nt 
disc o nti n u ati o n; t h e w ors e ni n g i m p os e d at t his ti m e p oi nt aff ects s u bs e q u e nt ti m e p oi nts vi a t h e c orr el ati o ns 
b et w e e n visits t h at ar e esti m at e d i n t h e i m p ut ati o n m o d el. Si nc e t h e i m p ut ati o n m o d el is esti m at e d fr o m t h e 
d at a of p ati e nts w h o h a d t h ei r P R Os c oll ect e d, t h e ass u m pti o n of t his a n al ysis is t h at t h e f ut ur e v al u es aft er t h e 
o n e -ti m e δ a dj ust m e nt w o ul d r es e m bl e t h e o utc o m es of p ati e nts w h o h a d a si mil ar tr aj ect or y pri or t o t h e 
p ati e nt’s missi n g v al u e.  
F or p att er n 2, t his i m p ut ati o n str at e g y a ss u m es t h at P R O sc or es will d et eri or at e ( b y s o m e a m o u nt δ) e v e n 
f urt h er aft er pr o gr essi o n i n b ot h tr e at m e nt ar ms. F or t his p att er n, t h e δ a dj ust m e nt will b e a p pli e d at e ac h visit, 
i n a d diti o n t o usi n g pr evi o usl y δ-a dj ust e d v al u es as pr e dict ors of s u bs e q u e n t P R Os. It ex plicitl y e nf orc es a n 
ass u m pti o n t h at pr o gr essi o n is ass oci at e d wit h w ors e ni n g t h at p ersists t hr o u g h o ut s u bs e q u e nt ti m e p oi nts 
c o m p ar e d t o p ati e nts  wit h o ut pr o gr essi o n a n d d o es n ot r el y excl usi v el y o n t h e esti m at e d c orr el ati o ns b et w e e n 
ti m e p oi nts e m b e d d e d i n t h e i m p ut ati o n m o d el i n or d er t o pr o p a g at e t h e eff ect of δ t hr o u g h ti m e.  
T h e δ v al u es w e will i m p os e ( w ors e ni n g) f or e ac h P R O sc or e f or p att er ns 1 a n d 2 c orr es p o n d t o t h e h alf of t h e 
est a blis h e d cli nic all y m e a ni n gf ul t hr es h ol d f or c h a n g e ( e. g ., 5 p oi nts).   
A t ot al of 1 0 0 m ulti pl y -i m p ut e d d at as ets will b e cr e at e d f or e ac h P R O. T h e r a n d o m n u m b er g e n er at or s e e d f or 
t h e i m p ut ati o n of n o n-m o n ot o n e missi n g v al u es usi n g M C M C will b e 5 4 1 4, a n d t h e r a n d o m s e e d f or i m p ut ati o n 
of m o n ot o n e missi n g v al u es  will b e 5 4 1 4 +k, f or k = 1, 2, … f or e ac h s e q u e nti al visit wit h m o n ot o n e missi n g d at a.  
A n A N C O V A m o d el ( n ot r e p e at e d m e as ur es, a n d wit h n o r a n d o m eff ects) wit h t h e s a m e c o v ari at es as i n t h e 
pri m ar y a n al ysis will b e p erf or m e d at W e ek 1 2 usi n g t h e S A S Mix e d pr oc e d ur e.  
T h e S A S MI A n al yz e pr oc e d ur e will b e us e d t o c o m bi n e t h e r es ults of t h es e a n al ys es f or t h e i m p ut ati o ns. F or a 
m or e d et ail e d d escri pti o n of t h e i m pl e m e nt ati o n M N A R i m p ut ati o n, s e e R atitc h B a n d O’ K ell y  M 7.  
T h e tr e at m e nt diff er e nc es will b e esti m at e d fr o m t h e fi n al m o d el wit h L S -m e a ns diff er e nc es. T h e L S m e a n 
tr e at m e nt diff er e nc e, 9 5 % CI, a n d p-v al u e will b e pr es e nt e d  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 6  of 7 5  
 
1 9. 3.  E X PL O R A T O R Y E F FI C A C Y  
1 9. 3. 1.  
E X PL O R A T O R Y E F FI C A C Y V A RI A BL E S &  D E RI V A TI O N S  
1 9. 3. 1. 1.  
Q Tc F  f oll o wi n g tr e at m e nt wit h iri n ot ec an li p os o m e i nj ecti o n  
F or P art 1 p ati e nts t h e Q Tc will b e c oll ect e d a n d d eri v e d usi n g Fri d erici a’ s c orr ecti o n m et h o d as f oll o w: 
 
1 9. 3. 1. 2.  
Ti m e t o Tr e at m e nt F ail ur e ( T T F)  
Tr e at m e nt f ail ur e , ass ess e d i n P art 2 o nl y, is d efi n e d as tr e at m e nt disc o nti n u ati o n f or a n y r e as o n s uc h as dis e as e 
pr o gr essi o n, d e at h or t oxicit y .  Ti m e t o tr e at m e nt f ail ur e is c o m p ut e d as: 
T T F  ( m o nt hs)= (e arli est d at e of [ P D, d e at h, st u d y tr e at m e nt disc o nti n u ati o n] –  d at e of r a n d o miz ati o n + 
1) / 3 0. 4 3 7 5. 
T h e tr e at m e nt -f ail ur e d at e f or p ati e nts w h o disc o nti n u e f or r e as o ns ot h er t h a n R E CI S T V ersi o n 1. 1 pr o gr essi o n 
will b e t h e d at e of t h e l ast st u d y dr u g a d mi nistr ati o n.  P ati e nts w h o h a v e n ot disc o nti n u e d tr e at m e nt pri or t o t h e 
d at a c ut -off d at e will b e c e ns or e d at t h e d at e of l ast t u m or ass ess m e nt d oc u m e nti n g n o o bj ecti v e pr o gr essi o n.  
1 9. 3. 1. 3.  
E O R T C -QL Q -C 3 0 a n d L C 1 3  
T h e f oll o wi n g sc or es will b e d eri v e d as p er t h e P R O S A P.  
E O R T C QL Q -C 3 0  
- 
Gl o b al H e alt h St at us  
- 
F u ncti o n al sc al es:  
o  
P h ysic al f u ncti o ni n g  
o  
R ol e f u ncti o ni n g  
o  
E m oti o n al f u ncti o ni n g  
o  
C o g niti v e f u ncti o ni n g  
o  
S oci al f u ncti o ni n g  
- 
S y m pt o m sc al es/it e ms:  
o  
F ati g u e  
o  
N a us e a a n d v o miti n g  
o  
P ai n  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 7  of 7 5  
 
o  
D ys p n e a  
o  
I ns o m ni a 
o  
A p p etit e l oss  
o  
C o nsti p ati o n  
o  
Di arr h e a  
o  
Fi n a nci al diffic ulti es  
E O R T C QL Q -L C 1 3 
- 
S y m pt o m sc al es/it e ms:  
o  
C o u g hi n g  
o  
H e m o pt ysis  
o  
D ys p n e a  
o  
S or e m o ut h  
o  
D ys p h a gi a  
o  
P eri p h er al n e ur o p at h y  
o  
Al o p eci a  
o  
P ai n i n c h est  
o  
P ai n i n ar m/s h o ul d er  
o  
P ai n i n ot h er p arts  
1 9. 3. 1. 4.  
P ati e nt Gl o b al I m pr essi o n of C h a n g e ( P GI -C) a n d S ev erit y ( P GI -S)  
T h e f oll o wi n g r es p o ns es will b e a n al ys e d  as p er t h e P R O S A P.  
P GI -S:  
- 
N o n e  
- 
Mil d  
- 
M o d er at e  
- 
S ev er e  
- 
V er y S e v er e  
P GI -C:  
- 
V er y m uc h i m pr o v e d 
- 
M uc h i m pr o v e d  
- 
Mi ni m all y i m pr o v e d  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 8  of 7 5  
 
- 
N o c h a n g e  
- 
Mi ni m all y w ors e  
- 
M uc h w ors e  
- 
V er y m uc h w ors e  
1 9. 3. 1. 5.  
  E Q -5 D -5L  
T h e f oll o wi n g r es p o ns es will b e a n al ys e d  p er t h e P R O S A P.  
- 
M o bilit y  
o  
N o pr o bl e ms i n w al ki n g  
o  
Sli g ht pr o bl e ms i n w al ki n g  
o  
M o d er at e pr o bl e ms i n w al ki n g  
o  
S ev e r e pr o bl e ms i n w al ki n g 
o  
U n a bl e t o w al k  
- 
S elf -C ar e  
o  
N o pr o bl e ms w as hi n g or dr essi n g  
o  
Sli g ht pr o bl e ms w as hi n g or dr essi n g  
o  
M o d er at e pr o bl e ms w as hi n g or dr essi n g  
o  
S ev er e pr o bl e ms w as hi n g or dr essi n g  
o  
U n a bl e t o w as h or dr ess  
- 
Us u al acti viti es  
o  
N o pr o bl e ms d oi n g us u al acti viti es  
o  
Sli g ht pr o bl e ms d oi n g us u al acti viti es  
o  
M o d er at e pr o bl e ms d oi n g us u al acti viti es  
o  
S ev er e pr o bl e ms d oi n g us u al acti viti es  
o  
U n a bl e t o d o us u al acti viti es  
- 
P ai n/ Disc o mf ort  
o  
N o p ai n or disc o mf ort  
o  
Sli g ht p ai n or disc o mf ort  
o  
M o d er at e p ai n or disc o mf ort  
o  
S ev e r e p ai n or disc o mf ort 
o  
Extr e m e p ai n or disc o mf ort  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 4 9  of 7 5  
 
- 
A nxi et y/ D e pr essi o n  
o  
N ot a nxi o us or d e pr ess e d  
o  
Sli g htl y a nxi o us or d e pr ess e d  
o  
M o d er at el y a nxi o us or d e pr ess e d  
o  
S ev er el y a nxi o us or d e pr ess e d  
o  
Extr e m el y a nxi o us or d e pr ess e d  
1 9. 3. 1. 6.  
  Ti m e t o C N S pr o gr essi o n  ( P art 2) 
T h e t i m e t o C N S pr o gr essi o n is d efi n e d as t h e ti m e fr o m r a n d o miz ati o n t o t h e d ev el o p m e nt of C N S pr o gr essi o n 
as d efi n e d b y  t h e R A N O-B M w or ki n g gr o u p  r es p o ns e ass ess m e nt crit eri a, b y BI C R a n d b y i n v esti g at or 
ass ess m e nt .  T h e o v er all ass ess m e nt will b e t a k e n fr o m t h e C R F p a g e a n d will n ot b e pr o gr a m m e d. 
 [ Pr o gr essi o n d at e fr o m t h e R A N O-B M w or ki n g gr o u p crit eri a –  r a n d o miz ati o n d at e + 1]/ 3 0. 4 3 7 5 
P ati e nts w h o d o n ot h a v e pr o gr essi v e dis e as e acc or di n g t o R A N O -B M  crit eri a, will b e c e ns or e d t o t h e l ast v ali d 
R A N O -B M ev al u ati o n.  
1 9. 3. 2.  
A N AL Y SI S O F E X PL O R A T O R Y E F FI C A C Y V A RI A BL E S  
Ex pl or at or y a n al ys es will b e p erf or m e d o n t h e P art 1 S af et y P o p ul ati o n f or P art 1 a n al ys es, a n d I nt e nt -t o-Tr e at 
P o p ul ati o n f or P art 2 a n al ys es.   
1 9. 3. 2. 1.  
Q Tc F a n alysis ( P art 1  o nl y ) 
D escri pti v e s u m m ari es of o bs er v e d a n d c h a n g e fr o m b as eli n e v al u es will b e pr es e nt e d f or Q Tc i nt er v al usi n g 
Fri d erici a’s c orr ecti o n m et h o d.  
1 9. 3. 2. 2.  
Ti m e t o Tr e at m e nt F ail ur e ( T T F)  
F or P art 2, t i m e t o tr e at m e nt f ail ur e ( T T F) will b e c o m p ar e d b et w e en t h e 2 tr e at m e nt ar ms usi n g str atifi e d 
l o gr a n k t ests.  K a pl a n-M ei er a n al ys es will b e p erf or m e d o n  e ac h tr e at m e nt gr o u p t o o bt ai n  t h e m e di a n T T F wit h 
t h e 9 5 % CI.  A str atifi e d C ox pr o p orti o n al h az ar ds r e gr essi o n will b e us e d t o esti m at e t h e h az ar d r ati os a n d t h eir 
c orr es p o ndi n g 9 5 % c o nfi d e nc e i nt er v als.  
T h e s u m m ar y f or T T F will pr es e nt t h e fr e q u e nc y distri b uti o n of T T F st at us (tr e at m e nt f ail ur e, d e at h or c e ns or e d), 
fr e q u e nc y distri b uti o n of t h e r e as o ns f or c e ns ori n g at t h e ti m e of t h e d at a c ut ( ali v e a n d n ot f ail e d tr e at m e nt, 
wit h dr a w n fr o m st u d y, l ost t o  f oll o w-u p), K a pl a n -M ei er esti m at es of m e di a n T T F, a n d t w o -si d e d p-v al u es fr o m 
t h e l o gr a n k t ests.  S u m m ari es a n d a n al ys es will b e pr es e nt e d f or t h e P art 2 I nt e nt -t o-Tr e at  p o p ul ati o n.  
A fi g ur e dis pl a yi n g t h e K a pl a n -M ei er T T F c ur v es f or e ac h tr e at m e nt will b e pr es e nt e d.  
T h e a n al ysis will b e p erf or m e d o n P art 1 a n d P art 2.  F or P art 1, o nl y d escri pti v e s u m m ar y will b e pr es e nt e d, n o 
c o m p aris o ns b et w e e n tr e at m e nt gr o u ps as t h er e is o nl y o n e tr e at m e nt gr o u p . 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 5 0  of 7 5  
 
1 9. 3. 2. 3.  
E O R T C -QL Q -C 3 0 a n d L C 1 3  
D escri pti v e s u m m ari es of o bs er v e d a n d c h a n g e fr o m b as eli n e v al u es will b e pr es e nt e d e ac h f u ncti o n.  
1 9. 3. 2. 4.  
P ati e nt Gl o b al I m pr essi o n of C h a n g e ( P GI -C) a n d S ev erit y ( P GI -S)  
P GI -S:  
F r e q u e nci es a n d p erc e nt a g es will b e pr es e nt e d f or e ac h of t h e r es p o ns es . 
P GI -C:  
F r e q u e nci es a n d p erc e nt a g es will b e p r es e nt e d f or e ac h of t h e r es p o ns es. 
1 9. 3. 2. 5.  
  E Q -5 D -5L  
Fr e q u e nc y a n d p erc e nt a g es will b e pr es e nt e d f or e ac h of t h e r es p o ns es f or e ac h it e m . 
 
T h e V A S sc or e o n h o w g o o d or b a d h e alt h is t o d a y will b e s u m m ariz e d d escri pti v el y.  
1 9. 3. 2. 6.  
  Ti m e t o C N S pr o gr essi o n  
F or P art 2, t i m e t o C N S pr o gr essi o n will b e c o m p ar e d b et w e e n t h e 2 tr e at m e nt ar ms usi n g str atifi e d l o gr a n k t ests 
(str atifi e d f or r e gi o n a n d pl ati n u m r esist a nt).  K a pl a n-M ei er a n al ys es will b e p erf or m e d o n e ac h tr e at m e nt gr o u p 
t o o bt ai n t h e m e di a n Ti m e t o C N S pr o gr essi on wit h t h e 9 5 % CI.  A str atifi e d C ox pr o p orti o n al h az ar ds r e gr essi o n 
will b e us e d t o esti m at e t h e h az ar d r ati os a n d t h eir c orr es p o n di n g 9 5 % c o nfi d e nc e i nt er v als.  
T h e s u m m ar y f or Ti m e t o C N S pr o gr essi o n will pr es e nt t h e fr e q u e nc y distri b uti o n of Ti m e t o C N S  pr o gr essi o n 
st at us ( C N S pr o gr essi o n, d e at h or c e ns or e d), fr e q u e nc y distri b uti o n of t h e r e as o ns f or c e ns ori n g at t h e ti m e of 
t h e d at a c ut, K a pl a n-M ei er esti m at es of m e di a n ti m e t o C N S pr o gr essi o n, a n d t w o-si d e d p-v al u es fr o m t h e 
l o gr a n k t ests.  S u m m ari es a n d a n al ys es will b e pr es e nt e d f or t h e P art 2 I nt e nt -t o-Tr e at  p o p ul ati o n.  
A fi g ur e dis pl a yi n g t h e K a pl a n -M ei er Ti m e t o C N S pr o gr essi o n c ur v es f or e ac h tr e at m e nt will b e pr es e nt e d . 
2 0.  S A F E T Y O U T C O M E S  
All o ut p uts f or s af et y o utc o m es will b e b as e d o n t h e S af et y A n al ysis S et.  
T h er e will b e n o st atistic al c o m p aris o ns b et w e e n t h e tr e at m e nt gr o u ps f or s af et y d at a, u nl ess ot h er wis e 
s p ecifi e d wit h t h e r el e v a nt s ecti o n.  
All s af et y o utc o m es will b e pr es e nt e d s e p ar at el y f or t h e P art 1 a n d P art 2 of t h e st u d y  a n d b y U G T 1 A 1 * 2 8  all el e  
st at us ( h o m oz y g o us T A 7/ 7) f or r el e v a nt A E s u m m ari es. 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 5 1  of 7 5  
 
2 0. 1.  A D V E R S E E V E N T S  
A d v ers e E v e nts ( A Es) will b e c o d e d usi n g  t h e M e dic al Dicti o n ar y f or R e g ul at or y Acti viti es ( M e d D R A) c e ntr al 
c o di n g dicti o n ar y, usi n g c urr e nt v ersi o n . 
A d v ers e ev e nts will b e c o nsi d er e d tr e at m e nt -e m er g e nt if:  
•  
T h e e v e nt occ urs f or t h e first ti m e aft er t h e st art of st u d y tr e at m e nt a n d o n or b ef or e 3 0 d a ys aft er fi n al 
d os e of st u d y tr e at m e nt a n d w as n ot o bs er v e d pri or t o st art of st u d y tr e at m e nt 
•  
T h e e v e nt w as o bs er v e d pri or t o t h e st art of st u d y tr e at m e nt b ut i ncr e as e d i n N CI C T C A E v5. 0  gr a d e 
d uri n g st u d y tr e at m e nt.  
•  
A Es t h at st art o n t h e s a m e d a y as t h e first d os e of st u d y dr u g will b e c o nsi d er e d tr e at m e nt e m er g e nt.  
S e e A p p e n dix 2 f or h a n dli n g of p arti al d at es f or A Es.  I n t h e c as e w h er e it is n ot p ossi bl e t o d efi n e a n A E as 
tr e at m e nt e m er g e nt or n ot, t h e A E will b e cl assifi e d b y t h e w orst c as e; i. e. tr e at m e nt e m er g e nt.  
A n o v er all s u m m ar y of n u m b er of p ati e nt s wit hi n t h e c at e g ori es d escri b e d i n t h e s u b-s ectio n s b el o w, will b e 
pr o vi d e d as s p ecifi e d i n t h e t e m pl at es. S e p ar at e s u m m ari es will b e pr es e nt e d f or P art 1 a n d P art 2.  
Listi n gs will i ncl u d e T E A Es a n d N o n -T E A Es.  
2 0. 1. 1.  
A LL T E A E S  
I nci d e nc e of T E A Es will b e pr es e nt e d b y S yst e m Or g a n Cl ass ( S O C) a n d Pr ef err e d T er m ( P T).  P ati e nts wit h 
m ulti pl e a d v ers e e v e nts wit hi n a s yst e m or g a n cl ass or pr ef err e d t er m will o nl y b e c o u nt e d o nc e u n d er e ac h 
c at e g or y. A s e p ar at e t a bl e f or all ev e nts occ urri n g i n at l e ast 1 0 % of p ati e nts i n t h e Iri n ot ec a n Li p os o m e I nj ecti o n 
tr e at m e nt will als o b e pr es e nt e d.  
A s e p ar at e t a bl e b y pr ef err e d t er m o nl y will als o b e pr es e nt e d.  
2 0. 1. 2.  
A LL T E A E S B Y M A XI M U M C T C A E  G R A D E  
T a b ul ar s u m m ari es will b e pr es e nt e d b y m axi m u m C T C A E gr a d e.  P ati e nts will b e c o u nt e d o nc e at e ac h A E l e v el 
(S O C a n d P T), usi n g t h e hi g h est C T C A E gr a d e e v e nt f or cl assific ati o n.  
2 0. 1. 3.  
A LL T E A E S O F G R A D E 3  O R M O R E  
A s u m m ar y of all T E A Es of Gr a d e 3 or hi g h er b y S O C a n d P T will b e pr e p ar e d.  
A s e p ar at e t a bl e will b e pr o d uc e d f or T E A Es wit h N CI -C T C A E Gr a d e 3 or hi g h er.  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 5 2  of 7 5  
 
2 0. 1. 4.  
A LL R EL A T E D T E A E S 
R el at e d T E A E  ar e ev e nts r ec or d e d as s uc h b y t h e I n v esti g at or i n t h e C R F.  If a p ati e nt  r e p ort’s t h e s a m e A E m or e 
t h a n o nc e wit hi n t h at S O C a n d P T, t h e A E wit h t h e w orst c as e r el ati o ns hi p t o st u d y m e dic ati o n will b e us e d i n t h e 
c orr es p o n di n g r el ati o ns hi p s u m m ari es.  A s e p ar at e t a bl e f or all ev e nts occ urri n g i n at l e ast 1 0 % of p ati e nts i n t h e 
Iri n ot ec a n Li p os o m e I nj ecti o n tr e at m e nt will als o b e pr es e nt e d.  
A s e p ar at e t a bl e will b e pr o d uc e d f or R el at e d T E A Es wit h N CI-C T C A E Gr a d e 3 or hi g h er.  
A s e p ar at e t a bl e will b e pr o d uc e d f or t h e Iri n ot ec a n li p os o m e i nj ecti o n ar m i n P art 2 f or R el at e d T E A Es wit h 
t er ms i ncl u di n g c o m bi n e d s p ecifi e d pr ef err e d t er ms . 
2 0. 1. 5.  
A LL S E RI O U S T E A E S  
S eri o us a d v ers e e v e nts ( S A Es ) ar e t h os e e v e nts r ec or d e d as “S eri o us” o n t h e A dv ers e E v e nts  p a g e of t h e C R F. A 
s u m m ar y of s eri o us T E A Es b y S O C a n d P T will b e pr e p ar e d . A s e p ar at e t a bl e f or all ev e nts occ urri n g i n at l e ast 5 % 
of p ati e nts i n t h e Iri n ot ec a n Li p os o m e I nj ecti o n tr e at m e nt will als o b e pr es e nt e d . 
2 0. 1. 6.  
A LL S E RI O U S R EL A T E D T E A E S  
S eri o us a d v ers e e v e nts ( S A Es) ar e t h os e e v e nts r ec or d e d as “ S eri o us” o n t h e A dv ers e E v e nts  p a g e of t h e C R F a n d 
w h o r ec or d e d “ R el at e d” o n t h e A dv ers e E v e nts p a g e. A s u m m ar y of s eri o us R el at e d T E A Es b y S O C a n d P T will b e 
pr e p ar e d.   
2 0. 1. 7.  
T E A E S L E A DI N G T O D O S E A DJ U S T M E N T 
T E A Es l e a d i n g t o d os e d el a y e d/i nt err u pt e d/r e d uc e d will b e i d e ntifi e d  i n t h e acti o n t a k e n o n t h e C R F . A s e p ar at e 
t a bl e f or all ev e nts occ urri n g i n at l e ast 5 % of p ati e nts i n t h e Iri n ot ec a n Li p os o m e I nj ecti o n tr e at m e nt will als o b e 
pr es e nt e d . 
S u m m ari e s b y S O C a n d  P T will b e pr e p ar e d.   
2 0. 1. 8.  
T E A E S L E A DI N G T O T R E A T M E N T D I S C O N TI N U A TI O N 
T E A Es l e a di n g t o p er m a n e nt disc o nti n u ati o n of st u d y m e dic ati o n will b e i d e ntifi e d b y usi n g t h e “ disc o nti n u e d 
fr o m st u d y tr e at m e nt” i n acti o n t a k e n o n t h e C R F. A s e p ar at e t a bl e f or all e v e nts occ urri n g i n at l e ast 2 p ati e nts 
i n t h e Iri n ot ec a n Li p os o m e I nj ecti o n tr e at m e nt will als o b e pr es e nt e d. 
S u m m ari es b y S O C a n d P T will b e pr e p ar e d.   
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 5 3  of 7 5  
 
2 0. 1. 9.  
T E A E S  L E A DI N G T O D E A T H  
T E A Es l e a di n g t o D e at h ar e t h os e e v e nts w hic h ar e r ec or d e d as ” P ati e nt  Di e d ” o n t h e A dv ers e E v e nts O utc o m e  
p a g e of t h e C R F. A s u m m ar y of T E A Es l e a di n g t o d e at h b y S O C a n d P T will b e pr e p ar e d.  
2 0. 1. 1 0.  IN F U SI O N R EL A T E D T E A E S 
I nf usi o n r el at e d T E A Es ar e t h os e e v e nts w hic h a ns w er e d “ y es” t o t h e i nf usi o n r el at e d c h ec k b ox o n t h e C R F .   
S u m m ari es b y S O C a n d P T will b e pr e p ar e d.  
2 0. 1. 1 1.  D O S E L I MI TI N G T O XI CI TI E S ( DL TS) A E S 
F or P art 1 o nl y, DL T A Es w hic h ar e i n dic at e d b y t h e I n v esti g at or o n t h e C R F will b e s u m m ariz e d a n d list e d.  
2 0. 1. 1 2.  R EL A T E D T E A E S G R A D E 3  O R H I G H E R B Y P L A TI N U M S E N SI TI VI T Y  
R el at e d T E A Es of Gr a d e 3 or hi g h er will b e s u m m ariz e d b y pl ati n u m s e nsiti vit y ( pl ati n u m s e nsiti v e a n d pl ati n u m 
r esist a nt) i n all p art 2  p ati e nts  s plit b y tr e at m e nt gr o u p. A s e p ar at e t a bl e f or all e v e nts occ urri n g i n at l e ast 1 0 % 
of p ati e nts i n t h e Iri n ot ec a n Li p os o m e I nj ecti o n tr e at m e nt will als o b e pr es e nt e d.  
2 0. 1. 1 3.  S U B G R O U P S O F A D V E R S E E V E N T S  
T h e f oll o wi n g s u m m ari es will als o b e cr e at e d f or p ati e nts t h at ar e U G T 1 A 1  h o m oz y g o us  T A 7/ 7 : 
•  
O v er all s u m m ar y of a d v ers e e v e nts  
•  
All tr e at m e nt e m er g e nt a d v ers e e v e nts  
•  
All tr e at m e nt e m er g e nt a d v ers e e v e nts b y m axi m u m N CI -C T C A E gr a d e  ( all gr a d es, gr a d e 1, gr a d e 2, 
gr a d e 3, gr a d e 4 a n d gr a d e 5)  
•  
All r el at e d tr e at m e nt e m er g e nt a d v ers e ev e nts  
•  
All tr e at m e nt e m er g e nt a d v ers e e v e nts of N CI -C T C A E gr a d e 3 or hi g h er  
•  
All r el at e d tr e at m e nt e m er g e nt a d v ers e ev e nts of N CI -C T C A E gr a d e 3 or hi g h er  
•  
All tr e at m e nt e m er g e nt a d v ers e e v e nts l e a di n g t o tr e at m e nt disc o nti n u ati o n  
•  
All s eri o us tr e at m e nt e m er g e nt a d v ers e ev e nts  
•  
All s eri o us r el at e d tr e at m e nt e m er g e nt a d v ers e e v e nts  
•  
All tr e at m e nt e m er g e nt a d v ers e e v e nts l e a di n g t o d e at h  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 5 4  of 7 5  
 
2 0. 2.  D E A T H S  
If a n y p ati e nt s di e d uri n g t h e st u d y a s r ec or d e d o n t he D e at h D et ails  p a g e of t h e C R F , t h e i nf or m ati o n will b e 
pr es e nt e d i n a s u m m ar y  t a bl e a n d a d at a listi n g. 
2 0. 3.  LA B O R A T O R Y E V AL U A TI O N S  
L a b or at or y e v al u ati o ns ar e c oll ect e d b y Q 2 c e ntr al l a b or at or y.   
Sc h e d ul e d cli nic al s af et y l a b or at or y p ar a m et ers will b e s u m m ariz e d.  T h es e i ncl u d e:  
•  
H e m at ol o g y:  h e m o gl o bi n, h e m at ocrit, pl at el et c o u nt, R e d B l o o d C ells (R B C ), W hit e Bl o o d C ells ( W B C ) 
wit h diff er e nti al ( n e utr o p hils, l y m p h oc yt es, m o n oc yt es, e osi n o p hils, b as o p hils a n d ot h er c ells ) 
•  
C h e mistr y: el ectr ol yt e ( s o di u m, p ot assi u m, c hl ori d e a n d bic ar b o n at e), B l o o d U r e a N itr o g e n (B U N ), 
s er u m cr e ati ni n e, gl uc os e, bilir u bi n, A S T, AL T, al k ali n e p h os p h at as e, l act at e d e h y dr o g e n as e, uric aci d, 
t ot al pr ot ei n, al b u mi n, c alci u m, m a g n esi u m a n d p h os p h at e 
 
Pr es e nt ati o ns will us e SI U nits.  
Q u a ntit ati v e l a b or at or y m e as ur e m e nts r e p ort e d as “ < X”, i. e. b el o w t h e l o w er l i mit of q u a ntific ati o n ( BL Q), or 
“ > X”, i. e. a b o v e t h e u p p er li mit of q u a ntific ati o n ( UL Q), will b e c o n v ert e d t o  X f or t h e p ur p os e of q u a ntit ati v e 
s u m m ari es, b ut will b e pr es e nt e d as r ec or d e d, i. e. as “ < X” or “ > X” i n t h e listi n gs.  
T h e f oll o wi n g s u m m ari es  will b e pr o vi d e d f or l a b or at or y d at a:  
o  
Act u al a n d c h a n g e fr o m b as eli n e b y visit (f or q u a ntit ati v e m e as ur e m e nts)  
o  
S hift fr o m b as eli n e  t o e n d of st u d y acc or di n g t o C o m m o n T oxicit y ( C T C) gr a di n g syst e m  (se e 
A p p e n dix 3 ).  S hifts fr o m b as eli n e t o w orst p ost-d os e  (i. e. hi g h est gr a d e) i n C T C A E Gr a d e of 
l a b or at or y r es ults will als o b e s u m m ariz e d. 
o  
Listi n g of C T C A E gr a d e 3  a n d hi g h er v al u es.  I n t his listi n g, all o bs er v ati o ns f or a l a b p ar a m et er will 
b e dis pl a y e d f or a p ati e nt w h o h as a n y p ost -b as eli n e v al u e wit h C T C A E gr a d e gr e at er t h a n or e q u al 
t o 3 f or t h e p ar a m et er. 
o  
F or s p ecifi e d  l a b or at or y r es ults, t h e p erc e nt a g e of p ati e nts i n t h e iri n ot ec a n li p os o m e i nj ecti o n ar m 
i n P art 2 wit h w ors e ni n g l a b or at or y t est r es ults fr o m b as eli n e t o > = 2 0 % p ost b as eli n e r es ult (f or all 
p ati e nts wit h b as eli n e a n d p ost b as eli n e v al u e) f or a) all p ost b as eli n e gr a d es a n d b) f or all p ost 
b as eli n e gr a d es w h er e t h e w orst gr a d e is Gr a d e 3 or 4 acc or di n g t o C o m m o n T oxicit y ( C T C) gr a di n g 
syst e m (s e e A p p e n dix 3). 
2 0. 4.  E C G  E V AL U A TI O N S  
R es ults fr o m t h e c e ntr al E C G ( El ectr oc ar di o gr a m) R e a di n g C e ntr e will b e i ncl u d e d i n t h e r e p orti n g of t his st u d y 
f or P art 1 o nl y. 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 5 5  of 7 5  
 
T h e f oll o wi n g E C G p ar a m et ers will b e r e p ort e d f or t h e P art 1 o nl y a n d b e c oll ect e d at C ycl e 1 d a y 1( pr e -d os e, e n d 
o f i nf usi o n, 2 h o urs aft er inf us i o n), d a y 2  ( 2 4 h o urs aft er e n d of i nf usi o n), d a y 8 a n d d ay 1 5 ( pr e-d os e) . 
 
o  
H e art R at e ( b p m)  
o  
P R I nt er v al ( ms ec)  
o  
R R I nt er v al ( ms ec)  
o  
Q R S I nt er v al ( ms ec)  
o  
Q T I nt er v al ( ms ec)  
o  
O v er all ass ess m e nt of E C G (I n v esti g at or’s j u d g m e nt):  
 
N or m al  
 
A b n or m al, N ot Cli nic all y Si g nific a nt ( A N C S)  
 
A b n or m al, Cli nic all y Si g nific a nt ( A C S)  
 
T h e f oll o wi n g s u m m ari es will b e pr o vi d e d f or E C G d at a:  
 
o  
A ct u al a n d c h a n g e fr o m b as eli n e b y visit (f or q u a ntit ati v e m e as ur e m e nts)  
o  
Listi n g of p ati e nt s m e eti n g m ar k e dl y a b n or m al crit eri a  
o  
T h e n u m b er a n d p erc e nt a g e of p ati e nts wit h “ N or m al”, “ A b n or m al, n ot Cli nic all y Si g nific a nt” a n d 
“ A b n or m al, Cli nic all y Si g nific a nt” E C G r es ults will b e s u m m ariz e d b y tr e at m e nt at e ac h visit.  
2 0. 4. 1.  
E C G  M A R K E DL Y A B N O R M AL C RI T E RI A  
M ar k e dl y a b n or m al q u a ntit ativ e E C G m e as ur e m e nts will b e i d e ntifi e d i n acc or d a nc e wit h t h e f oll o wi n g 
pr e d efi n e d m ar k e dl y a b n or m al crit eri a:  
o  
A bs ol ut e v al u es f or Q T cF  I nt er v al cl assifi e d as:  
 
> 5 0 0  ms ec  
 
> 4 8 0 ms ec  a n d ≤ 5 0 0 ms ec  
 
> 4 5 0 ms ec a n d ≤ 4 8 0 ms ec  
 
C h a n g e fr o m B as eli n e > 3 0 a n d ≤ 6 0 ms ec  
 
C h a n g e fr o m B as eli n e > 6 0 ms ec  
2 0. 5.  V I T AL S I G N S 
T h e f oll o wi n g Vit al Si g ns m e as ur e m e nts will b e r e p ort e d f or t his st u d y:  
 
o  
R esti n g  S yst olic Bl o o d Pr ess ur e ( m m H g)  
o  
R esti n g Di ast olic Bl o o d Pr ess ur e ( m m H g)  
o  
R es pir at or y R at e  (r es p/ mi n) 
C CI






 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 5 8  of 7 5  
 
P o p ul ati o n P K r e p ort . 
2 0. 8. 2.  
P H A R M A C O KI N E TI C D A T A A N AL Y SI S  
P h ar m ac o ki n etics of t ot al iri n ot ec a n a n d S N -3 8 will b e q u a ntifi e d fr o m t h e c o nc e ntr ati o ns fr o m pl as m a s a m pl es 
usi n g n o nl i n e ar mix e d eff ect m o d eli n g ( N O N M E M). A P o p ul ati o n P K m o d el pr e vi o usl y d e v el o p e d o n hist oric al 
d at a will b e a p pli e d t o t his st u d y i n or d er t o c h ar act eriz e t h e P K i n 2L S CL C p ati e nt p o p ul ati o n, t o ass ess 
i nt eri n di vi d u al v ari a bilit y, a n d t o att e m pt t o ex pl ain p art of it b y t esti n g t h e i m p act of s o m e c o v ari at es. 
C o v ari at es e v al u at e d w o ul d i ncl u d e, b ut n ot b e li mit e d t o, a g e, g e n d er, r ac e, a n d U G T 1 A 1 * 2 8 g e n ot y p e . Pri m ar y 
a n d d eri v e d P K p ar a m et ers will b e c o m p ut e d fr o m t h e p o p ul ati o n P K m o d el ( e. g. m axi m u m o bs er v e d 
c o nc e ntr ati o n ( C m ax ), a v er a g e o bs er v e d c o nc e ntr ati o n ( Ca v er a g e), ar e a u n d er t h e c ur v e ( A U C), mi ni m u m 
c o nc e ntr ati o n (C mi n )). F ull d escri pti o n of t his P o p ul ati o n P K a n al ysis will b e c a pt ur e d s e p ar at el y i n a d at a a n alysis 
pl a n, a n d r es ults will b e r e p ort e d i n a st a n d al o n e r e p ort. 
2 0. 8. 3.  
P H A R M A C O KI N E TI C S /  P H A R M A C O D Y N A MI C S R EL A TI O N S HI P  
Gr a p hic al ex pl or ati o n will b e p erf or m e d t o i n v esti g at e a n y r el ati o ns hi p b et w e e n P K a n d p h ar m ac o d y n a mic 
e n d p oi nts (s af et y e. g. n e utr o p e ni a a n d di arr h e a; a n d effic ac y, e. g. O R R , O S, P F S). If a tr e n d is s h o w n, P K/ P D 
m o d elli n g will b e p erf or m e d a n d t his will b e d escri b e d i n a s e p ar at e D at a A n al ysis Pl a n a n d r e p ort e d i n a 
st a n d al o n e r e p ort. 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 5 9  of 7 5  
 
2 1.  R E F E R E N C E S  
H w a n g, I. K., S hi h, W. J., a n d D e C a ni, J. S. ( 1 9 9 0), " Gr o u p S e q u e nti al D esi g ns  Usi n g a F a mil y of T y p e I Err or 
Pr o b a bilit y S p e n di n g F u ncti o ns ," St atisti cs i n M e di ci n e , 9, 1 4 3 9– 1 4 4 5.  
O' K ell y, M., & R atitc h, B. ( 2 0 1 7). Cli nic al Tri al wit h Missi n g D at a: A G ui d e f or Pr actiti o n ers. J o h n Wil ey a n d S o ns, Lt d.  
E. A. Eis e n h a u er a, * , P. T h er ass e b , J. B o g a ertsc , L. H. Sc h w artz d , D. S ar g e nt e , R. F or df , J. D a nc ey g , S. Ar b uc k h , S. 
G wyt h eri , M. M o o n ey g , L. R u bi nst ei n g , L. S h a n k ar g , L. D o d d g , R. K a pl a nj , D. L ac o m b ec , J. V er w eij k “ N e w 
r es p o ns e e v al u ati o n crit eri a i n s oli d t u m o urs: R evis e d R E CI S T g ui d eli n e ( v ersi o n 1. 1)” E U R O P E A N J O U R N AL O F 
C A N C E R  4 5 ( 2 0 0 9) 2 2 8 –  2 4 7  
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 6 0  of 7 5  
 
A P P E N DI X 1.  R E P O R TI N G C O N V E N TI O N S  
 
P a g e L a y o u t: 
T h e S e cti o n 1 4 t a bl e s a n d A p p e n di x 1 6 li sti n g s s h o ul d b e i n l a n d s c a p e ori e nt ati o n b y d ef a ult.  
T h e o ut p ut i n S e cti o n 1 4 a n d A p p e n d i x 1 6 will b e i n R T F fil e f or m at  u si n g C o uri er N e w f o nt wit h 8 
p oi nt si z e.  
 
St ati sti c al c o n v e nti o n s : 
T h e p ati e nt p er c e nt a g e s ( %)  s h o ul d b e r o u n d e d t o o n e d e ci m al pl a c e.  
P er c e nt a g e s f or v al u e s i n t h e t a bl e s t h at ar e l e s s t h a n <  0. 1 s h o ul d b e pr e s e nt e d a s “ < 0. 1”.  
If “ %” i s p art of t h e c ol u m n h e a di n g, d o n ot r e p e at t h e “ %” si g n i n t h e b o d y of t h e t a bl e. 
If a v al u e i s z er o ( 0), t h e n d o n ot u s e 0 % a n d l e a v e t h e c orr e s p o n di n g p er c e nt a g e bl a n k. 
T h e f or m at f or r a n g e s h o ul d al w a y s b e “ Mi n, M a x”.  
If t h er e ar e mi s si n g d at a, t he n a mi s si n g r o w will b e a d d e d t o k e e p tr a c k of all p ati e nt s.  If t h er e ar e 
n o mi s si n g d at a, t h e n d el et e t h e mi s si n g r o w.  P er c e nt a g e s will n ot b e pr e s e nt e d o n t h e mi s si n g 
c at e g or y r o w.  
St a n d ar d D e vi ati o n s h o ul d b e a b br e vi at e d a s “ S D”, a n d St a n d ar d Err or s h o ul d b e a b br e vi at e d a s 
“ S E”; it i s pr e s e nt e d wit hi n p ar e nt h e si s n e xt t o t h e m e a n v al u e, wit h o ut a n y +/- si g n.  T h e St a n d ar d 
D e vi ati o n or St a n d ar d Err or s h o ul d h a v e o n e a d diti o n al d e ci m al p oi nt b e y o n d t h at of t h e m e a n (f or 
e x a m pl e, if t h e m e a n h a s o n e d e ci m al p oi nt, S D/ S E s h o ul d h a v e t w o d e ci m al p oi nt s).  M e a n a n d 
m e di a n s h o ul d h a v e o n e a d diti o n al d e ci m al p oi nt b e y o n d t h at of t h e d at a b ei n g s u m m ari z e d.  
“ N” will r e pr e s e nt t h e e ntir e tr e at m e nt gr o u p, w hil e “ n” will r e pr e s e nt a s u b s et of t h e tr e at m e nt 
gr o u p.  F or t a bl e s wit h p o p ul ati o n d e si g n at e d a s a r o w h e a di n g, “ N” s h o ul d b e u s e d (i. e. t a bl e s 
w h er e all t h e p arti ci p a nt d at a i s n ot a v ail a bl e f or e v er y v ari a bl e wit hi n a tr e at m e nt gr o u p).  A s a 
g ui d eli n e, if t h e n u m b er i s u s e d i n d e n o mi n at or t h at it s h o ul d b e pr e s e nt e d a s “ N”.  If t h e n u m b er i s 
u s e d i n n u m er at or it s h o ul d b e pr e s e nt e d a s “ n”.  
P -v al u e s will b e pr e s e nt e d wit h 4 d e ci m al s.  
 
 
C CI










 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 6 5  of 7 5  
 
A P P E N DI X 3.  
C T C A E  G R A DI N G F O R N U M E RI C LA B V AL U E S  
Fr o m  
htt p s:// ct e p. c a n c er. g o v/ pr ot o c ol D e v el o p m e nt/ el e ctr o ni c _ a p pli c ati o n s/ d o c s/ C T C A E _ v 5 _ Q ui c k _ R ef er e n c
e _ 5 x 7. p df  
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 6 6  of 7 5  
 
P ar a meter  
Gr a de 1  
Gr a de 2  
Gr a de 3  
Gr a de 4  
He m o gl o bi n 
decrease d  
6. 2 m m ol/ L - 
< L L N  
4. 9  m m ol/ L -  
< 6. 2 m m ol/ L  
< 4. 9 m m ol/ L  
 
He m o gl o bi n i ncrease  
↑ i n > 0 –  2 g/ d L 
a b o ve U L N  
or > B L if 
B L > U L N  
↑ i n > 2 –  4 g/ d L 
a b o ve U L N  
or > B L if 
B L >( U L N + 2)  
↑ i n > 4 g/ d L 
a b o ve U L N  
or > B L if 
B L >( U L N + 4)  
 
L y m p h oc yte decrease  
0. 8 x 1 0 9/ L –  
< L L N  
0. 5 x 1 0 9/ L  –  
< 0. 8 x 1 0 9/ L 
0. 2 x 1 0 9/ L  –  
< 0. 5 x 1 0 9/ L 
< 0. 2 x 1 0 9/ L   
Ne utr o p hils decrease  
1. 5 x 1 0 9/ L –  
< L L N  
1. 0 x 1 0 9/ L  –  
< 1. 5 x 1 0 9/ L 
0. 5 x 1 0 9/ L  –  
< 1. 0 x 1 0 9/ L 
< 0. 5 x 1 0 9/ L   
Platelets decrease  
7 5. 0 x 1 0 9/ L –  
< L L N  
5 0. 0 x 1 0 9/ L –  
< 7 5. 0 x 1 0 9/ L 
2 5. 0 x 1 0 9/ L –  
< 5 0. 0 x 1 0 9/ L 
< 2 5. 0 x 1 0 9/ L 
W B C decrease  
3. 0 x 1 0 9/ L –  
< L L N  
2. 0 x 1 0 9/ L –  
< 3. 0 x 1 0 9/ L 
1. 0 x 1 0 9/ L –  
< 2. 0 x 1 0 9/ L 
< 1. 0 x 1 0 9/ L 
A L T  
> 1 U L N –   
3 x U L N  
if 
baseli ne  
was 
n or mal; 
1. 5 
–  
3. 0 x baseli ne  
if 
baseli ne  
was 
a b n or mal 
> 3. 0 U L N –   
5. 0 x U L N if 
baseli ne was 
n or mal; 3. 0 –  
5. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 5. 0 U L N –   
2 0. 0 x U L N if 
baseli ne was 
n or mal; 5. 0 –  
2 0. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 2 0 x U L N  
if 
baseli ne  
was 
n or mal; 
> 2 0. 0 x baseli ne if 
baseli ne  
was 
a b n or mal 
Al kali ne P h os p hatase  
> 1 U L N –   
2. 5 x U L N  
if 
baseli ne  
was 
n or mal; 
2. 0 
–  
2. 5 x baseli ne  
if 
baseli ne  
was 
a b n or mal 
> 2. 5 U L N –   
5. 0 x U L N if 
baseli ne was 
n or mal; 2. 5 –  
5. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 5. 0 U L N –   
2 0. 0 x U L N if 
baseli ne was 
n or mal; 5. 0 –  
2 0. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 2 0 x U L N  
if 
baseli ne  
was 
n or mal; 
> 2 0. 0 x baseli ne if 
baseli ne  
was 
a b n or mal 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 6 7  of 7 5  
 
P ar a meter  
Gr a de 1  
Gr a de 2  
Gr a de 3  
Gr a de 4  
A S T  
> 1 U L N –   
3 x U L N  
if 
baseli ne  
was 
n or ma l; 
1. 5 
–  
3. 0 x baseli ne  
if 
baseli ne  
was 
a b n or mal 
> 3. 0 U L N –   
5. 0 x U L N if 
baseli ne was 
n or mal; 3. 0 –  
5. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 5. 0 U L N –   
2 0. 0 x U L N if 
baseli ne was 
n or mal; 5. 0 –  
2 0. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 2 0 x U L N  
if 
baseli ne  
was 
n or mal;  
> 2 0. 0 x baseli ne if 
baseli ne  
was 
a b n or mal 
T otal Bilir u bi n  
> 1 U L N –   
1. 5 x U L N  
if 
baseli ne  
was 
n or mal; 
> 1. 0 
–  
1. 5 x baseli ne  
if 
baseli ne  
was 
a b n or mal 
> 1. 5 U L N –   
3. 0 x U L N if 
baseli ne was 
n or mal; 1. 5 –  
3. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 3. 0 U L N –   
1 0. 0 x U L N if  
baseli ne was 
n or mal; 3. 0 –  
1 0. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 1 0 x U L N  
if 
baseli ne  
was 
n or mal; 
> 1 0. 0 x baseli ne if 
baseli ne  
was 
a b n or mal 
Creati ni ne  
> 1 x B L –  
1. 5 x B L or  
> 1 x U L N –  
1. 5 x U L N  
> 1. 5 x B L –  
3 x B L or  
> 1. 5 x U L N –  
3 x U L N  
> 3 x B L –  
6 x B L or  
> 3 x U L N –  
6 x U L N  
> 6 x B L or  
> 6 x U L N  
Calci u m i ncrease  
> U L N –  
< 2. 9 m m ol/ L  
> 2. 9 m m ol/ L –  
3. 1 m m ol/ L  
> 3. 1 m m ol/ L –  
3. 4 m m ol/ L  
> 3. 4 m m ol/ L  
Calci u m decrease  
2. 0 m m ol/ L –  
< L L N  
1. 7 5 m m ol/ L –   
< 2. 0 m m ol/ L  
1. 5 m m ol/ L –  
< 1. 7 5 m m ol/ L  
< 1. 5 m m ol/ L  
Al b u mi n  
3 g/ d L - < L L N  
2 g/ d L - < 3 g/ d L  
< 2 g/ d L  
 
Ma g nesi u m decrease  
0. 5 
m m ol/ L 
- 
< L L N  
0. 4 m m ol/ L - 
< 0. 5 m m ol/ L  
0. 3 m m ol/ L - 
< 0. 4 m m ol/ L  
< 0. 3 m m ol/ L  
Ma g nesi u m i ncrease  
> U L N 
–  
1. 2 3 
m m ol/ L  
 
> 1. 2 3 m m ol/ L –  
3. 3 0 m m ol/ L  
> 3. 3 0 m m ol/ L  
P otassi u m decrease  
3. 0 
m m ol/ L 
- 
< L L N  
 
2. 5 m m ol/ L < 3. 0 
m m ol/ L  
< 2. 5 m m ol/ L  
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 6 8  of 7 5  
 
P ar a meter  
Gr a de 1  
Gr a de 2  
Gr a de 3  
Gr a de 4  
P otassi u m i ncrease  
> U L N 
–  
5. 5 
m m ol/ L  
> 5. 5 m m ol/ L –  
6. 0 m m ol/ L  
> 6. 0 m m ol/ L –  
7. 0 m m ol/ L  
> 7. 0 m m ol/ L  
Gl uc ose  
3. 0 
m m ol/ L 
- 
< L L N  
2. 2 m m ol/ L - 
< L L N  
1. 7 m m ol/ L - 
< 2. 2 m m ol/ L  
< 1. 7 m m ol/ L  
S o di u m decrease  
1 3 0 
m m ol/ L 
- 
< L L N  
 
1 2 0 m m ol/ L - 
< 1 3 0 m m ol/ L  
< 1 2 0 m m ol/ L  
S o di u m i ncrease  
> U L N 
–  
1 5 0 
m m ol/ L  
> 1 5 0 m m ol/ L –  
1 5 5 m m ol/ L  
> 1 5 5 m m ol/ L –  
1 6 0 m m ol/ L  
> 1 6 0 m m ol/ L  
P h os p hate  
0. 8 
m m ol/ L 
- 
< L L U N  
0. 6 m m ol/ L - 
< 0. 8 m m ol/ L  
0. 3 m m ol/ L - 
< 0. 6 m m ol/ L  
< 0. 3 m m ol/ L  
Uric Aci d  
> U L N 
–  
0. 5 9 
m m ol/ L  
 
> 0. 5 9 m m ol/ L  
 
 
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 6 9  of 7 5  
 
A P P E N DI X  4:  E O R T C  QL Q -C 3 0  
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 7 0  of 7 5  
 
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 7 1  of 7 5  
 
T a bl e 7 . E O R T C Q L Q-C 3 0 S c ori n g G ui d e ( F a y er s et al 2 0 0 1)  
 
A b br evi ati o n  
N u m b er of 
it e ms 
It e m 
r a n g e * 
V ersi o n 3. 0 
It e m 
n u m b ers  
Gl o b al h e alt h st at us / Q oL  
 
 
 
 
Gl o b al h e alt h st at us/ Q oL (r evis e d) †  
QL 2  
2  
6  
2 9, 3 0  
F u ncti o n al d o m ai ns  
 
 
 
 
P h ysic al f u ncti o ni n g (r e vis e d) †  
P F 2  
5  
3  
1 t o 5  
R ol e f u ncti o ni n g (r e vis e d) †  
R F 2  
2  
3  
6, 7  
E m oti o n al f u ncti o ni n g  
E F  
4  
3  
2 1 t o 2 4  
C o g niti v e f u ncti o ni n g  
C F  
2  
3  
2 0, 2 5  
S oci al f u ncti o ni n g  
S F  
2  
3  
2 6, 2 7  
S y m pt o m d o m ai ns / it e ms  
 
 
 
 
F ati g u e  
F A  
3  
3  
1 0, 1 2, 1 8  
N a us e a a n d v o miti n g  
N V  
2  
3  
1 4, 1 5  
P ai n  
P A  
2  
3  
9, 1 9  
D ys p n e a  
D Y  
1  
3  
8  
I ns o m ni a 
SL  
1  
3  
1 1  
A p p etit e l oss  
A P  
1  
3  
1 3  
C o nsti p ati o n  
C O  
1  
3  
1 6  
Di arr h e a  
DI  
1  
3  
1 7  
Fi n a nci al diffic ulti es  
FI  
1  
3  
2 8  
* It e m r a n g e i s t h e diff er e n c e b et w e e n t h e p o s si bl e m a xi m u m a n d t h e mi ni m u m r e s p o n s e t o 
i n di vi d u al it e m s; m o st it e m s t a k e v al u e s fr o m 1 t o 4, gi vi n g r a n g e = 3.  
 
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 7 2  of 7 5  
 
S c ori n g al g orit h m  
T h e E O R T C -Q L Q -C 3 0 i s c o m p o s e d of b ot h m ulti -it e m d o m ai n s a n d si n gl e-it e m m e a s ur e s. T h e s e 
i n cl u d e fi v e f u n cti o n al d o m ai n s, t hr e e s y m pt o m d o m ai n s, a gl o b al h e alt h st at u s / Q o L d o m ai n, a n d 
si x si n gl e it e m s. E a c h of t h e m ulti -it e m d o m ai n s i n cl u d e s a diff er e nt s et of it e m s - n o it e m o c c ur s 
i n m or e t h a n o n e d o m ai n. 
T h e pri n ci pl e f or s c ori n g t h e s e d o m ai n s i s t h e s a m e i n all c a s e s:  
1. E sti m at e t h e a v er a g e of t h e it e m s t h at c o ntri b ut e t o t h e d o m ai n; t hi s i s t h e r a w s c or e.  
2. U s e a li n e ar tr a n sf or m ati o n t o st a n d ar di z e t h e r a w s c or e, s o t h at s c or e s r a n g e fr o m 0 t o 1 0 0; a 
hi g h er s c or e r e pr e s e nt s a hi g h er (" b ett er") l e v el of f u n cti o ni n g, or a hi g h er (" w or s e") l e v el of 
s y m pt o m s.  
T h e t e c h ni c al d et ail s ar e pr o vi d e d b el o w.  
If it e ms I 1 , I2 , ... In  ar e i n cl u d e d i n a d o m ai n, t h e pr o c e d ur e i s a s f oll o w s:  
C al c ul at e t h e r a w s c or e ( R S) a s f oll o w s: R S =( I 1 +I 2 + ... +I n )/ n 
A p pl y t h e li n e ar tr a n sf or m ati o n a s f oll o w s:  
F u n cti o n al d o m ai n s: D o m ai n s c or e = 1 –  (( R S −1)/r a n g e) × 1 0 0 
S y m pt o m d o m ai n s /  it e m s: D o m ai n s c or e = ( R S −1)/r a n g e × 1 0 0 
Gl o b al h e alt h st at u s/ Q o L: D o m ai n s c or e = ( R S −1)/r a n g e × 1 0 0  
w h er e R a n g e i s t h e diff er e n c e b et w e e n t h e m a xi m u m p o s si bl e v al u e of R S a n d t h e mi ni m u m 
p o s si bl e v al u e. T h e E O R T C -Q L Q -C 3 0 h a s b e e n d e si g n e d s o t h at all it e m s  i n a n y d o m ai n t a k e t h e 
s a m e r a n g e of v al u e s. T h er ef or e, t h e r a n g e of R S e q u al s t h e r a n g e of t h e it e m v al u e s ( s e e  Err or! 
R ef er e n c e s o ur c e n ot f o u n d.  P R O V ari a bl e s  ).  
If at l e a st h alf t h e c o m p o n e nt s of a d o m ai n ar e pr e s e nt, t h e n t h e d o m ai n s c or e will b e c al c ul at e d 
u si n g t h e a v er a g e of all it e m s a n s w er e d a s t h e r a w s c or e; ot h er wi s e t h e s c or e will b e s et t o 
mi s si n g. F or si n gl e m e a s ur e s, it t h e it e m i s mi s si n g t h e d o m ai n s c or e i s s et  t o mi s si n g.  
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 7 3  of 7 5  
 
A P P E N DI X  5:  E O R T C  QL Q -L C 1 3 
 
 
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 7 4  of 7 5  
 
T a bl e 8 . E O R T C-QL Q -L C 1 3 L u n g C a nc er M o d ul e Sc ori n g G ui d e  
 
D o m ai n  
N u m b er of 
it e ms 
It e m r a n g e * 
It e m n u m b ers 
S y m pt o m d o m ai ns / it e ms  
 
D ys p n e a †  
L C D Y 
3  
3  
3 3, 3 4, 3 5  
C o u g hi n g  
L C C O 
1  
3  
3 1  
H e m o pt ysis  
L C H A 
1  
3  
3 2  
S or e m o ut h  
L C S M 
1  
3  
3 6  
D ys p h a gi a  
L C D S 
1  
3  
3 7  
P eri p h er al n e ur o p at h y  
L C P N 
1  
3  
3 8  
Al o p eci a  
L C H R 
1  
3  
3 9  
P ai n i n c h est  
L C P C 
1  
3  
4 0  
P ai n i n ar m or s h o ul d er  
L C P A 
1  
3  
4 1  
P ai n i n ot h er p arts  
L C P O 
1  
3  
4 2  
* “It e m r a n g e” is t h e diff er e nc e b et w e e n t h e p ossi bl e m axi m u m a n d t h e mi ni m u m r es p o ns e t o i n di vi d u al it e ms.  
† T h e d ys p n e a d o m ai n s h o ul d o nl y b e us e d if all t hr e e it e ms h a v e b e e n a ns w er e d. S o m e r es p o n d e nts i g n or e 
q u esti o n 3 5 b ec a us e t h ey n ev er cli m b st airs; i n t his c as e, t h e sc or e f or t h e d ys p n e a d o m ai n w o ul d b e bi as e d if it 
w er e b as e d u p o n t h e ot h er t w o it e ms. H e nc e if it e m 3 5 is missi n g t h e n it e ms 3 3 a n d 3 4 s h o ul d b e us e d as si n gl e -
it e m m e as ur es. 
I n a d diti o n, a n e w d o m ai n will b e c alc ul at e d, D ys p n e a Alt er n at e (L C D Y AL T) w hic h c o m bi n es t h e t hr e e E O R T C-
QL Q -L C 1 3 it e ms a n d t h e It e m 8 fr o m E O R T C-QL Q -C 3 0:  
L C D Y AL T = {[( Q 8 + Q 3 3 + Q 3 4 + Q 3 5)/ 4] -1}/ 3 * 1 0 0  
T h e sc ori n g a p pr o ac h f or t h e E O R T C -QL Q -L C 1 3 is i d e ntic al t o t h at f or t h e s y m pt o m d o m ai ns / si n gl e it e ms of t h e 
E O R T C -QL Q -C 3 0. A r a w sc or e is c alc ul at e d as t h e a v er a g e of t h e it e ms t h at c o ntri b ut e t o t h e d o m ai n a n d n ext a 
li n e ar tr a nsf or m ati o n is us e d t o st a n d ar diz e t h e r a w sc or e ( R S), s o t h at sc or es r a n g e fr o m 0 t o 1 0 0. T h e li n e ar 
tr a nsf or m ati o n is as f oll o ws: 
D o m ai n sc or e = ( R S −1)/r a n g e × 1 0 0  
w h er e R S =r a w sc or e a n d r a n g e = 3 (s e e T a bl e 8 ). 
If at l e ast h alf t h e c o m p o n e nts of a d o m ai n ar e pr es e nt, t h e n t h e d o m ai n sc or e will b e c alc ul at e d usi n g t h e 
a v er a g e of all it e ms a ns w er e d as t h e r a w sc or e; ot h er wi s e t h e sc or e will b e s et t o missi n g. F or si n gl e m e as ur es, it 
t h e it e m is missi n g t h e d o m ai n sc or e is s et t o missi n g.  
 
 
C CI


 
St ati sti c al A n al y si s Pl a n  
I P S E N Bi oscie nce, I nc 
P R O T O C O L M M -3 9 8 -0 1 -0 3 -0 4  
P a g e 7 5  of 7 5  
 
A P P E N DI X  6 : C O N FI R M E D B E S T O V E R ALL R E S P O N S E  
 
 
C CI