Conditions: Chemotherapy-induced Nausea and Vomiting
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 404
Healthy volunteers: no

Brief summary:
Multicenter, randomized, double-blind, double-dummy, parallel group, stratified study assessing the safety and describing the efficacy of a single dose of intravenous (IV) fosnetupitant/palonosetron (260 mg/0.25 mg) infusion \[test\] versus oral netupitant/palonosetron (300 mg/0.5 mg) combination \[control\]; each administered with oral dexamethasone prior to initial and repeated cycles of AC chemotherapy in female breast cancer patients.

Detailed description:

Arms:
arm 1: intravenous fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed-dose combination, administered as a 30-minute infusion of a 50 mL solution, on Day 1 of each cycle.

Oral dexamethasone will be administered on Day 1 of each cycle (12 mg) arm 2: oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination on Day 1 of each cycle.

Oral dexamethasone will be administered on Day 1 of each cycle (12 mg)

Interventions: intervention 1: fosnetupitant/ palonosetron intervention 2: netupitant/palonosetron intervention 3: dexamethasone
Intervention descriptions: intervention 1: intravenous fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed-dose combination intervention 2: oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination intervention 3: Oral dexamethasone (12 mg)

Protocol document:
Prot_000.pdf: 
NEPA-17-05 
Clinical Study Report / FINAL 02 JUL 2019 
16.1.1 Protocol and Protocol Amendments 
Helsinn Healthcare SA 
Confidential 
16.1.1 PROTOCOL AND PROTOCOL AMENDMENTS 
NEPA-17-05 Amended protocol (v3.1) 30 NOV 2017 
Amendment #3, 30 NOV 2017 
Only Protocol v3.1 dated 30Nov2017 was used for study patient enrollment purposes. All 
previous versions and related amendments are available in the eTMF. 
Page 1 of 120
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Study Title 
A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel group 
phase 3b study to assess the safety and to describe the efficacy of IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV NEPA FDC) compared to oral 
netupitant/palonosetron (300 mg/0.5 mg) combination (Akynzeo®) for the prevention of 
chemotherapy-induced nausea and vomiting in initial and repeated cycles of anthracycline-
cyclophosphamide (AC) chemotherapy in women with breast cancer  
 
Study Number 
NEPA-17-05 
Protocol Version 
Final (v3.1) 
Protocol Date 
30 NOV 2017 
Sponsor 
Helsinn Healthcare SA 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
Phone: +41 91 985 21 21 
Fax: +41 91 985 21 22 
CROs 
US Region: 
George Clinical Inc. 
6555 Quince, Suite 503  
Memphis, TN 38119 
Phone: +1 901.259.0888 
Fax: +1 901.259.8276 
 
Europe: 
PSI CRO AG 
Baarerstrasse 113a 
6300 Zug, Switzerland 
Phone: +41 41 228 10 00 
Fax: +41 41 228 10 99 
Confidential Information 
The information contained in this document is confidential. Acceptance of this document constitutes agreement by the recipient that no 
information contained herein will be published or disclosed without prior written authorization from an official of Helsinn except that 
this document may be disclosed to appropriate Institutional Review Boards and Ethics Committees or duly authorized representatives of 
a Regulatory Authority under the condition that they are requested to keep it confidential. 
The clinical trial will be conducted, and essential study documentation archived, in compliance with this protocol, applicable SOPs and 
standards, which incorporate the requirements of the ICH Guideline for Good Clinical Practice. 
 
 
 
Page 2 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
 
Document History 
With respect to v1.0, in v1.1 minor typing errors have been corrected in the numbering 
sequence of Inclusion criteria in the Synopsis and in Section 4.3.2 Inclusion criteria. 
With respect to v1.1, in v1.2 the study procedure has been modified allowing screening 
activities to be performed / completed on Day 1 (and consequently the date of Visit 1 and 
Visit 2 may coincide). Screening period is now therefore defined as the period from Day -
14 to Day 1. The text has been modified throughout the protocol where applicable 
accordingly.  
The number of planned study sites was updated from “approximately 45 sites in the US” 
to “approximately 50 to 75 sites in the US”. 
In addition, some wording has been slightly improved throughout the protocol, as well as 
some minor errors have been corrected. 
With respect to v1.2, in v2.0 the number of planned study countries and sites was updated 
from “approximately 50 to 75 sites in the US” to in addition “approximately 33 sites 
distributed in Russia, Ukraine, Belarus and Georgia”.  
An additional CRO, i.e., PSI CRO AG, has been added for activities related to EU region.  
A dedicated Section 4.1.1 Definition of patients naivety/non-naivety has been added to 
further improve definition of naivety/non-naivety to any chemotherapy. 
The factor “region” has been added to the list of stratification factors having an impact on 
Primary efficacy analysis. 
In addition, some wording related to these changes has been slightly improved 
throughout the protocol, i.e., in Section 5.5 Packaging and Shipment, 5.7 Drug Depots, 
5.9 Administration of Study Treatment, 5.11. Randomization-Use of IWRS, 5.14 Prior 
and Concomitant Medications. 
With respect to v2.0, in v3.0 the study design has been modified from a non-inferiority 
efficacy study to a safety study. The primary objective is now to assess safety of IV 
fosnetupitant/palonosetron combination (IV NEPA FDC), and the secondary objective is 
to describe the efficacy. As a result, there will be no formal inference testing included in 
the analysis and data will be subject to descriptive analysis only. 
The number of chemotherapy cycles was increased from one cycle to the first 4 
chemotherapy cycles (as maximum). Visit 4 will be the end of each “Study Cycle”, and 
Visit 5 (HEOR Extension) has been deleted.   
Sample size was also lowered to 400 patients equally randomized to each arm. Study 
drug assignment for Cycles 2 to 4 will be closed 7 days after the last (400th) patient is 
randomized, in order to permit patients already screened for a subsequent study cycle to 
be administered study drug. Patients still participating in the study at this time should 
complete their current cycle and will not be allowed to enter in a subsequent study cycle. 
 
Page 3 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Inclusion #4 has been changed to enrol patients naïve to moderately or highly emetogenic 
antineoplastic agents, rather than only naïve to AC chemotherapy. This change also 
eliminates the stratification by naivety to any emetogenic antineoplastic agent. Inclusion 
#5 has also been updated to specify that patients must be scheduled to receive at least 4 
consecutive cycles of an AC regimen, in line with the change in study design to include 
repeated cycles. Additional clarifications were also added regarding inclusion/exclusion 
criteria to be checked prior to each repeated cycle. 
In terms of safety, laboratory assessments have been added at Visit 1 and Visit 3 of each 
cycle, where select parameters will be measured and assessments (below, within and 
above normal range) will be summarized. The urine pregnancy test at Visit 3 was deleted. 
The definitions of treatment-emergent adverse events, the reporting periods for adverse 
events, and the planned summaries for adverse events, have all been updated to account 
for repeated cycles.  
For efficacy assessments, the patient diary will be administered during each cycle, while 
the FLIE questionnaire will only be administered during Cycle 1 and Cycle 2. Complete 
protection (CP) has been removed as an efficacy endpoint. All efficacy analyses will now 
be descriptive only. 
For the exploratory HEOR evaluations, information on emergency department and in-
patient admissions, as well as chemotherapy, will be collected during each cycle, while 
WPAI questionnaire will only be administered during Cycle 1 and Cycle 2. CINV 
prophylaxis will no longer be collected as all patients will remain on  either IV 
fosnetupitant/palonosetron or oral netupitant/palonosetron during each cycle in this study. 
Belarus has been removed as potential country for this study, and approximate numbers 
of study sites have been adjusted accordingly. Updates to Study Drug Mananagment 
procedures have also been made. In addition, the General Information section has been 
updated with appropriate CRO contacts. 
Wording related to these changes has been implemented throughout the protocol.  
With respect to v3.0, in v3.1 minor typing errors have been corrected in the numbering 
sequence of Exclusion criteria in Section 4.3.3 Exclusion criteria, steps in Section 5.4 
Dose and Administration, and reasons for discontinuations in Section 6.4 Premature 
Discontinuation. Study title on coverpage was also corrected as “nausea” was 
inadvertently omitted, and the main phone number for George Clinical was updated on 
the coverpage and in the General Information section. Detail about study drug 
administration was added to Section 5.9 Administration of Study Treatment. 
 
 
 
 
Page 4 of 120 
Confidential
=HEI..SINN 


Page 5 of 120 
Confidential
NEPA-17--05 
Final (v3. l) 30 NOV 2017 
Clinical Study Protocol 
Signature Page, Helsinn Healthcare SA 
(p ✓.l.€. C 2o 17-
(Date) 
 
 
 
4\)c(_W/\-
<Date) 
Statistician and Data Manager, Clinical Development 
Head of Drug Safety 
h 
:, 
Senior Director, Clinical Research & Strategy 
04 / :iZ./ l,.D("J-
(Date) 
(Date) 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Signature Page, George Clinical Inc. 
 
Project Manager: 
__________________ __________________ 
(Date) 
 
 
 
Page 6 of 120 
Confidential
llHELSINN 
05 Dec 2017


Page 7 of 120 
Confidential
NEPA-17-05 
Final (v3.1) 30 NOV 2017 
Signature Page, PSI 
Project Manager 
2• 
Clinical Study Protocol •• 
(Date) 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Signature Page, Study Site Investigator 
Study Title 
A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel 
group phase 3b study to assess the safety and to describe the efficacy of IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV NEPA FDC) compared to 
oral netupitant/palonosetron (300 mg/0.5 mg) combination (Akynzeo®) for the prevention 
of chemotherapy-induced nausea and vomiting in initial and repeated cycles of 
anthracycline-cyclophosphamide (AC) chemotherapy in women with breast cancer.  
 
Study Number 
NEPA-17-05 
 
I have read and understood all pages of this clinical trial protocol and appendices and I 
agree that they contain all information required to conduct this trial. I agree to conduct 
the trial as outlined in the protocol and to comply with all terms and conditions set out 
therein. I confirm that I will conduct the trial in accordance with local regulations, ICH 
GCP guidelines and the provisions of the Declaration of Helsinki. I will direct, assist and 
oversee Sub-Investigator(s) and other relevant staff members under my control and will 
ensure that all trial staff members have access to copies of this protocol and to all 
information relating to preclinical and prior clinical experience (e.g., Investigator’s 
Brochure), ICH GCP guidelines, local regulations and the Declaration of Helsinki to 
enable them to work in accordance with the provisions of these documents.  
I agree that all documentation supplied to me by Helsinn, George Clinical Inc. and PSI 
CRO AG concerning this trial will be kept in the strictest confidence. 
 
 
________________________________________ __________________ 
(Signature) 
(Date) 
Printed Name:  
 
Institution: 
 
 
 
Page 8 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
TABLE OF CONTENTS 
General Information ........................................................................................................11 
Study Synopsis ..................................................................................................................15 
Flow Chart ........................................................................................................................27 
1 
INTRODUCTION AND RATIONALE .................................................................32 
1.1 
Background Information ....................................................................................32 
1.2 
Pre-clinical and Clinical Data of Palonosetron .................................................34 
1.2.1 
Pre-clinical Data .............................................................................................34 
1.2.2 
Summary of Phase 1 Clinical Data (Human Pharmacokinetics)...............34 
1.2.3 
Clinical Data ...................................................................................................35 
1.3 
Pre-clinical and Clinical Data of Fosnetupitant and Netupitant .....................35 
1.3.1 
Pre-clinical Data .............................................................................................35 
1.3.2 
Summary of Phase 1 Clinical Data (Human Pharmacokinetics) of 
Fosnetupitant and Netupitant .......................................................................40 
1.3.3 
Clinical Data ...................................................................................................42 
1.4 
Conclusions ...........................................................................................................43 
1.5 
Study Rationale ....................................................................................................43 
2 
STUDY OBJECTIVES ............................................................................................45 
2.1 
Primary .................................................................................................................45 
2.2 
Secondary..............................................................................................................45 
2.3 
Exploratory ...........................................................................................................45 
3 
STUDY ENDPOINTS ..............................................................................................46 
3.1 
Efficacy Endpoints ...............................................................................................46 
3.2 
Safety Assessments ...............................................................................................46 
3.3 
Health Economics Outcome Research (HEOR) Assessments ..........................46 
4 
STUDY PLAN ...........................................................................................................48 
4.1 
Study Design .........................................................................................................48 
4.1.1 
Definition of naïve / non-naïve patients to moderately or highly 
emetogenic antineoplastic agent ...................................................................48 
4.2 
Study Duration .....................................................................................................48 
4.3 
Study Population ..................................................................................................50 
4.3.1 
Number of Subjects........................................................................................50 
4.3.2 
Inclusion Criteria ...........................................................................................50 
4.3.3 
Exclusion Criteria ..........................................................................................51 
5 
STUDY DRUG MANAGEMENT ...........................................................................55 
5.1 
Description of Investigational Medicinal Product ............................................55 
5.2 
Additional Non-investigational Study Drug ......................................................56 
5.3 
Treatment Groups ...............................................................................................57 
5.4 
Dose and Administration .....................................................................................57 
5.5 
Packaging and Shipment .....................................................................................58 
5.6 
Storage ..................................................................................................................59 
5.7 
Drug Depots ..........................................................................................................59 
5.8 
Accountability ......................................................................................................59 
5.9 
Administration of Study Treatment ...................................................................59 
4 
 
Page 9 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
5.10 
Blinding .................................................................................................................62 
5.10.1 
Emergency Unblinding Procedure ...............................................................62 
5.11 
Randomization - Use of IWRS ............................................................................62 
5.12 
Over-dosage ..........................................................................................................64 
5.13 
Occupational Safety .............................................................................................64 
5.14 
Prior and Concomitant Medications ..................................................................64 
5.14.1 
Prior and Concomitant Medications for the Prevention of Nausea 
and Vomiting or With Potential Anti-emetic Effect ...................................64 
5.14.2 
Prior and Concomitant Cancer Chemotherapy and Radiotherapy ..........65 
5.14.3 
Other Prior and Concomitant Medications .................................................66 
5.15 
Rescue Medication ...............................................................................................67 
5.16 
Treatment Compliance ........................................................................................67 
6 
STUDY CONDUCT..................................................................................................68 
6.1 
General Instructions ............................................................................................68 
6.2 
Study Procedures by Time Point ........................................................................69 
6.2.1 
Cycle 1 - Visit 1 (screening, Day -14 to Day 1) ............................................69 
6.2.2 
Cycle 1 - Visit 2 (randomization, Day 1) ......................................................69 
6.2.3 
Cycle 1 - Visit 3 (Day 6 [+2 days]) ................................................................71 
6.2.4 
Cycle 1 - Visit 4 (follow-up visit, Day 15 [+3 days] or Day 22 (± 3 
days]) ...............................................................................................................72 
6.2.5 
Cycles 2 to 4 - Visit 1 (screening, Day -7 to Day 1) .....................................72 
6.2.6 
Cycles 2 to 4 - Visit 2 (Day 1) ........................................................................72 
6.2.7 
Cycles 2 to 4 - Visit 3 (Day 6 [+2 days]) .......................................................72 
6.2.8 
Cycles 2 to 4 - Visit 4 (follow-up visit, Day 15 [+3 days] or Day 22 
(± 3 days]) ........................................................................................................73 
6.3 
Definition of Study Completion ..........................................................................73 
6.4 
Premature Discontinuation .................................................................................73 
7 
METHODS OF ASSESSMENT ..............................................................................75 
7.1 
Efficacy Assessments ...........................................................................................75 
7.1.1 
Emetic Episodes .............................................................................................75 
7.1.2 
Rescue Therapy ..............................................................................................76 
7.1.3 
Severity of Nausea ..........................................................................................76 
7.1.4 
Functional Living Index-Emesis (FLIE) Questionnaire .............................76 
7.2 
Safety Assessments ...............................................................................................77 
7.2.1 
Physical Examination ....................................................................................77 
7.2.2 
Vital Signs .......................................................................................................77 
7.2.3 
Clinical Laboratory Tests..............................................................................77 
7.3 
Health Economics Outcome Research (HEOR) Assessments ..........................78 
7.3.1 
Work Productivity and Activity Impairment (WPAI) 
Questionnaire .................................................................................................78 
7.3.2 
Emergency Department (ED) Use and In-Patient (IP) Admissions ..........78 
7.3.3 
Subsequent Cycle Start Date and Changes from Initial Schedule ............79 
8 
ADVERSE EVENTS ................................................................................................80 
8.1 
Definition of Adverse Events...............................................................................80 
8.1.1 
Classification of Adverse Events...................................................................81 
4 
 
Page 10 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
8.1.2 
Reporting Adverse Events .............................................................................83 
8.1.3 
Reporting Serious Adverse Events ...............................................................84 
8.1.4 
Pregnancy Report ..........................................................................................84 
9 
STATISTICS .............................................................................................................85 
9.1 
Sample Size Determination .................................................................................85 
9.2 
Definition of Study Populations for Analysis ....................................................85 
9.3 
Statistical Analysis ...............................................................................................86 
9.3.1 
General Considerations .................................................................................86 
9.3.2 
Analysis of Demographics and Baseline Variables .....................................87 
9.3.3 
Efficacy Analysis ............................................................................................87 
9.3.4 
Safety Analysis ...............................................................................................88 
9.3.5 
HEOR Analysis ..............................................................................................89 
9.4 
Interim Analysis ...................................................................................................89 
10 DATA SAFETY MONITORING BOARD ............................................................90 
11 ETHICAL AND REGULATORY CONSIDERATIONS .....................................90 
11.1 
Ethical Considerations.........................................................................................90 
11.1.1 
Laws and Regulations ....................................................................................90 
11.1.2 
Patient’s Information Sheet and Informed Consent Form ........................90 
11.1.3 
Protocol Amendments ...................................................................................91 
11.1.4 
Protocol Deviations ........................................................................................91 
11.1.5 
Data Collection ...............................................................................................91 
11.1.6 
Monitoring and Quality Assurance ..............................................................93 
11.1.7 
Study Documentation and Records Retention ............................................93 
11.1.8 
Confidentiality ................................................................................................94 
11.1.9 
Publication Policy...........................................................................................94 
11.1.10 
Insurance ........................................................................................................95 
12 REFERENCES .........................................................................................................96 
13 APPENDICES ...........................................................................................................98 
Appendix 1:  
Emetogenic Potential of IV and Oral Antineoplastic Agents 
(NCCN Clinical Practice Guidelines in Oncology, Version 2.2017, 
March 28, 2017 [7]) ..............................................................................................99 
Appendix 2: 
Eastern Cooperative Oncology Group Performance Status   
(ECOG PS) .........................................................................................................103 
Appendix 3: List of CYP3A4 Inducers, Strong and Moderate Inhibitors,  and 
Substrates............................................................................................................104 
4 
 
Page 11 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
GENERAL INFORMATION 
Sponsor 
Helsinn Healthcare SA 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
Phone: +41 91 985 21 21 
Fax: +41 91 985 21 22 
CROs  
US Region: 
George Clinical Inc. 
6555 Quince, Suite 503  
Memphis, TN 38119 
Phone: +1 901.259.0888 
Fax: +1 901.259.8276 
Europe: 
PSI CRO AG 
Baarerstrasse 113a 
6300 Zug, Switzerland 
Phone: +41 41 228 10 00 
Fax: +41 41 228 10 99 
24h-Contact 
for 
Serious 
Adverse Events (SAEs)  
E-mail address for incoming SAE reports: 
SafetyDesk@psi-cro.com 
Drug Safety Officer 
Helsinn: 
 
Helsinn Healthcare SA 
Phone: 
 
Fax: 
 
(copies to drug-safety@helsinn.com) 
CRO: 
US region: 
 
 
Europe: 
 
 
4 
 
Page 12 of 120 
Confidential
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Medical Expert 
Helsinn: 
 
 
  
Study Project Manager 
Helsinn: 
 
 
 
  
CROs: 
US Region: 
 
  
  
 
  
Europe: 
 
 
  
 
  
 
Statistics 
Helsinn: 
 
 
 
  
CRO: 
 
 
 
  
 
 
4 
 
Page 13 of 120 
Confidential
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Data Management 
Helsinn: 
 
 
  
CRO: 
 
  
 
 
 
 
Quality Assurance 
Helsinn: 
 
 
  
CROs: 
 
 
 
  
 
 
 
Clinical Study Supplies 
Packaging and Labeling 
Catalent Germany Schorndorf GmbH 
Steinbeisstr. 1-2 
D-73614 Schorndorf, Germany 
IWRS Provider 
Veracity Logic, LLC 
11312 US 15 501 Hwy North 
Chapel Hill, NC 27517 
Phone: +1 919.636.0655 
4 
 
Page 14 of 120 
Confidential
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
EDC Provider 
OmniComm (TrialMaster) 
2101 West Commerical Blvd. 
Suite 3500 
Fort Lauderdale, FL 33309 
Phone: +1 877.468.6332 
 
 
4 
 
Page 15 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
STUDY SYNOPSIS 
Study Title 
A multicenter, randomized, double-blind, double-dummy, 
active-controlled, parallel group phase 3b study to assess the 
safety 
and 
to 
describe 
the 
efficacy 
of 
IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination 
(IV NEPA FDC) compared to oral netupitant/palonosetron 
(300 mg/0.5 mg) combination (Akynzeo®) for the prevention 
of chemotherapy-induced nausea and vomiting in initial and 
repeated cycles of anthracycline-cyclophosphamide (AC) 
chemotherapy in women with breast cancer 
Study Number 
NEPA-17-05 
Sponsor 
Helsinn Healthcare SA, Via Pian Scairolo 9, 6912 Lugano, 
Switzerland 
Countries and Sites 
Approximately 50 sites in the US and approximately 30 sites 
distributed in Russia, Ukraine, and Georgia. If needed, 
additional sites and countries may be involved as well. 
Clinical Phase 
Phase 3b 
Indication 
Prevention of nausea and vomiting associated with 
Anthracycline-Cyclophosphamide (AC) based emetogenic 
cancer chemotherapy. 
Study Design 
Multicenter, randomized, double-blind, double-dummy, 
parallel group, stratified study assessing the safety and 
describing the efficacy of a single dose of intraveneous (IV) 
fosnetupitant/palonosetron (260 mg/0.25 mg) infusion [test] 
versus oral netupitant/palonosetron (300 mg/0.5 mg) 
combination 
[control]; 
each 
administered 
with 
oral 
dexamethasone prior to initial and repeated cycles of AC 
chemotherapy in female breast cancer patients.  
Objectives  
Primary: To evaluate the safety and tolerability of a single 
IV dose of fosnetupitant/palonosetron (260 mg/0.25 mg) 
combination administered as a 30-minute IV infusion with 
oral dexamethasone on Day 1 for the prevention of AC 
chemotherapy-induced nausea and vomiting in initial and 
repeated cycles. 
Secondary: To describe the efficacy of a single IV dose of 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination 
(IV NEPA FDC) administered as a 30-minute IV infusion 
versus a single oral dose of netupitant/palonosetron 
(300 mg/0.5 
mg) 
combination 
(oral 
NEPA 
FDC) 
4 
 
Page 16 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
administered as one capsule, during the acute (0-24 hours), 
delayed (>24-120 hours) and overall (0-120 hours) phases of 
initial and repeated cycles of AC chemotherapy. 
Exploratory: To evaluate the impact on economics and 
resource utilization through collection of Health Economics 
Outcomes Research (HEOR) parameters in initial and 
repeated cycles of AC chemotherapy. 
Treatment Groups 
Group 1 / Test group – intravenous fosnetupitant/ 
palonosetron (260 mg/0.25 mg) fixed-dose combination, 
administered as a 30-minute infusion of a 50 mL solution, 
on Day 1 of each cycle. 
Group 2 / Control group – oral netupitant/palonosetron 
(300 mg/0.50 mg) fixed-dose combination on Day 1 of each 
cycle.  
Oral dexamethasone will be administered on Day 1 of each 
cycle (12 mg) to both test and control groups. 
Drug Administration 
The administration of test and control drugs will be double-
blinded.  
Oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose 
combination capsule (or matching placebo capsule) will be 
administered on Day 1 of each cycle, 60 minutes prior to the 
start of AC chemotherapy.  
The 
30-minute 
IV 
fosnetupitant/palonosetron  
(260 mg/0.25 mg) fixed-dose combination infusion (or 
matching placebo infusion) will start 30 minutes prior to the 
start of the AC chemotherapy on Day 1 of each cycle. The 
IV infusion will be completed before starting chemotherapy 
administration.  
Administration of dexamethasone will not be blinded as the 
dosage and schedule are identical in both treatment groups, 
i.e., 12 mg on Day 1 of each cycle as a unique dose. On Day 
1 of each cycle, oral dexamethasone will be taken 30 
minutes prior to the start of the AC chemotherapy, 
immediately before the start of the 30-minute IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) fixed-dose 
combination or placebo infusion.  
Study Duration 
Each randomized patient is planned to participate in a 
maximum of 4 consecutive chemotherapy cycles assessed in 
this study. A total of 400 patients will be randomized. Study 
drug assignment for Cycles 2 to 4 will be closed 7 days after 
4 
 
Page 17 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
the last (400th) patient is randomized, in order to permit 
patients already screened for a subsequent study cycle to be 
administered study drug. Patients still participating in the 
study at this time should complete their current cycle and 
will not be allowed to enter in a subsequent cycle.   
For each cycle, patients will undergo a screening visit 
(Visit 1) up to 7 days (up to 14 days for Cycle 1 only) before 
study drug administration (Day 1; Visit 2). After receiving a 
single dose of active treatment on Day 1, patients will enter 
an efficacy evaluation period of 120 hours and then return to 
the clinical site on Day 6 (+2) for Visit 3. Patients will  
undergo a follow-up visit or  telephone call (Visit 4) either 
on Day 15 (+3 days) or Day 22 (±3 days) depending on the 
next chemotherapy cycle schedule (this Visit 4 will be 
considered as the end of each “Study Cycle”). Visit 4, or the 
corresponding telephone contact, either on Day 15 (+3 days) 
or on Day 22 (±3 days) is to be performed prior to 
administering the chemotherapy relevant to the next cycle 
and prior to any further moderately or highly emetogenic 
chemotherapeutic treatment administration.  
Total number of visits per patient: For each cycle, there will 
be a maximum of 4 visits or 3 visits plus 1 telephone 
contact. For all cycles, the screening visit and the study drug 
administration visit can be performed on the same day. The 
screening visit of a subsequent cycle can also coincide with 
the follow-up visit of the previous cycle. If all these visits 
are merged, Visit 4 of the previous cycle as well as Visit 1 
and Visit 2 of the next cycle are all three performed on the 
same day.  
Total number of cycles per patient: Each patient may 
participate in a maximum of 4 consecutive chemotherapy 
cycles, as long as they continue to fulfill the inclusion and 
exclusion criteria for the repeated cycles and as long as the 
study remains open.  
Maximum total study duration per patient is approximately  
14 weeks. This maximum total study duration per patient is 
based on the assumption that the patient participates in 4 
consecutive study cycles (maximum number of cycles 
allowed in the study) with 21 days interval between the Day 
1 of two consecutive cycles, and that follow-up visits of one 
cycle coincide with screening visits of the subsequent cycle. 
A minimum of 14 days and maximum of 35 days is allowed 
between the Day 1 of two consecutive cycles. 
4 
 
Page 18 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Number of Patients  
A total of 400 patients will be randomized according to a 1:1 
randomization ratio, stratified by region (US, non-US) and 
age class (age < 55 years, age ≥ 55 years).  
Target Study Population 
Adult female patients naïve to moderately or highly 
emetogenic antineoplastic agents with a diagnosis of breast 
cancer requiring treatment with an AC based chemotherapy 
regimen on Day 1.  
Inclusion Criteria 
Cycle 1: 
The following inclusion criteria must be checked prior to 
inclusion at Cycle 1: 
1. Patient read, understood and signed the written informed 
consent before any study related activity, agreeing to 
participate in the study and to comply with study 
requirements. 
2. Female patient ≥ 18 years of age. 
3. Histologically or cytologically confirmed breast cancer, 
including recurrent or metastatic. 
4. Naïve 
to 
 
moderately 
or 
highly 
emetogenic 
antineoplastic agents (see Appendix 1).  
5. Scheduled to receive at least 4 consecutive cycles of an 
AC combination regimen.  
 
Notes:  
a) additional not emetogenic, minimally or low 
emetogenic 
antineoplastic 
agents 
(see 
protocol  
Appendix 1) are permitted at any time after start of AC 
combination on Day 1. 
b) 
additional 
highly 
or 
moderately 
emetogenic 
antineoplastic agents (see protocol Appendix 1) are only 
allowed on Day 1 after the start of AC combination, 
provided their administration is completed within 6 hours 
from the start of the AC combination administration. 
6. ECOG Performance Status of 0 or 1. 
7. Patient shall be: a) of non-childbearing potential or b) of 
childbearing potential using reliable contraceptive 
measures and having a negative urine pregnancy test 
within 24 hours prior to dose of investigational product.  
4 
 
Page 19 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Notes:  
a) Female patients of non-childberaring potential are 
defined as being in post-menopausal state since at least 1 
year; or having documented surgical sterilization or 
hysterectomy 
at 
least 
3 
months 
before 
study 
participation.  
b) Reliable contraceptive measures include implants, 
injectables, combined oral contraceptives, intrauterine 
devices, vasectomized partner or complete (long term) 
sexual abstinence;  
8. Hematologic and metabolic status adequate for receiving 
a cycle of AC chemotherapy based on investigator’s 
assessment. 
9. If the patient has a known hepatic or renal impairment, 
she may be enrolled in the study at the discretion of the 
Investigator. 
10. Able to read, understand, follow the study procedure and 
complete the patient diary. 
All inclusion criteria will be checked at screening visit (Visit 
1 of Cycle 1); inclusion criteria #7 will be re-checked at Day 
1 (Visit 2). 
Cycles 2 to 4: 
The following inclusion criteria must be checked prior to 
inclusion at each repeated cycle: 
1. Participation in the study during the next cycle of 
chemotherapy is considered appropriate by the Investigator 
and does not pose unwarranted risk to the patient. 
2. Scheduled to receive an AC chemotherapy regimen or AC 
chemotherapy together with other chemotherapies as 
defined in Inclusion criterion #5 for Cycle 1. 
3. Patient shall be: a) of non-childbearing potential or b) of 
childbearing potential using reliable contraceptive measures 
and having a negative urine pregnancy test within 24 hours 
prior to dosing of investigational product. 
4. Adequate hematologic and metabolic status for receiving 
a cycle of AC chemotherapy according to the Investigator’s 
opinion.  
All inclusion criteria will be checked at screening visit 
4 
 
Page 20 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
(Visit 1); inclusion criterion #3 will be re-checked at Day 1 
(Visit 2). 
Exclusion Criteria 
Cycle 1: 
The following exclusion criteria must be checked prior to 
inclusion at Cycle 1:  
1. Lactating patient. 
2. Current use of illicit drugs or current evidence of alcohol 
abuse. 
3. Scheduled to receive moderately or highly emetogenic 
antineoplastic agent (see protocol Appendix 1) in 
addition to the AC regimen, from 6 hours after the start 
of the AC chemotherapy on Day 1 and up to Day 1 of 
Cycle 2. 
4. Received or is scheduled to receive radiation therapy to 
the abdomen or the pelvis within 1 week prior to the start 
of AC chemotherapy administration on Day 1 or between 
Days 1 to 5, inclusive. 
5. Any vomiting, retching, or nausea (grade ≥ 1 as defined 
by National Cancer Institute) within 24 hours prior to the 
start of AC chemotherapy administration on Day 1. 
6. Symptomatic primary or metastatic central nervous 
system (CNS) malignancy. 
7. Active peptic ulcer disease, gastrointestinal obstruction, 
increased intracranial pressure, hypercalcemia, an active 
infection or any illness or medical conditions (other than 
malignancy) that, in the opinion of the Investigator, may 
confound the results of the study, represent another 
potential etiology for emesis and nausea (other than 
chemotherapy-induced nausea and vomiting [CINV]) or 
pose unwarranted risks in administering the study drugs 
to the patient. 
8. Known 
hypersensitivity 
or 
contraindication 
to 
5 hydroxytryptamine type 3 (5-HT3) receptor antagonists 
(e.g., palonosetron, ondansetron, granisetron, dolasetron, 
tropisetron, ramosetron), to dexamethasone, or to 
neurokinin-1 (NK1) receptor antagonists (e.g., aprepitant, 
rolapitant).  
9. Known contraindication to the IV administration of 
50 mL 5% glucose solution. 
4 
 
Page 21 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
10. Participation in a previous clinical trial involving IV 
fosnetupitant or oral netupitant administered alone or in 
combination with palonosetron. 
11. Any investigational drugs taken within 4 weeks prior to 
Day 1, and/or is scheduled to receive any investigational 
drug (other than those planned by the study protocol) 
during the present study. 
12. Systemic corticosteroid therapy within 72 hours prior to 
the start of AC chemotherapy administration on Day 1, 
except the dexamethasone provided as additional study 
drug. However, topical and inhaled corticosteroids are 
permitted. 
13. Scheduled to receive bone marrow transplantation and/or 
stem cell rescue therapy during the study participation. 
14. Other than as administered as part of the study protocol, 
any medication with known or potential antiemetic 
activity within 24 hours prior to the start of AC 
chemotherapy administration on Day 1, including: 
• 5-HT3 receptor antagonists (e.g., ondansetron, 
granisetron, dolasetron, tropisetron, ramosetron, 
palonosetron) 
• NK1 receptor antagonists (e.g., aprepitant,  
fosaprepitant, rolapitant or any other new drug of 
this class) 
• benzamides (e.g., metoclopramide, alizapride) 
• phenothiazines 
(e.g., 
prochlorperazine, 
promethazine, 
fluphenazine, 
perphenazine, 
thiethylperazine, chlorpromazine) 
• benzodiazepines (except if the subject is receiving 
such medication for sleep or anxiety and has been 
on a stable dose for at least seven days prior to 
Day 1). 
• butyrophenones (e.g., haloperidol, droperidol) 
• anticholinergics (e.g., scopolamine, with the 
exception 
of 
inhaled 
anticholinergics 
for 
respiratory disorders, e.g., ipratropium bromide) 
• antihistamines 
(e.g., 
cyclizine, 
hydroxyzine, 
diphenhydramine, chlorpheniramine) 
• domperidone 
• mirtazapine 
• olanzapine 
• prescribed cannabinoids (e.g., 
4 
 
Page 22 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
tetrahydrocannabinol or nabilone) 
• Over The Counter (OTC) antiemetics, OTC cold 
or OTC allergy medications. 
15. Scheduled to receive any strong or moderate inhibitor of 
CYP3A4 (see protocol Appendix 3) during the efficacy 
assessment period (Day 1 to Day 5, inclusive) or its 
intake within 1 week prior to Day 1. 
16. Scheduled to receive any CYP3A4 inducer (see protocol 
Appendix 3) during the efficacy assessment period (Day 
1 to Day 5, inclusive) or its intake within 4 weeks prior 
to Day 1, with the exception of corticosteroids (for which 
exclusion criterion #12 applies). 
17. History 
or 
predisposition 
to 
cardiac 
conduction 
abnormalities, except for incomplete right bundle branch 
block. 
18. History of risk factors for Torsades de Pointes (heart 
failure, hypokalemia, family history of Long QT 
Syndrome). 
19. Severe 
or 
uncontrolled 
cardiovascular 
diseases, 
including myocardial infarction within 3 months prior to 
Day 1, unstable angina pectoris, significant valvular or 
pericardial disease, history of ventricular tachycardia, 
symptomatic Congestive Heart Failure (CHF) New York 
Heart Association (NYHA) class III-IV, and severe 
uncontrolled arterial hypertension. 
All exclusion criteria with the exception of criteria #5, #12, 
and #14 will be checked at screening visit (Visit 1). 
Exclusion criteria #5, #12, and #14 will be checked at Day 1 
(Visit 2) only.  
Exclusion criteria #3, #4, #7, #11, #13, #15, and #16 need to 
be re-checked at Day 1 (Visit 2). 
Cycles 2 to 4: 
The following exclusion criteria must be checked prior to 
inclusion at each repeated cycle: 
1. Scheduled to receive moderately or highly emetogenic 
antineoplastic agent (see protocol Appendix 1) in 
addition to the AC regimen, from 6 hours after the start 
of the AC chemotherapy on Day 1 of current cycle and 
up to Day 1 of the next cycle.  
4 
 
Page 23 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
2. Active infection or uncontrolled disease that may pose 
unwarranted risks in administering the study drugs to the 
patient. 
3. Started any of the prohibited medications (see protocol 
Section 5.14). 
4. Any vomiting, retching, or nausea (grade ≥ 1 as defined 
by National Cancer Institute) within 24 hours prior to the 
start of AC chemotherapy administration on Day 1.  
5. Received or is scheduled to receive radiation therapy to 
the abdomen or the pelvis within 1 week prior to the start 
of AC chemotherapy administration on Day 1 or 
between Days 1 to 5. 
6. Symptomatic primary or metastatic CNS malignancy.  
7. Any illness or medical condition that, in the opinion of 
the investigator, may confound the results of the study or 
pose 
unwarranted 
risks 
in 
administering 
the 
investigational product or dexamethasone to the patient. 
All exclusion criteria, with exception of criterion #4, will be 
checked at screening visit (Visit 1). Exclusion criterion #4 
will be checked at Day 1 (Visit 2) only. Exclusion criteria 
#2, #3 and #5 need to be re-checked at Day 1 (Visit 2). 
Efficacy Assessments 
Time-related efficacy study parameters assessment will start 
at “time 0” defined as the start time of the AC chemotherapy 
administration on Day 1 of each cycle.  
Efficacy parameters will be evaluated at each cycle in the 
acute, delayed and overall phases (time intervals 0 to 24 
hours, >24 to 120 hours and 0 to 120 hours after the start of 
AC chemotherapy, respectively), if not otherwise noted. 
The efficacy endpoints are defined as follows: 
• The proportion of patients with CR (defined as no emetic 
episodes and no rescue medication) during the acute, 
delayed and overall phases; 
• the proportion of patients with no emetic episodes during 
the acute, delayed and overall phases;  
• the proportion of patients with no rescue medication 
during the acute, delayed and overall phases; 
• the proportion of patients with no nausea (defined as 
maximum nausea intensity on a 100-mm visual analog 
scale (VAS) < 5mm) during the acute, delayed and 
overall phases; 
4 
 
Page 24 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
• the proportion of patients with no significant nausea 
(defined as maximum nausea intensity on a 100-mm 
VAS < 25mm) during the acute, delayed and overall 
phases; 
• the severity of nausea (defined as the maximum nausea 
intensity on the 100-mm VAS) in the acute, delayed and 
overall phases; 
• the proportion of patients with no impact on daily life 
(NIDL) activities in the overall phase of Cycle 1 and 2, 
only as assessed by the Functional Living Index-Emesis 
(FLIE) questionnaire. NIDL is defined as a score greater 
than 108 points, 54 points, and 6 points for total FLIE 
score, domain score and single item score, respectively; 
• the domain (nausea and vomiting) FLIE scores and the 
total FLIE score in the overall phase of Cycle 1 and 2, 
only. 
Safety Assessments 
The following safety assessments will be obtained in each 
Study Cycle: physical examination (PE), vital signs, 
laboratory tests and adverse events (AEs) assessment.  
HEOR Assessments 
The following exploratory HEOR assessments will be 
obtained:  
• Emergency Department (ED), and Inpatient Admissions 
(IP) and length of stay (LOS)  
• Lost work time and productivity assessed by the Work 
Productivity 
and 
Activity 
Impairment 
(WPAI) 
Questionnaire (Cycles 1 and 2 only) 
• Disruptions in initiation and dosing of intended next 
cycle of chemotherapy 
Additional data collected from patient diary or electronic 
Case Report Forms (eCRFs) may also be used for HEOR-
related analysis. All parameters of interest, endpoints and 
analysis methods will be specified in a separate Health 
Economics Analysis Plan. 
4 
 
Page 25 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Efficacy Analysis 
Analysis Population 
Population for efficacy analyses is defined as follows: 
The Full Analysis Set (FAS) includes all randomized 
patients who received the AC chemotherapy regimen and 
active study drug (including partial infusion). Following the 
intent-to-treat principle, patients will be assigned to the 
treatment group to which they were randomized. FAS will 
be used for demography, other baseline characteristics and 
all descriptive efficacy analyses. 
Efficacy Analysis 
At each cycle, for each phase (acute, delayed, and overall), 
numbers and proportions (including 95% confidence interval 
[CI]) of patients with CR, with no emetic episodes, with no 
rescue medication, with no nausea, and with no significant 
nausea will be descriptively summarized. 
Difference between groups in response rate and 95% CI will 
be presented without strata adjustment using the Newcombe-
Wilson method and with strata adjustment using the 
Cochran-Mantel-Haenszel (CMH) method with region and 
age class as strata. 
The severity of nausea will be descriptively summarized 
including difference between groups. 
For Cycles 1 and 2, numbers and proportions of patients 
with NIDL for total FLIE score and for domain scores in the 
overall phase will be descriptively summarized and 
difference between treatment groups presented without strata 
adjustment and with strata adjustment using the CMH 
method as mentioned above.The domain (nausea and 
vomiting) FLIE scores and the total FLIE score will be 
descriptively summarized including difference between 
groups.   
Safety Analysis 
 
 
 
 
Analysis Population 
Population for safety analyses is defined as follows: 
The Safety population includes all patients who received 
active study drug (including partial infusion). Patients will 
be assigned to treatment groups according to the actual 
treatment received. Safety population will be used for 
demography, other baseline characteristics and for all safety 
analyses.  
4 
 
Page 26 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
 
 
 
Safety Analysis 
Treatment-emergent AEs (TEAEs) will be listed and 
summarized by frequency tables. Summaries will be made 
with respect to the number and proportion of patients with 
events and the total number of events. A similar summary 
will be presented for Cycle 1 only. In addition, TEAEs of 
special interest, i.e. the ones related to local tolerability (e.g. 
injection 
site 
reaction, 
pain 
at 
injection 
site, 
thrombophlebitis) will be presented for each cycle. 
Vital signs will be summarized using descriptive statistics 
for observed values,  change from baseline, and change from 
pre-dose assessment, in addition to being listed. 
Proportion of laboratory values below, within and above 
normal range will be presented by frequency table for each 
timepoint. Shift table (below, within and above normal 
range) comparing baseline assessment with on-treatment 
assessment and comparing pre-dose assessment with Visit 3 
assessment of each cycle will also be presented. 
HEOR Analysis 
The HEOR analysis will be managed and conducted 
separately. Relevant patient data and results will be 
presented in a separate report. Further details (including 
detailed description of HEOR endpoints and analyses) will 
be outlined in the Health Economics Analysis Plan. 
 
 
4 
 
Page 27 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
FLOW CHART 
Study Phase 
Study Cycle  
(Cycle 1 / Repeated Cycles) 
Procedure/assessment 
Screening 
Day 
-14 to 1 days  
(Cycle 1 only) /  
-7 to Day 1 
(Cycles 2-4)a 
Day 1 
 
Day 6  
(+2 days) b 
 
On Day 15  
(+3 days) OR 
Day 22 (+/-3 
days) c 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
(Follow-up) 
Informed consent 
Xd 
 
 
 
Inclusion / exclusion criteria e 
X 
X 
 
 
Demography 
Xd 
 
 
 
Alcohol, tobacco and illicit drugs 
consumption 
X 
 
 
 
Reproductive status 
X 
 
 
 
Medical history (including 
current cancer history, and 
surgery) 
Xd 
 
 
 
ECOG performance status 
X 
 
 
 
Urine pregnancy test f 
X  
X  
 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
Physical examination g 
X  
 
X  
 
Vital signs h 
X 
X 
X 
 
Height and weight i 
 
X 
 
 
Blood chemistryj 
X 
 
X 
 
Hematologyj 
X 
 
X 
 
Pt. no assignment by IWRS 
Xd 
 
 
 
Randomization 
 
Xd 
 
 
Study drug assignment through 
IWRS 
 
X 
 
 
Study drugs administration 
 
X 
 
 
Dexamethasone administration k 
 
X 
 
 
AC chemotherapy 
 
X 
 
 
Patient Diary l 
 
X 
X 
 
FLIE questionnaire m 
 
X 
X 
 
WPAI questionnaire for HEORn 
 
X 
X 
 
ED/Hospitalization information 
for HEOR o  
 
 
 
X 
Chemotherapy information for 
HEOR p   
 
X 
 
 
Adverse events q 
X 
X 
X 
X 
4 
 
Page 28 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
a) Screening activities for Cycle 1 may be performed or completed between Day -14 and Day 1, included. In repeated 
cycles (i.e., cycles no. 2, 3 or 4), Visit 1 may be performed from Day -7 up to study Day 1 inclusive. For all cycles, 
Visit 1 and Visit 2 may occur on the same day (on study Day 1). In that case, the assessments planned at both Visit 1 
and Visit 2 have to be performed only once. 
b) Visit 3 (Day 6 [+ 2 days]) is to be scheduled on Day 6, not earlier than 120 hours after start of AC chemotherapy 
administration on Day 1. If Day 6 is a holiday or a weekend day, or in case Visit 3 cannot be performed on Day 6 after 
the end of the 120 hours period for any reason, Visit 3 may be scheduled within the two forthcoming days. 
c) Visit 4, follow-up visit, either as on-site visit or telephone contact, is to be performed either on Day 15 (+3 days) or on 
Day 22 (±3 days) depending on the next chemotherapy cycle schedule. The patient’s follow-up visit or contact is to be 
performed prior to administering the chemotherapy relevant to the next cycle and prior to any further moderately or 
highly emetogenic chemotherapeutic treatment administration to the patient. Visit 4 of a previous cycle, as well as 
Visit 1 and Visit 2 of the next cycle, can all coincide and be performed on the same day. 
d) Only at Cycle 1 
e) Some inclusion / exclusion criteria are to be verified at Screening visit (Visit 1) and confirmed at the Day 1 visit (Visit 
2); if Visit 1 and Visit 2 are performed on the same day (Day 1), a unique assessment of these criteria is sufficient; 
please refer to inclusion / exclusion criteria section for details. 
f) 
To be performed for females of childbearing potential within 24 hours prior to the IMP administration at each cycle 
(oral netupitant/palonosetron combination or placebo capsule) on Day 1. If the screening visit urine pregnancy test has 
been done within the 24 hours before the IMP administration, no urine pregnancy test is to be performed at Visit 2 (Day 
1). 
g) Complete PE (general appearance, head, eyes, ears, nose, throat, skin, neck, lungs, cardiovascular, breast, lymph nodes, 
abdomen, musculoskeletal and neurological) to be performed at Visit 1 and Visit 3 of each cycle. At Visit 3 and at 
subsequent cycles, only the general question “Was PE performed?” will be asked on the eCRF. Any new or worsening 
of pathological findings noted since previous examination should be reported on the Adverse Event eCRF form. 
h) Vital signs assessments include: pulse rate, systolic and diastolic blood pressure at Visit 1 (screening), Visit 2 (on Day 1 
at pre-dose, i.e., within 30 minutes before the oral netupitant/palonosetron combination or placebo capsule 
administration) and Visit 3 of each cycle. Pulse rate and systolic and diastolic blood pressure have to be measured after 
the patient has been in semi-supine position for at least 5 minutes. 
i) Height has to be measured only at Visit 2 (Day 1) of Cycle 1. Weight has to be measured at Visit 2 (Day 1) of each 
cycle, and should occur prior to the start of the AC chemotherapy administration. 
j) Local laboratories will be used for haematology and blood chemistry analysis throughout the study. 
k) Patients will receive 12 mg dexamethasone on Day 1 of each cycle. Dexamethasone is to be administered 30 minutes 
prior to the start of the AC chemotherapy administration (immediately before IV NEPA FDC or placebo infusion).  
l) The patient’s diary,  referring to the 0-120 hour period, will be distributed to the patients at the Day 1 Visit of each 
cycle. Patients will be asked to report date and time of onset of emetic episodes (episodes of retching or vomiting), 
date and time of intake of rescue medication, name of the rescue medication taken, and daily nausea intensity assessed 
by VAS on their diary. The patient’s completed diary will be retrieved and checked by the Investigator or designated 
responsible person during study Visit 3 of each cycle.  
m) FLIE questionnaire, referring to the 0-120 hour period, will be distributed to the patients at the Day 1 Visit, with 
explanations on how to perform the requested assessments; the patient’s completed FLIE will be retrieved and checked 
by the Investigator or designated responsible person during study Visit 3. FLIE questionnaire will only be 
administered during Cycle 1 and Cycle 2. 
n) The WPAI questionnaire, referring to the 0-120 hour period, will be distributed to the patient at the Day 1 Visit, with 
explanations on how to complete the questionnaire; the patient’s completed WPAI will be retrieved and checked by 
the Investigator or designated responsible during study Visit 3. WPAI questionnaire will only be administered during 
Cycle 1 and Cycle 2. 
o) Hospitalization information (including ED, IP and LOS, and initiation dates thereof), referring to the interval from Visit 
2 (Day 1) through Visit 4 of each cycle, will be recorded.  
p) Starting at Cycle 2 Visit 2 (Day 1), the Investigator will document if changes in chemotherapy administration from the 
previous cycle occurred and will note any delays in treatment for the current cycle.   
q) Adverse events will be collected from Informed Consent signature until end of the study (completion/discontinuation), 
as a minimum. If the patient exit the study less than 15 days after last study drug administration, the patient should be 
followed-up for AE recording up to 15 days after last study drug administration. All non-resolved AEs (including 
SAEs) beyond this date will be documented on the eCRF as “ongoing”. For SAE follow-up requirements, see Section 
8.1.3.1. 
4 
 
Page 29 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
LIST OF ABBREVIATIONS 
5-HT3 
5-hydroxytryptamine type 3 
AC 
Anthracycline-Cyclophosphamide 
ADL 
Activities of Daily Living 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AUC 
Area Under the Curve 
AST 
Aspartate Aminotransferase  
CHF 
Congestive Heart Failure  
CI 
Confidence Interval 
CINV 
Chemotherapy-Induced Nausea and Vomiting 
CL 
Clearance 
CLr 
Renal Clearance 
Cmax 
Maximum Plasma Concentration 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central Nervous System 
CR 
Complete Response 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome 
DMP 
Data Management Plan 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
EMA 
European Medicine Agency 
EU 
European Union 
FAS 
Full Analysis Set 
 
Page 30 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
FDA 
Food and Drug Administration 
FDC 
Fixed-Dose Combination 
FLIE 
Functional Living Index-Emesis 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transferase  
HEC 
Highly Emetogenic Chemotherapy 
HEK 
Human Embryonic Kidney  
HEOR 
Health Economics Outcomes Research 
hERG 
Human Ether-à-go-go-related Gene 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IKr 
Delayed Rectifier Potassium Current  
IND 
Investigational New Drug 
IMP 
Investigational Medicinal Product 
IP 
Inpatient Admission  
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
kg 
Kilogram 
LOCF 
Last Observation Carried Forward 
LOS 
Length of Stay  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MEC 
Moderately Emetogenic Chemotherapy 
min 
Minute 
NA 
Not Applicable 
NCCN 
National Comprehensive Cancer Network 
NEPA 
Netupitant and Palonosetron 
NIDL 
No Impact on Daily Life 
NK1 
Neurokinin-1 
NOEL 
No Observed Effect Level 
 
Page 31 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
NOAEL 
No Observed Adverse Effect Level 
NYHA 
New York Heart Association 
OTC 
Over The Counter 
PALO 
Palonosetron 
PE 
Physical Examination 
PK 
Pharmacokinetic 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions  
TEAE 
Treatment-Emergent Adverse Events 
tmax 
Time to Maximum (Plasma) Concentration 
US 
United States of America 
VAS 
Visual Analog Scale 
Vd 
Volume of Distribution 
WPAI 
Work Productivity and Activity Impairment 
 
Page 32 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
1 INTRODUCTION AND RATIONALE 
1.1 
Background Information 
Cancer chemotherapy is often associated with nausea and vomiting, which are among the 
most unpleasant and distressing subjective side effects [1, 2]. Chemotherapy-induced 
nausea and vomiting (CINV) reduces patient’s health related quality of life and may 
cause non-compliance or refusal of potentially life-saving chemotherapeutic regimens 
[2]. The severity and pattern of nausea and vomiting induced by a chemotherapeutic 
regimen depend on the agents used and the doses employed [1]. In this respect, 
chemotherapeutic regimens are classified as highly, moderately, low, and minimally 
emetogenic [1].  
Palonosetron hydrochloride is a specific 5-hydroxytryptamine type 3 (5-HT3) receptor 
antagonist used to prevent CINV when subjects receive moderately emetogenic 
chemotherapy (MEC) or highly emetogenic chemotherapy (HEC), and is a known 
chemical entity currently registered in the oral and intravenous (IV) forms in several 
countries [3, 4, 5]. 
In the US, in July 2003, the Food and Drug Administration (FDA) approved palonosetron 
0.25 mg IV given as a 30-second bolus, for the prevention of acute CINV associated with 
highly or moderately emetogenic chemotherapy and for prevention of delayed CINV 
associated with MEC (initial and repeat courses). In Europe, in March 2005, the 
European Medicine Agency (EMA) approved the product via the Centralized Procedure 
for the prevention of acute and delayed nausea and vomiting associated with highly 
emetogenic cisplatin-based cancer chemotherapy and moderately emetogenic cancer 
chemotherapy  
The oral palonosetron formulation (0.50 mg capsule) is approved in the US (August 
2008) and in the EU (January 2010) for the prevention of moderately emetogenic CINV. 
At present, the product is registered in more than 70 countries with different trademarks 
(Aloxi®, Onicit®, Paloxi®). 
Netupitant is a new, highly efficient, selective neurokinin-1 (NK1) receptor antagonist 
that blocks receptors located in the central nervous system (in the putative vomiting 
center in the nucleus tractus solitarii) and in the gastrointestinal tract wall (peripheral 
abdominal vagal afferents), and is a new chemical entity. [6] 
Helsinn developed an oral combination (NEPA FDC), which includes a 5-HT3 receptor 
antagonist (palonosetron, 0.5 mg) and an NK1 receptor antagonist (netupitant, 300 mg) in 
the form of a hard-gelatin capsule to be administered as a single dose 1 hour prior to 
chemotherapy.  
In the US oral NEPA FDC (Akynzeo®) was approved in October 2014, for the prevention 
of acute and delayed nausea and vomiting associated with initial and repeated courses of 
chemotherapy, including but not limited to HEC [6].  
 
Page 33 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Oral NEPA FDC (Akynzeo®) is currently officially recommended for MEC and HEC 
acute and delayed emesis prevention by the National Comprehensive Cancer Network  
(NCCN) guidelines. [7] 
Since netupitant is not water-soluble and, as such, early parenteral formulations did not 
show a satisfactory local tolerability profile, the Sponsor developed fosnetupitant, a 
water-soluble phosphorylated pro-drug of netupitant, which is rapidly converted to 
netupitant in vivo following IV administration. Fosnetupitant proved to overcome 
tolerability issues that were observed with former IV netupitant formulations [6]. 
Fosnetupitant was administered as a single dose by IV route at dosages of 19.5 mg up to 
390 mg to a total of 179 healthy male and female volunteers, showing a good safety 
profile.  
An IV formulation of fosnetupitant/palonosetron, IV NEPA FDC, was developed [8]. The 
fosnetupitant component dose in this formulation is 260 mg, which showed to be 
equivalent in exposure (Area Under the Curve, AUC) to the netupitant dose used in oral 
NEPA FDC (300 mg netupitant) (study PNET-12-23 [9]). The selected dose for the 
palonosetron component in the IV NEPA FDC is 0.25 mg, i.e., the registered dose of 
Aloxi® IV.  
Helsinn recently completed a phase 3, active-controlled, double-blind, randomized, 
multi-cycle safety study with IV NEPA FDC versus oral NEPA FDC in more than 
400 cancer patients mainly receiving HEC. Study patients were allowed to receive the 
study drug in up to 4 consecutive repeated chemotherapy cycles. Study results confirmed 
the good safety profile and the satisfactory antiemetic efficacy of IV NEPA FDC in 
cancer patients (Study NEPA-15-18, [13]). 
The sponsor also recently completed an open label pharmacokinetic (PK) study in cancer 
patients treated with IV NEPA FDC as a 30-minute infusion and receiving cisplatin based 
HEC (Study NEPA-15-19, [10]). The PK results obtained in cancer patients confirmed 
the rapid conversion of fosnetupitant into netupitant after IV administration previously 
shown in healthy volunteers. Study results in cancer patients also show that an IV dose of 
260 mg fosnetupitant/0.25 mg palonosetron yields a netupitant exposure equivalent to 
that of 300 mg netupitant oral dose, previously evidenced in healthy volunteers. With 
regards to palonosetron, the PK profile was superimposable to that observed in a previous 
PK study in healthy volunteers receiving 0.25 mg palonosetron IV bolus (Study PALO-
03-05), with the obvious exception of maximum concentration (Cmax) which was lower 
after 30-min infusion as compared to the IV bolus.  
NEPA-17-05 study will evaluate the safety and describe the efficacy of IV NEPA FDC 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination, given as a 30-minute infusion 
compared with oral netupitant/palonosetron (300 mg/0.5 mg) combination (oral NEPA 
FDC) in female breast cancer patients receiving AC chemotherapy, allowing to complete 
the information on the antiemetic efficacy and safety of IV NEPA FDC in the AC 
chemotherapy setting.  
In addition to the described oral or IV combination, study patients will also receive a 
regimen of oral dexamethasone as part of the anti-emetic treatment. 
 
Page 34 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
1.2 
Pre-clinical and Clinical Data of Palonosetron 
1.2.1 
Pre-clinical Data 
As described above, palonosetron is a well-known chemical entity that has been on the 
world market for more than 12 years as an IV formulation and for more than 5 years as an 
oral agent. For pre-clinical data on palonosetron, reference is made to the dedicated 
Investigator’s Brochure [4]. 
1.2.2 
Summary of Phase 1 Clinical Data (Human Pharmacokinetics) 
1.2.2.1 
Absorption 
Following IV administration, an initial decline in palonosetron plasma concentrations is 
followed by slow elimination from the body with a mean terminal elimination half-life of 
approximately 40 hours which is substantially longer than other 5-HT3 antagonists, i.e., 
ondansetron (4-6 h), granisetron (5-8 h), tropisetron (7 h) and dolasetron (7 h). Mean 
plasma Cmax and area under the concentration-time curve (AUC0-∞) are generally dose-
proportional over the dose range of 0.3-90 µg/kg in healthy subjects and in cancer 
patients. 
Following oral administration, palonosetron is well absorbed with its absolute 
bioavailability reaching 97% mean plasma Cmax and AUC are generally dose-proportional 
over the dose range of 0.3-90 μg/kg in healthy subjects and in cancer patients. The mean 
time to maximum plasma concentration (tmax) after oral solution administration was 
generally 4-6 hours. [4] 
1.2.2.2 
Distribution 
Following both oral and IV administrations, palonosetron is widely distributed in the 
body (volume of distribution of approximately 8.3±2.5 L/kg) and approximately 62% is 
bound to human-plasma proteins. Age, hepatic dysfunction or mild to moderate renal 
impairment has no clinically significant effect on the PK of palonosetron, although total 
systemic exposure increases by 28% in patients with severe renal impairment compared 
with healthy subjects. [4] 
1.2.2.3 
Metabolism 
Palonosetron is eliminated by dual routes, about 40% is eliminated through the kidney 
and approximately 50% is metabolized to form two primary metabolites: M9 N-
oxidepalonosetron (AUC approximately 12% of that of the parent drug) and M4 6-S-
hydroxypalonosetron (AUC approximately 3.8% of that of the parent drug). These 
metabolites have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. 
In vitro metabolism studies have suggested that palonosetron is metabolized primarily by 
CYP2D6 and to a lesser extent by CYP3A and CYP1A2. Palonosetron does not inhibit or 
induce cytochrome P450 isoenzymes at clinically relevant concentrations. Metabolite 
profiling demonstrated that the metabolism of palonosetron following oral administration 
was consistent with the metabolism following IV administration. [4] 
 
Page 35 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
1.2.2.4 
Elimination 
After a single IV dose of 10 μg/kg [14C]-palonosetron, approximately 80% of the dose is 
recovered within 144 hours in the urine, with palonosetron as unchanged active substance 
representing approximately 40% of the administered dose. After a single IV bolus 
administration in healthy Caucasian subjects, the total body clearance of palonosetron is 
173±73 mL/min and renal clearance is 53±29 mL/min. The low total body clearance and 
large volume of distribution results in a terminal elimination half-life of approximately 
40 hours, which is substantially longer than that of other 5-HT3 antagonists, i.e., 
ondansetron (4-6 hours), granisetron (5-8 hours), tropisetron (7 hours) and dolasetron 
(7 hours).Ten percent of patients revealed a mean terminal elimination half-life greater 
than 100 hours. Quantifiable concentrations of palonosetron following oral administration 
of a single dose (0.75 mg) of radiolabeled [14C]-palonosetron were reported for all 
subjects until at least 120 hours and between 192 and 216 hours post-dose in plasma and 
urine, respectively. Quantifiable concentrations of M9 metabolite were reported for all 
subjects until at least 24 hours and between 120 and 144 hours post-dose in plasma and 
urine, respectively. [4] 
1.2.3 
Clinical Data 
In clinical studies, adverse events (AEs) considered by Investigators to be related to 
palonosetron were consistent with those observed for other 5-HT3 receptor antagonists as 
a class, or with those expected in a cancer or surgical population, with occasional very 
minor, non-clinically relevant differences between palonosetron and active comparators 
[4]. Constipation and headache were the most frequently observed AEs in patients 
receiving IV or oral palonosetron. These AEs are frequently reported in patients receiving 
5-HT3 receptor antagonists for the prevention of nausea and vomiting associated with 
cancer chemotherapy or for the prevention of postoperative nausea and vomiting. 
For further information about palonosetron, including PK, pharmacodynamics, clinical 
efficacy and safety, please refer to the current edition of the Investigator’s Brochure [4]. 
1.3 
Pre-clinical and Clinical Data of Fosnetupitant and Netupitant 
Fosnetupitant is the water-soluble phosphorylated pro-drug of netupitant. Fosnetupitant is 
rapidly converted to netupitant in vivo following IV administration. Fosnetupitant proved 
to overcome tolerability issues that were observed with former IV netupitant formulations 
and was therefore used as the “netupitant component” in the IV netupitant/palonosetron 
combination formulation. [8] 
1.3.1 
Pre-clinical Data  
1.3.1.1 
Fosnetupitant 
A pre-clinical development program for fosnetupitant, in addition to specific pre-clinical 
studies with the combination of fosnetupitant and palonosetron, has been performed.  
 
Page 36 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Safety Pharmacology 
Central nervous system 
An Irwin test study in rats (PNET-12-01) was performed to evaluate the possible effects 
of fosnetupitant on general behavior parameters. A single IV administration of 
fosnetupitant at 13.16 and 39.47 mg/kg corresponding to 10 and 30 mg/kg of netupitant, 
respectively, did not induce any changes in behavioral, neurological or autonomic 
functions of rats. No clinical signs were observed on the day of dosing or during the 
subsequent 6-day observation period in animals of low and mid-dose groups. Pro-
convulsant (PNET-13-69) and anticonvulsant (PNET-13-70) activity were also assessed 
in rats with fosnetupitant. Fosnetupitant did not show any pro-convulsant nor 
anticonvulsant activity up to 79 mg/kg/day. 
Cardiovascular system 
The effects of fosnetupitant on the delayed rectifier potassium current (IKr) encoded by 
human ether-à-go-go-related gene (hERG) were studied at a stimulation frequency of 
6 pulses/min (0.1 Hz) in stably transfected Human Embryonic Kidney (HEK293) cells 
(PNET-12-06). A vehicle group (1 period with extracellular solution) was included in the 
study for comparison and terfenadine (1 µM) was used as reference substance. The 
results suggest that fosnetupitant up to 30 µM would possess no liability for prolonging 
QT interval (QT) in this model.  
A study assessing the cardiovascular functions in dogs (PNET-12-35) following 2-week 
IV fosnetupitant administration up to 13.2 mg/kg/day showed no effects on PR-, QT-, 
ST-, QTcV-, QTcF -, or RR- intervals or QRS complex duration.  
Respiratory, Renal, Urinary, and Gastrointestinal Systems 
Specific studies were planned and performed to evaluate possible effects on respiratory, 
renal, urinary, and gastrointestinal systems for fosnetupitant. No changes of toxicological 
relevance were detected in renal function at 13.2 mg/kg fosnetupitant dose level. 
Transient decrease in urine volume output and moderate significant decrease of 
electrolyte excretion were observed at 39.5 and 79.0 mg/kg (PNET-13-34). No changes 
of toxicological significance in respiratory parameters were observed with fosnetupitant 
up to 79.2 mg/kg (PNET-14-19). No effects on gastrointestinal motility (PNET-13-67) 
were observed in rats at doses up to 39.5 mg/kg. A statistically significant decrease in GI 
transit of the charcoal meal versus vehicle control was noted at 79.0 mg/kg. [8] 
Toxicology 
Several repeat dose toxicity studies with fosnetupitant were performed in rats and dogs 
following IV administration up to 4 weeks.  
In the 2-week study, the repeated IV administration of fosnetupitant to rats (PNET-11-21) 
at the doses of 3.95, 13.16, and 39.47 mg/kg/day (equivalent to 3, 10, and 30 mg of 
netupitant, respectively) resulted in slight toxic effects mainly affecting the liver of the 
rats receiving the highest dose. These effects were reversible after a 2-week recovery 
period. 
 
Page 37 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
In the 4-week IV toxicity study in rats (PNET-13-18) at the same doses of the 2-week 
study, the repeated administration of fosnetupitant resulted in a liver centrilobular 
hypertrophy in high dose and mid-dose groups. These changes correlated with increased 
liver weight. No significant differences were observed in liver weights after the 2 week 
recovery period. Liver changes observed were not associated with any other alteration 
and were not considered as adverse. On the basis of the results obtained in the study, the 
dose level of 13.16 mg/kg/day was considered as the No Observed Effect Level (NOEL) 
for systemic and local effects, and the dose level of 39.47 mg/kg/day was defined as the 
No Observed Adverse Effect Level (NOAEL) for local effects. 
In a 2-week study in dogs, the repeated daily IV administration of fosnetupitant (PNET-
11-22) at the same doses resulted in no toxic effects after 14 days of treatment. No 
statistically significant increments in QTc were observed. 
In the 4-week IV toxicity study in dogs (PNET-13-27) at dose levels 1.316, 3.95 and 
13.16 mg/kg/day, there were no changes in electrocardiographic parameters, hematology, 
coagulation, clinical chemistry or urinalysis. Decreases in body weight were noted in 
both sexes at the high-dose level during the dosing phase, associated with a decrease in 
food consumption. However, these changes were not considered as adverse and showed 
reversibility after the 2-week recovery period. At the microscopic examination, changes 
were noted in thymus of the high-dose group, in addition, minimal increases in multifocal 
necrotic lymphocytes were noted in the same group.  
No changes were noted in thymus weight and at microscopic observations after a 2-week 
treatment-free period. The NOAEL was 13.16 mg/kg/day for systemic and local effects 
and the NOEL was 3.95 mg/kg/day. 
Fosnetupitant did not show mutagenic activity in the Ames test (PNET-12-04). In the 
Chromosome aberrations test no structural aberrations were observed in human 
lymphocytes (PNET-12-05). 
The assessment of the ability of fosnetupitant to induce chromosomal damage was 
performed in the micronucleus test in rats following IV administration up to 
118.4 mg/kg/day (PNET-13-49). The study showed no clastogenic effect and no 
micronuclei in polychromatic erythrocytes. 
In general, studies showed that fosnetupitant had no hemolytic effect and showed a good 
tolerability profile when injected IV in rats and dogs daily for up to 14 days. 
Pharmacokinetics and metabolism in animals 
In rats and dogs, fosnetupitant is rapidly converted into netupitant after IV administration. 
In vitro metabolic stability data in lung, kidney, intestine and liver S9 and in vivo PK data 
suggest that the hydrolysis of fosnetupitant to netupitant occurs in multiple tissues and 
not only in the liver. The exposure (AUC) of netupitant in rats after equimolar 
administration of IV fosnetupitant and netupitant was comparable, which indicates a 1:1 
conversion. 
Three major circulating metabolites of netupitant have been identified: M1 (desmethyl 
derivative), M2 (N-oxide derivative), and M3 (OH-methyl derivative). In the 2 preclinical 
 
Page 38 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
species dosed IV with fosnetupitant, the exposure to netupitant and to the 3 main 
circulating metabolites, M1, M2 and M3, are comparable with the exposures measured 
after direct IV or oral administration of netupitant following single and multiple doses. In 
the 14-day toxicity study in rats (PNET-11-21), females seemed to be more exposed than 
male rats suggesting that the kinetics of the drug may be gender dependent. An 
accumulation of metabolite M1 and, in minor proportion, of metabolites M2 and M3 was 
observed. A 4th metabolite (M4) has been recently detected and studies aiming at better 
characterization of M4 showed that it is present in much smaller proportion than the other 
3 metabolites. 
The high fosnetupitant in vivo clearance in rats and dogs, which is higher than hepatic 
blood flow, and the high to moderate volume of distribution suggest that the fast 
hydrolysis of fosnetupitant to netupitant occurs in multiple tissues and not only in the 
liver. The subsequent in vivo elimination of netupitant is due to biliary excretion and 
hepatic metabolism (mainly mediated by cytochrome P450[CYP]3A4 and lesser extent 
by CYP2C9 and CYP2D6 in humans). Possible in vivo drug-drug interactions are 
predicted only with netupitant and not with its pro-drug. 
Fosnetupitant has a very short half-life of 12 to 28 min in rats and dogs. 
An overview of the PK parameters of fosnetupitant and netupitant after single IV 
administration, as well as a detailed description of the animal data on fosnetupitant, is 
provided in the current IB of IV NEPA FDC. [8] 
1.3.1.2 
Netupitant 
A detailed description of the netupitant animal data is provided in the current 
Investigator’s Brochure for the oral netupitant/palonosetron (300 mg/0.5 mg) fixed dose 
combination (oral NEPA FDC). [6] 
1.3.1.3 
Fosnetupitant in combination with Palonosetron  
Safety Pharmacology 
A 2-week IV cardiovascular functions study in dogs has been performed (NEPA-13-76). 
Alterations in atrio-ventricular conduction, ventricular depolarization and repolarization 
characterized by increases in PR, PQ, QT interval and QRS complex durations, ST 
segment as well as in corrected QT (QTc) and QT shift were observed at the top dosed 
group with fosnetupitant – palonosetron at 13.2/6 mg/kg/day. These effects tended to 
appear after 7 days of dosing and disappeared on the 14th dosing day. 
Toxicology 
A 4-week IV toxicity study in rats followed by a 2-week recovery period has been 
performed (NEPA-13-51). Assessment of fosnetupitant toxicity in combination with 
palonosetron was performed in rats after daily IV administration for 4 weeks including a 
2-week recovery period at the following doses: fosnetupitant/palonosetron 0, 3.95/1, 
13.16/3 and 39.47/10 mg/kg/day. The mortality evaluation showed that there was 
1 female in the high dose group, and 4 animals in the satellite groups (2 males in the high 
dose group, 1 female in the mid-dose group and 1 female in the high dose group). No 
 
Page 39 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
cause of death was identified for these animals. No relevant changes were observed in 
ophthalmoscopy, hematology, coagulation and urinalyses. In high dose group, increases 
of alanine aminotransferase, aspartate aminotransferase and cholesterol were detected. In 
addition, females from the same treated group showed a decrease of urea. The above 
changes could be related to the liver centrilobular hypertrophy observed at 
histopathological examination (centrilobular hypertrophy associated with increased 
cytoplasmic eosinophilia, being of moderate degree in the males and of mild degree in 
the females). Since it was not associated with any other alteration (i.e., necrosis or 
inflammation), it was not considered as an adverse effect. Changes recorded during the 
dosing phase showed complete reversibility, with a partial recovery for aspartate 
aminotransferase in males. All treated animals were exposed to fosnetupitant. The pro-
drug was highly distributed in the tissues and rapidly converted to netupitant which 
tended to accumulated after 28 days of treatment. M1 was the major metabolite present in 
plasma and brain and accumulate more than netupitant. All animals were exposed to 
palonosetron. There was a slight accumulation, however it was rapidly eliminated. The 
dose level of 13.16/3 mg/kg/day of fosnetupitant/palonosetron was the NOEL for 
systemic and local effects, and the dose level of 39.47/10 mg/kg/day the NOAEL for 
local and systemic effects. 
A 4-week IV toxicity study in dogs followed by a 2-week recovery period has been 
performed (NEPA-13-52). The potential toxicity of fosnetupitant was assessed when 
administered once daily to dogs by IV route for 4 weeks including a 2-week recovery 
period. 
The 
doses 
were 
fosnetupitant/palonosetron 
0, 
1.316/1, 
3.95/3 
or  
13.16/10-6 mg/kg/day (the dose level of palonosetron was decreased to 6 mg/kg/day from 
dosing day 15 for males and dosing day 14 for females). No mortality was observed over 
the course of this study. Transient clinical signs were observed (convulsive episodes, 
vocalization and startle movements) in 1/5 male and 2/5 females during the second week 
of dosing at the highest dose combination. Palonosetron in this combination was 
decreased from 10 to 6 mg/kg/day. Transient tremors and salivation, and 
indurations/swellings at the injection sites in the high dose group were also observed. 
Treatment-related decreased body weight gain occurred in males and females at all the 
three dose levels with the most severe effects in females at the highest dose level. These 
body weight effects were associated with a decrease in food consumption at both high 
and middle dose levels mainly observed during the two first weeks of the dosing phase. 
All these changes in body weight and food consumption were reversible after a 2-week 
treatment-free period and none of these changes were considered to be adverse. No 
treatment-related changes were recorded in ophthalmoscopy, clinical chemistry, 
hematology, coagulation, and urinalysis evaluations. ECG evaluations disclosed transient 
and reversible increased heart rate at mid dose (females only) and at high dose (both 
sexes) levels. These changes were associated with a transient and reversible increase 
(without dose-related effect) in QTc (QTcF and QTcV) intervals at the high dose level 
(male and female animals) and at the mid dose (males only). No treatment-related 
changes were noted in organ weights and no macroscopic findings were noted at the 
terminal or recovery sacrifice. Changes were noted at the injection sites of the females 
treated at the highest dose combination. Specifically, in some injected sites, subchronic 
inflammation of the blood vessels, as well as subchronic inflammation and necrosis at the 
 
Page 40 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
perivascular area, were noted. All treated animals were exposed to the combination 
fosnetupitant and palonosetron, in a quite proportional manner. Data indicated a quite 
rapid conversion of the fosnetupitant to netupitant. M1 was the main metabolite present 
in plasma, with an exposure which exceeded that of netupitant on Day 28. Accumulation 
was also observed in heart tissues for M1. No measurable levels of fosnetupitant and 
metabolite M2 were detected in heart samples of all treatment groups analyzed at 
termination. Mean heart concentration of netupitant in low dose animals was 
approximately 5-fold higher, when compared to plasma Cmax on Day 28. After 14 days 
treatment-free period, heart level of netupitant was reduced by 83% for males and 66% 
for females compared to Day 30. In addition, the presence of M1 was decreased almost 
completely in male animals. After a repeated administration of palonosetron in 
combination with fosnetupitant, no significant sex differences in exposure were noted. 
The NOEL was 1.316/1 mg/kg/day for fosnetupitant/palonosetron. 
1.3.1.4 
Summary  
Overall, the non-clinical safety profile of the IV NEPA FDC is comparable to that of the 
registered oral NEPA FDC (Akynzeo®).  
1.3.2 
Summary of Phase 1 Clinical Data (Human Pharmacokinetics) of 
Fosnetupitant and Netupitant 
1.3.2.1 
Absorption 
Fosnetupitant IV administration 
Fosnetupitant is rapidly converted to netupitant in vivo following IV administration in 
humans. The biotransformation of fosnetupitant to netupitant in vivo is almost completed 
(more than 99%) within 30-60 min after the end of the fosnetupitant infusion (study 
PNET-12-23 [9]). Residual fosnetupitant plasma concentrations lower than 5 ng/mL were 
still observed in plasma up to 3 to 6 hours after administration of the highest doses of 325 
and 390 mg fosnetupitant. Concentrations of netupitant released from its pro-drug raised 
progressively in plasma after IV fosnetupitant administration reaching peak plasma 
concentrations 0.5 – 0.8 hours after the end of the fosnetupitant infusion. [8] 
The recently completed PK study in cancer patients (NEPA-15-19, [10]) showed that 
maximum concentrations of fosnetupitant were achieved at the end of the 30-min IV 
NEPA FDC infusion. Unchanged fosnetupitant disappeared rapidly from the systemic 
circulation. Half-an-hour after the end of the infusion, the mean plasma concentration of 
fosnetupitant was less than 1% of the mean end-of-infusion concentration. Netupitant 
maximum concentrations were achieved in most of the patients at the end of the 
fosnetupitant infusion (median tmax 0.56 h), indicating fast formation of netupitant from 
its pro-drug.  
Netupitant exposure in patients after 260 mg IV fosnetupitant administration as IV NEPA 
FDC was similar to that reported in healthy volunteers after a single 260 mg IV 
fosnetupitant infusion (study PNET-12-23) [9]).  
 
Page 41 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Netupitant oral administration 
In single dose oral studies conducted with the administration to healthy volunteers, 
measurable plasma netupitant concentrations were detected between 45 minutes and 
3 hours after dosing. Plasma concentrations followed a first order absorption process and 
reached Cmax in approximately 5 hours. [6] 
1.3.2.2 
Distribution 
The mean volume of distribution (Vd) of netupitant in humans generally ranged from 
850 L to over 2000 L, indicating substantial distribution to tissues. The drug is highly 
bound to plasma proteins (> 99%) with apparently no large differences in free fraction 
between healthy subjects and patients with hepatic failure. [6] 
1.3.2.3 
Metabolism 
Netupitant is primarily excreted via hepatic/biliary routes, with renal clearance (CLr) 
accounting for less than 5% of CL. Netupitant is metabolized by CYP3A4 to several 
metabolites. The PK of a single 300 mg dose of netupitant were not affected by co-
administration of the CYP3A4 substrates erythromycin (500 mg) or midazolam (7.5mg). 
However, netupitant appears to inhibit the metabolism of both these substrates, resulting 
in an increase in exposure of erythromycin and midazolam proving that netupitant 
inhibits CYP3A4. Other CYP450 isoenzymes (CYP1A2, CYP2C19, CYP2D6) are not 
inhibited by netupitant. Netupitant is not an inducer of any CYP450 isoform including 
CYP2C9. In human liver microsomes, netupitant competitively inhibited the CYP3A4 
mediated hydroxylation of testosterone and midazolam (apparent Ki of 1.1 and 2.2 µM, 
respectively). Therefore, interactions of netupitant with drugs mainly metabolized by 
CYP3A4 were evaluated, in addition to other agents likely to be co-administered with 
netupitant, in the treatment of highly or moderately emetogenic CINV. [8] 
A possible interaction between dexamethasone (when given in a conventional dosing 
regimen) and netupitant was investigated in humans. An increase in the mean plasma 
concentrations of dexamethasone in the presence of orally administered netupitant was 
shown. This increase suggests that dexamethasone doses need to be reduced when given 
with netupitant. [8, 11] 
For interaction between dexamethasone and IV administered fosnetupitant, reference is 
made to Section 1.3.3 Clinical Data (PNET-13-63 [12]). 
Four metabolites have been identified in human plasma at netupitant doses ≥ 30mg; 
metabolites M1, M2, and M3 are considered major metabolites. In a human radio-labeled 
ADME study on oral netupitant, M1, M2 and M3 accounted for 29%, 14% and 33%, 
respectively, of total plasma radioactivity exposure (AUC). Exposure for M4 accounted 
for <10% of the parent. Median tmax for metabolite M2 was 5 hours and was about 17-32 
hours for M1 and M3. Oral netupitant and its 3 major metabolites are extensively bound 
(> 97%) to plasma protein and all metabolites have been shown to be pharmacologically 
active. 
 
Page 42 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
1.3.2.4 
Elimination 
The mean apparent terminal half-life of fosnetupitant ranges from 0.4 (at 65 mg 
fosnetupitant) to 1.2 hours (at 390 mg fosnetupitant).  
The apparent mean elimination half-life of netupitant generally ranged from 30 to 
approximately 100 hours (for oral doses of 30 mg to 450 mg). There was a slightly supra-
proportional increase in Cmax and AUC parameters for doses from 10 mg to 300 mg with 
dose proportional increases between 300 mg and 450 mg. No trends of CL or Vd changes 
were seen with increases in dose. [8] 
1.3.3 
Clinical Data  
1.3.3.1 
Fosnetupitant  
Fosnetupitant has been tested in human volunteers in two studies. The first study (PNET-
12-23 [9]) assessed the safety of IV fosnetupitant and determined the dose of IV 
fosnetupitant yielding equivalent exposure (in terms of netupitant AUC) as 300 mg oral 
netupitant from the oral NEPA FDC. PK data of fosnetupitant, netupitant and its 
metabolites M1, M2 and M3 in humans as well as safety data following IV fosnetupitant 
infusion at increasing doses and infusion rates were obtained. The second study (PNET-
13-63 [12]) evaluated the potential drug-drug interaction between netupitant from the 
infused pro-drug fosnetupitant and oral dexamethasone. This study was performed to 
determine the dosing of dexamethasone when co-administered with the IV NEPA FDC.  
Two studies have been performed in humans with fosnetupitant and, because 
fosnetupitant is rapidly converted to netupitant, an overview of netupitant clinical safety 
is additionally provided with the data of the two studies hereafter. 
1.3.3.2 
Netupitant Alone or in Combination with Palonosetron 
The oral formulation of netupitant, as single agent or in combination with other 
compounds including palonosetron, has been investigated in 27 studies; 20 of them were 
conducted in healthy volunteers. A total of 1,939 subjects received netupitant in 
combination with palonosetron and 206 subjects received oral netupitant alone. [6] 
Oral netupitant was generally well tolerated at all dose levels tested. In healthy 
volunteers, the most frequently reported treatment-emergent AEs (TEAEs) related to 
netupitant alone (not in combination) were headache, fatigue, somnolence, nausea, 
asthenia, lethargy, diarrhea and abdominal pain. In phase 2 and phase 3 studies in cancer 
patients, the oral NEPA FDC showed a good safety profile and proved to be effective for 
the prevention of acute and delayed nausea and vomiting associated with initial and 
repeated courses of MEC and HEC. [6] 
In the Phase 2 and Phase 3 studies leading to oral Akynzeo® approval, the type, 
frequency and intensity of AEs were comparable across treatment groups. There was no 
apparent dose-response effect and the safety profile of the oral NEPA FDC was similar to 
that of other dose combinations, to that of palonosetron alone and to that of aprepitant in 
combination with ondansetron or palonosetron (comparators in the Phase 2 and 3 
studies). There were no clinically significant changes in laboratory parameters. No 
 
Page 43 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
clinically significant changes in vital signs were reported across all studies. All data 
regarding electrocardiograms (ECGs) and QT intervals suggest no clinically relevant 
effects for QT prolongation in the Phase 1, Phase 2 and Phase 3 studies and in a thorough 
QTc study. 
Further details are provided in the in the current IB of oral NEPA FDC [6]. 
A recently completed phase 3, active-controlled, double-blind, randomized, multi-cycle 
safety study assessed IV NEPA FDC versus oral NEPA FDC in more than 400 cancer 
patients receiving HEC who were chemotherapy-naïve at study entry (NEPA-15-18, 
[13]). Study patients were allowed to receive the study drug in up to 4 consecutive 
repeated chemotherapy cycles. Study results confirmed the good safety profile and the 
satisfactory antiemetic efficacy of IV NEPA FDC in cancer patients receiving HEC. 
An additional 36 chemotherapy-naïve or non-naïve cancer patients undergoing HEC were 
treated with IV NEPA FDC in an open label, single cycle, PK study (NEPA-15-19, [10]). 
The study confirmed the good safety profile of IV NEPA FDC. 
1.4 
Conclusions 
Based on clinical and nonclinical data, the safety profile of the IV NEPA FDC product in 
humans was shown to be similar to that of oral NEPA FDC. 
1.5 
Study Rationale 
5-HT3 and NK1 receptor antagonists are among the drugs of choice for an optimal 
antiemetic prophylaxis in cancer patients undergoing emetogenic cancer chemotherapy. 
The concomitant use of these agents is currently recommended for patients receiving 
chemotherapy of high emetic risk, and recent NCCN version 2. 2017 guidelines classify 
the combination of an anthracycline and cyclophosphamide in patients with breast cancer 
as highly emetogenic [7].  
As mentioned, Helsinn recently completed a development program where the safety and 
tolerability of IV NEPA FDC was demonstrated in a phase 3 study in cancer patients 
receiving HEC in repeated chemotherapy cycles (NEPA-15-18). Despite various HEC 
regimens being allowed in this study, the majority of patients received cisplatin based 
chemotherapy. 
Given that according to NCCN guidelines, prevention of AC chemotherapy-induced 
nausea and vomiting also calls for treatment with 5-HT3 + NK1 receptor antagonist prior 
to chemotherapy administration, NEPA-17-05 study is now performed with the aim to 
assess the safety and describe the efficacy of IV NEPA FDC formulation in the AC 
chemotherapy setting. 
The dose of fosnetupitant and palonosetron to be used in the present study is the same as 
administered in the pivotal phase 3, double-blind, active-controlled, randomized, repeated 
cycle safety study NEPA-15-18 in cancer patients receiving HEC, as well as in the open 
label PK study in HEC cancer patients NEPA-15-19.  
The present study will evaluate the safety and describe the efficacy of IV NEPA FDC 
(fosnetupitant/palonosetron, 260 mg/0.25 mg), given as a 30-minute infusion, in 
 
Page 44 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
comparison with oral NEPA FDC (netupitant/palonosetron, 300 mg/0.5 mg), given as one 
capsule. Target population is female breast cancer patients, who are naïve to moderately 
or highly emetogenic antineoplastic agents and are scheduled to receive at least 4 cycles 
of an AC chemotherapy regimen starting on Day 1. In addition to the oral or IV 
combination, study patients will also receive a regimen of oral dexamethasone as part of 
the anti-emetic treatment on study Day 1 of each cycle. Similar to the design of NEPA-
15-18, patients will be allowed to receive the study drug in up to 4 consecutive AC 
chemotherapy cycles. 
This study also includes exploratory assessment of the impact of dosing IV NEPA FDC 
and oral NEPA FDC products on resource utilization and economics. 
 
 
 
Page 45 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
2 STUDY OBJECTIVES 
2.1 
Primary 
To evaluate the safety and tolerability of a single IV dose of fosnetupitant/palonosetron 
(260 mg/0.25 mg) combination administered as a 30-minute IV infusion with oral 
dexamethasone on Day 1 for the prevention of AC chemotherapy-induced nausea and 
vomiting in initial and repeated cycles.  
2.2 
Secondary 
To describe the efficacy of a single IV dose of fosnetupitant/palonosetron (260 mg/0.25 
mg) combination (IV NEPA FDC) administered as a 30-minute IV infusion versus a 
single oral dose of netupitant/palonosetron (300 mg/0.5 mg) combination (oral NEPA 
FDC) administered as one capsule, during the acute (0-24 hours), delayed (>24-120 
hours) and overall (0-120 hours) phases of initial and repeated cycles of AC 
chemotherapy. 
2.3 
Exploratory 
To evaluate the impact on economics and resource utilization through collection of 
Health Economics Outcomes Research (HEOR) parameters in initial and repeated cycles 
of AC chemotherapy.  
 
Page 46 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
3 STUDY ENDPOINTS  
3.1 
Efficacy Endpoints 
Time-related efficacy study parameters assessment will start at “time 0” defined as the 
start time of the AC chemotherapy administration on Day 1 of each cycle.  
Efficacy parameters will be evaluated at each cycle in the acute, delayed and overall 
phases (time intervals 0 to 24 hours, >24 to 120 hours and 0 to 120 hours after the start of 
the AC chemotherapy administration, respectively), if not otherwise noted. 
The efficacy endpoints are defined as follows: 
• The proportion of patients with CR (defined as no emetic episodes and no rescue 
medication) during the acute, delayed and overall phases; 
• the proportion of patients with no emetic episodes during the acute, delayed and 
overall phases; 
• the proportion of patients with no rescue medication during the acute, delayed and 
overall phases; 
• the proportion of patients with no nausea (defined as maximum nausea intensity on a 
100-mm visual analog scale (VAS) < 5mm) during the acute, delayed and overall 
phases; 
• the proportion of patients with no significant nausea (defined as maximum nausea 
intensity on a 100-mm VAS < 25mm) during the acute, delayed and overall phases; 
• the severity of nausea (defined as the maximum nausea intensity on the 100-mm 
VAS) in the acute, delayed and overall phases; 
• the proportion of patients with no impact on daily life (NIDL) activities in the overall 
phase of Cycle 1 and 2, only as assessed by the Functional Living Index-Emesis 
(FLIE) questionnaire. NIDL is defined as a score greater than 108 points, 54 points, 
and 6 points for total FLIE score, domain score, and single item score, respectively; 
• the domain (nausea and vomiting) FLIE scores and the total FLIE score in the overall 
phase of Cycle 1 and 2, only. 
3.2 
Safety Assessments 
Safety will be assessed in each Study Cycle, primarily by means of treatment-emergent 
AEs. See Section 8 ADVERSE EVENTS for specific definitions. 
Additionally, the assessment of safety will be based on: 
• Physical examination (PE) 
• Vital signs 
• Laboratory assessments (hematology and blood chemistry) 
3.3 
Health Economics Outcome Research (HEOR) Assessments 
The following exploratory HEOR assessments will be obtained:  
• Emergency Department (ED), Inpatient Admissions (IP) and length of stay (LOS)  
 
Page 47 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
• Lost work time and productivity assessed by the Work Productivity and Activity 
Impairment (WPAI) Questionnaire (Cycles 1 and 2 only) 
• Disruptions in initiation and dosing of intended next cycle of chemotherapy 
 
Additional data collected from patient diary or electronic Case Report Forms (eCRFs) 
may also be used for HEOR-related analysis. All parameters of interest, endpoints and 
analysis methods will be specified in a separate Health Economics Analysis Plan. 
 
Page 48 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
4 STUDY PLAN 
4.1 
Study Design 
Multicenter, randomized, double-blind, double-dummy, parallel group, stratified study 
assessing the safety and describing the efficacy of a single dose of IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) infusion versus oral netupitant/palonosetron 
(300 mg/0.5 mg) combination; each administered with oral dexamethasone prior to initial 
and repeated cycles of AC chemotherapy in female breast cancer patients. 
The study is planned to be performed in approximately 50 investigational sites in the US 
and in approximately 30 sites distributed in Russia, Ukraine and Georgia. If necessary, 
additional sites and countries may be involved as well. 
The present study will include female patients naïve to moderately or highly emetogenic 
antineoplastic agents (see section below). Adult female patients satisfying this naivety 
criterion, diagnosed with breast cancer and requiring treatment with an AC based 
chemotherapy regimen on Day 1, will be considered for enrollment in this study. 
Eligible patients, stratified by region (US, non-US) and age class (age < 55 years, age ≥ 
55 years), will be randomly allocated in a 1:1 fashion to receive one of the two treatment 
regimens (IV fosnetupitant/palonosetron 260 mg/0.25 mg administered as a 30-minute IV 
infusion [test] or oral netupitant/palonosetron 300 mg/0.5 mg combination) [control], 
before the start of AC chemotherapy on study Day 1 of Cycle 1. In subsequent cycles, 
patients will continue with the same study treatment they received in Cycle 1, while the 
dosage and components of the AC regimens administered in the repeated cycles may be 
different compared to Cycle 1, provided the regimen remains classified as AC. 
4.1.1 
Definition of naïve / non-naïve patients to moderately or highly 
emetogenic antineoplastic agent 
Protocol Appendix 1 provides a list of oral and IV antineoplastic agents divided into 4 
groups considering their emetogenic potential based on NCCN Clinical Practice 
Guidelines in Oncology [7]. 
A patient is considered “naïve to moderately or highly emetogenic antineoplastic 
agents” based on protocol Appendix 1 if she was never previously treated with any of 
the antineoplastic agents listed in Appendix 1 that fall within the high or moderate 
emetogenic levels for IV medications or that fall in the moderate to high emetogenic 
levels for oral medications. Previous antineoplastic treatment categorized as low or 
minimal emetogenic levels will be permitted. 
4.2 
Study Duration 
Each randomized patient is planned to participate in a maximum of 4 consecutive AC 
chemotherapy cycles assessed in this study. 
For each cycle, the study will include a screening visit (Visit 1) up to 7 days (up to 14 
days for Cycle 1 only) before study drug administration (Day 1, Visit 2). After receiving 
 
Page 49 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
a single dose of active treatment on Day 1, patients will enter an efficacy evaluation 
period of 120 hours and then return to the clinical site on Day 6 (+2) for Visit 3. Patients 
will undergo a follow-up visit or  telephone call (Visit 4) either on Day 15 (+3 days) or 
Day 22 (±3 days), depending on the next chemotherapy cycle schedule (this Visit 4 will 
be considered as the end of  each “Study Cycle”). Visit 4, or the corresponding telephone 
contact, either on Day 15 (+3 days) or on Day 22 (±3 days) is to be performed prior to 
administering the chemotherapy relevant to the next cycle and prior to any further 
moderately or highly emetogenic chemotherapeutic treatment administration. 
Total number of visits per patient: For each cycle, there will be a maximum of 4 visits or 
3 visits plus 1 telephone contact. For all cycles, the screening visit and the study drug 
administration visit can be performed on the same day. The screening visit of a 
subsequent cycle can also coincide with the follow-up visit of the previous cycle. If all 
these visits are merged, Visit 4 of the previous cycle as well as Visit 1 and Visit 2 of the 
next cycle are all three performed on the same day. Therefore,  actual number of visits in 
repeated cycles will depend on the number of combined visits. 
Total number of cycles per patient: Each patient may participate in a maximum of 4 
consecutive chemotherapy cycles, as long as they continue to fulfill the inclusion and 
exclusion criteria for the repeated cycles and as long as the study remains open (see 
below for details). 
Maximum total study duration per patient is approximately 14 weeks. This maximum 
total study duration per patient is based on the assumption that the patient participates in 
4 consecutive study cycles with 21 days interval between the Day 1 of two consecutive 
cycles, and that follow-up visits of one cycle coincide with screening visits of the 
subsequent cycle. A minimum of 14 days and maximum of 35 days is allowed between 
the Day 1 of two consecutive cycles. 
A total of 400 patients will be randomized.  Study drug assignment for Cycles 2 to 4 will 
be closed 7 days after the last (400th) patient is randomized, in order to permit patients 
already screened for a subsequent study cycle to be administered study drug. Patients still 
participating in the study at this time should complete their current cycle and will not be 
allowed to enter in a subsequent cycle. 
A patient will be defined as having completed a Study Cycle if she completes the follow-
up visit (Visit 4) of that cycle.  
A patient will be defined as “completed” if she completes Visit 4 (either as on-site visit or 
telephone contact) of Cycle 4. A patient will be defined as “completed cycle, not 
continuing” if she completes Visit 4 (either as on-site visit or telephone contact) of any 
cycle before Cycle 4 without continuing in the subsequent cycle. Study termination at a 
different time point other than Visit 4 of any cycle (including screening visit for one of 
the repeated cycles) will be considered as premature study discontinuation. 
The overall study completion date is defined as the date of last patient’s last visit or 
telephone contact. 
 
Page 50 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
4.3 
Study Population 
4.3.1 
Number of Subjects 
A total of 400 patients will be randomized, equally distributed in the two treatment 
groups (i.e., 200 patients/group). For further details on the sample size, please refer to 
Section 9.1 Sample Size Determination. 
4.3.2 
Inclusion Criteria 
Cycle 1: 
The following inclusion criteria must be checked prior to inclusion at Cycle 1: 
1. Patient read, understood and signed the written informed consent before any study 
related activity, agreeing to participate in the study and  to comply with study 
requirements. 
2. Female patient ≥ 18 years of age. 
3. Histologically or cytologically confirmed breast cancer, including recurrent or 
metastatic 
4. Naïve to moderately or highly emetogenic antineoplastic agents (see Appendix 1). 
5. Scheduled to receive at least 4 consecutive cycles of an AC combination regimen.  
Notes:  
a) additional not emetogenic, minimally or low emetogenic antineoplastic agents 
(see protocol Appendix 1) are permitted at any time after start of AC combination 
on Day 1.  
b) additional highly or moderately emetogenic antineoplastic agents (see protocol 
Appendix 1) are only allowed on Day 1 after the start of AC combination, 
provided their administration is completed within 6 hours from the start of the AC 
combination administration. 
6. ECOG Performance Status of 0 or 1. 
7. Patient shall be: a) of non-childbearing potential or b) of childbearing potential using 
reliable contraceptive measures and having a negative urine pregnancy test within 
24 hours prior to dose of investigational product.  
Notes:  
a) Female patients of non-childberaring potential are defined as being in post-
menopausal state since at least 1 year; or having documented surgical sterilization 
or hysterectomy at least 3 months before study participation.  
b) Reliable contraceptive measures include implants, injectables, combined oral 
contraceptives, intrauterine devices, vasectomized partner or complete (long term) 
sexual abstinence;  
 
Page 51 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
8. Hematologic and metabolic status adequate for receiving a cycle of AC chemotherapy 
based on investigator’s assessment. 
9. If the patient has a known hepatic or renal impairment, she may be enrolled in the 
study at the discretion of the Investigator. 
10. Able to read, understand, follow the study procedure and complete the patient diary. 
All inclusion criteria will be checked at screening visit (Visit 1 of Cycle 1); inclusion 
criteria #7 will be re-checked at Day 1 (Visit 2). 
Cycles 2 to 4: 
The following inclusion criteria must be checked prior to inclusion at each repeated 
cycle: 
1. Participation in the study during the next cycle of chemotherapy is considered 
appropriate by the Investigator and does not pose unwarranted risk to the patient. 
2. Scheduled to receive an AC chemotherapy regimen or AC chemotherapy together 
with other chemotherapies as defined in inclusion criterion #5 for Cycle 1. 
3. Patient shall be: a) of non-childbearing potential or b) of childbearing potential using 
reliable contraceptive measures and having a negative urine pregnancy test within 24 
hours prior to dosing of investigational product. 
4. Adequate hematologic and metabolic status for receiving a cycle of AC 
chemotherapy according to the Investigator’s opinion.  
All inclusion criteria will be checked at screening visit (Visit 1), and inclusion criterion 
#3 will be re-checked at Day 1 (Visit 2) for each repeated cycle. 
4.3.3 
Exclusion Criteria 
Cycle 1: 
The following exclusion criteria must be checked prior to inclusion at Cycle 1:  
1. Lactating patient. 
2. Current use of illicit drugs or current evidence of alcohol abuse. 
3. Scheduled to receive moderately or highly emetogenic antineoplastic agent (see 
protocol Appendix 1) in addition to the AC regimen, from 6 hours after the start of 
the AC chemotherapy on Day 1 and up to Day 1 of Cycle 2. 
4. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis 
within 1 week prior to the start of AC chemotherapy administration on Day 1 or 
between Days 1 to 5, inclusive. 
5. Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) 
within 24 hours prior to the start of AC chemotherapy administration on Day 1. 
6. Symptomatic primary or metastatic central nervous system (CNS) malignancy. 
 
Page 52 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
7. Active peptic ulcer disease, gastrointestinal obstruction, increased intracranial 
pressure, hypercalcemia, an active infection or any illness or medical conditions 
(other than malignancy) that, in the opinion of the Investigator, may confound the 
results of the study, represent another potential etiology for emesis and nausea (other 
than CINV) or pose unwarranted risks in administering the study drugs to the patient. 
8. Known hypersensitivity or contraindication to 5-HT3 receptor antagonists (e.g., 
palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron), to 
dexamethasone, or to NK1 receptor antagonists (e.g., aprepitant, rolapitant).  
9. Known contraindication to the IV administration of 50 mL 5% glucose solution. 
10. Participation in a previous clinical trial involving IV fosnetupitant or oral netupitant 
administered alone or in combination with palonosetron. 
11. Any investigational drugs taken within 4 weeks prior to Day 1, and/or is scheduled to 
receive any investigational drug (other than those planned by the study protocol) 
during the present study. 
12. Systemic corticosteroid therapy within 72 hours prior to the start of AC chemotherapy 
administration on Day 1, except the dexamethasone provided as additional study 
drug. However, topical and inhaled corticosteroids are permitted. 
13. Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy 
during the study participation. 
14. Other than as administered as part of the study protocol, any medication with known 
or potential antiemetic activity within 24 hours prior to the start of AC chemotherapy 
administration on Day 1, including: 
• 
5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, 
tropisetron, ramosetron, palonosetron) 
• 
NK1 receptor antagonists (e.g., fosaprepitant, aprepitant, rolapitant or any other 
new drug of this class) 
• 
benzamides (e.g., metoclopramide, alizapride) 
• 
phenothiazines 
(e.g., 
prochlorperazine, 
promethazine, 
fluphenazine, 
perphenazine, thiethylperazine, chlorpromazine) 
• 
benzodiazepines (except if the subject is receiving such medication for sleep or 
anxiety and has been on a stable dose for at least seven days prior to Day 1). 
• 
butyrophenones (e.g., haloperidol, droperidol) 
• 
anticholinergics 
(e.g., 
scopolamine, 
with 
the 
exception 
of 
inhaled 
anticholinergics for respiratory disorders, e.g., ipratropium bromide) 
• 
antihistamines 
(e.g., 
cyclizine, 
hydroxyzine, 
diphenhydramine, 
chlorpheniramine) 
• 
domperidone 
• 
mirtazapine 
• 
olanzapine 
• 
prescribed cannabinoids (e.g., tetrahydrocannabinol or nabilone) 
• 
Over The Counter (OTC) antiemetics, OTC cold or OTC allergy medications. 
 
Page 53 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
15. Scheduled to receive any strong or moderate inhibitor of CYP3A4 (see protocol 
Appendix 3) during the efficacy assessment period (Day 1 to Day 5, inclusive) or its 
intake within 1 week prior to Day 1. 
16. Scheduled to receive any CYP3A4 inducer (see protocol Appendix 3) during the 
efficacy assessment period (Day 1 to Day 5, inclusive) or its intake within 4 weeks 
prior to Day 1, with the exception of corticosteroids (for which exclusion criterion 
#12 applies). 
17. History or predisposition to cardiac conduction abnormalities, except for incomplete 
right bundle branch block. 
18. History of risk factors for Torsades de Pointes (heart failure, hypokalemia, family 
history of Long QT Syndrome). 
19. Severe or uncontrolled cardiovascular diseases, including myocardial infarction 
within 3 months prior to Day 1, unstable angina pectoris, significant valvular or 
pericardial disease, history of ventricular tachycardia, symptomatic Congestive Heart 
Failure (CHF) New York Heart Association (NYHA) class III-IV, and severe 
uncontrolled arterial hypertension. 
All exclusion criteria with the exception of criteria #5, #12, and #14 will be checked at 
screening visit (Visit 1). Exclusion criteria #5, #12, and #14 will be checked at Day 1 
(Visit 2) only. Exclusion criteria #3, #4, #11, #13, #15, and #16 need to be re-checked at 
Day 1 (Visit 2). 
Cycles 2 to 4: 
The following exclusion criteria must be checked prior to inclusion at each repeated 
cycle: 
1. Scheduled to receive moderately or highly emetogenic antineoplastic agent (see 
protocol Appendix 1) in addition to the AC regimen, from 6 hours after the start of 
the AC chemotherapy on Day 1 of current cycle and up to Day 1 of the next cycle.  
2. Active infection or uncontrolled disease that may pose unwarranted risks in 
administering the study drugs to the patient. 
3. Started any of the prohibited medications (see protocol Section 5.14). 
4. Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) 
within 24 hours prior to the start of AC chemotherapy administration on Day 1.  
5. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis 
within 1 week prior to the start of AC chemotherapy administration on Day 1 or 
between Days 1 to 5. 
6. Symptomatic primary or metastatic CNS malignancy.  
7. Any illness or medical condition that, in the opinion of the investigator, may 
confound the results of the study or pose unwarranted risks in administering the 
investigational product or dexamethasone to the patient.  
 
Page 54 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
All exclusion criteria, with exception of criterion #4, will be checked at screening visit 
(Visit 1). Exclusion criterion #4 will be checked at Day 1 (Visit 2) only. Exclusion 
criteria #2, #3 and #5 need to be re-checked at Day 1 (Visit 2). 
 
 
 
Page 55 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
5 STUDY DRUG MANAGEMENT 
5.1 
Description of Investigational Medicinal Product 
Test drug  
Name: 
IV fosnetupitant/palonosetron combination  
(IV NEPA FDC)  
Dosage form: 
Glass vial with lyophilized powder (for IV infusion) 
Strength: 
260 mg fosnetupitant*/0.25 mg palonosetron per vial 
Reconstitution: 
50 mL sterile 5% glucose solution per vial 
Reconstituted 
fosnetupitant/palonosetron 
solution; 
50 mL solution of 5.2 mg/mL fosnetupitant and 5 µg/mL 
palonosetron 
Dosing 
IV infusion of 30 minutes duration beginning 30 minutes 
prior to the start of AC chemotherapy administration 
Route of administration: 
IV infusion 
*260 mg fosnetupitant (chloride hydrochloride), corresponding to 235 mg fosnetupitant 
 
Control drug 
Name: 
Oral netupitant/palonosetron combination (oral Akynzeo ®) 
Dosage form: 
Blistered Hard gelatin capsule 
Strength: 
300 mg netupitant/0.50 mg palonosetron 
Dosing: 
To be administered 60 minutes prior to the start of AC 
chemotherapy administration 
Route of administration: 
Oral 
 
 
Page 56 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Placebo  for Test drug  
Name: 
Placebo for IV NEPA FDC  
Dosage form: 
Glass vial with lyophilized powder (for IV infusion) 
Strength: 
NA (not applicable) 
Reconstitution: 
50 mL sterile 5% glucose solution per vial 
Reconstituted placebo 
solution; 
50 mL placebo solution 
Dosing 
IV infusion of 30 minutes duration beginning 30 minutes 
prior to the start of AC chemotherapy administration 
Route of administration: 
IV infusion 
Placebo for Control drug 
Name: 
Placebo for oral Akynzeo® 
Dosage form: 
Blistered Hard gelatin capsule 
Strength: 
NA (not applicable) 
Dosing: 
To be administered 60 minutes prior to the start of AC 
chemotherapy administration 
Route of administration: 
Oral 
5.2 
Additional Non-investigational Study Drug 
Additional non-investigational study drug (administered to both treatment groups) 
Name: 
Dexamethasone 
Dosage form: 
Blistered tablets 
Strength: 
4 mg 
Dosing: 
Day 1: 3 tablets of 4 mg, 12 mg in total, once 
(30 minutes prior to the start of the AC chemotherapy 
administration [immediately before the start of the IV NEPA FDC 
or placebo infusion].  
Route of administration: 
Oral 
 
 
Page 57 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
5.3 
Treatment Groups 
Patients eligible for the study will be randomly assigned (1:1 ratio, stratified by region 
and age class) to one of the two treatment groups: 
Group 1 / Test group – IV fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV 
NEPA FDC) administered as a 30-minute infusion of a 50 mL solution on Day 1 of each 
cycle. 
Group 2 / Control group – oral netupitant/palonosetron (300 mg/0.50 mg) (oral NEPA 
FDC) on Day 1 of each cycle. 
Oral dexamethasone (12 mg) will be administered on Day 1 of each cycle to both test and 
control groups. 
5.4 
Dose and Administration 
Test drug: The 30-minute (+/-5 minutes) IV NEPA FDC infusion will start 30 minutes 
prior to the start of AC chemotherapy administration at each cycle. The IV infusion will 
be completed before starting chemotherapy administration.  
To minimize the loss of investigational medicinal product (IMP) remaining in the 
infusion line after the end of IMP infusion, the following process is to be followed: 
1. 
At the end of the 30 +/-5 min IMP or placebo infusion, the infusion line drip 
chamber is to be empty.  
2. The Investigator or designated responsible person will ensure completeness of 
IV infusion administration by rinsing the infusion line with 20 to 30 ml sterile 
5% glucose solution or sterile 0.9% saline solution. Calcium or magnesium 
containing solutions (e.g., Lactated Ringer solution, etc) are not allowed. The 
infusion line rinsing process is to be performed immediately after the end of 
IMP or placebo infusion and is to be completed before to start the AC 
chemotherapy administration. 
Control drug: Oral NEPA FDC (Akynzeo®) capsule will be administered 60 minutes 
prior to the start of AC chemotherapy administration at each cycle.  
For blinding purposes, the double-dummy technique will be applied. Patients will be 
administered with placebos for test and control drugs, as applicable (see Section 5.10 
Blinding). 
Additional non-investigational study drug (administered to both treatment groups):  
Oral dexamethasone administration will be performed in open fashion since dose and 
schedule are identical between test and control treatments.  
On Day 1 of each cycle, oral dexamethasone (3 tablets of 4 mg, for a total dose of 12 mg) 
will be taken 30 minutes prior to the start of the AC chemotherapy administration 
(immediately before the start of the IV NEPA FDC or placebo infusion).  
 
Page 58 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
5.5 
Packaging and Shipment 
The IMPs will be provided in a sealed, blinded and appropriately labeled study kit. Each 
study kit is patient-specific and will provide the necessary supply for one study cycle. 
Each study treatment kit will contain: 
• 1 capsule of oral treatment (oral NEPA FDC capsule or matching placebo capsule) 
• 1 vial for IV treatment (IV NEPA FDC or matching placebo vial) with lyophilized 
powder 
• 3 blistered dexamethasone 4 mg tablets  
• 1 container with 50 ml 5% glucose solution for infusion  
• 1 single use plastic device for reconstitution process (Ecoflac® Connect) 
The infusion line and the infusion line rinsing solution (either 5% glucose or 0.9% saline 
solution) will not be provided in the study kit. 
Sealed treatment kits, all identical in appearance and identified by a kit number, will be 
supplied in a blinded fashion. The first kit will be assigned to the patient at the time of 
randomization, after confirmation of eligibility criteria, by the Interactive Web Response 
System (IWRS). At each subsequent cycle, the IWRS will automatically allocate to the 
patient a kit of the same treatment group. 
Study kits may be either manufactured with single panel label in English only for 
exclusive use in US, or with multilanguage booklet labels intended for use in any of the 
study countries.  
The study drugs and their placebos will be identical in color, smell, size and appearance 
thereby enabling a double-blind design.  
The treatment kit’s outer box and all components contained will carry a label with the 
information in accordance with applicable rules.  
Study kit packaging will be performed by Catalent Germany Schorndorf GmbH. Local 
depots under control of Catalent will be considered for storage and distribution of the 
study kits to the sites in US, Russia, and Ukraine, while drug will be directly delivered 
from Catalent Schorndorf to Georgian sites. 
The study kits, together with relevant documentation, will be supplied from the depots  to 
a designated pharmacist at the hospital site or directly to the Investigator or designee, as 
applicable. 
Relevant labels will carry a removable portion (peel-off) to be applied on study records in 
order to certify the correct distribution, preparation and administration of the study drugs.  
The hospital pharmacist or a designated responsible person from the site staff will be 
requested at each cycle to select the IWRS-determined study kit, prepare and provide the 
study drugs and other materials to the Investigator or designee. At the time of preparing 
the study drug for dispensing to the Investigator or designee, the pharmacist or designated 
responsible person will fill in the blank space on the relevant label with the patient 
number appearing on the IWRS randomization confirmation.  
 
Page 59 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
All the necessary detailed information relative to the characteristics of the study drugs, 
their receipt, storage, preparation, administration and return is reported on the Study Drug 
Manual that will be provided to the sites prior to the start of the study. 
5.6 
Storage 
The study drug will be delivered and stored between 2 and 8°C (between 35.6 and 
46.4°F), in a secure area with limited access and protected from direct light. At the study 
site, the designated responsible person for storage of the investigational product (the site 
pharmacist or the Investigator or a designee) should also make sure that study drugs are 
kept separately from the other medications available on site and in no circumstance 
should be mixed up with any other medications used at the trial site. 
5.7 
Drug Depots 
The study kits are shipped from the Catalent central depot of Schorndorf (Germany) to 
local depots and, from there to the study sites. The study kits will be stored at the local 
depots until shipments to the investigational sites are triggered via IWRS. 
5.8 
Accountability 
Once the study kits are received at the study site, the pharmacist or designated 
responsible person will sign the drug receipt form and notify via IWRS the clinical 
supplies receipt. Adequate records of the receipt, dispensation and return of study kits 
must be maintained throughout the study. Used study kits will be retained until the drug 
accountability forms have been checked by a designated monitor. Unused study kits 
remaining at investigational sites at the end of the study will be destroyed by returning to 
the drug depots or using a local vendor for disposal. At the end of the study, delivery 
records will be reconciled with those of used and returned stocks. Any discrepancy will 
be accounted for. Destruction of unused medication will be documented in writing 
according to FDA Investigational New Drug (IND) regulation 21CFR312.59, ICH Good 
Clinical Practice (GCP) and the drug depot Standard Operating Procedures (SOPs). Any 
destruction of remaining study medication material by the study sites is to be first 
approved in writing by the study Sponsor.  
5.9 
Administration of Study Treatment 
At Day 1 (Visit 2) of Cycle 1, after confirming patient’s eligibility, the Investigator or 
designee will get connected to the IWRS to randomize the patient. The IWRS will assign 
a kit number to the patient and the Investigator (or Investigator’s designee) will receive 
the IWRS notification mentioning the kit number assigned to the patient for which the 
request was made. The hospital pharmacist, or designated responsible person, will select 
from the study kits stored at the site pharmacy the corresponding kit as indicated by the 
IWRS and fill-in the blank space(s) on the outer study kit label with the patient’s 
identification number which was assigned by IWRS during screening.  
In the case the pharmacist or designated responsible person is only involved in the site 
storage of the study kits but not in the preparation of the investigational products, the 
pharmacist or designated responsible person will: 
 
Page 60 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
• select the study kit 
• fill in the outer study kit box label with the patient identification number 
• document the selection and distribution of the entire and still sealed kit to the 
Investigator or Investigator’s designee for preparation by attaching the outer study kit 
box label peel-off onto the Study Drug Inventory log.  
In the case the pharmacist or designated responsible is involved in both the site storage of 
the study kits and in the preparation of the investigational products, the pharmacist or 
designated responsible person will: 
• select the study kit 
• fill in the outer study kit box label and the peel-off portions from the other study kit 
components with the patient identification number 
• document the selected kit by attaching the filled in outer study kit box label peel-off 
onto the Study Drug Inventory Log 
• open the kit and prepare the investigational products as detailed in the Study Drug 
Manual documenting the preparation by completing and attaching the study drug (or 
placebo) vial peel-off label onto the Study Drug Preparation & Administration Log 
• provide the ready to use study medication to the Investigator or designated person.  
The IV infusion prepared by the pharmacist or designated person (or Investigator’s 
designee) is to be kept at room temperature, protected from direct sunlight and is to be 
administered within 3 hours from end of preparation (reconstitution process). The end 
time of preparation and the end time of infusion are to be considered with respect to this 
requirement. 
Once the IV study drug (or placebo) and the wallet with oral study drug (oral Akynzeo® 
or placebo capsule) and dexamethasone tablets are ready, they will be provided to the 
Investigator or designee for patient’s administration.  
At each subsequent cycle (Cycles 2 to 4), the Investigator or designee will get connected 
to the IWRS to obtain a kit number for the repeated cycle and the same above described 
procedure will apply. 
Adequate written instructions (in form of a Study Drug Manual) for use for the 
pharmacist or designated person will be provided to him/her for the preparation of the 
study medication at each study site. 
The relevant labels on the study drug will be filled in according to the provided 
instructions.  
 
Page 61 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Administration process and relevant times: 
One (1) capsule of blinded study drug (either of netupitant/palonosetron combination or 
matching placebo) is to be taken with a glass of non carbonated water 60 minutes prior to 
the scheduled start of AC chemotherapy administration on Day 1. 
Thirty minutes prior to the scheduled AC chemotherapy administration start, the 
3 dexamethasone tablets (each containing 4 mg dexamethasone) are also to be taken by 
the patients with a glass of non carbonated water.  
Immediately after the administration of the oral dexamethasone on Day 1, the 30-minute 
(+/- 5 minutes) blinded IV infusion (either of fosnetupitant/palonosetron combination or 
matching placebo) solution will be started.  
The IV NEPA FDC or placebo vial content, previously reconstituted with 50 mL glucose 
5% solution for IV infusion, will be started as a 30-minute (+/- 5 minutes) infusion.  
At the end of the IV NEPA FDC or placebo infusion, the Investigator or designated 
person will ensure that the infusion line drip chamber is empty. The Investigator or 
responsible person will then immediately proceed with rinsing the infusion line with 
20 to 30 ml of sterile 5% glucose solution (or sterile 0.9% saline solution), to ensure 
complete administration of the IV NEPA FDC or placebo infusion. Calcium or 
magnesium containing solutions (i.e., Lactated Ringer solution, etc) are not allowed. The 
infusion line rinsing process is to be completed before to start the AC administration.  
The infusion of the scheduled AC chemotherapy will then be started immediately after 
the infusion line rinsing process is completed, and the starting time of AC will be 
considered as “time 0” for the antiemetic efficacy assessments (see Section 7.1 Efficacy 
Assessments).  
The administration of the AC components is to be performed according to local standard 
practice. 
Treatment administration schedules in chronological order and inclusive of the allowed 
time windows are provided below, including the infusion line rinsing process. For all 
time windows, reference is made to the start of AC chemotherapy infusion. 
 
 
Page 62 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
 
Group 1 (Test) 
Group 2 (Control) 
Day 1 
 
1 capsule NEPA FDC placebo oral, 60 
minutes before start of AC chemotherapy 
administration  
1 capsule Akynzeo® (300 mg netupitant/0.50 
mg palonosetron), oral., 60 minutes before 
start of AC chemotherapy administration 
Time window for capsule administration: the capsule administration is to be performed between 
75 and 55 min before start of AC 
3 tablets, 4 mg dexamethasone 30 minutes before start of AC chemotherapy (immediately 
before the start of the IV NEPA FDC infusion) 
Time window: 45 to 30 min before start of AC 
IMP infusion: 
1 vial, 260 mg fosnetupitant/ 0.25 mg 
palonosetron reconstituted with 50 mL 5% 
glucose solution and administered by IV as a 
30-minute (+/- 5 minutes) infusion, starting 30 
minutes before AC chemotherapy 
administration  
IMP placebo infusion: 
1 vial, fosnetupitant/palonosetron placebo 
reconstituted with 50 mL 5% glucose solution 
and administered by IV as a 30-minute (+/- 5 
minutes) infusion, starting 30 minutes before 
AC chemotherapy administration  
Time window for infusion administration: the 30min +/-5 min infusion of IMP is to be started 
between 45 and 30 minutes before the start of AC administration. 
Infusion line rinsing process: 
The infusion line rinsing with 20 to 30 ml solution (see above) is to be started immediately after 
the end of IMP or placebo infusion and is to be completed before the start of AC administration.  
5.10 Blinding 
The blinding of the study drugs is guaranteed by the use of identical placebos to the 
respective active drugs (double-dummy technique). 
5.10.1 
Emergency Unblinding Procedure 
The Investigator has the possibility to unblind the study treatment in case of an 
emergency situation, when he/she considers essential to know what treatments the patient 
has received. Any unblinding of the study treatment will be performed by IWRS (24-hour 
7-day coverage). If the code is broken by the Investigator, the patient should be 
discontinued from the study. The date and reason for unblinding are included in eCRF. 
The IWRS will promptly notify, in a blinded fashion, the Sponsor and the CRO Clinical 
Monitor when a treatment code has been unblinded by the Investigator. 
The unblinding procedure is described in detail in a specific document (IWRS User 
Manual) that will be provided separately to the Investigator. 
5.11 Randomization - Use of IWRS 
Randomization will be used to avoid bias in assigning treatments to patients. 
Randomization tends to produce treatment groups in which the distributions of prognostic 
 
Page 63 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
factors, known and unknown, are similar; it also enhances the validity and the efficiency 
of statistical comparisons between the treatment groups.  
Treatment assignment will be managed through a static central blocked randomization 
stratified by region (US, non-US) and age class (age < 55 years, age ≥ 55 years). 
Randomization scheme will be reproducible and will be prepared prior to start of the 
study via a computerized system by the IWRS vendor. A master randomization list copy 
will be filed securely by this vendor and the Sponsor in a manner that ensures that 
blindness is properly maintained throughout the trial. The biostatistician involved in the 
creation of randomization lists will not take part in any study activities. 
Considering the strata, eligible patients will be assigned to one of the two arms, in a 
balanced ratio (1:1), according to specific procedures using the IWRS.  
Separate lists (packaging list and patient’s randomization list) will be prepared for 
patients’ randomization and study medication packaging. Sealed cartons (kits) containing 
the study medications will be prepared according to the packaging list. An appropriate 
amount of treatment kits will be supplied to the designated person at the investigational 
sites at the beginning of the study, with further re-supplies scheduled once the number of 
available treatment kits decrease to a pre-set threshold at each site. 
At Day 1 (Visit 2) of Cycle 1, after confirmation of patient eligibility, the Investigator 
will get connected to the IWRS for randomization and communicate to the system the 
unique patient identification number (assigned by IWRS at the screening visit) and the 
patient’s date of birth.   
The system will then assign to the patient the treatment that corresponds to the first free 
treatment available in the relevant list and the IWRS will randomly select a kit number 
among the kits available at the site and containing the selected treatment. The IWRS 
notification form will be sent by e-mail to the Investigator, describing the kit number to 
be dispensed to the patient. The unique patient identification number, the kit number 
assigned to the patient, the patient randomization number as well as the other patient 
characteristics, are stored in the system. In particular, the patient randomization number 
is stored in the system but is not communicated to the Investigator. The randomization 
procedure only proceeds if kits of both treatments are available at site.  
The hospital pharmacist or designated responsible person will select the appropriate 
carton of study medication based on the kit number supplied by the IWRS.  
Relevant carton box peel-off label from the selected study kit will be attached to the 
Study Drug Inventory Log by the pharmacist or designated person to document the 
correct kit’s assignment. The peel-off labels from the other study kit component will then 
be applied on the Study Drug Preparation & Administration log by the Investigator as a 
proof that the correct medication has been prepared and administered to the patient. 
On Day 1 of each repeated cycle (i.e., Cycles 2 to 4), the Investigator will get connected 
to the IWRS to access the kit number to be assigned to the patient (i.e., a kit containing 
the same treatment as assigned in the first cycle will be automatically selected). An 
IWRS form will be sent by the system to the Investigator, communicating the selected kit 
number for the repeated cycle. 
 
Page 64 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Due to the blinded study design, neither the Sponsor, nor the pharmacist, the Investigator, 
the patient or the Contract Research Organization (CRO) will know which treatment is 
administered. The monitor who will check the drug accountability forms (the Study Drug 
Inventory Log with the peel-off from the carton box attached by the pharmacist and the 
Study Drug Preparation & Administration log with the peel-offs attached by the 
Investigator) will also be blinded with regard to the treatment administered. 
The Investigator has the possibility to unblind the study treatment in case of an 
emergency situation, when he/she considers essential to know what treatments the patient 
has received. For details, see Section 5.10.1 Emergency Unblinding Procedure. The 
IWRS will promptly notify, in a blinded fashion, the Sponsor and the CRO Clinical 
Monitor when a treatment code has been unblinded by the Investigator. 
5.12 Over-dosage 
In the unlikely event of overdose, the patient should be managed with supportive care. In 
case of symptomatic overdose, conservative management of signs and symptoms is 
advised. No case of over-dosage has been reported with netupitant/palonosetron to date. 
No antidote for palonosetron or netupitant overdose is known. 
5.13 Occupational Safety 
No studies have been performed on the ability to drive vehicles and operate machinery 
while receiving agents being evaluated in this study. If patients experience somnolence or 
tiredness, they should avoid potentially hazardous tasks such as driving or operating 
machinery.  
5.14 Prior and Concomitant Medications 
Information on prior and concomitant medications will be collected beginning 14 days 
prior to Day 1 of the first cycle up to Visit 4 (Day 15+3 days or Day 22 +/-3 days follow-
up visit) of the last cycle.  
Inclusion / exclusion criteria are to be carefully checked with reference to prohibited 
medications and relevant time periods. 
5.14.1 
Prior and Concomitant Medications for the Prevention of Nausea 
and Vomiting or With Potential Anti-emetic Effect 
With the exception of study medication and planned dexamethasone as per current 
protocol, the use of any medication for the prevention of nausea and vomiting, or to 
increase the expected preventive effects of the study medication, or any medication with 
potential anti-emetic effects within 24 hours prior to the start of AC chemotherapy 
administration on Day 1 of each cycle and for the following 120 hours is prohibited.  
The list of prohibited medications includes, but is not limited to: 
• 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, 
ramosetron, palonosetron) 
• NK1 receptor antagonists (e.g., fosaprepitant, aprepitant, rolapitant or any other new 
drug of this class) 
 
Page 65 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
• benzamides (e.g., metoclopramide, alizapride) 
• phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine, perphenazine, 
thiethylperazine, chlorpromazine) 
• benzodiazepines (except if the patient is receiving such medication for sleep or 
anxiety and has been on a stable dose for at least seven days prior to Day 1) 
• butyrophenones (e.g., haloperidol, droperidol) 
• anticholinergics (e.g., scopolamine, with the exception of inhaled anticholinergics for 
respiratory disorders, e.g., ipratropium bromide) 
• antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine, chlorpheniramine) 
• domperidone 
• mirtazapine 
• olanzapine 
• prescribed cannabinoids (e.g., tetrahydrocannabinol or nabilone) 
• Over The Counter (OTC) antiemetics, OTC cold or OTC allergy medications. 
Systemic corticosteroid therapy (including but not limited to dexamethasone, 
hydrocortisone, methylprednisolone, or prednisolone, and except the dexamethasone 
provided as additional study drug) taken within 72 hours prior to the start of AC 
chemotherapy administration on Day 1 and until 120 hours afterwards is not permitted. 
Topical and inhaled corticosteroids are allowed. 
Use of cannabinoids for non-medical purposes (e.g., recreational use), or other illicit 
drugs, is not permitted between within 24 hours prior to AC chemotherapy administration 
on Day 1 and until 120 hours afterwards. 
In addition to study treatment, rescue medication for treatment of nausea and vomiting is 
permitted at any time after the start of AC chemotherapy administration in case of need 
(see Section 5.15 Rescue Medication).  
5.14.2 
Prior and Concomitant Cancer Chemotherapy and Radiotherapy 
At study entry, patients must be naïve to moderately or highly emetogenic antineoplastic 
agents based on protocol Appendix 1. They must also be scheduled to begin the first 
cycle of an AC chemotherapy regimen starting on Day 1. 
Other antineoplastic agents are allowed in association to AC, provided the following 
conditions are satisfied: 
• any additional antineoplastic agent on Day 1 is to be administered after the start of the 
AC combination administration  
• additional not emetogenic, minimally or low emetogenic antineoplastic agents are 
permitted at any time after start of AC combination on Day 1 of Cycle 1  
• additional highly or moderately emetogenic antineoplastic agents are allowed on Day 
1 only of each study cycle, provided their administration is completed within 6 hours 
from the start of the AC combination administration. No moderately or highly 
emetogenic antineoplastic agents are allowed from 6 hours after the start of the AC 
chemotherapy on Day 1 of each cycle and up to Day 1 of the next cycle.  
 
Page 66 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Of note, in Cycles 2 to 4, the dosage and components of the AC regimens administered in 
the repeated cycles may be different compared to cycle 1, provided the regimen remains 
classified as AC. 
Please refer to Appendix 1 for classification of antineoplastic agents based on their 
emetogenicity level. 
Radiation therapy to the abdomen or the pelvis is not permitted within 1 week prior to 
Day 1 of each cycle, during Day 1 and during the period from Day 1 to Day 5, inclusive 
for each study cycle. 
5.14.3 
Other Prior and Concomitant Medications 
All medications taken by the patient within 14 days prior to Day 1 of Cycle 1, or 
administered as clinically indicated, during the study and up to Visit 4 of the last study 
cycle, are to be recorded on the appropriate eCRF pages.  
Regarding the use of CYP3A4 inducers and inhibitors (see Appendix 3 for list of 
examples): 
• Strong or moderate CYP3A4 inhibitors: are not allowed during the efficacy 
assessment periods (Day 1 to Day 5, inclusive of each study cycle) and within 1 
week prior to Day 1 of each cycle, in accordance with exclusion criterion #15.  
• CYP3A4 inducers: in accordance with exclusion criterion #16, CYP3A4 inducers 
are not allowed from 4 weeks prior to Day 1 of Cycle 1 (with the exclusion of 
glucocorticoids as described below) until Day 5 (inclusive) of the last study cycle.  
Despite classified as CYP3A4 inducers, systemic glucocorticoids are forbidden during 
the 72 hours before AC chemotherapy administration on Day 1, in accordance with 
exclusion criterion #12. 
In accordance with exclusion criteria, any investigational drugs taken within 4 weeks 
prior to Day 1 of Cycle 1 or planned during the study are not allowed. For this purpose 
“Other investigational product" has to be intended as any agents tested in clinical trials, 
even those which are tested for indications that are already approved (e.g., comparison of 
one type of chemotherapy versus another one). 
Prophylactic infusion of saline or other hydration solutions prior to or after chemotherapy 
in order to prevent toxic reactions related to chemotherapy is to be recorded on the 
appropriate eCRF page; this should also include rehydration events that occur outside of 
the clinical site. 
Infusion of blood products is to be recorded. 
All medications administered in relation to diagnostic procedures, e.g., anesthetics and 
antibiotics are to be recorded. 
 
Page 67 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
5.15 Rescue Medication 
Rescue medication is defined as any medication administered to alleviate established, 
refractory or persistent nausea or vomiting after the start of chemotherapy on Day 1 and 
up to Day 5, inclusive, of each cycle. 
Rescue medication will be permitted on an as-needed basis.  
NK1 receptor antagonists, commercial palonosetron (Aloxi®, Onicit®, Paloxi®) and 
commercial Akynzeo® are not allowed as rescue medications. Other 5-HT3 receptor 
antagonists should not be used as rescue medications. 
For additional details also refer to Section 7.1.2 Rescue Therapy. 
5.16 Treatment Compliance 
A patient will be considered to be compliant with therapy if she takes all study drugs 
(including dexamethasone) provided in the clinical study medication kit. Compliance will 
be defined overall and for each cycle.  
 
Page 68 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
6 STUDY CONDUCT 
6.1 
General Instructions 
In this study, each patient may participate in a maximum of 4 consecutive chemotherapy 
cycles. A minimum of 14 days and maximum of 35 days is allowed between the Day 1 of 
two consecutive cycles.  
Each “Study Cycle” will include Visit 1 (Screening Visit), Visit 2 (Day 1 Visit), Visit 3 
(Day 6 +2 days Visit) and Visit 4 follow-up (either as a visit or telephone contact) on Day 
15 (+3 days) or Day 22 (±3 days), depending on the chemotherapy cycle schedule. For all 
cycles, the screening visit and the study drug administration visit can be performed on the 
same day. The screening visit of a subsequent cycle can also coincide with the follow-up 
visit of the previous cycle. Therefore, Visit 4 of a previous cycle, as well as Visit 1 and 
Visit 2 of the next cycle, can all coincide and be performed on the same day. 
The study visits and contacts, and the main activities characterizing them are detailed by 
visit / contact here below (please, also see the study Flow Chart): 
Cycle 1 
• Visit 1, screening visit up to 14 days prior to Day 1, during which patients will be 
assessed for eligibility; 
• Visit 2, randomization visit at Day 1, during which patients fulfilling selection 
criteria will be randomized to one of the 2 treatment groups and will be treated; 
patient diary, FLIE questionnaire and the WPAI questionnaire will be dispensed; 
• Visit 3, routine visit at Day 6 (+2), during which patients will be assessed for 
safety and patient diary and questionnaires will be retrieved; 
• Visit 4, follow-up visit on Day 15 (+3 days) or on Day 22 (+/-3 days) on-site or 
phone contact for AEs and concomitant medications data collection; HEOR-
related information on ED/hospitalization will also be collected. 
Cycles 2 to 4 
• Visit 1, screening visit up to 7 days prior to Day 1, during which patients will be 
assessed prior to receiving each repeated cycle of chemotherapy; 
• Visit 2, Day 1, during which patients will be administered the same treatment 
assigned on Cycle 1 Day 1, patient diary, FLIE questionnaire and the WPAI 
questionnaire will be dispensed at Cycle 2 only; HEOR-related information on 
chemotherapy will also be collected; 
• Visit 3, routine visit at Day 6 (+2), during which patients will be assessed for 
safety and patient diary retrieved; FLIE questionnaire and the WPAI 
questionnaire will be retrieved at Cycle 2 only; 
• Visit 4, follow-up visit on Day 15 (+3 days) or on Day 22 (+/-3 days) on-site or 
phone contact for AEs and concomitant medications data collection. HEOR-
related information information on ED/hospitalization will also be collected. 
Page 69 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
6.2 
Study Procedures by Time Point 
6.2.1 
Cycle 1 - Visit 1 (screening, Day -14 to Day 1) 
If the Investigator considers a patient to be potentially eligible for the study, written 
informed consent for participation in the study must be obtained before any study-related 
procedures. The patient will be screened within 14 days prior to randomization and study 
drug administration; the following procedures will be performed and data collected 
during this visit: 
• Informed consent 
• Eligibility criteria  
• Demographic data (gender, race, date of birth) 
• Alcohol, tobacco and illicit drug consumption 
• Reproductive status 
• Significant medical history, including surgery, based on Investigator assessment. 
• Histologically or cytologically confirmed breast cancer, including recurrent or 
metastatic (current cancer history) 
• ECOG Performance Status 
• Urine pregnancy test for females of childbearing potential 
• Prior and concomitant medications 
• Complete physical examination (general appearance, head, eyes, ears, nose, throat, 
skin, neck, lungs, cardiovascular, breast, lymph nodes, abdomen, musculoskeletal and 
neurological) 
• Vital signs (pulse rate, systolic and diastolic blood pressure after at least 5 minutes 
rest in semi-supine position) 
• Laboratory tests, including hematology and blood chemistry 
• Patient identification number assignment through IWRS 
• AE assessment 
Based on the relevant above mentioned assessments outcome, the Investigator will decide 
if the patient is eligible for the study. 
6.2.2 
Cycle 1 - Visit 2 (randomization, Day 1) 
The following procedures will have to be completed: 
• The relevant inclusion / exclusion criteria will be assessed for patient’s eligibility 
confirmation (for details, see Section 4.3.2 Inclusion Criteria and Section 4.3.3 
Exclusion Criteria); 
• The patient will undergo pre-dose assessments, including predose vital signs (pulse 
rate, systolic and diastolic blood pressure after resting in semi-supine position for at 
least 5 minutes; weight and height); 
• Urine pregnancy test for females of childbearing potential: in case the screening urine 
pregnancy test was performed less than 24 hours prior to the administration of the 
first (oral capsule) investigational product, the test is not to be repeated at Visit 2); 
After confirmation of patient eligibility, the patient will be randomized to one of the two 
treatment groups using the IWRS.  
Page 70 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
The IWRS will provide the kit number to be dispensed to the patient. The study treatment 
administration schedule is the following (please also refer to Section 5.9 Administration 
of Study Treatment for relevant time windows): 
• 60 minutes prior to the start of AC chemotherapy infusion, the patient will receive 
1 capsule of study drug (oral Akynzeo®) or matching placebo; 
• 30 minutes prior to the start of AC chemotherapy infusion, the patient will receive 
3 tablets of 4 mg dexamethasone; 
• immediately after the oral dexamethasone administration (30 minutes prior to the start 
of AC chemotherapy infusion), the patient will receive a 30-minute (+/-5 minutes) 
infusion of study drug (IV NEPA FDC) or matching placebo;  
At the end of the IV infusion, and before to start AC administration, the infusion line 
used for the IMP infusion is to be rinsed with 20 to 30 ml sterile 5% glucose solution, or 
sterile 0.9% saline solution, to ensure complete IMP administration. See details below. 
The date and the precise time (hh:mm) of the study drug (oral capsule) and additional 
study drug administration (dexamethasone tablets) must be recorded in the source records 
as well as on the relevant eCRF page.  
For the IV NEPA FDC or placebo infusion, start and stop times (including any 
interruptions and re-start, if applicable) are to be collected.  
The relevant tear-off labels from the study drug kit will be attached to the Study Drug 
Inventory Log (by the pharmacist or designated responsible person) and drug 
administration form (by the Investigator) (see Section 5.9 Administration of Study 
Treatment).  
For the IV NEPA FDC or placebo infusion, information on the patient’s arm where the 
infusion will be applied, or any other information regarding infusion location will also be 
collected in the eCRF. 
Infusion Line rinsing process after the end of IV NEPA FDC or placebo infusion: 
The infusion line rinsing at the end of the IMP or placebo infusion is to be performed 
with 20 to 30 ml of either sterile 5% glucose solution or sterile 0.9% saline solution. 
Calcium or magnesium containing solutions (i.e., Lactated Ringer solution, etc) are not 
allowed. The line rinsing is to start immediately after the end of the IV NEPA FDC or 
placebo infusion, following verification that the drip chamber is empty. The rinsing 
process is aimed at ensuring the complete IMP administration. The infusion line rinsing 
process is to be completed before to start the AC administration. Confirmation of the 
performed rinsing process and the type of solution used will be documented in the eCRF.  
• One (1) hour after the administration of the oral capsule, after the end of the 30-
minute (+/- 5 minutes) IV infusion and after completion of the infusion line 
rinsing process, the AC chemotherapy will be administered to the patient. 
Information on the infusion arm or any other infusion location selected for the 
AC chemotherapy administration will be collected in the eCRF. The starting 
time of AC administration on Day 1 is the “time 0” for the time related efficacy 
assessments; the starting time of AC administration will be collected in source 
records and in the eCRF.  
Page 71 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
• Before the start of the AC chemotherapy administration, the Investigator will 
provide the patient with the patient’s diary and instruct her on how to complete 
it. The patient will start completing the diary from the start of AC chemotherapy 
infusion on Day 1 (time 0 for the time related efficacy assessments) and will 
maintain it through the following 5 days, i.e., until Day 6, 120 hours after the 
start of AC chemotherapy administration. The patient will be instructed to bring 
the diary back to the site at Visit 3. 
• Concomitant Medications check and recording. 
• AE assessment. 
• The Investigator will provide the FLIE and WPAI questionnaires to the patient, 
instructing her on how to complete them and reminding the patient to bring the 
completed questionnaires to Visit 3. 
6.2.3 
Cycle 1 - Visit 3 (Day 6 [+2 days]) 
This visit is to be planned on Day 6, not earlier than 120 hours after start of AC 
chemotherapy on Day 1. In the case the visit day would fall during the week end, or in 
case Visit 3 cannot be performed on Day 6 after the end of the 120 hours period for any 
reason, a +2 days time window is allowed for the execution of this visit. The patient will 
return to the site to undergo the following study procedures/assessments: 
• Concomitant medications 
• AE assessment 
• Complete physical examination (general appearance, head, eyes, ears, nose, throat, 
skin, neck, lungs, cardiovascular, breast, lymph nodes, abdomen, musculoskeletal and 
neurological). Any new or worsening of pathological findings noted since previous  
examination are to be reported on the Adverse Event eCRF form. 
• Vital signs (pulse rate, systolic and diastolic blood pressure after resting in semi-
supine position for at least 5 minutes) 
• Laboratory tests, including hematology and blood chemistry 
• Check and retrieval of the completed patient diary 
• Check and retrieval of the completed FLIE  
• For HEOR-related assessments: 
o Check and retrieval of the completed WPAI questionnaire  
At this visit, the Investigator will schedule Visit 4 (follow-up Visit), either as on site visit 
or telephone contact. Visit 4, follow-up visit, is to be performed either on Day 15 +3 days 
or on Day 22+/-3 days, depending on the next chemotherapy cycle schedule. The 
patient’s follow-up visit or contact is to be performed prior to administering the 
chemotherapy relevant to the next cycle and prior to any further moderately or 
highly emetogenic chemotherapeutic treatment administration. 
If, for any reason, no further chemotherapy cycle is planned, Visit 4 follow-up should be 
performed on Day 22 (+3 days). 
Page 72 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
6.2.4 
Cycle 1 - Visit 4 (follow-up visit, Day 15 [+3 days] or Day 22 (± 3 
days])  
Visit 4, follow-up visit, can be performed either as on site visit or telephone contact.  
During Visit 4, the patient will be questioned about any new AEs appeared since the last 
visit or about any ongoing AE at last visit; concomitant medications, either new or 
ongoing will be verified and relevant data collected. For HEOR-related assessments, 
ED/IP/LOS information for events occurring since Day 1 will be documented. 
The follow-up visit for Cycle 1 and the screening visit for Cycle 2 may coincide. 
6.2.5 
Cycles 2 to 4 - Visit 1 (screening, Day -7 to Day 1) 
If the Investigator considers a patient to be suitable to continue the subsequent cycle of 
AC chemotherapy in the study, the patient will be re-assessed within 7 days prior to Day 
1 of the subsequent (repeated) cycle: inclusion/exclusion criteria verification, complete 
physical examination, ECOG performance status, vital signs, and laboratory tests will be 
performed as for Visit 1 of Cycle 1. Females of childbearing potential will have to 
perform a urine pregnancy test.  
The study Visit 1 may be performed from Day -7 up to study Day 1 inclusive (i.e., Visit 1 
and Visit 2 may occur on the same day on study Day 1). In that case, the assessments 
planned at both Visit 1 and Visit 2 have to be performed only once. In addition, the 
follow-up visit of one cycle and the screening visit of the subsequent cycle may coincide. 
6.2.6 
Cycles 2 to 4 - Visit 2 (Day 1) 
After patient has been re-evaluated for eligibility, the Investigator will get connected to 
the IWRS for the assignment of a new treatment kit number. The patient will be 
administered the same treatment assigned at Cycle 1 (Day 1, Visit 2). The procedures to 
be completed are the same as for Cycle 1 (Day 1, Visit 2), except for (a) randomization, 
i.e., for repeated cycles IWRS will only provide a new kit number for the patient, 
according to the patient’s randomization at Cycle 1, and (b) the FLIE questionnaire and 
the WPAI questionnaire will be dispensed in Cycle 2, but not in Cycle 3 or Cycle 4. In 
addition, starting at Cycle 2 Visit 2 (Day 1), the Investigator will document if changes in 
chemotherapy administration from the previous cycle occurred and will note any delays 
in treatment for the current cycle.  
6.2.7 
Cycles 2 to 4 - Visit 3 (Day 6 [+2 days]) 
On Day 6 (+2), the patient will return to the site and will undergo the same study 
procedures/assessments as for Visit 3 of Cycle 1. However, the FLIE questionnaire and 
the WPAI questionnaire will not be administered during Cycle 3 and Cycle 4. 
Page 73 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
6.2.8 
Cycles 2 to 4 - Visit 4 (follow-up visit, Day 15 [+3 days] or Day 22 
(± 3 days])  
Visit 4, the follow-up visit, can be performed either as on site visit or telephone contact, 
and the patient will undergo the same study procedures/assessments as for Visit 4 of 
Cycle 1. 
The follow-up visit of one cycle and the screening visit of the subsequent cycle may 
coincide. 
6.3 
Definition of Study Completion 
A patient will be defined as having completed a Study Cycle if she completes the follow-
up visit (Visit 4) of that cycle.  
A patient will be defined as “completed” if she completes Visit 4 (either as on-site visit or 
telephone contact) of Cycle 4. A patient will be defined as “completed cycle, not 
continuing” if she completes Visit 4 (either as on-site visit or telephone contact) of any 
cycle before Cycle 4 without continuing in the subsequent cycle. Study termination at a 
different time point other than Visit 4 of any cycle (including screening visit for one of 
the repeated cycles) will be considered as premature study discontinuation. 
Overall study end date is defined as the date of last patient’s last visit or telephone 
contact. 
6.4 
Premature Discontinuation 
Patients may discontinue the study at any time for any of the following reasons: 
1. An AE occurs that, in the opinion of the Investigator, makes it unsafe for the patient 
to continue in the study. 
2. The patient is lost to follow-up. 
3. The patient dies. 
4. The patient withdraws consent. 
5. The Investigator, for any reason, terminates his/her participation in the study, or 
terminates the study for that patient; or the attending physician requests that the 
patient be withdrawn for any medical reason. 
6. The Sponsor or the Regulatory Authorities or the Ethics Committee(s), for any 
reason, terminates the entire study, or terminates the study for this trial site or this 
particular patient. 
Additionally to the above mentioned reasons, patients who successfully completed any of 
the study cycles may not continue to a subsequent study cycle for any of the following 
reasons: 
• The patient is unwilling to participate in further chemotherapy cycles. 
• The patient is no longer scheduled to receive any additional chemotherapy. 
Page 74 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
• The inclusion/exclusion criteria are no more satisfied for performing a repeated cycle 
• The whole study is closed as per protocol definition. 
If a patient is discontinued from the study after treatment with the investigational 
medicinal product, the Investigator must try his/her best to contact the patient 15 days 
after Day 1 of the last performed cycle in view of completing the study safety assessment 
by collecting information that may be suggestive of AEs. 
Patients discontinued after randomization will not be replaced. 
Page 75 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
7 METHODS OF ASSESSMENT 
7.1 
Efficacy Assessments 
Efficacy evaluations will be primarily based on the patients’ documentation of emetic 
episodes (episodes of retching or vomiting), intake of rescue medication and nausea 
severity assessed daily by VAS during the period from 0 to 120 hours after the start of the 
AC chemotherapy administration on Day 1 of each cycle. To collect these data, a patient 
paper diary covering the 0-120 hours period after the start of AC chemotherapy, will be 
used. 
In addition FLIE questionnaire covering the 5 days after start of AC chemotherapy will 
be collected during Cycle 1 and Cycle 2 only. 
Given the precisely defined starting timepoint for the efficacy assessment period (i.e., the 
starting time of AC administration on Day 1) and the duration of such period (120 hours), 
the starting time and date of the AC chemotherapy infusion are to be carefully and 
precisely collected in the eCRF and reported on the patient diary to remind patient the 
correct time-frame of data to be collected in the diary. 
The date of AC chemotherapy administration will determine study Day 1 and the starting 
time of its administration will define the study “time 0” for the assessment of time-related 
efficacy parameters.  
Efficacy parameters will be evaluated in the overall, acute and delayed phases (time 
intervals 0 to 120 hours, 0 to 24 hours and >24 to 120 hours after the start of the AC 
chemotherapy administration, respectively). 
For the detailed description of the efficacy endpoints see Section 3.1 Efficacy Endpoints.  
7.1.1 
Emetic Episodes 
An emetic episode is defined as one or more continuous vomits (expulsion of stomach 
contents through the mouth) or retches (an attempt to vomit that is not productive of 
stomach contents). Emetic episodes are considered distinct if separated by absence of 
vomiting and retching for at least 1 minute. All patients will be asked to document in the 
patient diary all details about their emetic episodes occurring during the 120 hours after 
the start of AC chemotherapy administration.  
These details will include: 
- 
Each episode of retching or vomiting  
- 
Date of each retching or vomiting episode 
- 
Exact time of onset of each retching or vomiting episode. 
Each emetic episode, as well as date and time of occurrence, will then be documented on 
the eCRF in accordance with the patient diary records. 
Page 76 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
7.1.2 
Rescue Therapy 
Rescue medication is defined in Section 5.15 Rescue Medication. 
Rescue medication will be permitted on an as-needed basis. The patient will record in the 
patient diary the drug name, dosage and date/time of intake for each medication taken for 
the treatment of nausea and vomiting during the 0-120 hour interval (Day 1 to Day 5). 
Each rescue medication trade or generic name, dosage and route of administration, as 
well as the time and date of intake, will then be documented on the eCRF in accordance 
with the patient diary records. 
7.1.3 
Severity of Nausea 
Severity of nausea will be evaluated by the patient in the patient diary for each day of the 
0-120 hour interval (Days 1 to 5, inclusive), using a 100-mm horizontal VAS. The left 
end of the scale (0 mm) will be labeled as ‘no nausea’ and the right end of the scale 
(100 mm) will be labeled as ‘nausea as bad as it could be’. 
Each day starting from Day 2 and up to Day 6 of each cycle, the patient will be asked to 
record her assessment of the average degree of nausea during the preceding 24 hours 
(“How much nausea did you experience on average during the last 24 hours?”). The 
patient’s assessment of the average severity of nausea in the preceding 24 hours will be 
performed by placing a vertical mark on the scale. Severity of nausea will then be 
documented on the eCRF in accordance with the patient diary records. 
7.1.4 
Functional Living Index-Emesis (FLIE) Questionnaire 
The FLIE is a nausea and vomiting specific self report instrument comprised of two 
domains (nausea and vomiting) with nine identical items in each domain. FLIE was 
originally developed and validated to assess the impact on patient’s daily life over the 
three days following chemotherapy. The measurement characteristics of the FLIE are also 
acceptable when administered with a 5-day recall period [14]. 
The items assess the impact of nausea and vomiting on multiple aspects of a patient’s 
daily life. Each item is answered using a 100-mm (1 to 7 points) VAS with anchors 
corresponding to “none”/”not at all” and “a great deal”. Items within the domain are 
weighted equally, reversed as required for some items (items with the scale anchors in the 
opposite direction) and summed to create the domain score according to the FLIE 
Scoring and Administration Manual. The two domain scores are then summed to create 
the total FLIE score. Higher FLIE scores indicate less impairment on daily life as a result 
of nausea and vomiting. 
The FLIE questionnaire will be provided on paper to the patient during Visit 2 (Day 1) of 
Cycle 1 and Cycle 2, with adequate instructions on how to fill it. The patient will 
complete the FLIE questionnaire reflecting the impact of nausea and vomiting during the 
5-day recall period after AC chemotherapy administration on Day 1. 
Page 77 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
The FLIE will then be collected and checked by the Investigator at Visit 3 (Day 6+2) of 
Cycle 1 and Cycle 2 and answers documented on the eCRF in accordance with the paper 
patient copy. 
7.2 
Safety Assessments 
Safety is the primary objective of this study and will be assessed primarily by means of 
AEs collection and reporting. See Section 8 ADVERSE EVENTS for specific definitions. 
Additionally, details of other safety assessments are decribed in detail below. 
7.2.1 
Physical Examination 
A complete physical examination will be performed at Visit 1 (screening) and at Visit 3 
(Day 6 +2 days) of each cycle. This evaluation will include an examination of general 
appearance, head, eyes, ears, nose, throat, skin, neck, lungs, cardiovascular, breast, lymph 
nodes, abdomen, musculoskeletal and neurological. At Visit 3 and at subsequent cycles, 
only the  general question “Was the physical examination performed?” will be asked on 
the eCRF. 
Information about the physical examinations will be recorded in the source 
documentation at the site and any abnormalities at screening will be recorded in the 
eCRF. After signing the informed consent, any new or worsening of existing pathological 
findings noted since previous examination performed under the present protocol should 
be reported on the Adverse Event eCRF form. 
7.2.2 
Vital Signs 
Vital signs assessments will include: pulse rate, systolic and diastolic blood pressure (at 
Visit 1, Visit 2 predose and Visit 3 of each cycle), height (Visit 2 of Cycle 1 only) and 
body weight (Visit 2 [Day 1 visit] of each cycle, at predose). Pulse rate, systolic and 
diastolic blood pressure will be measured after the patient has been resting in the semi-
supine position for at least 5 minutes at Visit 1 (screening), Visit 2 (pre-dose i.e., before 
the oral NEPA FDC or matching placebo capsule administration) and Visit 3 (Day 6 + 2 
days). 
The following time windows will be applied for the measurement of vital signs:  
• Visit 2 (Day 1 Visit), predose: within 30 minutes before oral NEPA FDC capsule 
or matching placebo capsule administration. 
• Visit 3 (Day 6 +2 days visit): between 120 hours and 168 hours from start of AC 
administration on Day 1. 
7.2.3 Clinical Laboratory Tests 
At the screening visit for each cycle, the Investigator will be responsible to assess the 
adequacy of the patient to receive AC chemotherapy (see inclusion criteria), including 
laboratory parameters assessments. The following laboratory parameters will be assessed 
at Visit 1 and Visit 3 of each cycle using local laboratories: 
• Hematology: hemoglobin, erythrocytes, leukocytes, platelets 
Page 78 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
• Blood Chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
gamma-glutamyl transferase (GGT), bilirubin, alkaline phosphatase, creatinine and 
creatinine clearance (derived from blood creatinine value by application of the 
Cockcroft-Gault formula). 
Females of childbearing potential will have to perform a urine (dipstick) pregnancy test at 
the Screening Visit and within 24 hours prior to the first dose (oral NEPA FDC or 
matching placebo capsule) of investigational drug administration at Day 1 of each cycle. 
In case the Screening Visit urine pregnancy test was performed within 24 hours prior to 
IMP, the urine test is not to be repeated on Day 1. 
See Section 6.2 Study Procedures by Time Point and Study Flow Chart for additional 
details.  
Upon receipt and after review, the Investigator must sign and date each local laboratory 
report and document in the relevant EDC form if the parameter is below, within or above 
normal ranges. The Investigator will review the values outside the normal range and 
repeat the test, if needed. In case clinically significant laboratory abnormalities are 
detected, the etiology of the abnormality should be identified and the diagnosis should be 
recorded as an AE. Otherwise, if the etiology cannot be identified, the laboratory 
abnormality as such should be recorded as AE.  
Similarly, clinically significant laboratory abnormalities detected at Cycle 1 screening, if 
not justified by an underlying disease already recorded in the medical history, are to be 
recorded as AEs. 
7.3 
Health Economics Outcome Research (HEOR) Assessments  
HEOR assessments in this study will include hospitalization information, lost work time, 
and details related to any changes in chemotherapy administration during the repeated 
cycles. Details of each are described in the sections below. 
Additionally, other data collected from patient diary or eCRFs may also be used for 
HEOR-related analysis. All parameters of interest, endpoints and analysis methods will 
be pre-specified in a separate Health Economics Analysis Plan. 
7.3.1 
Work Productivity and Activity Impairment (WPAI) Questionnaire 
The WPAI is a questionnaire used to document lost work time [15]. Actual lost work 
time (hours) will be recorded by patients on the WPAI and returned at Visit 3 
(Day 6 +2 days), referring to the past five days since start of AC chemotherapy 
administration on Day 1. WPAI questionnaire will only be administered during Cycle 1 
and Cycle 2. 
7.3.2 
Emergency Department (ED) Use and In-Patient (IP) Admissions 
Patients will be asked dates of ED events and IP events. For each IP event, the length of 
stay in number of calendar days will be documented (i.e., minimum of 2). This 
information, referring to the interval from Visit 2 (Day 1) through Visit 4 of each cycle, 
will be recorded at Visit 4 of each cycle.  
Page 79 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
7.3.3 
Subsequent Cycle Start Date and Changes from Initial Schedule 
Starting at Cycle 2 Visit 2 (Day 1), the Investigator will document if changes in 
chemotherapy administration from the previous cycle occurred and will note any delays 
in treatment for the current cycle. If a subsequent cycle is not yet initiated by Visit 4, that 
shall be noted as well.  
 
 
Page 80 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
8 ADVERSE EVENTS 
AE recording will begin at the time the informed consent form is signed until end of the 
study (completion/discontinuation), as a minimum. If the patient exit the study less than 
15 days after last study drug administration, the patient should be followed-up for AEs 
recording up to 15 days after last study drug administration. AEs will be ascertained by 
asking the patient how she has been since the last visit. 
8.1 
Definition of Adverse Events 
Adverse Event (AE) 
As defined by the current ICH Guideline for Good Clinical Practice [16, 17] an Adverse 
Event (AE) is: 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product. 
Within the scope of this study, such untoward medical occurrences would be considered 
as “AEs” even if the subject was not administered the study drugs but had already signed 
the Informed Consent Form. 
AEs include the following types of occurrences: 
− Suspected adverse drug reactions 
− Other medical experiences, regardless of their relationship to the study drugs, such as 
injury, surgery, accidents, increased severity of pre-existing symptoms, apparently 
unrelated illnesses, and significant abnormalities in clinical laboratory values, 
physiological testing, or physical examination findings 
− Reactions from drug overdose, abuse, withdrawal, hypersensitivity, or toxicity. 
Planned procedures, surgical interventions or planned hospitalizations scheduled prior to 
the informed consent but performed during the study (study procedures, chemotherapy 
cycles, etc.) should not be considered (serious) AEs.  
Signs and symptoms considered as lack of efficacy (nausea and vomiting) and occurring 
during the study up to 5 days after the study drugs administration, will not be recorded on 
the AEs section of the eCRF, except on the condition that, in the Investigator’s opinion, 
nausea and vomiting are caused by any reason different from lack of efficacy of study 
treatment or meet the definition of serious AE. 
Treatment-emergent adverse events (TEAEs) are defined as those AEs that start after the 
first study treatment administration on Day 1 of Cycle 1 until Visit 4 of the last study 
cycle.  
Page 81 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Serious Adverse Event (SAE) 
A serious adverse event is any event that suggests a significant hazard, contraindication, 
side effect, or precaution, whether or not it is considered to be associated with the study 
product. A SAE is an AE that meets any of the following criteria: 
− Results in death. This includes any death that occurs during the conduct of a 
clinical study, including deaths that appear to be completely unrelated to the study 
drugs (e.g., car accident). 
− Is life-threatening. This includes any AE during which the subject is, in the view 
of the Investigator, at immediate risk of death from the event as it occurs. This 
definition does not include events that may have caused death if they had 
occurred in a more severe form. 
− Requires inpatient hospitalization or prolongation of existing hospitalization 
− Results in persistent or significant disability or incapacity 
− Is a congenital anomaly or birth defect 
− Other medical events that based upon appropriate medical judgment are thought 
to jeopardize the patient and/or require medical or surgical intervention to prevent 
one of the outcomes defining a SAE. 
Unexpected Adverse Event 
An Unexpected Adverse Event is any experience not previously reported (in nature, 
severity or incidence) in the current Investigator’s Brochure for IV NEPA FDC. [8] 
Pre-existing Condition 
A pre-existing condition is one that is present at the start of the study. A pre-existing 
condition is to be recorded as an AE if the frequency, intensity, or the character of the 
condition worsens during the study period. 
8.1.1 
Classification of Adverse Events 
The Investigator will classify AEs based on their severity and relationship to IMP and 
dexamethasone. Every effort must be made by the Investigator to categorize each AE 
according to its severity (see Section 8.1.1.1 Severity), and its relationship  
(see Section 8.1.1.2 Relationship to Investigational Medicinal Product and 
Dexamethasone). 
8.1.1.1 
Severity 
The severity of an AE will be rated by the Investigator according to the descriptions and 
grading scales of the Common Terminology Criteria for Adverse Events (CTCAE) (for 
details please refer to the integral document Terminology Criteria for Adverse Events 
(CTCAE, Version 4.0, published: May 28, 2009 [v4.03: June 14, 2010]); U.S. 
Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute) [18], as summarized below: 
Page 82 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Severity of AE according to CTC Grading Scale and related Guideline 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)*; 
Grade 3  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**; 
Grade 4  
Life-threatening consequences; urgent intervention indicated; 
Grade 5  
Death related to AE. 
(*) Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.  
(**) Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
8.1.1.2 
Relationship to Investigational Medicinal Product and 
Dexamethasone 
For this trial, an AE cause and effect relationship to the study drug and dexamethasone 
will be classified by the Investigator as reported hereafter. 
Definitely related 
The event: 
− Follows, in a reasonable temporal sequence, the administration of the drug or the drug 
level that has been established in body fluids or tissues. 
− Follows a known or expected response pattern of the suspected drug. 
− Is confirmed by improvement after de-challenge or dosage reduction of the drug. 
− Reappears after repeated exposure (re-challenge). 
Probably related 
The event: 
− Follows, in a reasonable temporal sequence, the administration of the drug. 
− Follows a known or expected response pattern of the suspected drug. 
− Is confirmed by improvement after de-challenge or dosage reduction of the drug. 
− Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state. 
− No re-challenge test or laboratory confirmation is available. 
Possibly related 
The event: 
− Follows, in a reasonable temporal sequence, the administration of the drug. 
− Follows a known or expected response pattern of the suspected drug but could have 
been easily produced by a number of other etiologies. 
Page 83 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Unlikely related 
There is no reasonable temporal association between the drug and the AE or the event 
could have been related to the subject’s clinical state or concomitant treatment(s), or 
another cause adequately explaining the AE is known or is much more probable. 
Not related / None 
Sufficient information exists indicating that the etiology is unrelated to the drug. 
Unassessable 
The data are insufficient or contradictory to make a meaningful medical assessment. This 
criterion should be used only in case of insufficient evidence, conflicting data or poor 
documentation. Every effort should be done by the Investigator to make appropriate 
assessment of causal relationship (i.e., either related to the IMP, dexamethasone or both). 
8.1.2 
Reporting Adverse Events 
AE reporting has to be in accordance with the ICH E6 Guidance on GCP and ICH E2A 
Guidance on Clinical Safety Management. [16, 17] 
During the study, all AEs (including SAEs), irrespective of the relatedness to the study 
drugs, must be recorded in detail in the source records and transcribed onto the AEs 
pages of the eCRF. During each monitoring visit, the Investigator and the site monitor 
will review all AEs and perform Source Data Verification (SDV). The Investigator will 
be responsible for ensuring that the correct information concerning all AEs is entered on 
the appropriate eCRF pages. 
In case clinically significant laboratory abnormalities are detected, the etiology of the 
abnormality should be identified and the diagnosis should be recorded as an AE. 
Otherwise, if the etiology can not be identified, the laboratory abnormality as such should 
be recorded as the AE.  
Similarly, clinically significant laboratory abnormalities detected at the screening visit 
(before any administration of the investigational medicinal product or additional non-
investigational drug), if not justified by an underlying disease already recorded in the 
medical history, are to be recorded as AEs. 
The reporting period for AEs during the Study is the period starting from the time of 
Informed 
Consent 
signature 
and 
lasting 
until 
end 
of 
the 
study 
(completion/discontinuation), as a minimum. If the patient exit the study less than 15 
days after last study drug administration, the patient should be followed-up for AEs 
recording up to 15 days after last study drug administration. All unresolved AEs 
(including SAEs) at the end of the reporting period will be documented on the eCRF as 
“ongoing”. 
Page 84 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
8.1.3 
Reporting Serious Adverse Events 
All SAEs occurring from the time of signing of the informed consent until Visit 4 (either 
Day 15 +3 days or Day 22 ±3 days follow-up visit) of the last cycle, must be reported 
immediately to the CRO pharmacovigilance. Contact information is provided in the 
Investigator file as well as in the General Information Section of the present protocol. 
The Investigator or designated study coordinator must complete the Investigational 
Serious AE Form and send it to the CRO within 24 hours of observation or notification of 
a serious AE. All of these events must also be recorded on the appropriate eCRF pages. 
It is the responsibility of the Investigator to inform his or her local Institutional Review 
Board (IRB)/Ethics Committee (EC) about SAEs occurring during the Study, according 
to the local IRB/EC requirements. It is the responsibility of the Sponsor (or Sponsor’s 
designee) to submit applicable SAE Reports to the Competent Authorities. Reporting of 
suspected unexpected serious adverse reactions (SUSARs) to the relevant IRB/EC, in 
accordance with the the US Code of Federal Regulations 313.32, ICH E6 Guidance on 
GCP, and ICH E2A Guidance on Clinical Safety Management, will also be the 
responsibility of the Sponsor (or Sponsor’s designee). [16, 17] 
A safety contact sheet will be provided to the Investigator and will be maintained in the 
Investigator file at the site. Sites will be instructed to refer to the instructions and 
definitions for completing the Investigational SAE Form for submitting all SAEs to the 
CRO. 
8.1.3.1 
Follow-up of Serious Adverse Events 
SAEs occurring during the study will be followed by the Investigator until the outcome is 
resolved, has reached a stable condition in the Investigator’s opinion, or until the patient 
is lost to follow-up. When the investigational site receives any information about an SAE 
which changes or adds to the information on the initial investigational SAE form, the site 
will fill out a new investigational SAE form and tick the ”follow-up” box of the SAE 
form and email it within 24 hours to the CRO. 
8.1.4 
Pregnancy Report 
Female patients who are of childbearing potential must use an effective 
contraceptive/birth control measure while participating on study and have a negative 
urine pregnancy test at study entry. In the unlikely eventuality that a patient becomes 
pregnant during the trial, the Investigator will be requested to complete the Pregnancy 
Report Form and any relevant document. They must be forwarded to the CRO e-mail 
address  (see Section General Information). After check of consistency, designated 
personnel at the CRO will then forward the information to the Sponsor within 24 hours of 
becoming aware of the pregnancy. Even though pregnancy is not considered as SAE 
itself, pregnancy has to be reported within the timelines as defined for SAE. 
Pregnant patients will be followed by the Investigator and CRO / Sponsor until the fetus / 
newborn is delivered or the pregnancy is terminated. The subject’s primary care 
physician (or obstetrician) will be requested by the Investigator to provide further 
information on the pregnancy using the Pregnancy Outcome Information Form. At the 
study end and database closure, reports of Pregnancy Outcome will be sent by the sites 
directly to Helsinn Drug Safety. 
 
Page 85 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
9 STATISTICS 
This section summarizes the statistical principles and methods planned to analyze the 
data for this clinical study. The reference document is the ICH Topic E9 Statistical 
Principles for Clinical Trials: Note for Guidance on Statistical Principles in Clinical 
Trials [19]. 
Further details of the statistical analyses and data presentations to be used in reporting the 
study will be provided in the Statistical Analysis Plan (SAP), which will be finalized 
prior to breaking the blind. Changes from analyses planned in this protocol will be 
documented in the SAP and/or study report. The database will be locked after all queries 
are resolved, and a blinded review of data is performed and decisions made about study 
populations and handling of unused or missing data. 
9.1 
Sample Size Determination 
A total of 400 patients will be randomized, equally distributed in two groups (i.e., 200 
patients/group). 
Patients will be randomized according to a randomization ratio 1:1, stratified by region 
and age class. 
The primary goal of this study is to characterize the safety profile of IV NEPA FDC over 
a reasonable duration of time consistent with the intended use of this drug. Although no 
formal comparison is planned with the randomized control group, the presence of a 
concurrent control group in the same patient population may help interpret any 
unexpected safety finding in the test group.  
9.2 
Definition of Study Populations for Analysis 
Study populations are defined as follows: 
The Full Analysis Set (FAS) includes all patients who have been randomized to 
treatment and received AC chemotherapy regimen and active study drug (oral NEPA 
FDC or IV NEPA FDC, including partial infusion). Following the intent-to-treat 
principle, patients will be assigned to the study treatment group according to the 
treatment to which they have been randomized. 
FAS will be used for demography, other baseline characteristics, all descriptive efficacy 
analyses. 
The Safety population includes all patients who received active study drug (oral NEPA 
FDC or IV NEPA FDC, including partial infusion). Patients will be assigned to study 
treatment groups according to the actual treatment received. 
Safety population will be used for demography, other baseline characteristics and for all 
safety analyses. 
Page 86 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
9.3 
Statistical Analysis 
9.3.1 
General Considerations 
General descriptive statistics for numeric variables will include n (number of observed 
values), mean, standard deviation, median, minimum and maximum values. For 
categorical variables, the number and percentage of subjects will be presented. 
9.3.1.1 
Missing Data 
Due to the short efficacy assessment period within each study cycle (a maximum of 120 h 
considering all the efficacy assessments), a very low number of drop-outs and minimal 
missing data is expected during the cycle.  
For efficacy analyses, any patient who does not provide data about occurrence of emetic 
episodes and rescue medication intake is to be considered as treatment failure (i.e., non-
responder) for CR in the overall phase. The same approach is to be applied also to CR in 
the acute and delayed phases. For consistency, the same approach for handling missing 
data as described for CR will also to be applied to emetic episodes and rescue medication 
intake. 
For safety analyses, no imputations will be performed on missing values.  
Since there might be cases where emetic episodes and rescue medications intake in the 
0-120 hours from start of AC chemotherapy are, by mistake, recorded in the eCRF 
Adverse Events and Prior and Concomitant medications form only (and not in the patient 
diary), in accordance with the definition of CR, such cases will be taken into account for 
efficacy analyses and patients considered as failures.  
For nausea intensity data collected daily, missing values in the 0-24 hour interval or 
missing data preceding any available data will be replaced using the worst case principle 
i.e., using the highest value observed in the same treatment and time interval among all 
patients with the same stratifications factors (i.e., region, age class and naivety). Missing 
data after at least one available value will be replaced using Last Observation Carried 
Forward (LOCF). The worst value will be evaluated after applying LOCF to other 
missing data.  
Patients with no nausea and with no significant nausea will be then derived from the 
complete data after imputation of missing data. 
Concerning the FLIE scores, for the purpose of calculating the score for a domain (either 
nausea or vomiting), at least 5 of the 9 FLIE items (i.e., > 50% overall item response rate) 
in the domain must be non-missing. The score, expressed in mm, of each domain will be 
calculated as: 
9
answered
  
items
  
no.
)
mm
(in 
 
scores
 
item
 
mm)
(in 
 
score
Domain 
×
= ∑
 
Page 87 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
To obtain the score expressed in FLIE points, the above mentioned domain score 
expressed in mm is multiplied by 0.06, as a final step 9 will then be added. 
(
) 9
06
.0
mm)
(in 
 
score
Domain 
points)
 
FLIE
(in 
 
score
Domain 
+
×
=
 
For the calculation of the total FLIE score (i.e., sum of the nausea and vomiting domain 
scores), at least 12 out of the 18 FLIE items (i.e., ≥ 66% overall item response rate) must 
be non-missing and both the vomiting and nausea domains must be non-missing. 
A missing single item will not be replaced. A missing entire domain score will be 
replaced using the worst case principle i.e., using the lowest score observed in the same 
treatment among all patients with same age class. The total FLIE score will be then 
calculated from the complete data after imputation of missing data. 
9.3.1.2 
Multiplicity 
Since no formal comparisons between treatments are planned, no multiplicity adjustment 
is foreseen. 
9.3.1.3 
Covariates, Interactions and Subgroups 
It is expected that region (US, non-US) and age class (<55 years, ≥55 years) could 
influence the study endpoints. For this reason, these factors will be taken into 
consideration for randomization (see Section 5.11 Randomization - Use of IWRS) so to 
minimize possible unbalance between groups. 
Selected efficacy endpoints at Cycle 1 (CR in the acute, delayed and overall phases) will 
be also summarized by region and by age group. 
9.3.2 
Analysis of Demographics and Baseline Variables 
Demographics and baseline variables will be summarized by treatment arm using 
descriptive statistics. 
9.3.3 
Efficacy Analysis 
Analyses of efficacy endpoints will be performed on FAS. 
All results will be interpreted in descriptive manner only. 
At each cycle, for each phase (acute, delayed, and overall), numbers and proportions 
(including 95% CI using Wilson score method) of patients with CR, with no emetic 
episodes, with no rescue medication, with no nausea, and with no significant nausea will 
be descriptively summarized. 
In addition, for Cycle 1, CR in the acute, delay and overall phases will be summarized by 
region and by age group (strata).  
Since VAS is assessed daily, for no significant nausea and no nausea in the delayed and 
overall phases, the maximum VAS value in the relevant phase will be considered (i.e., the 
Page 88 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
maximum value for Day 2 to 5 for delayed phase and for Day 1 to 5 for the overall 
phase). 
For the above mentioned variables, differences between groups will be presented using 
the CMH method for the risk difference (including region and age class as strata) and 
relative two-sided 95% CI. The treatment difference and 95% CI for the difference will 
also be presented without strata adjustment, using the Newcombe-Wilson’s method. 
The severity of nausea in the acute, delayed and overall phase, will be descriptively 
summarized including treatment difference and relative two-sided 95% CI. 
Antiemetic rescue medications will be tabulated by treatment arm.  
In Cycle 1 and Cycle 2, only, to assess the impact of nausea and vomiting on patients’ 
quality of life, the FLIE with a 5-day recall will be used. A total FLIE score (expressed in 
FLIE points) greater than 108 will be categorized as having No Impact on Daily Life 
(NIDL) [14]. A FLIE domain score (either nausea or vomiting, expressed in FLIE points) 
greater than 54 will be categorized as NIDL [14]. A response to an individual question on 
the FLIE will be categorized as NIDL if the score expressed in FLIE points is greater 
than 6. 
Number and percentage (including 95% CI) of patients with NIDL (overall, by domain 
and by individual item), will be summarized by treatment. Differences between groups 
for total FLIE score and domain scores (nausea and vomiting) will be presented using the 
CMH method for the risk difference and relative two-sided 95% CI. The treatment 
difference and 95% CI will also be presented without strata adjustment. 
The mean nausea and vomiting domain FLIE scores and the mean total score will be will 
be descriptively summarized including treatment difference and relative two-sided 95% 
CI. 
9.3.4 
Safety Analysis 
The safety analysis will be performed on the Safety population. 
Clinical evaluations for safety assessments will include physical examinations, vital 
signs, and laboratory tests during each cycle (Visit 1 through Visit 4), and monitoring of 
AEs through the study period.  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary (the version will be provided in the SAP and in the Data Management Plan 
[DMP]) to give a preferred term (PT) and a system organ class (SOC) for each event. The 
number and percentage of patients who experienced at least one TEAE, drug-related 
TEAE (defined as AEs with relationship classified by the investigator as definitely, 
probably, possibly, unassessable or missing), serious TEAE, serious related, severe 
TEAE (i.e., TEAE with CTCAE grade ≥ 3) and the number and percentage of patients 
withdrawn due to TEAE will be summarized by treatment arm. Summaries will be made 
with respect to the proportion of patients with events and the total number of events 
throughout the study. A similar summary will be presented for Cycle 1 only. 
Page 89 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
For each SOC and PT, summaries will be made with respect to the proportion of patients 
having at least one occurrence of that event during the study and the total number of 
events. The incidence of TEAEs in each treatment arm will be presented overall, by SOC 
and PT, and by additional grouping by severity according to the CTCAE grade and 
relationship to the study treatment. Tables of TEAEs will be presented by relationship to 
study drug and to dexamethasone. Additional tables including any relationship (either to 
study drug or dexamethasone) will be presented. Summary will be presented considering 
all the performed cycles (i.e., throughout the study) and for Cycle 1, only. 
In addition, TEAEs of special interest, i.e. the ones related to local tolerability (e.g. 
injection site reaction, pain at injection site, thrombophlebitis) will be summarized for 
each cycle. 
No formal test will be used for “between groups” comparison. All AEs will be listed. Pre-
treatment AEs will be listed separately from TEAEs. 
Vital signs will be summarized by treatment using descriptive statistics for absolute 
values, change from baseline (i.e., last value before first study drug intake), and change 
from pre-dose assessment of each cycle in addition to being listed. 
Physical examination results at screening will be summarized in a frequency table 
(normal/abnormal). Results and relevant findings will be listed. 
Proportion of laboratory values below, within and above normal range will be presented 
by frequency table for each timepoint. Shift table (below, within and above normal range) 
comparing baseline (i.e., last value before first study drug intake) assessment  with on-
treatment assessment and comparing pre-dose assessment with Visit 3 assessment of each 
cycle will also presented. 
9.3.5 
HEOR Analysis 
The HEOR analysis will be managed and conducted separately. Relevant patient data and 
results will be presented in a separate dedicated report. Further details (including detailed 
description of HEOR endpoints and analyses) will be outlined in the Health Economics 
Analysis Plan.  
9.4 
Interim Analysis 
No formal interim analysis is planned for this study. 
Descriptive statistics of data elements from exploratory HEOR assessments may be 
calculated on blinded data at intervals to-be-determined based on study enrollment. Data 
from a minimum of 50 patients will be available prior to creating this summary. 
Page 90 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
10 DATA SAFETY MONITORING BOARD 
No data safety monitoring board is planned for this study. 
11 ETHICAL AND REGULATORY CONSIDERATIONS 
11.1 
Ethical Considerations 
The study will be performed in accordance with the principles outlined in the Declaration 
of Helsinki [23] as amended by the World Medical Association in Fortaleza in 2013, and 
the ICH GCP guidelines as well as all local laws and regulations of the countries in which 
the study is conducted. 
11.1.1 
Laws and Regulations 
This clinical study will be conducted in compliance with all international laws and 
regulations and national laws and regulations of the countries in which the trial is 
performed, as well as any applicable guidelines.  
11.1.2 
Patient’s Information Sheet and Informed Consent Form 
All patients invited to participate in the clinical trial are entitled to make their decision 
based on all current available information provided to them by the Investigator/designee. 
In addition, they will be given a document in native language written in clear concise lay 
language for review and consideration. The document will previously have been 
approved by relevant independent Ethics Committee(s) (EC[s]/Institutional Review 
Boards [IRBs]) and may further be updated as new important information becomes 
available that may affect subject’s willingness to participate or continue in the trial. This 
document will tell potentially eligible subjects about the nature of the study drugs, their 
efficacy and safety profile, the route of administration, and the human experience 
available. It will also outline the steps of the protocol as they will apply to the individual, 
including the number of visits and types of procedures/assessments/measurements to be 
performed so that the individual has a clear picture of the risks, inconveniences and 
benefits that may accrue from the trial. The patient must be made aware that she may 
refuse to join the trial or may withdraw her consent at any time without prejudicing 
further medical care and that she is covered by the Sponsor's indemnity insurance in the 
event of a trial related injury. Contact details to report and discuss suspected trial-related 
injuries will be provided. Patients must also know that their personal medical records 
may be reviewed in confidence by the Sponsor's staff or representatives and by 
Regulatory Authorities and IRB/EC and that personal information will be collected and 
retained in a confidential database. Conditions for ensuring the anonymity of data and the 
security and confidentiality of the database should be explained. Consent will always be 
given in writing after the patient has had adequate time to review the information and ask 
questions, if need be. The patient and the Investigator or responsible site staff member 
conducting the informed consent discussion will both personally write their name, sign 
and date the consent form. Patients will be given a copy of their executed informed 
Page 91 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
consent. The study is being performed in the United States, Russia, Ukraine, and Georgia. 
US maintain descriptions of clinical studies in the participating countries on the internet. 
As required by the US FDA, the informed consent form must contain the following text: 
“A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web site 
at any time.” 
11.1.3 
Protocol Amendments 
Changes to the protocol may only be made by means of a written amendment, which has 
to be approved and signed by the authorized individuals of the Sponsor and by the 
Investigator. The study code, the title of the study, the progressive number and the date of 
the amendment must be recorded on the first page of the document. Exhaustive 
justifications that motivate the amendment to the protocol should clearly be addressed in 
the document. All protocol amendments must be submitted to the IRB/EC for review and 
approval unless it covers administrative issues only. In this case, the IRB/EC will be 
notified of the amendment for information purposes only. 
11.1.4 
Protocol Deviations 
The Investigator has to conduct the study in accordance with the approved current 
protocol and will not be allowed to make any changes with the only exception when 
immediate changes are necessary to protect the safety, rights, and welfare of the subjects. 
In order to obtain interpretable results, neither the Investigator nor the Sponsor/CRO will 
alter the study conditions agreed upon and set out in this protocol.  
In the event of an isolated, unforeseen instance resulting in a protocol deviation, the 
Investigator is to document this deviation and notify it to the CRO as soon as possible, in 
writing. In no instance should this increase the subject’s risk or affect the validity of the 
study data. 
11.1.5 
Data Collection  
Electronic Case Report Forms (eCRFs) will be used for recording patient’s study data 
using a validated web-based Electronic Data Capture (EDC) system. It is the 
responsibility of the Investigator to ensure that the eCRFs are properly and completely 
filled in. The eCRFs must be completed for all patients who have been included in the 
study.  
Each authorized site personnel will be assigned a login and password to enter the EDC 
system via a secure network. Each login uniquely identifies the user and appropriate 
permissions will be set-up according to the user role. The access to the system will be 
granted once the user’s training will be completed and documented.  
Queries will be used to validate/clarify data entered on an eCRF page. Some queries will 
be generated automatically by the system when the user saves data that does not meet the 
criteria pre-defined for the data field. In addition, others will be created manually in the 
Page 92 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
system and sent either by the study monitor (as result of Source Data Verification) or by 
Clinical Data Management. 
Discrepancies raised will be reviewed online to determine the corrective action needed. 
Changes will be made directly by authorized site staff. The EDC system’s audit trail will 
keep track of any information entered, modified and deleted. The audit trail will include, 
as a minimum, what was entered/changed/modified, who made the action and when the 
action was made. Any answered query will be reviewed and closed by authorized users. 
The Investigator will electronically sign the eCRF to validate the content. 
Patient’s source documentation (i.e., hospital charts) will be maintained at the clinic. 
Source data to be recorded directly onto the eCRFs will be communicated in advance. In 
cases where source documents are not eCRFs, the information on the eCRFs must match 
the source documents. Source data verification will be regularly performed by the blinded 
study monitor.  
Laboratory values will be assessed according to local laboratories normal ranges. 
Assessments (below, within and above normal range) will be reported directly into the 
eCRF by the study personnel. All data will be checked by the monitor. 
Paper patient diaries will be used to collect emetic episodes (i.e., retching and vomiting 
episodes), rescue medication intake and daily nausea assessment. Taking into account the 
patient population, the short re-call period (i.e., 120 hours for efficacy endpoints) and the 
fact that rescue medication intake and emetic episodes are objective data, the paper diary 
is considered to be a reliable method of data collection and the most suitable for this 
patient population. The Investigator will review the filled in paper diary at Visit 3 (Day 
6+2) of each cycle and discuss with the patient any issues or missing/incomplete data, so 
that the patient makes all necessary corrections, if any, during the visit. The Investigator 
or designee will review, sign, date and collect the complete patient diaries after it is 
returned at Visit 3 of each cycle and will also transfer all data from the paper diary to the 
eCRF. The paper diaries will be kept at the trial site and considered as source documents. 
A paper FLIE questionnaire with a 5-day recall period will be used to assess the impact 
of nausea and vomiting on patients’ quality of life. The FLIE questionnaire will be filled 
in by the patient on Day 6 of Cycle 1 and Cycle 2, covering the past 5 days and checked 
and retrieved by the Investigator during study Visit 3 (Day 6+2) of Cycle 1 and Cycle 2. 
FLIE data will be then reported in the relevant eCRF page by the Investigator. 
Additional HEOR-related assessments will also be captured. Emergency department,  in-
patient admissions and length of stay will be documented by the Investigator or 
designated responsible person at Visit 4 of each cycle for events occurring since Day 1 of 
that cycle. Additionally, starting at Cycle 2 Visit 2 (Day 1), the Investigator will 
document if changes in chemotherapy administration from the previous cycle occurred 
and will note any delays in treatment for the current cycle.  
A paper WPAI questionnaire with a 5-day recall period will be used to assess the effect 
of CINV on patients’ ability to work and perform regular activities, including 
documentation of lost work time. The WPAI questionnaire will be filled in by the patient 
on Day 6 of Cycle 1 and Cycle 2, covering the past 5 days and checked and retrieved by 
Page 93 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
the Investigator during study Visit 3 (Day 6 +2 days) of Cycle 1 and Cycle 2. WPAI data 
will be then reported in the relevant eCRF page by the Investigator. 
11.1.6 
Monitoring and Quality Assurance 
The study will be monitored by CRO’s adequately qualified and trained clinical monitors 
on a regular basis throughout the study period to ensure the proper conduct of the clinical 
trial. The purposes of clinical trial monitoring are to verify that the rights and well-being 
of study patients are protected, that the reported trial data are accurate, complete and 
verifiable against the source documents, and that the study is conducted in accordance 
with the current protocol, Good Clinical Practice guideline and applicable regulatory 
requirements. During the monitoring visits, monitors will verify the following including 
but not limited to: patient informed consent, patient’s eligibility, safety data and 
reporting, quality of source documents and eCRF data against patient’s medical records. 
If inconsistencies are identified, the corresponding corrections to the eCRF data will have 
to be made by the Investigator. Monitors will also check patient compliance, accrual, 
drug handling, including dispensing procedures and accountability logs, delegation of 
responsibilities within the Investigator’s team, relevant communications with family 
doctors, if any, ancillary equipment and facilities, including refrigerators and freezers, 
local labs, etc. The Investigator and other site staff involved in the study must allocate 
enough time to the monitor at these visits. 
Upon request by the Sponsor, or following the CRO’s audit plan, on-site study audits 
may be conducted in order to ensure the study is in compliance with GCP, applicable 
regulatory requirements, and the study protocol. The auditing activities may also be 
conducted after study completion. 
In addition, Regulatory Authorities may wish to conduct on-site inspections (during the 
study or after its completion). If a Regulatory Authority notifies the Investigator of an 
inspection or visits the site unannounced for purposes of conducting an inspection, the 
Investigator must inform the study Sponsor and CRO immediately. The Investigator will 
make all efforts to facilitate the conduct of the audits and inspections giving access to all 
necessary facilities, data and documents. 
11.1.7 
Study Documentation and Records Retention 
The medical (hospital) files of trial patients should be retained in accordance with 
national legislation (and in accordance with the maximum period of time permitted by the 
hospital (or institution/private practice). 
The Sponsor should ensure that it is specified in the protocol or other written agreement 
that the Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/EC 
review, and regulatory inspection(s), providing direct access to source data/documents. 
All the essential study documents should be retained at the sites until when the Sponsor 
informs the Investigators/institutions in writing about the date when the trial related 
records are no longer needed and in any case in accordance with FDA regulation 21 CFR 
312.62(b) and (c) and ICH-GCP guidelines [15]. Should the Investigator wish to assign 
Page 94 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
the study documentation to another party or move to another location, the Sponsor should 
promptly be notified. 
11.1.8 
Confidentiality 
The Sponsor and the CRO must ensure that the Investigator keeps secret from third 
parties any confidential information disclosed or provided by the Sponsor and regarding 
the Sponsor and its study-related products. The Investigator agrees to use such 
information only to accomplish the present study tasks and not to use it for any other 
purposes without prior written consent by the Sponsor. Prior to the study start-up, each 
Investigator as well as each subcontractor to be involved in the study should sign a 
confidentiality agreement with the CRO acting for and on behalf of the Sponsor. 
11.1.9 
Publication Policy 
As a general rule, the Sponsor and the Investigator(s) agree that no publications 
presenting or discussing data and/or results from clinical trials sponsored by Helsinn 
Healthcare SA will take place until the participating center(s) has/have completed the 
study, the data have been interpreted, and the final report has been issued. As a rule, the 
Sponsor is free to use the data collected in the sponsored study for the drug registration, 
world-wide scientific product documentation, and for publication. In general, the Sponsor 
has no objections if the Investigator publishes the results of the study obtained by the 
Investigator/Institution sponsored by Helsinn Healthcare SA; however, the Investigator is 
requested to provide the Sponsor with a copy of the manuscript for review before 
submitting it to the publisher with a cover letter informing the Sponsor about the 
intention to publish the study results. Such a procedure is necessary to prevent premature 
disclosure of trade secrets or otherwise patent-protected material and is not intended as a 
restrictive measure concerning the study results or the opinions of the Investigators. After 
the review of the manuscript by the Sponsor, the Investigator will be provided with the 
Sponsor’s comments, if any, and the opinion of the Sponsor regarding study results 
publication. The Investigator shall however consider the Sponsor’s comments and 
proposed revisions. If requested by the Sponsor, the Investigator shall delay the 
presentation or publication of the study data in order to allow the Sponsor sufficient time 
to obtain Intellectual Property Protection. The Sponsor is entitled to include as authors of 
the publication all Sponsor’s personnel who have contributed substantially to the 
theoretical or experimental activities and also to make a decision on the order in which 
the authors’ names will be given. Costs for publication must be regulated by written 
agreement between the parties. For multicenter studies, the Investigators who will be 
quoted as authors of the publication(s) should be agreed upon with the Sponsor. If 
publication of the results of the study, either in part or in full, is prepared by the Sponsor, 
the Investigator(s) will be asked in writing if he/she/they agree(s) to be listed as one of 
the authors of the publication. Answers should be sent in writing to the Sponsor within a 
reasonable time limit (30 days). 
Page 95 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
11.1.10 
Insurance 
The Sponsor/designee will obtain liability insurance, which covers health impairments 
resulting from drugs and/or substances/investigational products administered in the 
course of this study for which the patient has given his/her written informed consent. This 
liability insurance also covers health impairments resulting from study procedures. 
Page 96 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
Clinical Study Protocol 
12 REFERENCES 
1. Grunberg SM. Overview of chemotherapy-induced nausea and vomiting. Clin Adv
Hematol Oncol. 2013 Feb;11(2 Suppl 1):1-18.
2. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008 Jun
5;358(23):2482-2494.
3. Rojas C, Raje M, Tsukamoto T, Slusher BS. Molecular mechanisms of 5-HT3 and
NK1 receptor antagonists in prevention of emesis. Eur J Pharmacol. 2014 Jan
5;722:26-37.
4. Palonosetron Investigator’s Drug Brochure, Revised Edition: April 2017.
5. Palonosetron (Aloxi®) EU SPC, 2010; Palonosetron (Aloxi®) FDA Prescribing
Information, 2013.
6. Investigator’s Brochure. Oral Netupitant and Palonosetron Fixed-dose Combination,
Revised Edition: 20 December 2016.
7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Antiemesis
Version 2, 2017, http://www.nccn.org/. 28 MAR 2017.
8. Investigator’s Brochure IV FOSNETUPITANT/PALONOSETRON Infusion;
Edition May 2017.
9. Study Report PNET-12-23. A Phase I, double-blind, controlled, parallel groups,
unbalanced single ascending dose study to assess the safety of intravenously
administered fosnetupitant combined with crossover study extensions to estimate the
dose of intravenous fosnetupitant yielding equivalent drug exposure as oral
netupitant 300 mg/palonosetron 0.5 mg fixed-dose combination in healthy male and
female volunteers. April 2015.
10. Study Report NEPA-15-19. A Phase 1, open label study to evaluate the
pharmacokinetic profile and safety of IV NEPA FDC administered for the prevention
of chemotherapy-induced nausea and vomiting in cancer patients receiving a single
cycle of highly emetogenic chemotherapy. March 2017.
11. Lanzarotti C. and Rossi G. Effect of netupitant, a highly selective NK1-receptor
antagonist, on the pharmacokinetics of midazolam, erythromycin, and
dexamethasone. Support Care Cancer. 2013; 21(10): 2783-2791.
12. Study Report PNET-13-63. Evaluation of the pharmacokinetic interaction between
three doses of intravenous fosnetupitant and oral dexamethasone regimen: a
randomized three period crossover study in healthy male and female volunteers. May
2015.
13. Study Report NEPA-15-18. A phase 3, multicenter, randomized, double-blind, active
control study to evaluate the safety and efficacy of IV pro-netupitant/palonosetron
(260 mg/0.25 mg) combination for the prevention of chemotherapy-induced nausea
and vomiting in repeated chemotherapy cycles in patients receiving highly
emetogenic chemotherapy. March 2017.
14. Martin AR, Pearson JD, Cai B, et al. Assessing the impact of chemotherapyinduced
nausea and vomiting on patients’ daily lives: a modified version of the Functional
Living Index – Emesis (FLIE) with 5-day recall. Support Care Cancer 2003; 11: 522-
527.
Page 97 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
Clinical Study Protocol 
15. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work
productivity and activity impairment instrument. PharmacoEconomics 1993;
4(5):353-365.
16. International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use. ICH – Efficacy Topic 6(R1):
Guideline for Good Clinical Practice, Step 4, 10 June 1996 and Step 5, 9 May 1997.
17. International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use. ICH – Efficacy Topic E2A: Clinical
Safety Data Management: Definition and Standards for Expedite reporting, 27
October 1994
18. Common Terminology Criteria for Adverse Events (CTCAE) (Terminology Criteria
for Adverse Events (CTCAE, Version 4.0, published: May 28, 2009 [v4.03: June 14,
2010]).
19. International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use. ICH – Efficacy Topic 9: Guidance
on Statistical Principles for Clinical Trials, 5 February 1998.
20. EMEA CPMP/EWP/908/99 “Point to consider on multiplicity issues in clinical
trials”, 19 September 2002.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/
09/WC500003640.pdf.
21. O'Gorman TW, Woolson RF, Jones MP. A comparison of two methods of estimating
a common risk difference in a stratified analysis of a multicenter clinical trial.
Control Clin Trials. 1994 Apr;15(2):135-153.
22. Koch, GG, Carr, GJ, Amara, IA, Stokes, ME, and Uryniak, TJ. Categorical Data
Analysis. in: DA Berry (Ed.) Statistical Methodology in the Pharmaceutical
Sciences. Marcel Dekker, New York; 1989: 414–421.
23. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving
Human Subjects. 64th WMA General Assembly, Brazil, Fortaleza, October 2013.
24. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP.
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group; Am J
ClinOncol 5:649-655; 1982.
Page 98 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
Clinical Study Protocol 
13 APPENDICES 
Appendix 1:  
Emetogenic Potential of IV and Oral Antineoplastic Agents (NCCN 
Clinical Practice Guidelines in Oncology, Version 2.2017, March 28, 
2017) 
Appendix 2: 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
Appendix 3:  
List of CYP3A4 Inducers, Strong and Doderate Inhibitors, and Substrates 
Page 99 of 120 
Confidential
=HEI..SINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
Clinical Study Protocol 
Appendix 1:  
Emetogenic Potential of IV and Oral Antineoplastic 
Agents (NCCN Clinical Practice Guidelines in Oncology, Version 2.2017, 
March 28, 2017 [7]) 
Emetogenicity Level 
IV Agentsa, b 
High  
(>90% frequency of emesisc) 
AC combination defined as any chemotherapy regimen 
that contains anthracycline and cyclophosphamide 
Carboplatin AUC ≥ 4 
Carmustine > 250 mg/m2 
Cisplatin 
Cyclophosphamide ≥1500 mg/m2 
Dacarbazine 
Doxorubicin ≥ 60 mg/m2  
Epirubicin >90 mg/m2  
Ifosfamide ≥ 2 g/m2 per dose 
Mechlorethamine 
Streptozocin 
Moderate  
(>30%-90% frequency of emesisc) 
Alemtuzumab >12-15 million IU/m2 
Amifostine > 300 mg/m2  
Arsenic trioxide 
Azacitidine 
Bendamustine 
Busulfan 
Carboplatin AUC <4d 
Carmustine ≤ 250 mg/m2 
Clofarabine 
Cyclophosphamide ≤ 1500 mg/m2 
Cytarabine >200 mg/m2 
Dactinomycind 
Daunorubicind 
Dinutuximab 
Doxorubicin d < 60 mg/m2   
Epirubicin d ≤ 90 mg/m2  
Idarubicin  
Ifosfamide d < 2 g/m2 per dose 
Interferon alfa ≥ 10 million IU/m2 
Irinotecan d 
Melphalan 
Methotrexate d ≥ 250 mg/m2   
Oxaliplatin d 
Temozolomide 
Trabectedin d
Page 100 of 120 
Confidential
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Emetogenicity Level 
IV Agentsa, b 
Low  
(10%-30% frequency of emesisc) 
Ado-trastuzumab emtansine 
Aldesleukin ≤ 12 million IU/m2 
Amifostine ≤ 300 mg/m2 
Atezolizumab 
Belinostat 
Blinatumomab 
Brentuximab vedotin 
Cabazitaxel 
Carfilzomib 
Cytarabine (low dose) 100-200 mg/m2 
Docetaxel 
Doxorubicin (liposomal) 
Eribulin 
Etoposide 
5-Fluorouracil 
Floxuridine 
Gemcitabine 
Interferon alfa > 5- <10 million IU/m2 
Irinotecan (liposomal) 
Ixabepilone 
Methotrexate > 50 mg/m2 - <250 mg/m2 
Mitomycin 
Mitoxantrone 
Necitumumab 
Omacetaxine 
Paclitaxel 
Paclitaxel-albumin 
Pemetrexed 
Pentostatin 
Pralatrexate 
Romidepsin 
Talimogene laherparepvec 
Thiotepa 
Topotecan 
Ziv-aflibercept 
Page 101 of 120 
Confidential
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Emetogenicity Level 
IV Agentsa, b 
Minimal  
(<10% frequency of emesisc) 
Alemtuzumab 
Asparaginase 
Bevacizumab 
Bleomycin 
Bortezomib 
Cetuximab 
Cladribine (2-chlorodeoxyadenosine) 
Cytarabine < 100 mg/m2 
Daratumumab 
Decitabine 
Denileukin diftitox 
Dexrazoxane 
Elotuzumab 
Fludarabine 
Interferon alpha ≤ 5 million IU/m2 
Ipilimumab 
Methotrexate ≤ 50 mg/m2 
Nelarabine 
Nivolumab 
Obinutuzumab 
Ofatumumab 
Panitumumab 
Pegaspargase 
Peginterferon 
Pembrolizumab 
Pertuzumab 
Ramucirumab 
Rituximab 
Siltuxumab 
Temsirolimus 
Trastuzumab 
Valrubicin 
Vinblastine 
Vincristine 
Vincristine (liposomal) 
Vinorelbine  
a) Continuous infusion may make an agent less emetogenic. 
b) Potential drug interactions between antineoplastic agents/antiemetic therapies and various 
other drugs should always be considered. 
c) Proportion of patients who experience emesis in the absence of effective antiemetic 
prophylaxis. 
d) These agents may be highly emetogenic in certain patients. 
 
Page 102 of 120 
Confidential
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Emetogenicity Level 
Oral Agentsa 
Moderate to High   
(≥30% frequency of emesisb) 
Altretamine 
Busulfan (≥4 mg/d) 
Ceritinib 
Crizotinib 
Cyclophosphamide  (≥100 mg/m2/d) 
Estramustine 
Etoposide 
Lenvatinib 
Lomustine (single day) 
Mitotane 
Minimal to Low  
(<30% frequency of emesisb) 
Afatinib 
Alectinib 
Axitinib 
Bexarotene 
Bosutinib 
Busulfan (<4 mg/d) 
Cabozantinib 
Capecitabine 
Chlorambucil 
Cobimetinib 
Cyclophosphamide  
(<100 mg/m2/d) 
Dasatinib 
Dabrafenib 
Erlotinib 
Everolimus 
Fludarabine 
Gefitinib 
Hydroxyurea 
Ibrutinib 
Idelalisib 
Imatinib 
Ixazomib 
Lapatinib 
Lenalidomide 
Melphan 
Mercaptopurine 
Methotrexate 
Nilotinib 
Osimertinib 
Palbociclib 
Pazopanib 
Pomalidomide 
Ponatinib 
Regorafenib 
Ruxolitinib 
Sonidegib 
Sorafenib 
Sunitinib 
Temozolomide (≤75 
mg/m2/d) 
Thalidomide 
Thioguanine 
Topotecan 
Tretinoin 
Vandetanib 
Venetoclax 
Vismodegib 
Vorinostat 
a) Potential drug interactions between antineoplastic agents/antiemetic therapies and various other 
drugs should always be considered. 
b) Proportion of patients who experience emesis in the absence of effective antiemetic 
prophylaxis. 
 
Page 103 of 120 
Confidential
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Appendix 2: Eastern Cooperative Oncology Group Performance Status  
 
(ECOG PS) 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair 
5 
Dead 
 
*As published in Am. J. Clin. Oncol.:  
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group; Am J ClinOncol 5:649-
655; 1982. [24] 
 
 
Page 104 of 120 
Confidential
llHELSINN 


NEPA-17-05  
Final (v3.1) 30 NOV 2017 
 
Clinical Study Protocol 
 
 
 
Appendix 3: List of CYP3A4 Inducers, Strong and Moderate Inhibitors,  
and Substrates 
Examples of inducers, strong and moderate inhibitors, and Substrates of CYP 3A4 
Type 
Agent 
Inducers 
HIV Antivirals: efavirenz, nevirapine, barbiturates, carbamazepine, efavirenz, 
glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, 
pioglitazone, rifabutin, rifampin, St. John's wort, troglitazone 
Strong and 
moderate 
Inhibitors 
 
Strong inhibitors: A strong inhibitor for a specific CYP is defined as an inhibitor 
that increases the AUC of a substrate for that CYP by equal or more than 5-fold. 
Strong Inhibitors are: Boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole  
 
Moderate inhibitors: A moderate inhibitor for a specific CYP is defined as an 
inhibitor that increases the AUC of a sensitive substrate for that CYP by less than 
5-fold but equal to or more than 2-fold. 
Moderate Inhibitors are: Amprenavir, aprepitant, atazanavir, ciprofloxacin, 
darunavir/ritonavir, 
diltiazem, 
erythromycin, 
fluconazole, 
miconazole, 
fosamprenavir, grapefruit juice, imatinib, verapamil, atazanavir, amiodarone 
 
Substrates 
Terfenadine, cisapride, astemizole, pimozide 
 
For strong and moderate inhibitors of CYP3A, see 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm  
 
 
Page 105 of 120 
Confidential
llHELSINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
Study Title
A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel group 
phase 3b study to assess the safety and to describe the efficacy of IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV NEPA FDC) compared to oral 
netupitant/palonosetron (300 mg/0.5 mg) combination (Akynzeo®) for the prevention of 
chemotherapy-induced nausea and vomiting in initial and repeated cycles of anthracycline-
cyclophosphamide (AC) chemotherapy in women with breast cancer 
Study Number
NEPA-17-05
Protocol Date
22 Jun 2017
Protocol Amendment #1 (v2.0)
14 Sep 2017
Protocol Amendment #2 (v3.0)
14 Nov 2017
Protocol Amendment # 3 (v3.1)
30 Nov 2017
Sponsor
Helsinn Healthcare SA
Via Pian Scairolo 9
6912 Lugano, Switzerland
CROs
US Region:
George Clinical Inc.
6555 Quince, Suite 503 
Memphis, TN 38119
Phone: +1 901.259.0888
Fax: +1 901.259.8276
Europe:
PSI CRO AG
Baarerstrasse 113a
6300 Zug, Switzerland
Phone: +41 41 228 10 00
Fax: +41 41 228 10 99
Confidential Information
The information contained in this document is confidential. Acceptance of this document constitutes agreement 
by the recipient that no information contained herein will be published or disclosed without prior written 
authorization from an official of Helsinn except that this document may be disclosed to appropriate Institutional 
Review Boards and Ethics Committees or duly authorized representatives of a Regulatory Authority under the
condition that they are requested to keep it confidential.
The clinical trial will be conducted, and essential study documentation archived, in compliance with this protocol, 
applicable SOP’s and standards, which incorporate the requirements of the EU Clinical Trials Directive 
2001/20/EC and ICH Guideline for Good Clinical Practice.
Page 106 of 120 
Confidential
IIHE£SINN 


Page 107 of 120 
Confidential
NEPA-l7-05 
Final/30 Nov 20 I 7 
Protocol Amendment #3 
Signature Page, Helsinn Healthcare SA 
4 /J-EC. 2c ,;.. 
{Date) 
Study Coordinf t'f-
y ])ec_ 20\'f 
(Date} 
Clinical Operations Manager, Clinical Development 
Statistician: 
4 t£C. 7,QA/\.. 
(Date} 
Statistician and Data Manager, Clinical Development 
Drug Safety Officer: 
Head of Drug Safety 
ott(1>£c/2.01?-
(Dae) 
1 
Senior Clinical Research Scientist. Clinciaf Research & Strategy 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
Signature Page, George Clinical Inc.
Project Manager:
________________________________________
__________________
(Signature)
(Date)
MSc
Project Manager
Page 108 of 120 
Confidential
llHELSINN 
05 Dec 2017


Page 109 of 120 
Confidential
NEPA-17-05 
Final/30 Nov 2017 
Protocol Amendment #3 
Signature Page, PSI 
Project Manager 
(Date) 
•• 
•• 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
Signature Page, Study Site Investigator
Study Title
A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel 
group phase 3b study to assess safety and to describe the efficacy of IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV NEPA FDC) compared to 
oral netupitant/palonosetron (300 mg/0.5 mg) combination (Akynzeo®) for the prevention 
of chemotherapy-induced nausea and vomiting in initial and repeated cycles of 
anthracycline-cyclophosphamide (AC) chemotherapy  in women with breast cancer 
Study Number
NEPA-17-05
I have read and understood all pages of Protocol Amendment #3 and agree to abide by all 
the conditions and instructions contained therein.
________________________________________
__________________
(Signature)
(Date)
Printed Name: 
Institution:
Page 110 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
1
REASONS FOR AMENDMENT
A new protocol version v3.1 dated 30 Nov 2017 is issued to revise the protocol final 
version v3.0 dated 14 Nov 2017. 
With respect to v3.0, in v3.1 minor typing errors have been corrected in the numbering 
sequence of Exclusion criteria in Section 4.3.3 Exclusion criteria, steps in Section 5.4 
Dose and Administration, and reasons for discontinuations in Section 6.4 Premature 
Discontinuation. Study title on coverpage was also corrected as “nausea” was 
inadvertently omitted and the main phone number for George Clinical was updated. 
Detail about study drug administration was added to Section 5.9 Administration of Study 
Treatment.
2
SITES TO WHICH THE AMENDMENT IS APPLICABLE
This Amendment #3 is applicable to all sites in the study.
3
LIST OF CHANGES
Specific changes to the protocol are as follows. Amended text is struck through (xxx), 
where appropriate, to aid identification of text deletion, while added new text is in italic 
font, underlined.  
The final new text is reported in italic font under “Now reads”.
4
PROTOCOL CHANGES
Section: Study Title
Amended text: 
“Study Title
A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel 
group phase 3b study to assess the safety and to describe the efficacy of IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV NEPA FDC) compared to 
oral netupitant/palonosetron (300 mg/0.5 mg) combination (Akynzeo®) for the prevention 
of chemotherapy-induced nausea and vomiting in initial and repeated cycles of 
anthracycline-cyclophosphamide (AC) chemotherapy in women with breast cancer”
Now reads:
“Study Title
Page 111 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel 
group phase 3b study to assess the safety and to describe the efficacy of IV 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV NEPA FDC) compared to 
oral netupitant/palonosetron (300 mg/0.5 mg) combination (Akynzeo®) for the prevention 
of chemotherapy-induced nausea and vomiting in initial and repeated cycles of 
anthracycline-cyclophosphamide (AC) chemotherapy in women with breast cancer”
Reason: To align with correction made to the study protocol title.
Section: COVER PAGE AND GENERAL INFORMATION
Amended text: 
CROs:
US Region: George Clinical Inc., 6555 Quince, Suite 503, Memphis, TN 38119
Phone: +1 901.435.5570; Phone: +1 901.259.0888
Now reads:
CROs:
US Region: George Clinical Inc., 6555 Quince, Suite 503, Memphis, TN 38119
Phone: +1 901.259.0888
Reason: To align with updated phone number for George Clinical.
Section 4. STUDY PLAN: 4.3 Study Population
4.3.3 Exclusion Criteria 
Amended text:
“Cycle 1:
The following exclusion criteria must be checked prior to inclusion at Cycle 1:
51. Lactating patient.
62. Current use of illicit drugs or current evidence of alcohol abuse.
73. Scheduled to receive moderately or highly emetogenic antineoplastic agent (see 
protocol Appendix 1) in addition to the AC regimen, from 6 hours after the start of the 
AC chemotherapy on Day 1 and up to Day 1 of Cycle 2.
84. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis 
within 1 week prior to the start of AC chemotherapy administration on Day 1 or between 
Days 1 to 5, inclusive.
Page 112 of 120 
Confidential
llHELSINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
95. Any vomiting, retching, or nausea (grade ・1 as defined by National Cancer Institute)
within 24 hours prior to the start of AC chemotherapy administration on Day 1.
106. Symptomatic primary or metastatic central nervous system (CNS) malignancy.
117. Active peptic ulcer disease, gastrointestinal obstruction, increased intracranial 
pressure, hypercalcemia, an active infection or any illness or medical conditions (other 
than malignancy) that, in the opinion of the Investigator, may confound the results of the 
study, represent another potential etiology for emesis and nausea (other than CINV) or 
pose unwarranted risks in administering the study drugs to the patient.
128. Known hypersensitivity or contraindication to 5-HT3 receptor antagonists (e.g., 
palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron), to 
dexamethasone, or to NK1 receptor antagonists (e.g., aprepitant, rolapitant).
139. Known contraindication to the IV administration of 50 mL 5% glucose solution.
1410. Participation in a previous clinical trial involving IV fosnetupitant or oral 
netupitant administered alone or in combination with palonosetron.
1511. Any investigational drugs taken within 4 weeks prior to Day 1, and/or is scheduled 
to receive any investigational drug (other than those planned by the study protocol) 
during the present study.
1612. Systemic corticosteroid therapy within 72 hours prior to the start of AC 
chemotherapy administration on Day 1, except the dexamethasone provided as additional 
study drug. However, topical and inhaled corticosteroids are permitted.
1713. Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy 
during the study participation.
1814. Other than as administered as part of the study protocol, any medication with 
known or potential antiemetic activity within 24 hours prior to the start of AC 
chemotherapy administration on Day 1, including:
・5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, 
ramosetron, palonosetron)
・NK1 receptor antagonists (e.g., fosaprepitant, aprepitant, rolapitant or any other new 
drug of this class)
・benzamides (e.g., metoclopramide, alizapride)
・phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine, perphenazine, 
thiethylperazine, chlorpromazine)
・benzodiazepines (except if the subject is receiving such medication for sleep or
anxiety and has been on a stable dose for at least seven days prior to Day 1).
・butyrophenones (e.g., haloperidol, droperidol)
・anticholinergics (e.g., scopolamine, with the exception of inhaled anticholinergics for 
respiratory disorders, e.g., ipratropium bromide)
Page 113 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
・antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine, chlorpheniramine)
・domperidone
・mirtazapine
・olanzapine
・prescribed cannabinoids (e.g., tetrahydrocannabinol or nabilone)
・Over The Counter (OTC) antiemetics, OTC cold or OTC allergy medications.
1915. Scheduled to receive any strong or moderate inhibitor of CYP3A4 (see protocol 
Appendix 3) during the efficacy assessment period (Day 1 to Day 5, inclusive) or its 
intake within 1 week prior to Day 1.
2016. Scheduled to receive any CYP3A4 inducer (see protocol Appendix 3) during the 
efficacy assessment period (Day 1 to Day 5, inclusive) or its intake within 4 weeks prior 
to Day 1, with the exception of corticosteroids (for which exclusion criterion #12 applies).
2117. History or predisposition to cardiac conduction abnormalities, except for 
incomplete right bundle branch block.
2218. History of risk factors for Torsades de Pointes (heart failure, hypokalemia, family 
history of Long QT Syndrome).
2319. Severe or uncontrolled cardiovascular diseases, including myocardial infarction 
within 3 months prior to Day 1, unstable angina pectoris, significant valvular or 
pericardial disease, history of ventricular tachycardia, symptomatic Congestive Heart 
Failure (CHF) New York Heart Association (NYHA) class III-IV, and severe 
uncontrolled arterial hypertension.
All exclusion criteria with the exception of criteria #5, #12, and #14 will be checked at 
screening visit (Visit 1). Exclusion criteria #5, #12, and #14 will be checked at Day 1 
(Visit 2) only. Exclusion criteria #3, #4, #11, #13, #15, and #16 need to be re-checked at 
Day 1 (Visit 2).
Cycles 2 to 4:
The following exclusion criteria must be checked prior to inclusion at each repeated cycle:
241. Scheduled to receive moderately or highly emetogenic antineoplastic agent (see 
protocol Appendix 1) in addition to the AC regimen, from 6 hours after the start of the 
AC chemotherapy on Day 1 of current cycle and up to Day 1 of the next cycle.
252. Active infection or uncontrolled disease that may pose unwarranted risks in 
administering the study drugs to the patient.
263. Started any of the prohibited medications (see protocol Section 5.14).
274. Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) 
within 24 hours prior to the start of AC chemotherapy administration on Day 1.
Page 114 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
285. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis 
within 1 week prior to the start of AC chemotherapy administration on Day 1 or between 
Days 1 to 5.
296. Symptomatic primary or metastatic CNS malignancy.
307. Any illness or medical condition that, in the opinion of the investigator, may 
confound the results of the study or pose unwarranted risks in administering the 
investigational product or dexamethasone to the patient.
All exclusion criteria, with exception of criterion #4, will be checked at screening visit 
(Visit 1). Exclusion criterion #4 will be checked at Day 1 (Visit 2) only. Exclusion 
criteria #2, #3 and #5 need to be re-checked at Day 1 (Visit 2).”
Now reads:
“Cycle 1:
The following exclusion criteria must be checked prior to inclusion at Cycle 1:
1. Lactating patient.
2. Current use of illicit drugs or current evidence of alcohol abuse.
3. Scheduled to receive moderately or highly emetogenic antineoplastic agent (see 
protocol Appendix 1) in addition to the AC regimen, from 6 hours after the start of the 
AC chemotherapy on Day 1 and up to Day 1 of Cycle 2.
4. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis 
within 1 week prior to the start of AC chemotherapy administration on Day 1 or between 
Days 1 to 5, inclusive.
5. Any vomiting, retching, or nausea (grade ・1 as defined by National Cancer Institute)
within 24 hours prior to the start of AC chemotherapy administration on Day 1.
6. Symptomatic primary or metastatic central nervous system (CNS) malignancy.
7. Active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, 
hypercalcemia, an active infection or any illness or medical conditions (other than 
malignancy) that, in the opinion of the Investigator, may confound the results of the study, 
represent another potential etiology for emesis and nausea (other than CINV) or pose 
unwarranted risks in administering the study drugs to the patient.
8. Known hypersensitivity or contraindication to 5-HT3 receptor antagonists (e.g., 
palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron), to 
dexamethasone, or to NK1 receptor antagonists (e.g., aprepitant, rolapitant).
9. Known contraindication to the IV administration of 50 mL 5% glucose solution.
10. Participation in a previous clinical trial involving IV fosnetupitant or oral netupitant 
administered alone or in combination with palonosetron.
Page 115 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
11. Any investigational drugs taken within 4 weeks prior to Day 1, and/or is scheduled to 
receive any investigational drug (other than those planned by the study protocol) during 
the present study.
12. Systemic corticosteroid therapy within 72 hours prior to the start of AC chemotherapy 
administration on Day 1, except the dexamethasone provided as additional study drug. 
However, topical and inhaled corticosteroids are permitted.
13. Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy 
during the study participation.
14. Other than as administered as part of the study protocol, any medication with known 
or potential antiemetic activity within 24 hours prior to the start of AC chemotherapy 
administration on Day 1, including:
・5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, 
ramosetron, palonosetron)
・NK1 receptor antagonists (e.g., fosaprepitant, aprepitant, rolapitant or any other new 
drug of this class)
・benzamides (e.g., metoclopramide, alizapride)
・phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine, perphenazine, 
thiethylperazine, chlorpromazine)
・benzodiazepines (except if the subject is receiving such medication for sleep or
anxiety and has been on a stable dose for at least seven days prior to Day 1).
・butyrophenones (e.g., haloperidol, droperidol)
・anticholinergics (e.g., scopolamine, with the exception of inhaled anticholinergics for 
respiratory disorders, e.g., ipratropium bromide)
・antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine, chlorpheniramine)
・domperidone
・mirtazapine
・olanzapine
・prescribed cannabinoids (e.g., tetrahydrocannabinol or nabilone)
・Over The Counter (OTC) antiemetics, OTC cold or OTC allergy medications.
15. Scheduled to receive any strong or moderate inhibitor of CYP3A4 (see protocol 
Appendix 3) during the efficacy assessment period (Day 1 to Day 5, inclusive) or its 
intake within 1 week prior to Day 1.
16. Scheduled to receive any CYP3A4 inducer (see protocol Appendix 3) during the 
efficacy assessment period (Day 1 to Day 5, inclusive) or its intake within 4 weeks prior 
to Day 1, with the exception of corticosteroids (for which exclusion criterion #12 applies).
Page 116 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
17. History or predisposition to cardiac conduction abnormalities, except for incomplete 
right bundle branch block.
18. History of risk factors for Torsades de Pointes (heart failure, hypokalemia, family 
history of Long QT Syndrome).
19. Severe or uncontrolled cardiovascular diseases, including myocardial infarction 
within 3 months prior to Day 1, unstable angina pectoris, significant valvular or 
pericardial disease, history of ventricular tachycardia, symptomatic Congestive Heart 
Failure (CHF) New York Heart Association (NYHA) class III-IV, and severe 
uncontrolled arterial hypertension.
All exclusion criteria with the exception of criteria #5, #12, and #14 will be checked at 
screening visit (Visit 1). Exclusion criteria #5, #12, and #14 will be checked at Day 1 
(Visit 2) only. Exclusion criteria #3, #4, #11, #13, #15, and #16 need to be re-checked at 
Day 1 (Visit 2).
Cycles 2 to 4:
The following exclusion criteria must be checked prior to inclusion at each repeated cycle:
1. Scheduled to receive moderately or highly emetogenic antineoplastic agent (see 
protocol Appendix 1) in addition to the AC regimen, from 6 hours after the start of the 
AC chemotherapy on Day 1 of current cycle and up to Day 1 of the next cycle.
2. Active infection or uncontrolled disease that may pose unwarranted risks in 
administering the study drugs to the patient.
3. Started any of the prohibited medications (see protocol Section 5.14).
4. Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) 
within 24 hours prior to the start of AC chemotherapy administration on Day 1.
5. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis 
within 1 week prior to the start of AC chemotherapy administration on Day 1 or between 
Days 1 to 5.
6. Symptomatic primary or metastatic CNS malignancy.
7. Any illness or medical condition that, in the opinion of the investigator, may confound 
the results of the study or pose unwarranted risks in administering the investigational 
product or dexamethasone to the patient.
All exclusion criteria, with exception of criterion #4, will be checked at screening visit 
(Visit 1). Exclusion criterion #4 will be checked at Day 1 (Visit 2) only. Exclusion 
criteria #2, #3 and #5 need to be re-checked at Day 1 (Visit 2).”
Reason: To align with minor typing errors in the numbering sequence of Exclusion 
criteria.
Section 5. STUDY DRUG MANAGEMENT – 5.4 Dose and Administration
Amended text:
Page 117 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
“Test drug: The 30-minute (+/-5 minutes) IV NEPA FDC infusion will start 30 minutes 
prior to the start of AC chemotherapy administration at each cycle. The IV infusion will 
be completed before starting chemotherapy administration. 
To minimize the loss of investigational medicinal product (IMP) remaining in the 
infusion line after the end of IMP infusion, the following process is to be followed:
31.1. At the end of the 30 +/-5 min IMP or placebo infusion, the infusion line drip 
chamber is to be empty. 
32.2. The Investigator or designated responsible person will ensure completeness of 
IV infusion administration by rinsing the infusion line with 20 to 30 ml sterile 5% 
glucose solution or sterile 0.9% saline solution. Calcium or magnesium containing 
solutions (e.g., Lactated Ringer solution, etc) are not allowed. The infusion line 
rinsing process is to be performed immediately after the end of IMP or placebo 
infusion and is to be completed before to start the AC chemotherapy administration.”
Now reads:
“Test drug: The 30-minute (+/-5 minutes) IV NEPA FDC infusion will start 30 minutes 
prior to the start of AC chemotherapy administration at each cycle. The IV infusion will 
be completed before starting chemotherapy administration. 
To minimize the loss of investigational medicinal product (IMP) remaining in the 
infusion line after the end of IMP infusion, the following process is to be followed:
1. At the end of the 30 +/-5 min IMP or placebo infusion, the infusion line drip 
chamber is to be empty. 
2. The Investigator or designated responsible person will ensure completeness of 
IV infusion administration by rinsing the infusion line with 20 to 30 ml sterile 
5% glucose solution or sterile 0.9% saline solution. Calcium or magnesium 
containing solutions (e.g., Lactated Ringer solution, etc) are not allowed. The 
infusion line rinsing process is to be performed immediately after the end of 
IMP or placebo infusion and is to be completed before to start the AC 
chemotherapy administration.”
Reason: To align with minor typing errors in the numbering sequence.
5.9 Administration of Study Treatment
Amended text:
Page 118 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
Administration process and relevant times:
One (1) capsule of blinded study drug (either of netupitant/palonosetron combination or 
matching placebo) is to be taken with a glass of non carbonated water 60 minutes prior to 
the scheduled start of AC chemotherapy administration on Day 1.
Now reads:
Administration process and relevant times:
One (1) capsule of blinded study drug (either of netupitant/palonosetron combination or 
matching placebo) is to be taken with a glass of non carbonated water 60 minutes prior to 
the scheduled start of AC chemotherapy administration on Day 1.
Reason: To add details about study drug administration.
Section 6. STUDY CONDUCT 6.4  Premature Discontinuation
Amended text:
“Patients may discontinue the study at any time for any of the following reasons:
33. 1. An AE occurs that, in the opinion of the Investigator, makes it unsafe for the 
patient to continue in the study.
34. 2. The patient is lost to follow-up.
35. 3. The patient dies.
36. 4. The patient withdraws consent.
37. 5. The Investigator, for any reason, terminates his/her participation in the study, or
terminates the study for that patient; or the attending physician requests that the patient be 
withdrawn for any medical reason.
38. 6. The Sponsor or the Regulatory Authorities or the Ethics Committee(s), for any 
reason, terminates the entire study, or terminates the study for this trial site or this 
particular patient.”
Now reads:
“Patients may discontinue the study at any time for any of the following reasons:
1. An AE occurs that, in the opinion of the Investigator, makes it unsafe for the patient 
to continue in the study.
2. The patient is lost to follow-up.
3. The patient dies.
4. The patient withdraws consent.
Page 119 of 120 
Confidential
IIHE£SINN 


NEPA-17-05 
Final/30 Nov 2017
Protocol Amendment #3
5. The Investigator, for any reason, terminates his/her participation in the study, or
terminates the study for that patient; or the attending physician requests that the 
patient be withdrawn for any medical reason.
6. The Sponsor or the Regulatory Authorities or the Ethics Committee(s), for any reason, 
terminates the entire study, or terminates the study for this trial site or this particular 
patient.”
Reason: To align with minor typing errors in the numbering sequence.
Page 120 of 120 
Confidential
IIHE£SINN 

SAP_001.pdf: 
PROTOCOL NEPA-17-05 
A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel group 
phase 3b study to assess the safety and to describe the efficacy of 
IV fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV NEPA FDC) compared to 
oral netupitant/palonosetron (300 mg/0.5 mg) combination (Akynzeo®) for the prevention 
of chemotherapy-induced nausea and vomiting in initial and repeated cycles of 
anthracycline-cyclophosphamide (AC) chemotherapy in women with breast cancer 
Statistical Analysis Plan 
Prepared for: 
Helsinn Healthcare SA 
Final Version 1.0, 12 December 2018 
Prepared by: 
EMB Statistical Solutions, LLC 
Page 2 of 121
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 
Revision History 
Version 
Date 
Revision Author 
Comments 
This document is the confidential information of Helsinn Healthcare SA.  It may not be disclosed 
to parties not associated with the clinical investigation or used for any purpose without the prior 
written consent of Helsinn Healthcare SA. 
Page 3 of 121
Confidential


Page 4 of 121 
Confidential
PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
A multicenter, randomized, double-blind, double-dummy, active-controlled, parallel group 
phase 3b study to assess the safety and to describe the efficacy of 
IV fosnetupitant/palonosetron (260 mg/0.25 mg) combination (IV NEPA FDC) compared to 
oral netupitant/palonosetron (300 mg/0.5 mg) combination (Akynzeo®) for the prevention 
of chemotherapy-induced nausea and vomiting in initial and repeated cycles of 
anthracycJine-cyclophosphamide (AC) chemotherapy in women with breast cancer 
Principal Biostatistician 
EMB Statistical Solutions, LLC 
SIGNATURE PAGE 
Helsinn Healthcare SA 
Helsinn Healthcare SA 
Helsinn Healthcare SA 
Confidential 
Date 
,.,{~ r:Dec 20l f 
Date 


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
TABLE OF CONTENTS 
1 
INTRODUCTION ..................................................................................................................8 
2 
BACKGROUND INFORMATION .......................................................................................8 
3 
STUDY OBJECTIVES ........................................................................................................10 
3.1 
Primary Objective ............................................................................................................10 
3.2 
Secondary Objective ........................................................................................................10 
3.3 
Exploratory Objective .....................................................................................................10 
4 
TREATMENT PLAN AND STUDY DESIGN ...................................................................10 
4.1 
General Design ................................................................................................................10 
4.2 
Blinding and Randomization ...........................................................................................12 
4.3 
Determination of Sample Size .........................................................................................12 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ...........13 
5.1 
Changes in the Conduct of the Study ..............................................................................13 
5.2 
Changes from the Analyses Planned in the Protocol .......................................................13 
6 
BASELINE, EFFICACY, AND SAFETY ASSESSMENTS ..............................................13 
6.1 
Schedule of Evaluations ..................................................................................................13 
6.2 
Definitions/Terminology .................................................................................................13 
6.3 
Efficacy Endpoints ..........................................................................................................15 
6.4 
Safety Assessments .........................................................................................................16 
6.4.1 
Adverse Events ...........................................................................................................16 
6.4.2 
Clinical Laboratory Evaluations .................................................................................16 
6.4.3 
Vital Signs ..................................................................................................................17 
6.4.4 
Physical Examinations ................................................................................................17 
7 
STATISTICAL METHODS ................................................................................................17 
7.1 
General Methodology ......................................................................................................17 
7.2 
Interim Analyses ..............................................................................................................18 
7.3 
Final Analyses and Reporting .........................................................................................18 
7.4 
Handling of Missing Data ...............................................................................................18 
7.5 
Analysis Populations .......................................................................................................20 
7.6 
Protocol Deviations .........................................................................................................21 
7.7 
Patient Disposition ...........................................................................................................21 
7.8 
Analysis of Demographics, Other Baseline Characteristics and Conditions ..................21 
7.8.1 
Demographic and Baseline Characteristics ................................................................21 
7.8.2 
Anthracycline-Cyclophosphamide and Concomitant Chemotherapies ......................22 
7.8.3 
Medical Diseases ........................................................................................................22 
7.8.4 
Baseline Physical Examination ...................................................................................22 
Page 5 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
7.8.5 
Prior and Concomitant Medications/Radiotherapies ..................................................22 
7.8.6 
Prior and Concomitant Procedures .............................................................................23 
7.8.7 
Compliance .................................................................................................................23 
7.9 
Efficacy Analysis .............................................................................................................23 
7.9.1 
Complete Response, No Emetic Episodes, No Rescue Intake, No Nausea, and 
No Significant Nausea ................................................................................................23 
7.9.2 
Severity of Nausea ......................................................................................................24 
7.9.3 
Functional Living Index-Emesis Scores and No Impact on Daily Life ......................24 
7.10 
Subgroup Analyses ..........................................................................................................24 
7.11 
Safety Analysis ................................................................................................................25 
7.11.1 
Extent of Exposure .....................................................................................................25 
7.11.2 
Adverse Events ...........................................................................................................25 
7.11.3 
Clinical Laboratory Evaluations .................................................................................27 
7.11.4 
Vital Signs and Weight ...............................................................................................28 
8 
REPORTING CONVENTIONS ..........................................................................................28 
9 
REFERENCES .....................................................................................................................29 
APPENDIX A: 
FLOW CHART ............................................................................................30 
 
 
Page 6 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
LIST OF ABBREVIATIONS 
5-HT3 
5-hydroxytryptamine type 3 
AC 
Anthracycline-Cyclophosphamide 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BDRM 
Blinded Data Review Meeting 
CI 
Confidence Interval 
CINV 
Chemotherapy-Induced Nausea and Vomiting 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EMA 
European Medicine Agency 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDC 
Fixed-Dose Combination 
FLIE 
Functional Living Index-Emesis 
GGT 
Gamma-Glutamyl Transferase 
HEC 
Highly Emetogenic Chemotherapy 
HEOR 
Health Economics Outcome Research 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IV 
Intravenous 
IWRS 
Interactive Web-Based Response System 
LOCF 
Last Observation Carried Forward 
Page 7 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 
LOS 
Length of Stay 
MEC 
Moderately Emetogenic Chemotherapy 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mg 
mL 
Milligram 
Milliliter 
mm 
Millimeter 
N 
Number of patients 
NCCN 
National Comprehensive Cancer Network 
NCS 
Not Clinically Significant 
NEPA 
Netupitant and Palonosetron 
NIDL 
No Impact on Daily Life 
NK1 
Neurokinin-1 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States 
VAS 
Visual Analog Scale 
WHODD 
World Health Organization Drug Dictionary 
WPAI 
Work Productivity and Activity Impairment 
Page 8 of 121
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the analysis variables and statistical procedures that 
will be used to analyze and report the results from Protocol NEPA-17-05 (v3.1), dated 
30 NOV 2017.  This SAP will be finalized prior to breaking the blind.  The formats for the tables 
and listings described in this SAP are provided in a companion document.  EMB Statistical 
Solutions will have responsibility for performing these analyses. 
The following documents were reviewed in preparation of this SAP: 
 Study Protocol NEPA-17-05 v3.1, issued on 30 NOV 2017, 
 electronic Case Report Form (eCRF) NEPA-17-05 v16.0, issued 23 OCT 2018. 
The reader of this SAP is encouraged to also read the clinical protocol for details on the conduct 
of this study, and the operational aspects of clinical assessments and timing for completing a 
patient in this study. 
The SAP was written in accordance with the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH-E3 Guideline, entitled “Guidance for Industry: 
Structure and Content of Clinical Study Reports”. 
The primary goal of this study is to characterize the safety profile of the test drug.  No formal 
statistical comparisons are planned with the control group.  All results will be interpreted in a 
descriptive manner only. 
The analysis for Health Economics Outcome Research (HEOR) data will be addressed in a 
separate document, which includes data for hospitalization information, lost work time and 
productivity assessed by the Work Productivity and Activity Impairment (WPAI) Questionnaire, 
and disruptions in initiation and dosing of intended next cycle of chemotherapy. 
2 
BACKGROUND INFORMATION 
Cancer chemotherapy is often associated with nausea and vomiting, which are among the most 
unpleasant and distressing subjective side effects [1, 2].  Chemotherapy-induced nausea and 
vomiting (CINV) reduces patient’s health related quality of life and may cause non-compliance 
or refusal of potentially life-saving chemotherapeutic regimens [2].  The severity and pattern of 
nausea and vomiting induced by a chemotherapeutic regimen depend on the agents used and the 
doses employed [1].  In this respect, chemotherapeutic regimens are classified as highly, 
moderately, low, and minimally emetogenic [1]. 
Palonosetron hydrochloride is a specific 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist 
used to prevent CINV when patients receive moderately emetogenic chemotherapy (MEC) or 
highly emetogenic chemotherapy (HEC), and is a known chemical entity currently registered in 
the oral and intravenous (IV) forms in several countries [3, 4, 5]. 
Page 9 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
In the United States (US), in July 2003, the Food and Drug Administration (FDA) approved 
palonosetron 0.25 mg IV given as a 30-second bolus, for the prevention of acute CINV 
associated with highly or moderately emetogenic chemotherapy and for prevention of delayed 
CINV associated with MEC (initial and repeat courses).  In Europe, in March 2005, the 
European Medicine Agency (EMA) approved the product via the Centralized Procedure for the 
prevention of acute and delayed nausea and vomiting associated with highly emetogenic 
cisplatin-based cancer chemotherapy and MEC. 
The oral palonosetron formulation (0.50 mg capsule) is approved in the US (August 2008) and in 
the European Union (EU) (January 2010) for the prevention of moderately emetogenic CINV. 
At present, the product is registered in more than 70 countries with different trademarks 
(Aloxi®, Onicit®, Paloxi®). 
Netupitant is a highly efficient, selective neurokinin-1 (NK1) receptor antagonist that blocks 
receptors located in the central nervous system (in the putative vomiting center in the nucleus 
tractus solitarii) and in the gastrointestinal tract wall (peripheral abdominal vagal afferents) [6]. 
Helsinn developed an oral combination (NEPA FDC), which includes a 5-HT3 receptor 
antagonist (palonosetron, 0.5 mg) and an NK1 receptor antagonist (netupitant, 300 mg) in the 
form of a hard-gelatin capsule to be administered as a single dose 1 hour prior to chemotherapy. 
In the US, oral NEPA FDC (Akynzeo®) was approved in October 2014, in combination with 
dexamethasone, in adults for the prevention of acute and delayed nausea and vomiting associated 
with initial and repeated courses of chemotherapy, including but not limited to HEC [6]. 
Oral NEPA FDC (Akynzeo®) is currently officially recommended for MEC and HEC acute and 
delayed emesis prevention by the National Comprehensive Cancer Network (NCCN) 
guidelines [7]. 
Since netupitant is not water-soluble and, as such, early parenteral formulations did not show a 
satisfactory local tolerability profile, the Sponsor developed fosnetupitant, a water-soluble 
phosphorylated pro-drug of netupitant, which is rapidly converted to netupitant in vivo following 
IV administration.  Fosnetupitant proved to overcome tolerability issues that were observed with 
the former IV netupitant formulations [6]. 
An IV formulation of fosnetupitant/palonosetron, IV NEPA FDC, was developed [8].  The 
fosnetupitant chloride hydrochloride component dose in this formulation is 260 mg, which 
showed to be equivalent in exposure (Area Under the Curve, AUC) to the netupitant dose used in 
oral NEPA FDC (300 mg netupitant) (study PNET-12-23 [9]).  The selected dose for the 
palonosetron component in the IV NEPA FDC is 0.25 mg, i.e., the registered dose of Aloxi® IV. 
In the US, IV NEPA FDC (Akynzeo®) was approved in April 2018, in combination with 
dexamethasone, in adults for the prevention of acute and delayed nausea and vomiting associated 
with initial and repeated courses of HEC [10]. 
The NEPA-17-05 study will evaluate the safety and describe the efficacy of IV NEPA FDC 
fosnetupitant/palonosetron (260 mg/0.25 mg) combination, given as a 30-minute infusion 
Page 10 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 
compared with oral netupitant/palonosetron (300 mg/0.5 mg) combination (oral NEPA FDC) in 
female breast cancer patients receiving AC chemotherapy, allowing completion of information 
on the antiemetic efficacy and safety of IV NEPA FDC in the AC chemotherapy setting. 
In addition to the described oral or IV combination, study patients will also receive a regimen of 
oral dexamethasone as part of the anti-emetic treatment. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
To evaluate the safety and tolerability of a single IV dose of fosnetupitant/palonosetron 
(260 mg/0.25 mg) combination (IV NEPA FDC) administered as a 30-minute IV infusion with 
oral dexamethasone on Day 1 for the prevention of AC chemotherapy-induced nausea and 
vomiting in initial and repeated cycles. 
3.2 
Secondary Objective 
To describe the efficacy of a single IV dose of fosnetupitant/palonosetron (260 mg/0.25 mg) 
combination (IV NEPA FDC) administered as a 30-minute IV infusion versus a single oral dose 
of netupitant/palonosetron (300 mg/0.5 mg) combination (oral NEPA FDC) administered as one 
capsule, during the acute (0-24 hours), delayed (> 24-120 hours), and overall (0-120 hours) 
phases of initial and repeated cycles of AC chemotherapy. 
3.3 
Exploratory Objective 
To evaluate the impact on economics and resource utilization through collection of HEOR 
parameters in initial and repeated cycles of AC chemotherapy. 
4 
TREATMENT PLAN AND STUDY DESIGN 
4.1 
General Design 
This is a multicenter, randomized, double-blind, double-dummy, parallel group, stratified study 
assessing the safety and describing the efficacy of a single dose of IV fosnetupitant/palonosetron 
(260 mg/0.25 mg) infusion (IV NEPA FDC) versus oral netupitant/palonosetron 
(300 mg/0.5 mg) combination (oral NEPA FDC); each administered with oral dexamethasone 
prior to initial and repeated cycles of AC chemotherapy in female breast cancer patients. 
The study is planned to be performed in approximately 50 investigational sites in the US and in 
approximately 30 sites distributed in Russia, Ukraine, and Georgia.  If necessary, additional sites 
and countries may be involved as well. 
The present study will include female patients naïve to moderately or highly emetogenic 
antineoplastic agents.  Adult female patients satisfying this naivety criterion, diagnosed with 
breast cancer and requiring treatment with an AC based chemotherapy regimen on Day 1, will be 
considered for enrollment in this study. 
Page 11 of 121
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
Eligible patients, stratified by region (US, non-US) and age class (age < 55 years, 
age ≥ 55 years), will be randomly allocated in a 1:1 fashion to receive one of the two treatment 
regimens (IV fosnetupitant/palonosetron 260 mg/0.25 mg administered as a 30-minute 
IV infusion [test] or oral netupitant/palonosetron 300 mg/0.5 mg combination [control]), before 
the start of AC chemotherapy on study Day 1 of Cycle 1.  In subsequent cycles, patients will 
continue with the same study treatment they received in Cycle 1, while the dosage and 
components of the AC regimens administered in the repeated cycles may be different compared 
to Cycle 1, provided the regimen remains classified as AC.  Oral NEPA FDC (or matching 
placebo) is to be administered 60 minutes prior to the start of AC chemotherapy administration.  
IV NEPA FDC (or matching placebo) 30-minute infusion is to begin 30 minutes prior to the start 
of AC chemotherapy administration, and is to be completed before starting AC chemotherapy.  
Dexamethasone (3 tablets of 4 mg, 12 mg total) is to be given immediately before the start of the 
IV NEPA FDC (or matching placebo) infusion.     
Each randomized patient is planned to participate in a maximum of 4 consecutive AC 
chemotherapy cycles assessed in this study. 
For each cycle, the study will include a screening visit (Visit 1) up to 7 days (up to 14 days for 
Cycle 1 only) before study drug administration (Day 1, Visit 2).  After receiving a single dose of 
active treatment on Day 1 and AC chemotherapy, patients will enter an efficacy evaluation 
period of 120 hours and then return to the clinical site on Day 6 (+ 2 days) for Visit 3.  Patients 
will undergo a follow-up visit or telephone call (Visit 4) either on Day 15 (+ 3 days) or Day 22 
(± 3 days), depending on the next chemotherapy cycle schedule (this Visit 4 will be considered 
as the end of each “Study Cycle”).  Visit 4, or the corresponding telephone contact, is to be 
performed prior to administering the chemotherapy relevant to the next cycle and prior to any 
further moderately or highly emetogenic chemotherapeutic treatment administration. 
Total number of visits per patient:  For each cycle, there will be a maximum of 4 visits or 3 visits 
plus 1 telephone contact.  For all cycles, the screening visit (Visit 1) and the study drug 
administration visit (Visit 2) can be performed on the same day.  The screening visit of a 
subsequent cycle can also coincide with the follow-up visit (Visit 4) of the previous cycle.  If all 
these visits are merged, Visit 4 of the previous cycle as well as Visit 1 and Visit 2 of the next 
cycle are all three performed on the same day.  Therefore, the actual number of visits in repeated 
cycles will depend on the number of combined visits. 
Total number of cycles per patient:  Each patient may participate in a maximum of 4 consecutive 
AC chemotherapy cycles, as long as they continue to fulfill the inclusion and exclusion criteria 
for the repeated cycles and as long as the study remains open. 
Maximum total study duration per patient is approximately 14 weeks. This maximum total study 
duration per patient is based on the assumption that the patient participates in 4 consecutive 
study cycles with a 21-day interval between the Day 1 of two consecutive cycles, and that 
follow-up visits of one cycle coincide with screening visits of the subsequent cycle.  A minimum 
of 14 days and maximum of 35 days is allowed between the Day 1 of two consecutive cycles. 
A total of 400 patients will be randomized.  Study drug assignment for Cycles 2 to 4 will be 
closed 7 days after the last (400th) patient is randomized, in order to permit patients already 
Page 12 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
screened for a subsequent study cycle to have study drug administered.  Patients still 
participating in the study at this time should complete their current cycle and will not be allowed 
to enter in a subsequent study cycle. 
A patient will be defined as having completed a Study Cycle if she completes the follow-up visit 
(Visit 4) of that cycle. 
A patient will be defined as “completed” if she completes Visit 4 (either as on-site visit or 
telephone contact) of Cycle 4.  A patient will be defined as “completed cycle, not continuing” if 
she completes Visit 4 (either as on-site visit or telephone contact) of any cycle before Cycle 4 
without continuing in the subsequent study cycle.  Study termination at a different time point 
other than Visit 4 of any cycle (including screening visit for one of the repeated cycles) will be 
considered as premature study discontinuation. 
The overall study completion date is defined as the date of last patient’s last visit or telephone 
contact. 
See Appendix A for a flow chart of assessments to be collected, activities to be performed, and 
relevant study visits.   
4.2 
Blinding and Randomization 
This is a double-blind study.  The blinding of the study drugs is guaranteed by the use of 
identical placebos to the respective active drugs (double-dummy technique). 
Treatment assignment will be managed through a static central blocked randomization stratified 
by region (US, non-US) and age class (age < 55 years, age ≥ 55 years).  Randomization scheme 
will be reproducible and will be prepared prior to start of the study via a computerized system by 
a statistician at EMB Statistical Solutions not assigned to the study team, who will keep the study 
team blinded to the codes and all other information (e.g., the seed) that could break the blind of 
the study.  A master randomization list copy will be filed securely by EMB and the Sponsor in a 
manner that ensures that blindness is properly maintained throughout the trial.  The 
biostatistician involved in the creation of the randomization lists will not take part in any study 
activities. 
Considering the strata, eligible patients will be assigned to one of the two arms, in a balanced 
ratio (1:1), according to specific procedures using an Interactive Web Response System (IWRS).  
Separate lists (packaging list and patient’s randomization list) will be prepared for patients’ 
randomization and study medication packaging.  Sealed cartons (kits) containing the study 
medications will be prepared according to the packaging list.  An appropriate amount of 
treatment kits will be supplied to the designated person at the investigational sites at the 
beginning of the study, with further re-supplies scheduled once the number of available treatment 
kits decrease to a pre-set threshold at each site. 
4.3 
Determination of Sample Size 
A total of 400 patients will be randomized, equally distributed in two groups (i.e., 
200 patients/group). 
Page 13 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
Patients will be randomized according to a randomization ratio 1:1, stratified by region and age 
class. 
The primary goal of this study is to characterize the safety profile of IV NEPA FDC over a 
reasonable duration of time consistent with the intended use of this drug.  Although no formal 
comparison is planned with the randomized control group, the presence of a concurrent control 
group in the same patient population may help in the interpretation of any unexpected safety 
finding in the test group. 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
5.1 
Changes in the Conduct of the Study 
There have been the following versions of the protocol:  v1.0, v1.1, v1.2, v2.0, v3.0, and v3.1.  
No patients were enrolled prior to Protocol v3.1 dated 30 Nov 2017, and this first SAP version is 
based on Protocol v3.1.   
5.2 
Changes from the Analyses Planned in the Protocol 
This analysis plan details analyses to be conducted for the study.  Some of the analyses detailed 
here may be more explicit than those stated in the protocol.  In case of differences, this SAP 
provides details of the changes and supersedes the statistical sections in the protocol. 
6 
BASELINE, EFFICACY, AND SAFETY ASSESSMENTS 
6.1 
Schedule of Evaluations 
The assessments to be conducted at each scheduled visit are displayed in Appendix A. 
6.2 
Definitions/Terminology 
 Baseline:  the last non-missing evaluation which was collected prior to the first study drug 
(oral and IV NEPA FDC or matching placebo) intake in Cycle 1.  Some by-cycle change 
summaries are also planned using the pre-dose assessment from each cycle (i.e., last non-
missing evaluation which was collected prior to study drug intake in that cycle) in addition to 
a change summary using Baseline; such cases will be indicated. 
 Disposition: 
o Completed study patient:  completes Visit 4 (either as on-site visit or telephone contact) 
of Cycle 4. 
o Completed cycle, not continuing patient:  completes Visit 4 (either as on-site visit or 
telephone contact) of any cycle before Cycle 4 without continuing in the subsequent 
cycle. 
o Premature study discontinuation:  Study termination at a different time point other than 
Visit 4 of any cycle (including screening visit for one of the repeated cycles).   
Page 14 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
 Medications: 
o Prior medications:  all medications taken prior to the date of first study drug (oral and IV 
NEPA FDC or matching placebo) intake in Cycle 1. 
o Concomitant medications:  all medications taken on or after the day of first study drug 
(oral and IV NEPA FDC or matching placebo) intake in Cycle 1.  Note that a medication 
taken within 14 days prior to Day 1 of Cycle 1 and ongoing at the time of the start of 
study treatment will be considered as both a prior and concomitant medication. 
o Compliant patient:  takes all study drugs (oral NEPA FDC/Placebo, IV NEPA 
FDC/Placebo, and dexamethasone).  Defined overall and for each cycle. 
 Chemotherapies: 
o Concomitant chemotherapies:  chemotherapies taken any time in the interval Day 1-5 of 
each cycle. 
 Efficacy: 
o Time 0:  start time of the AC chemotherapy administration on Day 1 of each cycle.  
o Phases:  acute, delayed, and overall are time intervals 0 to 24 hours, > 24 to 120 hours 
and 0 to 120 hours after the start of the AC chemotherapy administration, respectively.  
o Emetic episode:  one or more continuous vomits (expulsion of stomach contents through 
the mouth) or retches (an attempt to vomit that is not productive of stomach contents).  
Emetic episodes are considered distinct if separated by absence of vomiting and retching 
for at least 1 minute.       
o Rescue medication:  any medication administered to alleviate established, refractory, or 
persistent nausea or vomiting after the start of chemotherapy on Day 1 and up to Day 5, 
inclusive, of each cycle.  Permitted on an as-needed basis. 
o Complete response (CR):  no emetic episodes (vomit or retch) and no use of rescue 
medication during applicable phase. 
o Nausea severity:  defined using maximum nausea intensity on a 100-mm horizontal 
visual analog scale (VAS).  The left end of the scale (0 mm) is labeled as ‘no nausea’, 
and the right end of the scale (100 mm) is labeled as ‘nausea as bad as it could be’. 
o No nausea:  maximum nausea intensity on a 100-mm VAS of < 5 mm during applicable 
phase.  
o No significant nausea:  maximum nausea intensity on a 100-mm VAS of < 25 mm during 
applicable phase.  
o No impact on daily life (NIDL):  a 5-day Functional Living Index-Emesis (FLIE) 
questionnaire score greater than 108 points, 54 points, and 6 points for the total score, 
domain score, and single item score, respectively [11].     
Page 15 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
 Safety: 
o Pre-treatment adverse events (AEs):  AEs that start prior to the first study drug (oral and 
IV NEPA FDC or matching placebo) administration on Day 1 of Cycle 1.   
o Treatment-emergent adverse events (TEAEs):  AEs that start or worsen in severity after 
the first study drug (oral and IV NEPA FDC or matching placebo) administration on 
Day 1 of Cycle 1 until Visit 4 of the last study cycle. 
o Drug-related AEs:  AEs with study drug (oral and IV NEPA FDC or matching placebo) 
relationship classified by investigator as definitely, probably, possibly, unassessable, or 
missing. 
6.3 
Efficacy Endpoints 
Efficacy is the secondary objective of the study and will be assessed by the following efficacy 
endpoints: 
 Proportion of patients with CR during the acute, delayed, and overall phases; 
 Proportion of patients with no emetic episodes during the acute, delayed, and overall phases; 
 Proportion of patients with no rescue medication during the acute, delayed, and overall 
phases; 
 Proportion of patients with no nausea during the acute, delayed, and overall phases; 
 Proportion of patients with no significant nausea during the acute, delayed, and overall 
phases; 
 Severity of nausea in the acute, delayed, and overall phases; 
 Proportion of patients with NIDL activities in the overall phase of Cycle 1 and 2, only as 
assessed by the FLIE questionnaire;  
 Domain (nausea and vomiting) FLIE scores and the total FLIE score in the overall phase of 
Cycle 1 and 2 only. 
Note: since the nausea VAS is assessed daily, for no nausea, no significant nausea, and severity 
of nausea in the delayed and overall phases, the maximum VAS value in the relevant phase will 
be considered (i.e., the maximum value for Day 2 to 5 for delayed phase and the maximum value 
for Day 1 to 5 for the overall phase). 
Note:  The manual for the FLIE questionnaire indicates that the scale anchors are in the opposite 
direction on Items 3, 6, 11, 15, and 18 compared to the other items, and so a respondent may 
answer one or more items incorrectly as a result.  A response on one of these items can be 
considered invalid if the item score is ± 50 mm or more from the mean score of the items from 
the same domain (excluding items 3, 6, 11, 15, and 18).  In these cases, as is recommended by 
the manual, the item, domain, and total scores will be calculated and reported “as is” (i.e., using 
Page 16 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
the value marked by the respondent).  If the percentage of invalid scores is ≥10%, then a 
sensitivity analysis will be performed to assess the impact of these errors by setting the invalid 
item(s) to missing before calculating the domain and total scores.   
6.4 
Safety Assessments 
Safety is the primary objective of the study and will be assessed primarily by means of: 
  TEAEs.  
Additionally, the assessment of safety will be based on: 
  clinical laboratory values (hematology and blood chemistry), 
  vital signs, and 
  physical examinations.   
Additional key details for safety assessments are provided in the sections below. 
6.4.1 
Adverse Events 
AE recording will begin at the time the informed consent form is signed until end of the study 
(completion/discontinuation), as a minimum.   
Signs and symptoms considered as lack of efficacy (nausea and vomiting) and occurring during 
the study up to 5 days after the study drugs administration, will not be recorded on the AE 
section of the eCRF, except on the condition that, in the Investigator’s opinion, nausea and 
vomiting are caused by any reason different from lack of efficacy of study treatment or meet the 
definition of serious AE. 
The Investigator will classify AEs based on their severity (Grades 1-5) and relationship to 
Investigational Medicinal Product (IMP) and dexamethasone (definitely related, probably 
related, possibly related, unlikely related, not related/none, and unassessable).  The severity of an 
AE will be rated by the Investigator according to the descriptions and grading scales of the 
Common Terminology Criteria for Adverse Events (CTCAE) [12]. 
6.4.2 
Clinical Laboratory Evaluations 
At the screening visit for each cycle, the Investigator will be responsible for assessing a patient’s 
eligibility to receive AC chemotherapy, including the assessment of laboratory parameters.  The 
following laboratory parameters will be assessed at Visit 1 (Screening) and Visit 3 
(Day 6 + 2 days) of each cycle using local laboratories: 
 Hematology:  hemoglobin, erythrocytes, leukocytes, and platelets; 
 Blood Chemistry:  aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
gamma-glutamyl transferase (GGT), bilirubin, alkaline phosphatase, creatinine, and 
Page 17 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
creatinine clearance (derived from blood creatinine value by application of the Cockcroft-
Gault formula). 
Upon receipt and after review, the Investigator must sign and date each local laboratory report 
and document in the relevant eCRF form if the parameter is below, within, or above normal 
ranges and, in case of abnormal values, if they are clinically significant.   
Laboratory values, units, and ranges will not be entered in the eCRF nor provided to EMB via an 
external data transfer.  
6.4.3 
Vital Signs 
Vital signs assessments will include pulse rate, systolic and diastolic blood pressure (at Visit 1, 
Visit 2 pre-dose and Visit 3 of each cycle); height (Visit 2 of Cycle 1 only); and body weight, 
body surface area, and body mass index (Visit 2 [Day 1 visit] of each cycle, at pre-dose).  Pulse 
rate and systolic and diastolic blood pressure will be measured after the patient has been resting 
in the semi-supine position for at least 5 minutes. 
6.4.4 
Physical Examinations 
A complete physical examination will be performed at Visit 1 (Screening) and Visit 3 
(Day 6 + 2 days) of each cycle.  This evaluation will include an examination of general 
appearance, head, eyes, ears, nose, throat, skin, neck, lungs, cardiovascular, breast, lymph nodes, 
abdomen, musculoskeletal, and neurological.  Full results for each test will only be recorded in 
the eCRF for Cycle 1 Visit 1 (Screening).  
7 
STATISTICAL METHODS 
7.1 
General Methodology 
Data will be summarized using descriptive statistics (number of patients [N], mean, standard 
deviation [SD], median, minimum, and maximum) for continuous variables and using frequency 
and percentage for discrete and categorical variables. 
The summaries will be presented by the two treatment arms the patients are randomized to: 
(1) IV NEPA FDC or (2) Oral NEPA FDC. 
Patient listings of data from the eCRFs as well as derived variables will be provided.  An 
indication of specific listings for each data type will not be indicated in the text of subsequent 
sections.  The specific listings planned, along with their formats, are provided in a companion 
shell document. 
Procedures, Adverse Events, and Medical Diseases (including current cancer history) will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.0.  The 
verbatim term will be mapped to System Organ Class (SOC), High Level Group Term, High 
Level Term, Preferred Term (PT), and Low Level Term.   
Page 18 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 
Prior and Concomitant Medications (including rescue medications recorded in patient diary and 
chemotherapies) will be coded using the World Health Organization Drug Dictionary (WHODD) 
March 2018 enhanced version.  Medications will be coded to generic name and Anatomical 
Therapeutic Chemical (ATC) classification of ingredients (i.e., therapeutic class). 
7.2 
Interim Analyses 
No formal interim analyses are planned for this study. 
Descriptive statistics of data elements from exploratory HEOR assessments may be calculated on 
blinded data at intervals to be determined based on study enrollment.  Data from a minimum of 
50 patients will be available prior to creating this summary. 
7.3 
Final Analyses and Reporting 
A blinded data review meeting (BDRM) will be held prior to database lock.  This SAP should be 
approved before study unblinding. 
Tables and Listings will be made available following database lock and unblinding and prior to 
completion of the final Clinical Study Report (CSR). 
Any post-hoc analyses completed to support planned study analyses which were not identified in 
this SAP, will be documented and reported in appendices to the CSR.  Any results from these 
unplanned analyses will also be clearly identified in the text of the CSR. 
7.4 
Handling of Missing Data 
No imputations will be performed on missing demographics, background, or safety data and only 
observed cases will be reported unless otherwise noted in this SAP.  See Section 7.8.5 below for 
the handling of missing start dates to determine prior and concomitant medications.  See Section 
7.11.2 below for the handling of missing AE start dates to determine treatment-emergent status, 
missing AE severity, and missing AE relationship to study treatment.    
For efficacy analyses, the procedures for handling missing data are described below and will be 
applied to the Full Analysis Set (FAS). 
Due to the short efficacy assessment period within each study cycle (a maximum of 120 hours 
considering all efficacy assessments), a very low number of drop-outs and minimal missing data 
is expected during a cycle. 
The following bullets provide a description for procedures related to CR determination: 

For efficacy analyses, a patient will be considered as having CR only if there is documented
evidence of both no occurrence of emetic episodes and no rescue medication intake.  Any
patient who does not provide data about occurrence of emetic episodes and rescue
medication intake is to be considered as a treatment failure (i.e., non-responder) for CR in the
overall phase.  The same approach is to be applied also to CR in the acute and delayed
phases.
Page 19 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 

For consistency, the same approach for handling missing data as described for CR will also
be applied to emetic episodes and rescue medication intake.

Emetic episodes recorded on the patient diary that occurred outside the time window of
0-120 hours with reference to start of AC chemotherapy administration will be kept but will
not be used for the statistical analysis of CR.  Vomiting and retching episodes will be
combined first, then episodes outside of the 0-120 hour window will be dropped (i.e., drop
episodes starting before AC chemotherapy administration or starting after 120 hours).  If all
episodes recorded on the patient diary actually occurred outside the 0-120 hour window, the
answer to the general question about emetic episodes should be consistently considered
"No".  A similar approach will be applied to rescue medication intake.

Since there might be cases where emetic episodes and rescue medications intake in the
0-120 hours from start of AC chemotherapy are recorded in the eCRF Adverse Events and
Prior and Concomitant Medications forms only (and not, as it should, in the patient diary), in
accordance with the definition of CR, such cases will be taken into account for efficacy
analyses and patients considered as failures.  In this respect, AEs with PTs “Vomiting” and
“Retching” will be considered.  The start and stop dates of the AE episode will be used to
determine AEs for the 0-120 hour time interval.  If no start and stop times are recorded for
the AEs, only those events that clearly occurred in the 0-120 hour time interval will be
considered for efficacy analysis, i.e., if an AE stops on the first day of the 0-120 hour period
or starts on the last day of the 0-120 hour period, then this AE episode will not be taken into
consideration for efficacy analysis since assumed these cases were correctly recorded by the
investigator.  For the AEs that clearly occurred in the 0-120 hour time interval, if there is
evidence that they were actually due to lack of efficacy, they will be taken into account for
efficacy but not for safety analyses.

In cases where an emetic episode has been recorded twice, once as a clinical event in the
diary and once as an adverse event in the AE form, but with exactly the same start and end
date and time values, it will be considered for both the efficacy and safety analyses.

For concomitant medications, drugs with an indication for treatment of nausea, vomit, CINV,
emesis, retching, or similar will be considered.  Start and stop dates will be used to determine
rescue medications taken in the 0-120 hour time interval.  If no start and/or stop time are
recorded, only the intakes that clearly occurred in the 0-120 hour time interval will be
considered for efficacy analysis.  A time value of “00:00” will be imputed for missing times
for the determination of phase for such cases.

All TEAEs and concomitant medications meeting any of the above criteria will be identified
and a listing will be created for review at the BDRM.  Decisions on how to deal with these
cases will be fully documented and appended to the BDRM minutes, which will be finalized
before database lock.  Records from AEs and the concomitant medications forms used for the
CR determination will be flagged in the efficacy listings for emetic episodes and rescue
medication intake.
For nausea intensity data collected daily, missing values in the 0-24 hour interval or missing data 
preceding any available data will be replaced using the worst case principle, i.e., using the 
Page 20 of 121
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
highest value observed in the same treatment and time interval among all patients with the same 
stratifications factors (region and age class).  Missing data after at least one available value will 
be replaced using Last Observation Carried Forward (LOCF).  The worst value will be evaluated 
after applying LOCF to other missing data.  Patients with no nausea and with no significant 
nausea will be then derived from the complete data after imputation of missing data. 
Concerning the FLIE scores, for the purpose of calculating the score for a domain (either nausea 
or vomiting), at least 5 of the 9 FLIE items (i.e., > 50% overall item response rate) in the domain 
must be non-missing.  The score of each domain, expressed in mm (after reversing items with the 
scale anchors in the opposite direction), will be calculated as: 
 
 
To obtain the score expressed in FLIE points, the above mentioned domain score expressed in 
mm is multiplied by 0.06, as a final step 9 will then be added as follows:  
Domain score (in FLIE points) = (Domain score (in mm) × 0.06) + 9 
For the calculation of the total FLIE score (i.e., sum of the nausea and vomiting domain scores), 
at least 12 out of the 18 FLIE items (i.e., ≥ 66% overall item response rate) must be non-missing 
and both the vomiting and nausea domains must be non-missing. 
A missing FLIE single item will not be replaced.  A missing entire FLIE domain score will be 
replaced using the worst case principle, i.e., using the lowest score observed in the same 
treatment among all patients with same age class and same region.  The total FLIE score will be 
then calculated from the complete data after imputation of missing data. 
7.5 
Analysis Populations 
The study populations are defined as follows: 
 Full Analysis Set (FAS) - all patients who have been randomized to treatment and received 
AC chemotherapy regimen and active study drug (oral NEPA FDC or IV NEPA FDC, 
including partial infusion). 
Following the intent-to-treat principle, patients will be assigned to the study treatment group 
according to the treatment to which they have been randomized.  The FAS population will be 
used for demography, other baseline characteristics, and all descriptive efficacy analyses. 
 Safety population - all patients who received active study drug (oral NEPA FDC or IV 
NEPA FDC, including partial infusion). 
 
Patients will be assigned to study treatment groups according to the actual treatment 
received.  The Safety population will be used for demography, other baseline characteristics, 
and all safety analyses.   
 
Page 21 of 121 
Confidential
Domain s.c.ore (in mm) = L it.em scoi:;es (iin mm) 
· 
x 9 
no. items .wswei:ed 


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 
If any patients receive incorrectly administered kits that result in different active treatments 
received by cycle, they will be handled as follows for tables in the Safety population: 
o
Tables for demography, other baseline characteristics, prior and concomitant medical
diseases/medications/radiologic treatments/procedures, and overall study drug
compliance/exposure will use actual treatment received from Cycle 1.
o
Tables for study drug compliance/exposure, adverse events, laboratory values, and
vital signs that summarize data by cycle will use actual treatment received from the
applicable cycle.
7.6 
Protocol Deviations 
A list of potential deviations is included in the Protocol Deviations Document.  Since the main 
study objective is the assessment of the safety profile of the IV study drug combination, 
deviations will be defined but they will not determine the exclusion of patients from any 
populations (i.e., no Per-Protocol population is defined, see Section 7.5). 
Deviations include, but are not limited to, inclusion/exclusion criteria not met, missing diaries, 
intake of non-permitted medications, and incorrect randomizations.  All deviations will be 
reviewed and discussed case by case during the BDRM and decisions will be described in the 
blind data review document/minutes, which will be finalized prior to database lock.  The IMP 
deviations requiring knowledge of active or placebo treatment receipt to determine a major 
versus minor grade will be assigned as major prior to database lock, which then may be 
downgraded to minor after unblinding if applicable.       
The number and percentage of patients with deviations will be tabulated by deviation, by 
treatment group, and overall for all randomized patients.   
7.7 
Patient Disposition 
The number of patients screened, failed screening, randomized, completed study, completed 
cycle/not continuing, and with premature study discontinuation will be summarized descriptively 
by treatment group and overall.  The primary reasons for premature study discontinuation will 
also be presented (including patients defined as “completed a cycle, not continuing”). 
For each cycle, the number of patients scheduled for treatment (i.e., had a study drug kit assigned 
for that cycle); treated; completed Visit 4 of cycle, continuing; completed cycle, not continuing; 
and discontinued during that cycle will be also displayed. 
The number of patients included in the Safety and FAS populations and reasons for exclusion 
from those populations will also be tabulated by treatment group and overall for randomized 
patients. 
7.8 
Analysis of Demographics, Other Baseline Characteristics and Conditions 
7.8.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics (age, age class, region, gender, fertility status, race, 
ethnicity, height, weight, body mass index, body surface area, Eastern Cooperative Oncology 
Page 22 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
Group Performance Status [ECOG PS], tobacco consumption, number of cigarettes/cigars per 
day, alcohol consumption, and illicit drug use) will be summarized descriptively by treatment 
group and overall for the Safety and FAS populations.  These characteristics will be also 
summarized by stratification factors, i.e., by age class and region. 
A separate table for the Safety population will descriptively summarize current cancer diagnosis 
(location, histological/pathological type, time since histological diagnosis [days], extent at study 
entry, and site of metastasis) by treatment group and overall.  Current cancer history also will be 
summarized by MedDRA High Level Group Term and Preferred Term and by treatment arm and 
overall. 
7.8.2 
Anthracycline-Cyclophosphamide and Concomitant Chemotherapies 
A separate table for each cycle will descriptively summarize the number and percentage of 
patients by AC regimens in the FAS population, which will display the combination of the 
chemotherapeutic drugs administered by concatenating the generic medication names received 
by a patient.  E.g., CYCLOPHOSPHAMIDE + DOXORUBICIN, CYCLOPHOSPHAMIDE + 
EPIRUBICIN, etc.  
Summary statistics for dose (actual dose on Day 1 expressed in mg and as mg/m2) for each of the 
components of the AC regimen will be presented by cycle as well. 
Number and percentage of patients taking concomitant chemotherapies agents (chemotherapies 
taken any time in the interval Day 1-5) by time of intake with respect to AC regimen (i.e., Day 1 
only or Days 1-5) will be presented for each cycle.  Concomitant chemotherapies received in 
addition to the AC regimen will be presented in a frequency table by WHODD generic 
medication name for each cycle. 
A similar presentation will be displayed for patients taking chemotherapies with a start date 
> 120 hours after AC chemotherapy administration at each cycle.  
7.8.3 
Medical Diseases 
Medical diseases will be tabulated by MedDRA SOC and PT for the Safety population for each 
treatment group and overall, separately for prior and for concomitant diseases.  Medical disease 
terms with ongoing checked ‘No’ will be considered as prior diseases, and with ongoing checked 
‘Yes’ as concomitant diseases. 
7.8.4 
Baseline Physical Examination 
The Cycle 1 Visit 1 (Screening) physical examination findings (normal/abnormal/not done) will 
be summarized descriptively for the Safety population by treatment group. 
7.8.5 
Prior and Concomitant Medications/Radiotherapies  
Prior medications and concomitant medications (excluding rescue medications) will be 
summarized separately by treatment group and overall for the Safety population by displaying 
frequency counts and percentages by WHODD ATC Class Level 4 (if Level 4 is not available, 
Page 23 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
will use the highest class available) and WHODD generic name.  A patient will be counted only 
once per therapeutic class or generic name. 
Since prior and concomitant radiologic treatment verbatim terms are not planned to be coded, 
only the number of patients with at least one prior and with at least one concomitant radiologic 
treatment will be presented by treatment group and overall for the Safety population.  Treatment 
details for individual patients will be listed.    
The following approach will be taken to determine whether a medication is to be considered 
prior or concomitant, where an incomplete start date exists: 
1) When the month and year are known but the day is missing:  If the first study drug 
administration is during or prior to that month, then the medication is to be considered as 
concomitant.  If the first study drug administration is after that month, then the medication is 
to be considered a prior medication; in addition, if the medication is continued after the first 
study drug administration then it will be counted as both a prior medication and a 
concomitant medication. 
2) When the year is known but both the day and the month are missing:  If the first study drug 
administration is during or prior to that year, then the medication is to be considered as 
concomitant.  If the first study drug administration is after that year, then the medication is to 
be considered a prior medication; in addition, if the medication is continued after the first 
study drug administration then it will be counted as both a prior medication and a 
concomitant medication. 
7.8.6 
Prior and Concomitant Procedures 
Prior and concomitant diagnostic/therapeutic/surgical procedures will be summarized by 
MedDRA SOC and PT and by treatment arm and overall for the Safety population.  Prior 
procedures and concomitant procedures will be presented separately. 
7.8.7 
Compliance 
A summary of investigational study drug and dexamethasone compliance overall and by cycle 
will be provided by treatment group for the Safety population.   
7.9 
Efficacy Analysis 
Analyses of efficacy endpoints will be performed using the FAS population.  All results will be 
interpreted in a descriptive manner only. 
7.9.1 
Complete Response, No Emetic Episodes, No Rescue Intake, No Nausea, and No 
Significant Nausea 
At each cycle, for each phase (acute, delayed, and overall), numbers and proportions (including 
two-sided 95% confidence interval [CI] using Wilson score method) of patients with CR, with no 
emetic episodes, with no rescue medication, with no nausea, and with no significant nausea will 
be descriptively summarized by treatment group.  For these variables, the treatment difference 
Page 24 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
(IV-oral NEPA FDC) in response rate will be presented with a two-sided 95% CI using the 
Cochran-Mantel-Haenszel (CMH) method adjusted for region and age class strata.  A treatment 
difference two-sided 95% CI using Newcombe-Wilson’s method without strata adjustment will 
also be presented. 
In addition for Cycle 1, CR in the acute, delayed, and overall phases will be summarized for each 
treatment group by region strata and separately by age group strata.  Numbers and proportions 
(including two-sided 95% CI using Wilson score method) of patients with CR will be provided, 
as well as treatment difference with a two-sided 95% CI using Newcombe-Wilson’s method 
without strata adjustment.  
Overall phase CR will be summarized by region and investigative site for Cycle 1 with numbers 
and proportions.   
In addition, rescue medications for individual cycles will be summarized by treatment group and 
overall for the FAS population by displaying frequency counts and percentages by WHODD 
ATC Class Level 4 (if Level 4 is not available, will use the highest available) and WHODD 
generic name.  A patient will be counted only once per therapeutic class or generic name. 
7.9.2 
Severity of Nausea 
For each cycle, the maximum severity of nausea based on the 100-mm VAS in the acute, delayed 
and overall phases will be descriptively summarized by treatment group.  The difference of 
means (IV-oral NEPA FDC) will be presented with a two-sided 95% CI, using the t-test method 
without strata adjustment. 
7.9.3 
Functional Living Index-Emesis Scores and No Impact on Daily Life 
In Cycle 1 and Cycle 2 only, the number and proportion (including two-sided 95% CI using 
Wilson score method) of patients with NIDL based on FLIE scores (overall, by domain, and by 
individual item) will be summarized by treatment group.  Differences between treatment groups 
for total FLIE score and domain scores (nausea and vomiting) will be presented with two-sided 
95% CIs using the CMH method adjusted for region and age class strata and also using 
Newcombe-Wilson’s method without strata adjustment.   
For Cycle 1 and Cycle 2, the nausea and vomiting domain FLIE scores and the total score will be 
descriptively summarized by treatment group.  The difference of means (IV-oral NEPA FDC) 
will be presented with a two-sided 95% CI, using the t-test method without strata adjustment. 
7.10 
Subgroup Analyses 
It is expected that region (US, non-US) and age class (< 55 years, ≥ 55 years) could influence the 
study endpoints.  For this reason, these factors will be taken into consideration for randomization 
so to minimize possible imbalance between groups. 
Selected efficacy endpoints at Cycle 1 (i.e., CR in the acute, delayed, and overall phases) will be 
also summarized by region and by age group. 
Page 25 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
7.11 
Safety Analysis 
Summaries of safety data will be based on the Safety population.  No formal tests will be 
performed to compare treatment groups. 
7.11.1 
Extent of Exposure 
A table with exposure to study drug and dexamethasone for the Safety population for each cycle 
will summarize by treatment group whether or not patients received the Oral NEPA 
FDC/Placebo capsule, oral dexamethasone (12 mg, 8 mg, or 4 mg total), and IV NEPA 
FDC/Placebo infusion.  In addition, the location of the IV NEPA FDC/Placebo infusion (left 
arm, right arm, central access, or other), whether or not the infusion was interrupted, the 
cumulative infusion volume administered (mL), and whether or not the infusion line was rinsed 
will be summarized. 
A table with exposure to study drug and dexamethasone for the Safety population for the entire 
study will summarize by treatment group the total number of Oral NEPA FDC/Placebo capsules 
and IV NEPA FDC/Placebo infusions received, the total cumulative volume of IV NEPA 
FDC/Placebo solution administered, and the total number of oral dexamethasone tablets 
received. 
7.11.2 
Adverse Events 
A conservative approach will be used to handle incomplete dates for AEs. As a general principle, 
AEs with missing or incomplete date of onset will be assumed to be treatment emergent, unless 
there is clear evidence (through comparison of partial date with date of first study drug 
administration) that the AE started prior to the first dose of study treatment.  
If the onset date is unknown but the stop date is available and is before first study drug 
administration, then the AE will not be considered as a TEAE.  
The rules for handling incomplete AE onset dates will be as follows: 
1) When the month and year are known and the day is missing:  If first study drug 
administration is during or prior to that month, then the AE is to be considered treatment 
emergent; if first study drug administration is after that month, then the AE is not to be 
considered as treatment emergent. 
2) When the year is known and both the day and the month are missing:  If the first study drug 
administration is during or prior to that year, then the AE is considered to be treatment 
emergent; if first study drug administration is after that year, then the AE is not to be 
considered treatment emergent. 
Date imputation rules will be specified in the study analysis dataset specifications with further 
details. 
AEs with missing severity or relationship to study treatment will have the assessment considered 
as “unknown” (missing) for AE listings.  For AE tables, events with missing severity will be 
Page 26 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
treated as Grade 3 (severe) and with missing or unassessable relationship to study treatment will 
be considered as related. 
TEAEs will be summarized by SOC and PT, sorted alphabetically by SOC and in decreasing 
overall frequency across both treatment groups by PT, unless specified otherwise.  For patient 
counts, a patient will only be counted once per SOC and once per PT in cases where multiple 
events are reported for a patient within SOC or PT.  For event counts, patients with multiple 
events in a category will be counted for each event. 
Patient counts and percentages will be presented for the following summaries by treatment 
group: 
1) Overall summary of TEAEs for all cycles and separately for Cycle 1:  patients with at least 
one TEAE, patients with at least one TEAE classified as drug-related, serious, drug-related 
serious, with fatal outcome, drug-related with fatal outcome, severe (Grade ≥ 3), drug-
related severe, leading to premature study discontinuation, and drug-related leading to 
premature study discontinuation.  The total number of events in each category will also be 
provided in the same table.  
2) TEAEs by SOC and PT for all cycles and separately for Cycle 1.  The total number of 
events in each category will also be provided in the same table.   
3) TEAEs by SOC, PT, and maximum severity (Grade 1 through 5) for all cycles and 
separately for Cycle 1.   
4) Severe (Grade ≥ 3) TEAEs by SOC and PT for all cycles and separately for Cycle 1. 
5) TEAEs by SOC, PT, and strongest relationship to study drug for all cycles and separately 
for Cycle 1.  Categories displayed will be definitely, probably, possibly, unlikely, none, and 
unassessable/missing.  Similar tables for relationship to dexamethasone and for relationship 
to study drug or dexamethasone will be provided. 
6) Drug-related TEAEs by SOC and PT for all cycles and separately for Cycle 1. 
7) TEAEs occurring in at least 5% of patients in any treatment group by SOC and PT for all 
cycles and separately for Cycle 1. 
8) Drug-related TEAEs occurring in at least 2% of patients in any treatment group by SOC and 
PT for all cycles and separately for Cycle 1. 
9) TEAEs of special interest, i.e., “infusion site TEAEs” by PT for all cycles and by cycle.  An 
initial list of terms to be considered for infusion site AEs includes: “Pain, Erythema, 
Swelling, Hives, Extravasation, Deep vein thrombosis, Superficial thrombosis, 
Phlebitis/Thrombophlebitis, Vein discoloration, Venous engorgement, Venous 
hardening/induration, Local scarring, Itching sensation, and Heat sensation” [13, 14].  Since 
some terms are general (e.g., pain, erythema), location will be needed to determine if the AE 
is to be categorized as an “infusion site AE” or not.  Other terms may be identified by 
Page 27 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 
clinicians during the study and prior to database lock.  The final list of PTs will be reviewed 
and approved at the BDRM.  
10) Drug-related infusion site TEAEs by PT for all cycles and by cycle.
11) Serious TEAEs by SOC and PT for all cycles and separately for Cycle 1.
12) Drug-related serious TEAEs by SOC and PT for all cycles and separately for Cycle 1.
13) TEAEs leading to premature study discontinuation by SOC and PT for all cycles and
separately for Cycle 1.
14) Drug-related TEAEs leading to premature study discontinuation by SOC and PT for all
cycles and separately for Cycle 1.
15) TEAEs with fatal outcome by SOC and PT for all cycles.
16) Drug-related TEAEs with fatal outcome by SOC and PT for all cycles.
For the summary of TEAEs by severity, if a patient has multiple events occurring in the same 
SOC or same PT, then the event with the highest severity will be counted.  Similarly for 
tabulations by relationship to study drug, a patient will be counted once in the category with 
strongest relationship to study drug.   
Separate listings will be provided for pre-treatment AEs, all TEAEs (including onset day relative 
to first and last study drug intake), all TEAEs with fatal outcome, all serious TEAEs, and all 
TEAEs leading to premature study discontinuation.   
In addition a specific listing for “infusion site TEAEs” will be created, including details for 
location of AC chemotherapy and IV NEPA FDC/placebo infusion.  
7.11.3 
Clinical Laboratory Evaluations 
As mentioned in Section 6.4.2, each abnormal laboratory value, relative to local normal 
laboratory range, will be assessed as clinically significant (CS) or not clinically significant 
(NCS) by the investigator. 
Proportion of laboratory values low (low CS, low NCS), normal, and high (high NCS, high CS) 
will be presented by frequency table for each time point and treatment group. 
In addition, shift tables (low, normal, high) will be presented by treatment group and cycle 
comparing Visit 3 (Day 6) value to Baseline and, for Cycle 2 onwards, comparing Visit 1 
(Screening) also to the Baseline assessment.  Shift tables comparing Visit 3 (Day 6) value to 
Visit 1 (Screening) within cycle will also be produced. 
For patients who have a clinically significant abnormal laboratory value, a listing will display 
individual assessments for that analyte across all visits. 
Page 28 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 
7.11.4 
Vital Signs and Weight 
Vital signs (pulse rate, systolic, and diastolic blood pressure) and weight based measures will be 
summarized by treatment group and time point using descriptive statistics for absolute values 
and change from Baseline.  In addition for Cycle 2 vital signs onwards, change from pre-dose 
assessment of each cycle will be summarized.   
8 
REPORTING CONVENTIONS 
All analyses will be performed using Version 9.4 or later of SAS software.  All summary 
tables and data listings will be prepared utilizing SAS software.  All SAS programs used in the 
production of statistical summary outputs will be validated with independent programming prior 
to finalization.  In addition, all program outputs will be independently reviewed.  The validation 
process will be used to confirm that all data manipulations and calculations were accurately 
done.  Once validation is complete, a senior statistical reviewer will perform a final review of the 
documents to ensure the accuracy and consistency with this plan and consistency within tables.  
Upon completion of validation and quality review procedures, all documentation will be 
collected and filed by the project statistician or designee. 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, the 
mean and median will be presented to one extra decimal place compared to the raw data, and the 
standard deviation will be displayed to two extra decimal places compared to the raw data. 
Unless otherwise specified, frequency tabulations will be presented by number and percentage, 
where the percentage is presented in parentheses to one decimal place.  Frequency and 
percentage values of 0 will be presented as ‘0’ without ‘0.0%’. 
All summary tables will indicate the analysis population sample size (i.e., number of patients).  
All listings will be sorted by treatment group, patient number, assessment dates, and/or time 
point. 
Page 29 of 121
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
9 
REFERENCES 
1. Grunberg SM. Overview of chemotherapy-induced nausea and vomiting.  Clin Adv 
Hematol Oncol.  2013 Feb;11(2 Suppl 1):1-18. 
2. Hesketh PJ. Chemotherapy-induced nausea and vomiting.  N Engl J Med. 
2008 Jun 5;358(23):2482-2494. 
3. Rojas C, Raje M, Tsukamoto T, Slusher BS. Molecular mechanisms of 5-HT3 and NK1 
receptor antagonists in prevention of emesis.  Eur J Pharmacol.  2014 Jan 5;722:26-37. 
4. Palonosetron Investigator’s Drug Brochure, Revised Edition: April 2017. 
5. Palonosetron (Aloxi®) EU SPC, 2010; Palonosetron (Aloxi®) FDA Prescribing 
Information, 2014. 
6. Investigator’s Brochure. Oral Netupitant and Palonosetron Fixed-dose Combination, 
Revised Edition: December 2017. 
7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Antiemesis 
Version 2, 2017, http://www.nccn.org/.  28 MAR 2017. 
8. Investigator’s Brochure IV FOSNETUPITANT/PALONOSETRON Infusion; 
Edition May 2017. 
9. Study Report PNET-12-23.  A Phase I, double-blind, controlled, parallel groups, unbalanced 
single ascending dose study to assess the safety of intravenously administered fosnetupitant 
combined with crossover study extensions to estimate the dose of intravenous fosnetupitant 
yielding equivalent drug exposure as oral netupitant 300 mg/palonosetron 0.5 mg fixed-dose 
combination in healthy male and female volunteers.  April 2015. 
10.  Netupitant/palonosetron (Akynzeo®) FDA Prescribing Information, 2018. 
11. Martin AR, Pearson JD, Cai B, et al. Assessing the impact of chemotherapy induced nausea 
and vomiting on patients’ daily lives: a modified version of the Functional Living Index – 
Emesis (FLIE) with 5-day recall. Support Care Cancer 2003; 11: 522-527. 
12. Common Terminology Criteria for Adverse Events (CTCAE) (Terminology Criteria for 
Adverse Events (CTCAE, Version 4.0, published: May 28, 2009 [v4.03: June 14, 2010]). 
13. Leal, AD. Fosaprepitant-induced Phlebitis: A Focus on Patients receiving Doxorubicin/ 
Cyclophosphamide Therapy. Support Care Cancer 2014 May 25; 22(5): 1313-1317.  
14. Tsuda T, et al. Infusion site adverse events in breast cancer receiving highly emetic 
chemotherapy with prophylactic anti-emetic treatment with aprepitant and fosaprepitant: 
A retrospective comparison. Molecular and Clinical Oncology 4; 603-606, 2016. 
 
Page 30 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
 
Helsinn Healthcare SA 
Confidential 
APPENDIX A: 
FLOW CHART 
Study Phase 
Study Cycle  
(Cycle 1 / Repeated Cycles) 
Procedure/assessment 
Screening 
Day -14 to 1 (Cycle 1 only) /  
Day -7 to 1 (Cycles 2-4) a 
Day 1 
Day 6 
(+ 2 days) b 
On Day 15  
(+ 3 days) OR 
Day 22 (± 3 days) c 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 (Follow-up) 
Informed consent 
X d 
 
 
 
Inclusion / exclusion criteria e 
X 
X 
 
 
Demography 
X d 
 
 
 
Alcohol, tobacco and illicit drugs 
consumption 
X 
 
 
 
Reproductive status 
X 
 
 
 
Medical history (including 
current cancer history, and 
surgery) 
X d 
 
 
 
ECOG performance status 
X 
 
 
 
Urine pregnancy test f 
X  
X  
 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
Physical examination g 
X  
 
X  
 
Vital signs h 
X 
X 
X 
 
Height and weight i 
 
X 
 
 
Blood chemistry j 
X 
 
X 
 
Hematology j 
X 
 
X 
 
Pt. no assignment by IWRS 
X d 
 
 
 
Randomization 
 
X d 
 
 
Study drug assignment through 
IWRS 
 
X 
 
 
Study drugs administration 
 
X 
 
 
Dexamethasone administration k 
 
X 
 
 
AC chemotherapy 
 
X 
 
 
Patient Diary l 
 
X 
X 
 
FLIE questionnaire m 
 
X 
X 
 
WPAI questionnaire for HEOR n 
 
X 
X 
 
ED/Hospitalization information 
for HEOR o  
 
 
 
X 
Chemotherapy information for 
HEOR p   
 
X 
 
 
Adverse events q 
X 
X 
X 
X 
Page 31 of 121 
Confidential


PROTOCOL NEPA-17-05 
Statistical Analysis Plan, Final Version 1.0, 12 Dec 2018 
Helsinn Healthcare SA 
Confidential 
a) Screening activities for Cycle 1 may be performed or completed between Day -14 and Day 1, included. In repeated cycles
(i.e., cycles no. 2, 3 or 4), the Visit 1 may be performed from Day -7 up to study Day 1 inclusive. For all cycles, Visit 1 
and Visit 2 may occur on the same day (on study Day 1). In that case, the assessments planned at both Visit 1 and Visit 2 
have to be performed only once. 
b) Visit 3 (Day 6 [+ 2 days]) is to be scheduled on Day 6, not earlier than 120 hours after start of AC chemotherapy
administration on Day 1. If Day 6 is a holiday or a weekend day, or in case Visit 3 cannot be performed on Day 6 after the 
end of the 120 hours period for any reason, Visit 3 may be scheduled within the two forthcoming days. 
c) Visit 4, follow-up visit, either as on-site visit or telephone contact, is to be performed either on Day 15 (+ 3 days) or on
Day 22 (± 3 days) depending on the next chemotherapy cycle schedule. The patient’s follow-up visit or contact is to be 
performed prior to administering the chemotherapy relevant to the next cycle and prior to any further moderately or highly 
emetogenic chemotherapeutic treatment administration to the patient. Visit 4 of a previous cycle, as well as Visit 1 and 
Visit 2 of the next cycle, can all coincide and be performed on the same day. 
d) Only at Cycle 1.
e) Some inclusion / exclusion criteria are to be verified at Screening visit (Visit 1) and confirmed at the Day 1 visit (Visit 2); if
Visit 1 and Visit 2 are performed on the same day (Day 1), a unique assessment of these criteria is sufficient; please refer 
to inclusion / exclusion criteria section of the protocol for details. 
f)
To be performed for females of childbearing potential within 24 hours prior to the IMP administration at each cycle (oral
netupitant/palonosetron combination or placebo capsule) on Day 1. If the screening visit urine pregnancy test has been done
within the 24 hours before the IMP administration, no urine pregnancy test is to be performed at Visit 2 (Day 1).
g) Complete PE (general appearance, head, eyes, ears, nose, throat, skin, neck, lungs, cardiovascular, breast, lymph nodes,
abdomen, musculoskeletal and neurological) to be performed at Visit 1 and Visit 3 of each cycle. At Visit 3 and at 
subsequent cycles, only the general question “Was PE performed?” will be asked on the eCRF. Any new or worsening of 
pathological findings noted since previous examination should be reported on the Adverse Event eCRF form. 
h) Vital signs assessments include: pulse rate, systolic and diastolic blood pressure at Visit 1 (screening), Visit 2 (on Day 1 at
pre-dose, i.e., within 30 minutes before the oral netupitant/palonosetron combination or placebo capsule administration) and
Visit 3 of each cycle. Pulse rate and systolic and diastolic blood pressure has to be measured after the patient has been in
semi-supine position for at least 5 minutes.
i) Height has to be measured only at Visit 2 (Day 1) of Cycle 1. Weight has to be measured at Visit 2 (Day 1) of each cycle,
and should occur prior to the start of the AC chemotherapy administration. 
j) Local laboratories will be used for hematology and blood chemistry analysis throughout the study.
k) Patients will receive 12 mg dexamethasone on Day 1 of each cycle. Dexamethasone is to be administered 30 minutes prior
to the start of the AC chemotherapy administration (immediately before IV NEPA FDC or placebo infusion). 
l) The patient’s diary, referring to the 0-120 hour period, will be distributed to the patients at the Day 1 Visit of each cycle.
Patients will be asked to report date and time of onset of emetic episodes (episodes of retching or vomiting), date and time 
of intake of rescue medication, name of the rescue medication taken, and daily nausea intensity assessed by VAS on their 
diary. The patient’s completed diary will be retrieved and checked by the Investigator or designated responsible person 
during study Visit 3 of each cycle.  
m) FLIE questionnaire, referring to the 0-120 hour period, will be distributed to the patients at the Day 1 Visit, with
explanations on how to perform the requested assessments; the patient’s completed FLIE will be retrieved and checked by 
the Investigator or designated responsible person during study Visit 3. FLIE questionnaire will only be administered during 
Cycle 1 and Cycle 2. 
n) The WPAI questionnaire, referring to the 0-120 hour period, will be distributed to the patient at the Day 1 Visit, with
explanations on how to complete the questionnaire; the patient’s completed WPAI will be retrieved and checked by the 
Investigator or designated responsible during study Visit 3. WPAI questionnaire will only be administered during Cycle 
1 and Cycle 2. 
o) Hospitalization information (including ED, IP and LOS, and initiation dates thereof), referring to the interval from Visit 2
(Day 1) through Visit 4 of each cycle, will be recorded. 
p) Starting at Cycle 2 Visit 2 (Day 1), the Investigator will document if changes in chemotherapy administration from the
previous cycle occurred and will note any delays in treatment for the current cycle. 
q) Adverse events will be collected from Informed consent until end of the study (completion/discontinuation), as a minimum.
If the patient exits the study less than 15 days after last study drug administration, the patient should be followed-up for AE 
recording up to 15 days after last study drug administration. All non-resolved AEs (including SAEs) beyond this date will 
be documented on the eCRF as “ongoing”. For SAE follow-up requirements, see Protocol Section 8.1.3.1. 
Page 32 of 121
Confidential