Clinical trial NCT03204279
Conditions: Chemotherapy-induced Nausea and Vomiting (CINV)
Sponsor: Helsinn Healthcare SA
Start date: 2017-08-31; Completion date: 2019-09-30
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is Phase 2 pharmacokinetic (PK) and pharmacodynamic (PD) dose-finding study of oral netupitant administered concomitantly with oral palonosetron in pediatric cancer patients for the prevention of nausea and vomiting associated with emetogenic chemotherapy. Two different netupitant dosages will be tested in patients aged from 3 months to \< 18 years: 1.33 mg/kg up to a maximum of 100 mg, and 4 mg/kg up to a maximum of 300 mg. All netupitant doses in all age classes will be concomitantly administered with palonosetron 20 μg/kg (up to a maximum dose of 1.5 mg) which is the IV palonosetron dose approved by USA FDA for the pediatric population. The primary objective is to investigate the PK/PD relationship between netupitant exposure (AUC, Cmax) and antiemetic efficacy (CR in delayed phase) after a single oral netupitant administration, concomitantly with oral palonosetron in pediatric cancer patients receiving Moderately Emetogenic Chemotherapy (MEC) or Highly Emetogenic Chemotherapy (HEC) cycles. Efficacy parameter to be used in the correlation is the proportion of patients with Complete Response (CR i.e., no emetic episodes and no rescue medication) during (\> 24-120 h after the start of chemotherapy on Day 1).

The secondary objectives are to assess the safety and tolerability after single oral administration of netupitant given concomitantly with a single oral administration of palonosetron; to evaluate the pharmacokinetic (AUC, Cmax, tmax and t1/2) of oral palonosetron at the fixed dose of 20 μg/kg in pediatric patients with the concomitant administration of netupitant. A total of 92 pediatric cancer patients receiving either HEC or MEC will be enrolled in the study.

Detailed description:

Arms: arm 1: Single oral dose of Netupitant 1.33 mg/kg up to a maximum of 100 mg (for patients \< 3 months of age the netupitant dose will be 0.8 mg/kg) administered with single oral dose of 20 μg/kg palonosetron up to a maximum of 1.5 mg. arm 2: Single oral dose of Netupitant 4 mg/kg up to a maximum of 300 mg (for patients \< 3 months of age the netupitant dose will be 2.4 mg/kg) administered with single oral dose 20 μg/kg palonosetron up to a maximum of 1.5 mg.
Interventions: intervention 1: Netupitant intervention 2: Palonosetron intervention 3: Netupitant intervention 4: Palonosetron
Intervention descriptions: intervention 1: Netupitant 1.33 mg/kg oral suspension up to a maximum of 100 mg intervention 2: Palonosetron 20 μg/kg solution for oral use up to a maximum of 1.5 mg intervention 3: Netupitant 4 mg/kg oral suspension up to a maximum of 300 mg intervention 4: Palonosetron 20 μg/kg solution for oral use up to a maximum of 1.5 mg

Protocol documents:
Prot_SAP_001.pdf: 
NEPA-15-31 
Final (v. 5.0)/11 Feb 2019 
Clinical Study Protocol
Page 1 of 98
CONFIDENTIAL
Study Title
A 
multicenter, 
multinational, 
randomized, 
double-blind, 
pharmacokinetic 
and 
pharmacodynamic (PK/PD) dose-finding study of oral netupitant administered 
concomitantly with oral palonosetron in pediatric cancer patients for the prevention of 
nausea and vomiting associated with emetogenic chemotherapy.
Study Number
NEPA-15-31
Protocol Version
Final (v. 5.0)
Protocol Date
11 Feb 2019
Sponsor
Helsinn Healthcare SA
Via Pian Scairolo 9,
6912 Lugano/Pazzallo, Switzerland
IND Number:
73,493
CRO
PSI CRO AG 
Baarerstrasse 113a, 
6300 Zug, Switzerland
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 ICH Guideline for 
Good Clinical Practice.
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Document History
With respect to final protocol version 3.0, dated 07 Feb 2017, the following changes were 
introduced in version 4.0:
Inclusion criterion #4 was updated to add imaging for initial diagnosis of nephrobastoma 
since European standard of care for nephroblastoma consists of adjuvant chemotherapy 
followed by nephrectomy and histology reports could be received several weeks later, 
after the patient completes the study.
Inclusion criteria were updated to include specific thresholds for laboratory parameters 
(ALT, AST, bilirubin, eGFR) as recommended by DSMB. Schwartz equation was 
provided as a recommended tool to calculate eGFR.
Exclusion criteria were updated to include specific thresholds for QTc parameters, as 
well as other safety precautions related to patients’ concomitant conditions and laboratory 
abnormalities, as recommended by DSMB.
Clarifications related to the assessment of patients’ eligibility based on local laboratory 
parameters/automated interpretation of cardiac parameters by ECG machine were added 
to the corresponding eligibility criteria sections and throughout the protocol as applicable.
Time window for palonosetron administration (interval after netupitant administration) 
was added.
Administrative changes in the names of service provider companies and their 
representatives were made.
A misprint in footnote #3 of the Flow Chart on page 27 was corrected.
The definitions of emetic episode and regurgitation were added.
Clarification on criteria for evaluating chemotherapy schedule (single day vs. multiple 
days) was added.
Information on emetogenicity of intravenous temozolomide was provided in Appendix 2 
following POGO Guideline.
With respect to final protocol version 4.0, dated 06 Nov 2017, the following changes 
have been introduced in version 5.0:
Following a specific recommendation from FDA (US FDA Deferral Extension letter 
dated 15 Jan 2019), for purposes of facilitating enrollment in the study, enrollment of the 
age cohorts 3 < 6 months and 1 < 3 months and birth < 1 month is allowed in parallel 
(instead of sequentially), keeping the original treatment dose escalation scheme (i.e., first 
lowest doses are to be given in parallel in all remaining age cohorts, then highest doses 
are to be given in parallel in all the remaining age cohorts). This approach was also 
endorsed by DSMB members.
In Section 4.10.3 Other Prior and Concomitant Medications, an additional clarification 
was provided concerning the use of any drugs or substances known to be inhibitors of 
CYP3A4 and CYP2D6 enzymes (including any of the narrow therapeutic range CYP3A4 
substrates), which are to be avoided within 1 week prior to Day 1 or during the overall 
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CONFIDENTIAL
study period (until Visit 5 inclusive). It has also been clarified that the intake of drugs or 
substances known to be inducers of CYP3A4 enzymes within 4 weeks prior to the dosing 
day or use of such medications during the overall study period (until Visit 5 inclusive) is 
not permitted.
Consistent with the regulatory recommendations set forth in document entitled “Ethical 
considerations for clinical trials on medicinal products conducted with minors, developed 
by the European Commission expert group on clinical trials”, the volume of blood 
collected for the purposes of the clinical study in small children with body weight less 
than 5.4 kg should be limited. Therefore, Section 6.1 Pharmacokinetics Assessments was 
updated as follows: for small children less than 5.4 kg the volume of PK samples was 
adjusted from 2 mL to 1 mL and the total blood volume collected per patient has to be 
approximately 3.0 mL. Moreover, each plasma sample has to be immediately divided into 
2 aliquots in the pre-labeled polypropylene tubes: 1 aliquot ≥130 µL for the analysis of 
netupitant and its metabolites (M1, M2 and M3), and 1 aliquot of ≥250 µL for the 
analysis of palonosetron – no back-up samples are to be obtained.
In Section 11. References, the references 14 and 17 of the Investigator’s Brochures for 
Palonosetron and Oral NEPA FDC respectively were updated to be with the latest 
versions.
Finally, in General information some information was corrected (e.g., phone numbers, a 
new Sponsor’s Medical Expert for the study) or updated (changed company the name of 
bioanalytical lab was changed). 
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Page 213 of 323
NEPA-15-31 
Final (v. 5.0)/ 11 Feb 2019 
Clinical Study Protocol ::HBLSINN 
Signature Page, Helsion Healthcare SA 
(Date) 
Study Coordinator: 
~iA dO ~{9:) 
(Signature) 
(Date) 
Maria Elisa Borroni, MSc PharrnD 
Clinical Operations Manager, Clinical Research & Development 
Statistician: 
. ,.., ( 
..... CG\~.u.L_Wl~ /o..
.__u. __ ?tf© 
____ ~ 
............. ----
-M -n::.-B - 2o19 
(Signature) 
(Date) 
Corinna Lanzarotti, MSc 
Statistics and Data Management Manager, Clinical Research & Development 
Clinical Pharmacologist: 
S?f:b0M .®)~J 
./1~ - FF[:) - 00/j 
(Signature) 
Alberto Bernareggi, MSc PharmD 
Director, Clinical Research & Development 
(Date) 
Drug Safety Specialist: 
-°1'-~-c/\-~ 
..... 
< O\~R,__o_s_~-- A:1 --~~ 2-o ~3 
(Signature) 
(Date) 
Giorgia Rossi, MD 
Drug Safety Physician, Drug Safety 
Medical Writer: 
L A~N"'~ 
(Signature) 
(Date) 
Lara Ambrosetti, MSc 
Medical Writing Manager, Clinical Research & Development 
Page 4 of98 
CONFIDENTIAL 


Page 214 of 323
NEPA-1 5-3 1 
Final (v. 5.0)/1 1 Feh 2019 
Signature Page, PSI CRO AG 
ProjectW== 
(Signature) 
Anastasia Eremceva, MSc 
Project Manager 
Projzz~ 
(Signature) 
Alexander Malitsky. MSc 
" 
Senior Group Leader Biostatistics 
Clinical Study Protocol 
(Date) 
l/.02 . 2ol3 
(Date) 
Page 5 of98 
CONFIDENTIAL 


Page 215 of 323
NEPA-15-31 
.. 
Final (v. 5.0)/11 Feb 2019 
Clinical Study Protocol 
•• ELSI 'N 
Signature Page, Certara Strategic Consulting 
Executive Director: 
M ~-======= 
(Signature) 
Henri Merdjan, PharmD 
Executive Director 
13- (EB- £9 t 1 
(Date) 
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Signature Page, Principal Investigator 
Study Title
A 
multicenter, 
multinational, 
randomized, 
double-blind, 
pharmacokinetic 
and 
pharmacodynamic (PK/PD) dose-finding study of oral netupitant administered 
concomitantly with oral palonosetron in pediatric cancer patients for the prevention of 
nausea and vomiting associated with emetogenic chemotherapy.
Study Number
NEPA-15-31
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 and CRO concerning this trial 
will be kept in the strictest confidence.
________________________________________ __________________
(Signature)
(Date)
Printed Name: 
Institution:
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TABLE OF CONTENTS
General Information....................................................................................................11
Study Synopsis.............................................................................................................14
Flow Chart...................................................................................................................27
LIST OF ABBREVIATIONS......................................................................................29
1
Introduction and Rationale ..................................................................................33
1.1
Background Information.................................................................................33
1.2
Pre-clinical and Clinical Data of Palonosetron ...............................................35
1.2.1
Pre-clinical Data.........................................................................................35
1.2.2
Summary of Phase 1 Clinical Data (Human pharmacokinetics)..............35
1.2.3
Clinical Data...............................................................................................38
1.3
Pre-clinical and Clinical Data of Netupitant...................................................40
1.3.1
Pre-clinical data..........................................................................................40
1.3.2
Summary of Phase 1 Clinical Data (Human pharmacokinetics) of 
Netupitant...................................................................................................40
1.3.3
Clinical Data...............................................................................................41
1.4
Study Rationale................................................................................................42
2
STUDY OBJECTIVES.........................................................................................44
2.1
Primary.............................................................................................................44
2.2
Secondary .........................................................................................................44
3
STUDY PLAN.......................................................................................................45
3.1
Study Design.....................................................................................................45
3.2
Study Duration.................................................................................................46
3.3
Study Population..............................................................................................46
3.3.1
Number of Patients.....................................................................................47
3.3.2
Inclusion Criteria .......................................................................................47
3.3.3
Exclusion Criteria ......................................................................................48
4
STUDY DRUG MANAGEMENT........................................................................51
4.1
Description of Investigational Medicinal Products.........................................51
4.2
Treatment Groups............................................................................................52
4.3
Dose and Administration .................................................................................52
4.4
Packaging and Shipment .................................................................................53
4.5
Storage..............................................................................................................54
4.6
Drug Depots......................................................................................................54
4.7
Accountability ..................................................................................................54
4.8
Randomization, Blinding and Assignment of Study Drug..............................54
4.8.1
Emergency Unblinding Procedure ............................................................55
4.9
Over-dosage......................................................................................................56
4.10
Prior and Concomitant Medications...............................................................56
4.10.1
Prior and Concomitant Treatments for the Prevention of Nausea 
and Vomiting or with Potential Antiemetic Effect....................................56
4.10.2
Prior and Concomitant Cancer Chemotherapy and Radiotherapy .........58
4.10.3
Other Prior and Concomitant Medications...............................................58
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4.11
Rescue Medication ...........................................................................................58
5
STUDY CONDUCT..............................................................................................60
5.1
General Instructions ........................................................................................60
5.2
Study Procedures by Time Point.....................................................................60
5.2.1
Visit 1 (screening, Day -14 to -1 or Day -7 to -1 for patients aged < 
2 years)........................................................................................................60
5.2.2
Visit 2 (Day 1).............................................................................................61
5.2.3
Visit 3 (Day 2, 3, 4 and/or 5 depending on the PK sampling times) .........62
5.2.4
Visit 4 (final visit, Day 6, 7 or 8 depending on PK sampling times) .........62
5.2.5
Visit 5 (follow up visit, Day 14 [+3]) ..........................................................63
5.3
Definition of Completion..................................................................................63
5.4
Premature Discontinuation..............................................................................63
6
METHODS OF ASSESSMENT...........................................................................65
6.1
Pharmacokinetic Assessments .........................................................................65
6.1.1
PK Sampling and Sample Handling..........................................................66
6.1.2
Analytical Procedures ................................................................................66
6.2
Efficacy Assessments........................................................................................67
6.2.1
Primary Endpoint ......................................................................................67
6.2.2
Secondary Endpoints .................................................................................67
6.3
Safety Assessments...........................................................................................69
6.3.1
Physical Examination.................................................................................69
6.3.2
Vital Signs...................................................................................................69
6.3.3
12-lead ECG ...............................................................................................69
6.3.4
Clinical Laboratory Tests ..........................................................................70
7
ADVERSE EVENTS ............................................................................................71
7.1
Method of Assessment......................................................................................71
7.1.1
Definition of Adverse Events......................................................................71
7.1.2
Classification of Adverse Events................................................................72
7.1.3
Reporting of Adverse Events .....................................................................74
7.1.4
Reporting of Serious Adverse Events ........................................................74
7.1.5
Pregnancy Report.......................................................................................75
8
STATISTICS ........................................................................................................76
8.1
Sample Size Determination..............................................................................76
8.2
Definition of Study Populations for Analysis..................................................77
8.3
Statistical Analysis ...........................................................................................78
8.3.1
Missing Data...............................................................................................78
8.3.2
Covariates, Interactions and Subgroups ...................................................78
8.3.3
Analysis of Demographics and Baseline Variables ...................................78
8.3.4
Pharmacokinetic Analysis..........................................................................79
8.3.5
Efficacy Analyses........................................................................................79
8.3.6
Pharmacokinetic/Pharmacodynamic Analysis..........................................80
8.3.7
Safety Analyses...........................................................................................80
8.4
Interim Analysis...............................................................................................80
9
DATA SAFETY MONITORING BOARD..........................................................81
10
ETHICAL AND REGULATORY CONSIDERATIONS ...................................82
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10.1
Ethical Considerations.....................................................................................82
10.1.1
Laws and Regulations ................................................................................82
10.1.2
Patient’s Information Sheet, Informed Consent Form and Assent 
Form ...........................................................................................................82
10.1.3
Protocol Amendments................................................................................83
10.1.4
Protocol Deviations ....................................................................................83
10.1.5
Data Collection ...........................................................................................83
10.1.6
Monitoring and Quality Assurance ...........................................................84
10.1.7
Study Documentation and Records Retention ..........................................85
10.1.8
Confidentiality............................................................................................85
10.1.9
Publication Policy.......................................................................................85
10.1.10
Insurance ....................................................................................................86
11
REFERENCES .....................................................................................................87
12
APPENDICES ......................................................................................................91
Appendix 1:
Treatment Scheme..........................................................................92
Appendix 2:
POGO Guideline for Classification of the Acute 
Emetogenic Potential of Antineoplastic Medication in Pediatric 
Cancer Patients [35]*.......................................................................................93
Appendix 3:
Eastern Cooperative Oncology Group Performance Status   
(ECOG PS).......................................................................................................96
Appendix 4:
CYP3A4 and CYP2D6 Inhibitors, Inducers and Substrates.........97
Appendix 5:
Schwartz equation for determining estimated glomerular 
filtration rate (eGFR).......................................................................................98
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GENERAL INFORMATION
Sponsor
Helsinn Healthcare SA
Via Pian Scairolo 9
6912 Lugano/Pazzallo, Switzerland
Phone: +41 91 985 21 21
Fax: +41 91 985 21 22
CRO 
PSI CRO AG 
Baarerstrasse 113a, 
6300 Zug, Switzerland 
Phone: +41 (41) 228 1000
Fax: +41 (41) 228 1099
24h-Contact 
for 
Serious 
Adverse Events (SAEs)
Toll-free 24 hours CRO Contact for Safety Issues: 
SafetyDesk@psi-cro.com 
Country–specific toll-free fax lines will be provided in a 
separate document filed in the onsite site file.
Sponsor Drug Safety Officer
Giorgia Rossi, MD
Phone: +41 91 985 19 35
Fax: +41 91 985 21 22
E-mail: Giorgia.Rossi@helsinn.com
(copies to drug-safety@helsinn.com)
Sponsor Medical Expert
Ruben Giorgino, MD, PhD, MBA
Phone: +41 91 985 21 61
Fax: +41 91 985 21 22
E-mail: Ruben.Giorgino@helsinn.com  
Study Coordinator
Helsinn:
Maria Elisa Borroni, MSc PharmD
Phone: +41 91 985 19 16
Fax: +41 91 985 21 22
E-mail: MariaElisa.Borroni@helsinn.com
PSI CRO AG:
Anastasia Eremeeva, MSc
Phone: +7812 320 38 55
Fax: +7812 320 38 50
E-mail: Anastasia.Eremeeva@psi-cro.com
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Statistics 
Helsinn:
Corinna Lanzarotti, MSc
Phone: +41 91 985 19 84
Fax: +41 91 985 21 22
E-mail: corinna.lanzarotti@helsinn.com
PSI CRO AG: 
Alexander Malitsky, MSc
Phone: +7812 320 38 55
Fax: +7812 320 38 50
E-mail: Alexander.Malitsky@psi-cro.com
Data Management
Helsinn:
Riccardo Bezzo, MSc
Phone: +41 91 985 19 83
Fax: +41 91 985 21 22
E-mail: Riccardo.Bezzo@helsinn.com
PSI CRO AG:
Ekaterina Osipova, MD, PhD
Phone: +7812 320 38 55
Fax: +7812 320 38 50
E-mail: Ekaterina.Osipova@psi-cro.com
Clinical Pharmacology 
Alberto Bernareggi, MSc PharmD
Phone: +41 91 985 19 34
Fax: +41 91 985 21 22
E-mail: Alberto.Bernareggi@helsinn.com
Quality Assurance
Helsinn:
Franco Faiella, MD
Phone: +41 91 985 21 64
Fax: +41 91 985 21 22
E-mail: Franco.Faiella@helsinn.com
PSI CRO AG:
Olga Golubeva MD, PhD, MRQA
Phone: +7812 320 38 55
Fax: +7812 320 38 50
E-mail: Olga.Golubeva@psi-cro.com
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Central Laboratory
ACM Global Central Laboratory (ACM)
23 Hospital Fields Road ,York, UK YO10 4DZ
160 Elmgrove Park Rochester, New York 14624
Central ECG Reading
ERT
1818 Market St., Suite 1000 Philadelphia, PA
EDC and IWRS System 
Provider
Medidata Solution Inc.
Metro Bldg, 1 Butterwick, Hammersmith, 
United Kingdom W6 8DL
Clinical Study Supplies
Packaging and Labeling
CSM Europe SA (previously B&C Group)
Watson & Crick Hill
Rue Granbonpré 11, B-1435 Mont-Saint-Guibert, Belgium
Bioanalytical Lab for PK 
Assessment
Ardena Biochemical Laboratory B.V. (ABL)
W.A. Scholtenstraat 7
9403 AJ Assen, The Netherlands
Population 
PK/PD 
Data 
Analysis 
CERTARA
37-39 avenue Ledru Rollin
75012 Paris
Henri Merdjan, PharmD
Executive Director
Direct Phone: +33 1 56 95 17 09
Mobile: +33 (0)6 25 67 74 19
Fax : +33 1 56 95 16 16
E-mail: henri.merdjan@certara.com
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CONFIDENTIAL
STUDY SYNOPSIS
Study Title
A 
multicenter, 
multinational, 
randomized, 
double-blind, 
pharmacokinetic and pharmacodynamic (PK/PD) dose-finding 
study of oral netupitant administered concomitantly with oral 
palonosetron in pediatric cancer patients for the prevention of 
nausea and vomiting associated with emetogenic chemotherapy.
Study Number
NEPA-15-31
Sponsor
Helsinn 
Healthcare 
SA, 
Via 
Pian 
Scairolo 
9, 
6912 Lugano/Pazzallo, Switzerland
Countries and Sites
A minimum of approximately 16 sites in USA, Russia, Ukraine and 
Serbia; more sites and/or countries may be added if necessary. 
Clinical Phase
Phase 2
Indication
Chemotherapy-induced nausea and vomiting (CINV)
Study Design
This is a multicenter, multinational, randomized, double-blind, 
stratified (by age class; by emetogenicity; by chemotherapy 
schedule), dose-finding study involving two treatment groups 
receiving 
a 
single 
oral 
dose 
of 
netupitant 
administered 
concomitantly with a single oral dose of 20 µg/kg oral palonosetron 
(up to a maximum of 1.5 mg).
Netupitant dose treatment groups: 
Treatment group 1: 1.33 mg/kg up to a maximum of 100 mg. For 
patients aged < 3 months, the netupitant dose will be 0.8 mg/kg.
Treatment group 2: 4 mg/kg up to a maximum of 300 mg. For 
patients aged < 3 months, the netupitant dose will be 2.4 mg/kg.
Pediatric population will be split in the following age classes:
Birth to < 1 month
1 month to < 3 months
3 months to < 6 months
6 months to < 12 months
1 year to < 2 years
2 years to < 5 years
5 years to < 12 years
12 years to < 18 years.
At the beginning of the study, enrolment is open only to:
patients aged 1 year, who will be randomized to one of the two 
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CONFIDENTIAL
netupitant doses 
patients aged 6 months to < 12 months who will be treated with 
the netupitant lower dose (1.33 mg/kg).
At the beginning of the study three patients aged 6 to < 12 months
will be first enrolled in the lower netupitant dose group (1.33 
mg/kg). As soon as these first 3 patients have completed the study, 
without safety and tolerability concerns as assessed by Data Safety 
Monitoring Board (DSMB), enrolment in the higher netupitant dose 
group (4 mg/kg) of the same age class (6 to < 12 months) can start. 
As soon as 6 patients in the age class 6 to < 12 months (3 patients 
for each netupitant dose group) have completed the study without 
safety and tolerability concerns, decision by DSMB will have to be 
taken whether a) all remaining patients 6 to <12 months can be 
randomized to one of the two netupitant treatment doses and start 
the assigned treatment, and b) the lower age class 3 to < 6 months
may start the treatment with the lower dose. 
The enrollment of the remaining cohorts will occur in parallel 
keeping the original treatment dose escalation scheme: 3 patients 
will be first treated with the lower netupitant dose. As soon as these 
first 3 patients will have completed the study and no safety and 
tolerability concerns are shown, as assessed by the DSMB, 
enrolment in the higher dose group in the same age class will start.
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Study Objectives 
Primary Objective: 
To investigate the PK/PD correlation between netupitant exposure 
and antiemetic efficacy after a single oral netupitant administration, 
concomitantly with oral palonosetron in pediatric cancer patients 
receiving moderately emetogenic chemotherapy (MEC) or highly 
emetogenic chemotherapy (HEC) treatments. Efficacy parameter to 
be used in the correlation is the proportion of patients with complete 
response (CR, i.e., no emetic episodes and no rescue medication) 
during the delayed phase (> 24-120 h after the start of 
chemotherapy on Day 1).
Secondary Objectives: 
To assess the safety and tolerability after single oral administration 
of netupitant given concomitantly with a single oral administration 
of palonosetron.
To evaluate the PK profile of oral palonosetron at the fixed dose of 
20 µg/kg in pediatric patients with the concomitant administration 
of netupitant.
Treatment Groups
A total of 92 pediatric cancer patients will be enrolled to one of the 
two treatment groups (46 patients in each treatment group): 
Treatment group 1 – patients ≥ 3 months of age will receive a 
single oral netupitant dose of 1.33 mg/kg (up to a maximum of 
100 mg for patients weighting 75 kg or more) concomitantly 
with a single oral palonosetron dose of 20 µg/kg (up to a 
maximum of 1.5 mg for patients weighting 75 kg or more). For 
patients < 3 months of age the netupitant dose will be 0.8 mg/kg.
Treatment group 2 – patients ≥ 3 months of age will receive a 
single oral netupitant dose of 4 mg/kg (up to a maximum of 
300 mg for patients weighting 75 kg or more) concomitantly 
with a single oral palonosetron dose of 20 µg/kg (up to a 
maximum of 1.5 mg for patients weighting 75 kg or more). For 
patients < 3 months of age the netupitant dose will be 2.4 mg/kg.
Dosage and 
Administration
In order to allow the administration of the study drug according to 
the two netupitant treatment doses, three Investigational Medicinal 
Products (IMPs) will be used in the study:
IMP 1: Oral liquid formulation of netupitant (100 mg/7 mL) suitable 
for use in all pediatric age classes. Netupitant will be administered 
based on the body weight as a single oral dose 1 h (± 10 minutes)
prior to start of emetogenic chemotherapy (HEC or MEC) on Day 1. 
IMP 2: Oral liquid formulation of netupitant (300 mg/7 mL) suitable 
for use in all pediatric age classes. Netupitant will be administered 
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based on the body weight as a single oral dose 1 h (± 10 minutes) 
prior to start of emetogenic chemotherapy (HEC or MEC) on Day 1. 
IMP 3: Palonosetron will be administered orally using the 
0.75 mg/5 mL solution for IV use. Palonosetron will be 
administered based on the body weight, immediately (within 5 
minutes) after netupitant, i.e., 1 h (± 10 minutes) prior to start of 
emetogenic chemotherapy (HEC or MEC) on Day 1. 
Target Study 
Population
Male and female pediatric cancer patients from birth up to < 18 
years, scheduled to receive HEC or MEC to be administered as 
single day chemotherapy on Day 1 only or for multiple days.
Number of Patients A total of 92 pediatric patients will be enrolled to one of the two 
treatment groups (i.e., 46 in each treatment group). 
For each age class included in the stratification, the relevant planned 
number of patients to be enrolled is provided below.
-
Birth to < 1 month: 12 patients
-
1 to < 3 months: 12 patients
-
3 to < 6 months: 8 patients
-
6 to < 12 months: 8 patients
-
1 to < 2 years: 8 patients
-
2 to < 5 years: 12 patients
-
5 to < 12 years: 16 patients
-
12 to < 18 years: 16 patients
Stratification
The study is stratified by:
-
Age class:
•
Birth to < 1 month 
•
1 to < 3 months 
•
3 to < 6 months 
•
6 to < 12 months 
•
1 to < 2 years
•
2 to < 5 years 
•
5 to < 12 years 
•
12 to < 18 years 
-
Emetogenicity: 
•
HEC
•
MEC
-
Chemotherapy schedule: 
•
HEC/MEC on Day 1 only
•
HEC/MEC on multiple days
Note that the Emetogenicity and Chemotherapy schedule strata do 
not apply for patients < 1 year of age (i.e., all age classes < 12 
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months).
Chemotherapy 
Regimens
Any chemotherapy regimen of moderate or high emetogenicity to 
be administered as single day chemotherapy on Day 1 only or on 
multiple days can be used in this study. For consistency of 
interpretation, “multiple days” schedule would include regimens 
with additional HEC/MEC given between Day 1 and Day 6 (within 
120 hours from the start of first HEC/MEC administration on Day 
1). Any low emetogenic chemotherapy (LEC) agent or minimally 
emetogenic 
chemotherapy 
agent 
given, 
as 
part 
of 
the 
aforementioned chemotherapy regimens using HEC or MEC, is 
allowed at any time.
Rescue Medication
Rescue medication is defined as any medication taken to alleviate 
nausea or vomiting (i.e., with indication nausea or vomiting) during 
the period from start of HEC or MEC to 120 h later.
The choice of rescue medication will be at the discretion of the 
Investigator. Use of palonosetron or netupitant other than study 
drugs administration is not permitted. Use of metoclopramide is not 
allowed. 
Inclusion Criteria
The following inclusion criteria must be checked prior to inclusion:
1.
Signed written informed consent by parent(s)/legal guardians of 
the pediatric patient in compliance with the local laws and 
regulations. In addition signed children’s assent form according 
to local requirements.
2.
Male or female in- or out-patient from birth to < 18 years at the 
time of randomization.
3.
Patient weight at least 3.3 kg.
4.
Naïve or non-naïve patient with histologically, and/or 
cytologically (or imaging in the case of brain tumors or 
nephroblastoma) confirmed malignant disease.
5.
Scheduled and eligible to receive at least one moderately or 
highly emetogenic chemotherapeutic agent on Day 1 only or for 
multiple days.
6.
For patient aged ≥ 10 years: Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) ≤ 2.
7.
Adequate hepatic function defined as serum ALT and AST ≤ 
2.5 ULN, and total bilirubin ≤ 1.5 ULN.
8.
Adequate renal function defined as estimated glomerular 
filtration rate (eGFR) ≥ 70 ml/min/1.73m2 (≥50 ml/min/1.73m2
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for children < 3 months old). The eGFR should be calculated 
using the modified Schwartz equation.
9.
For patient with known history or predisposition to cardiac 
abnormalities: 
in 
the 
Investigator’s 
opinion 
the 
history/predisposition should not jeopardize patient’s safety 
during the study.
10. If the patient is female, she shall: a) not have attained menarche 
yet or b) have attained menarche and have a negative pregnancy 
test at the screening visit and at Day 1. 
11. Male or female fertile patient using reliable contraceptive 
measures (such measures, for patient and sexual partner, 
include: implants, injectables, combined oral contraceptives, 
intrauterine devices, vasectomized/sterilized partner, use of a 
double-barrier method or sexual abstinence). The patient and 
his/her parent(s)/legal guardians must be counseled on the 
importance of avoiding pregnancy before or during the study.
All inclusion criteria will be checked at screening visit (Visit 1). 
Inclusion criteria #3, 5, 10 will be re-checked at Day 1 (Visit 2).
Local laboratory results from an appropriately certified local 
laboratory could be used at the discretion of Investigator to evaluate 
patients’ eligibility.
Exclusion Criteria
The following exclusion criteria must be checked prior to inclusion:
1.
The patient and/or parents/caregivers are expected by the 
Investigator to be non-compliant with the study procedures. 
2.
Patient has received or is scheduled to receive total body 
irradiation, total nodal irradiation, upper abdomen radiotherapy, 
half or upper body irradiation, radiotherapy of the cranium, 
craniospinal regions, head and neck, lower thorax region or the 
pelvis within 1 week prior to study entry (Day 1) or within 
120 h after start of chemotherapy administration on Day 1. 
3.
Known history of allergy to any component or other 
contraindications to any NK1 or 5-HT3 receptor antagonists.
4.
Active infection.
5. Any illness or condition that, in the opinion of the Investigator, 
may pose unwarranted risks in administering the investigational 
product to the patient.
6.
Patient suffering from ongoing vomiting from any organic 
etiology (including patients with history of gastric outlet 
obstruction or intestinal obstruction due to adhesions or 
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volvulus, patients with a symptomatic CNS tumor causing 
nausea and/or vomiting) or patient with hydrocephalus. 
7. Patient who experienced any vomiting, retching, or nausea 
within 24 h prior to the administration of the study drug (note: 
functional vomiting for infants, which is normally seen during 
the first 3 months of life, is not to be considered as vomiting).
8.
Patient who received any drug with potential anti-emetic effect 
within 24 h prior to the start of reference chemotherapy, 
including but not limited to:
-
NK1- receptor antagonists (e.g., aprepitant or any other new 
drug of this class); 
-
5-HT3 receptor antagonists (e.g., ondansetron, granisetron, 
dolasetron, tropisetron, ramosetron);
-
Benzamides (e.g., metoclopramide, alizapride);
-
Phenothiazines 
(e.g., 
prochlorperazine, 
promethazine, 
perphenazine, 
fluphenazine, 
chlorpromazine, 
theithylperazine);
-
Benzodiazepines initiated 48 h prior to study drug 
administration or expected to be received within 120 h 
following initiation of chemotherapy, except for single doses 
of midazolam, temazepam or triazolam;
- Butyrophenones (e.g., droperidol, haloperidol);
-
Anticholinergics (e.g., scopolamine, with the exception of 
inhaled anticholinergics for respiratory disorders e.g., 
ipratropium bromide); 
-
Antihistamines 
(e.g., 
diphenhydramine, 
cyclizine, 
hydroxyzine, 
chlorphenhyramine, 
dimenhydrinate, 
meclizine);
-
Domperidone; 
-
Mirtazapine; 
-
Olanzapine; 
-
Prescribed 
cannabinoides 
(e.g., 
tetrahydrocannabinol, 
nabilone);
- Over the Counter (OTC) antiemetics, OTC cold or OTC 
allergy medications;
- Herbal preparations containing ephedra or ginger.
9.
Patient who received palonosetron within 1 week prior to 
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administration of study drug. 
10. Patient who has been started on systemic corticosteroid therapy 
within 72 h prior to study drug administration or is planned to 
receive a corticosteroid as part of the chemotherapy regimen.
Exceptions:
-
Patient who is receiving chronic (> 72 h), daily steroid 
therapy can be enrolled provided the steroid dose is not 
> 0.14 mg/kg (up to 10 mg) of prednisone daily or 
equivalent.
-
For supportive care, patient is permitted to receive a single
dose of corticosteroid within the 72 h prior to study drug 
administration (but not < 12 h prior to study drug 
administration) provided it is less than the equivalent of 
20 mg of prednisone.
11. Patient aged < 6 years who received any investigational drug 
(defined as a medication with no marketing authorization 
granted for any age class and any indication) within 90 days 
prior to Day 1, or patient aged 6 years who received any 
investigational drug within 30 days prior to Day 1 or is 
expected to receive investigational drugs prior to study 
completion.
12. Intake of alcohol, food or beverages (e.g., grapefruit, cranberry,
pomegranate and aloe vera juices, German chamomile) known 
to interfere with either CYP3A4 or CYP2D6 metabolic 
enzymes within 1 week prior to Day 1 and during the overall 
study period.
13. Use of any drugs or substances known to be strong or moderate 
inhibitors of CYP3A4 and CYP2D6 enzymes within 1 week 
prior to Day 1 or planned to be used during the overall study 
period.
14. Use of any drugs or substances known to be CYP3A4 
substrates with narrow therapeutic range within 1 week prior to 
Day 1, or planned to be used during the overall study period.
15. Use of any drugs or substances known to be inducers of 
CYP3A4 enzymes within 4 weeks prior to Day 1 or planned to 
be used during the overall study period.
16. Lactating female patient. 
17. Patient with clinically relevant Grade 3 or 4 non-hematological 
abnormal laboratory values.
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20. Enrolment in a previous study with netupitant (either alone or in 
combination with palonosetron).
21. Marked baseline prolongation of QTc interval [QTcB or QTcF > 
460 msec] at screening.
NOTE: Exclusion criteria ## 18 and 19 were skipped intentionally 
to maintain consistency in exclusion criteria numbering between 
protocol amendments.
All exclusion criteria will be checked at screening visit (Visit 1). 
Exclusion criteria #2, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 21 will be 
re-checked at Day 1 (Visit 2). In case of ERT central ECG report 
pending, the assessment of compliance with exclusion criterion #21 
could be made based on automatic interpretation of QTcB and 
QTcF results by ECG machine at the discretion of Investigator.
All eligible patients must be approved for randomization by 
authorized Medical Monitor.
Study Duration
The planned duration of the study for each pediatric patient is a 
maximum of 31 days, which includes screening up to 14 days 
before randomization (up to 7 days for patients aged < 2 years), day 
of enrolment/randomization, administration of study drugs and 
chemotherapy (Study Day 1), and the PK visit (Study Days 2 to 5). 
The final visit will be 6 to 8 days after study drug administration, 
and a follow up visit/telephone contact will be performed between 
14 and 17 days after study drug administration. 
Study Endpoints
Primary Endpoint:
PK/PD relationship between netupitant exposure (AUC, Cmax) and 
antiemetic efficacy in the delayed phase after a single oral 
netupitant administration, concomitantly with oral palonosetron, in 
pediatric cancer patients receiving HEC or MEC treatments. 
Efficacy parameter to be used in the correlation is the proportion of 
patients with complete response (CR, i.e., no emetic episodes and 
no rescue medication) during the delayed phase (> 24-120 h after 
the start of chemotherapy on Day 1). 
Secondary Endpoints:
-
Pharmacokinetic (PK) endpoints: 
•
AUC, Cmax, tmax and t1/2 of netupitant, netupitant metabolites 
M1, M2, M3, and palonosetron.
-
Pharmacodynamic (PD) endpoints: 
•
proportion of patients with complete response (CR, i.e., no 
emetic episodes and no rescue medication) during the delayed 
(> 24-120 h), acute (0-24 h) and overall phases (0-120 h) after 
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start of chemotherapy administration on Day 1.
•
proportion of patients with no emetic episodes during the 
delayed (>24-120 h), acute (0-24 h) and overall phases (0-120 
h) after start of chemotherapy administration on Day 1.
•
proportion of patients with no rescue medication during the 
delayed (>24-120 h), acute (0-24 h) and overall phases 
(0-120 h) after start of chemotherapy administration on 
Day 1. 
Assessment of the 
Pharmacokinetic 
Profile
The PK profiles of netupitant, its active metabolites M1, M2, M3, 
and palonosetron will be evaluated in pediatric cancer patients 
according to a sparse sampling schedule and a population PK 
approach. 
A single blood sample will be collected from each patient in each of 
the following time windows:

Pediatric patients ≥ 5 years: from 2 to 8 h, from 24 to 48 h, 
from 72 to 96 h, and from 120 to 168 h after netupitant 
administration.

Pediatric patients < 5 years: from 2 to 8 h, from 24 to 48 h, 
and from 120 to 168 h after netupitant administration.
The nominal number of plasma samples collected from all patients 
after each of the two treatments will be 154. The expected total 
number of plasma samples collected after the two treatments will be 
308. 
The volume of each blood sample will be 2.0 mL. For patient with 
body weight < 5.4 kg, the volume of each blood sample will be 1.0 
mL.
Data modelling will be based on a previous population PK study in 
adults receiving oral NEPA (study NETU-10-02). 
If the same structural models apply to the pediatric population, the 
typical values (TV) of the following structural model parameters 
will be assessed for netupitant and palonosetron: 
-
Ka: absorption rate constant for netupitant or formation rate 
constant for netupitant metabolites
-
tlag: lag time
-
Vi/F: apparent volume of compartment i, i.e., central and 
peripheral compartment(s), for extravascular administration
-
CL/F: 
apparent 
systemic 
clearance 
for 
extravascular 
administration
-
Q/F: inter-compartmental clearance
F is the absolute oral bioavailability for the parent compounds 
netupitant and palonosetron. 
Different structural models could also be explored for netupitant, its 
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metabolites, and palonosetron according to the findings of the 
present PK/PD study in pediatric patients after oral administration 
of netupitant and palonosetron. The final model parameters will 
reflect the model structure and include possible continuous or 
categorical covariates that significantly correlate with PK 
parameters and explain inter-subject variability. 
Individual model-predicted PK parameter values will be estimated 
from the final population pharmacokinetic models, based on mean 
population parameter values (typical values, TVs) and on the 
individual random effect (ηi). From final model parameters, 
individual plasma concentration-time profiles will be simulated and 
secondary PK parameters such as Cmax, tmax, AUC and t1/2 estimated 
by non-compartmental methods.
Efficacy 
Assessments
Efficacy assessments will be collected through a paper diary, which 
will be used to record emetic episodes and use of rescue medication. 
Patients, parent’s guardians or caregivers should complete the 
diaries.
Safety 
Assessments
Safety assessments will consist of physical examination (PE) and 
clinical laboratory tests (serum chemistry, hematology, urinalysis): 
these assessments will be performed at screening and at final visit. 
Moreover, vital signs measurements (pulse rate, systolic and
diastolic blood pressure) and 12-lead ECGs (single recordings) will 
be obtained at screening, on Day 1 at 4-6 h after study drug 
administration, and at final visit. 
Adverse events (AEs) will be monitored throughout the study.
During the conduct of the study, a Data Safety Monitoring Board 
(DSMB) will review safety data, as foreseen by the study design 
and at periodical intervals.
PK/PD Correlation
PK/PD relationships between predicted individual exposure metrics 
(Cmax and AUC) of netupitant at different dose levels versus 
efficacy (CR delayed) will be investigated via graphical exploratory 
analyses. In addition, a logistic regression analysis will be used to 
link the exposure metrics to categorical response (CR delayed). The 
dose-exposure relationship and the PK/PD correlation (exposure-
response relationship) for netupitant in pediatric cancer patients will 
support the dose selection for a subsequent Phase 3 study. 
Pharmacokinetic 
Analyses
Exploratory analyses will be applied to evaluate in the pediatric 
population the PK characteristics of netupitant (and its metabolites) 
and palonosetron after concomitant administration. The initial 
population PK models (base models) will be developed by 
comparing structural models and random error models based on 
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parameters such as the objective function values, the log-likelihood 
values, the Akaike’s and the Bayesian’s Information Criteria (AIC 
and BIC), the residual errors, the random distribution in conditional 
weighted residual plots, the graphical correlation between the 
observed versus predicted concentration values.
The final population PK models will include possible additional 
fixed effects represented by relevant covariates that will prove to 
correlate with one or more population PK parameters and contribute 
to significantly explain and minimize the inter-subject variability. 
The final model will be qualified via a visual predictive check.
Inter-subject / inter-occasion variability (level 1 random-effect) and 
observation-level random error (level 2 random effect) will also be 
modeled.
Individual model-predicted PK parameter values will be estimated 
from the final population pharmacokinetic models, based on mean 
population parameter values (typical values, TVs) and on the 
individual random effect (ηi). From final model parameters, 
individual plasma concentration-time profiles will be simulated and 
secondary PK parameters such as Cmax, tmax, AUC and t1/2 estimated 
by non-compartmental methods.
Mean and coefficient of variation (CV) of the pharmacokinetic 
parameters will be calculated from the individual predictions.
The effect of continuous and categorical covariates on the PK 
parameter variability will be evaluated by step-wise forward 
addition and backward elimination procedures. Continuous 
covariates will include at least age, BW, albumin, total bilirubin, 
creatinine,
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP). Categorical 
covariates will include at least gender, HEC/MEC, chemotherapy 
schedule, rescue medication (yes/no), concomitant medications.
Data from previous population PK study NETU-10-02 in adult 
cancer patients receiving oral NEPA FDC administration (300mg 
netupitant/0.5mg palonosetron) will be used as prior information 
and included in the analysis. 
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Efficacy Analysis
All results will be interpreted in a descriptive manner, since the 
study is not powered to compare the treatment groups for the 
efficacy assessments.
For each phase (delayed, acute, and overall), numbers and 
percentages (including 95% CI) of patients with complete response, 
with no emetic episodes and no rescue medication will be 
summarized by treatment. The difference in response rate between 
the two groups and relevant 95% CI will be provided as well.
Efficacy analysis will be presented for the overall population and by 
strata.
Safety Analysis
All AEs will be listed by SOC, described and summarized by 
frequency tables. Summaries will be made by treatment arm with 
respect to the percentage of patients having at least one occurrence 
of that event during the study and the total number of events.
For safety analysis, the laboratory data will be analyzed and 
described as follows: listings (including flag for values outside the 
normal range), count (number and percentage) of value below, 
within and above normal range, descriptive statistics for change 
from baseline values. Shift tables with respect to normal range 
(Low/Normal/High) will be presented. ECG data will be 
summarized highlighting differences from baseline for quantitative 
variables and frequencies of treatment emergent abnormalities. Vital 
signs will be summarized using descriptive statistics for observed 
values and change from baseline, in addition to being listed. 
Safety analysis will be presented for the overall safety population 
and by strata.
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FLOW CHART
Visit
V1
V2
V3
V4
V514
Timepoint (Day)
-14 to -1;
-7 to -1 
for < 2 years
1
2, 3, 4 
and/or 5
6, 7 or 8
14 [+3]
Assessments
Screening
Randomization
/ Treatment
PK Visit
Final Visit
Follow up
Informed Consent/Assent
X
Inclusion/Exclusion Criteria
X
X10
Demography, medical and surgical 
history (including current cancer 
history, naivety to chemotherapy)
X
History of nausea and vomiting in 
previous chemotherapy1
X
ECOG status2
X
Hematology, Serum chemistry, 
Urinalysis3
X
X
Pregnancy test (urine)4
X
X
Physical examination
X
X
Vital signs
X
X11, 12
X11
Height/Length
X
Weight
X
X
12-lead ECG5
X
X12, 13
X13
Randomization / Treatment 
assignment
X
Study drugs administration6
X
Record efficacy parameters
Recording up to 120h
Patient Diary
Instruction
Filled in up to 120h
Collection of Patient Diary7
X
Prior and concomitant medication 
recording
X
X
X
X
X
Adverse event monitoring8
X
X
X
X
X
PK sampling9
X
X
X
1
Only if applicable (for non-naïve patients).
2
ECOG status will be assessed for patients aged ≥ 10 years.
3
Whole blood, serum and urine samples will be sent to a central laboratory. Urine sample will be obtained only if the 
patient is capable of providing a urine sample. At the final visit (Visit 4) only, serum sample will also be used for 
pregnancy test.
4
For female patients having reached menarche only. If screening is performed on Day -1, it is not necessary to repeat the 
test on Day 1.
5
12-lead ECG (single recording) will be evaluated in a central reading facility.
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6
Study drugs will be administered as follows: 
-
Netupitant will be administered based on the body weight as a single oral dose 1 h (± 10 minutes) prior to the start 
of emetogenic (HEC or MEC) chemotherapy on Day 1.
-
Oral palonosetron will be administered based on weight immediately (within 5 minutes) after netupitant, i.e., 1 h 
(± 10 minutes) prior to start of emetogenic (HEC or MEC) chemotherapy on Day 1.
-
Any LEC or minimally emetogenic agent given, as part of the aforementioned chemotherapy regimens using HEC 
or MEC, is allowed at any time during the study and does not have any impact on the time of study drugs 
administration.
7
The patient will be instructed to bring the diary back to the site at each visit so that the Investigator is able to ensure it 
has been completed in a timely and appropriate manner.
8
Starting at the screening visit, immediately after informed consent/assent, up to the follow up visit/telephone contact.
9
A single blood sample will be collected from each patient in each of the following time windows: 
-
Pediatric patients ≥ 5 years: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h, and from 120 to 168 h after netupitant 
administration. 
-
Pediatric patients < 5 years: from 2 to 8 h, from 24 to 48 h, and from 120 to 168 h after netupitant administration.
10
On Day 1, inclusion criteria #3, 5, 10 and Exclusion criteria #2, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 21 should be re-
checked prior to randomization/enrollment (local laboratory results from an appropriately certified local laboratory 
could be used at the discretion of Investigator to evaluate patients’ eligibility; in case of ERT central ECG report 
pending, the assessment of compliance with exclusion criterion #21 could be made based on automatic interpretation of 
QTcB and QTcF results by ECG machine at the discretion of Investigator).
11
Vital signs to be measured before PK sampling or at least 30 minutes after PK sampling.
12
Vital signs and 12-lead ECGs (single recording) will be obtained at 4-6 h after study drugs administration.
13
12-lead ECGs (single recording) to be obtained before PK sampling or at least 30 minutes after PK sampling.
14
Follow up Visit / Telephone Contact (14 [+3] days after drug administration).
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LIST OF ABBREVIATIONS
5-HT3
5-hydroxytryptamine
ADE
Age-dependent exponent
ADL
Activities of Daily Living
ADME
Absorption, distribution, metabolism, excretion
AE
Adverse Event
AIC
Akaike’s Information Criteria
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
API
Active Pharmaceutical Ingredients
AST
Aspartate aminotransferase
AUC
Area Under the Plasma Concentration-Time Curve
BIC
Bayesian’s Information Criteria
BW
Body weight
CDC
Centers for Disease Control and Prevention 
CI
Confidence Interval
CL
Systemic (or total) Clearance
CK
Creatine kinase
CL/F
Apparent systemic clearance for extravascular administration
CLR
Renal clearance
CINV
Chemotherapy-Induced Nausea and Vomiting
Cmax
Maximum Plasma Concentration
CR
Complete response
CRO
Contract Research Organization
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
CV
Coefficient of variation
DCF
Data Clarification Form
DSMB
Data Safety Monitoring Board
EC
Ethics Committee
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ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEA
eGFR
ESMO
European Economic Area
Estimated Glomerular Filtration Rate
European Society for Medical Oncology
EU
European Union
F
Oral Bioavailability
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDC
Fixed-dose combination
GCP
Good Clinical Practice
h
Hour
HEC
Highly Emetogenic Chemotherapy
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IV
Intravenous
IWRS
Interactive Web Response System
Ka
Absorption Rate Constant
K2-EDTA
Di-potassium Ethylenediaminetetraacetic acid
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LEC
Low Emetogenic Chemotherapy
LLOQ
Lower limits of quantification
MASCC 
Multinational Association of Supportive Care in Cancer
M1,2,3
Metabolites 1,2,3
MEC
Moderately Emetogenic Chemotherapy
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NEPA
Netupitant plus Palonosetron
NCCN
National Comprehensive Cancer Network
NK1
Neurokinin-1
NEPA FDC
Oral Netupitant plus Palonosetron Fixed Dose Combination
NETU
Netupitant
ηi
Individual random effect
OECD
Organisation for Economic Co-operation and Development
OTC
Over The Counter
PALO
Palonosetron
PD
Pharmacodynamic
PE
Physical Examination
PK
Pharmacokinetic
POGO
Pediatric Oncology Group of Ontario
PONV
Post-operative nausea and vomiting
Q/F
Inter-compartmental clearance
QTc
QT Interval Corrected
QTcB
QT Interval Corrected by Heart Rate Using the Bazett formula
QTcF
QT Interval Corrected by Heart Rate Using the Fridericia formula
RBC
Red Blood Cells
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDV
Source Data Verification
SE
Standard Error
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions 
TBD
To be defined
TEAE
Treatment-Emergent Adverse Event
tlag
Lag Time
tmax
Time to reach maximum (peak) plasma concentration following drug 
administration
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t1/2
Terminal half-life
TV
Typical values
ULN
US/USA
Upper limit of normal
United States/United States of America
Vd
Apparent Volume of Distribution
Vi/F
Apparent volume of compartment
i, 
i.e., central and peripheral 
compartment(s), for extravascular administration
WBC
White Blood Cells
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1
INTRODUCTION AND RATIONALE
1.1
Background Information
Chemotherapy-induced nausea and vomiting (CINV) is a common and distressing side-
effect of cancer chemotherapy regimens in adults, but is also a major problem in the 
treatment of childhood malignancies. [1, 2, 3] 
Adult patients in whom CINV is left uncontrolled, experience a severe deterioration in 
their quality of life and may experience malnourishment, anxiety, and depression. Fear of 
CINV is sufficient for many patients to postpone or even refuse potentially life-saving 
treatment. [3, 4, 5, 6] However, antiemetics can improve quality of life, increase 
treatment compliance and effectiveness, and therefore improve patient outcome. [7] 
Antiemetics counter CINV by antagonising the 5-hydroxytryptamine subtype 3 (5-HT3) 
receptor or the neurokinin-1 (NK1) receptor. Currently, in adult patients undergoing 
highly emetogenic chemotherapy, the administration of a 5-HT3 receptor antagonist 
alongside with a NK1 receptor antagonist, in association with dexamethasone, is 
recommended for the treatment of acute CINV. [8, 9] 
For patients undergoing a moderately emetogenic chemotherapy regimen, not including a 
combination of anthracycline plus cyclophosphamide, the 5-HT3 receptor antagonist 
palonosetron hydrochloride (Aloxi®) plus dexamethasone is recommended. [9]
In pediatric patients, Multinational Association of Supportive Care in Cancer (MASCC) 
and European Society for Medical Oncology (ESMO) guidelines recommend 
prophylactic antiemetic therapy comprising a 5-HT3
receptor antagonist and 
dexamethasone to prevent acute CINV in patients scheduled to receive HEC or MEC. For 
prevention of delayed CINV, no appropriate studies in children are so far available and 
therefore no formal recommendation is possible. According to MASCC/ESMO 
guidelines, however, many panelists suggest that children should be treated in a manner 
similar to that of adults receiving chemotherapy of this risk, and that doses should be 
adjusted appropriately for children. [2, 9] The Pediatric Oncology Group of Ontario 
(POGO) Guideline for the Prevention of Acute Nausea and Vomiting due to 
Antineoplastic Medication in Pediatric Cancer Patients recommend that children 
scheduled to receive highly emetogenic chemotherapy (HEC) should be administered 
with antiemetic prophylactic therapy of ondansetron or granisetron plus dexamethasone 
and aprepitant (≥ 12 years of age and receiving antineoplastic agents not known to 
interact with aprepitant) or ondansetron or granisetron plus dexamethasone (< 12 years of 
age or receiving aprepitant interacting agents). For patients scheduled to receive 
moderately emetogenic chemotherapy (MEC), the recommendation was that patients 
should receive ondansetron or granisetron plus dexamethasone. [10] 
The role of the NK1 receptor antagonists in children has to be further investigated. It has 
recently been suggested that the addition of the oral NK1 receptor antagonist aprepitant to 
ondansetron with or without dexamethasone may be effective in the prevention of CINV 
in pediatric patients aged 6 months to 17 years receiving MEC or HEC regimens. [11]
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In adults palonosetron hydrochloride administered by the intravenous (IV) and oral routes 
has a demonstrated efficacy for the management of nausea and vomiting associated with 
cancer chemotherapy. Its prolonged duration of action offers significant advantages over 
other 5-HT3
receptor antagonists. Pharmacological experiments indicate that 
palonosetron interacts with 5-HT3 receptors very differently than granisetron or 
ondansetron and that this differential interaction triggers a receptor alteration or 
internalization resulting in a long lived inhibition of receptor function. These 
pharmacological findings may have clinical relevance and contribute to explain the 
extended antiemetic protection conferred by palonosetron. [12]
In July 2003 the United States (US) Food and Drug Administration (FDA) approved 
palonosetron 0.25mg IV as a 30-second bolus for the prevention of acute CINV 
associated with HEC or MEC, and for prevention of delayed CINV associated with MEC 
(initial and repeat courses) in adults. In Europe, IV palonosetron was approved via the 
Centralized Procedure in March 2005. Palonosetron is registered in several countries with 
different trademarks (Aloxi®, Onicit®, Paloxi®). [13]
Safety and efficacy of palonosetron for the prevention of CINV in pediatric population 
has been so far evaluated in the following clinical studies.
The pediatric study PALO-99-07 [14] evaluated 3 and 10 µg/kg doses of IV palonosetron 
for preventing highly and moderately emetogenic CINV in the acute phase, in a limited 
number of pediatric patients (n=35, and n=37, respectively). In the pooled analysis which 
included randomized and open-label patients, the proportion of patients with a complete 
response (CR; no emesis and no rescue) during the first 24 h after chemotherapy was 
higher in the palonosetron 10 µg/kg group than in the 3 µg/kg group (54.1% vs. 37.1%). 
[14]
The efficacy of two different doses of palonosetron was also tested in pediatric patients 
undergoing single and repeated cycles of HEC or MEC (PALO-10-20). Overall, the 
efficacy of palonosetron 20 μg/kg was comparable to that of ondansetron, while the 
efficacy of palonosetron 10 μg/kg tended to be slightly lower than that of ondansetron. 
Safety assessments were consistent with the established safety profiles of palonosetron in 
adults and did not indicate a significant risk to pediatric patients receiving HEC or MEC 
for up to 4 consecutive cycles. [15]
Palonosetron as intravenous formulation at the dosage of 20 µg/kg (max 1.5 mg) infused 
over 15 minutes was approved in the US on May 27th, 2014 for pediatric use in patients 
aged from 1 month to less than 17 years for the prevention of acute nausea and vomiting 
associated with initial and repeated courses of emetogenic cancer chemotherapy, 
including HEC. Similarly, palonosetron intravenous formulation with indication of CINV 
prevention was extended on February 24th, 2015 in European Economic Area (EEA) to 
pediatric patients 1 month of age and older.
Helsinn developed an oral fixed-dose combination (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-gelatine capsule (oral NEPA FDC) to be administered to 
adults patients as a single administration 1 h prior to chemotherapy. 
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Netupitant is a new, high-efficient, selective 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). [16]
The oral NEPA FDC has been approved in 2014 in the US for the prevention of acute and 
delayed nausea and vomiting in adult patients associated with initial and repeated courses 
of chemotherapy, including but not limited to, HEC, and in the EU for the prevention of 
acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based 
cancer chemotherapy and moderately emetogenic cancer chemotherapy. [16]
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 in adults. [17]
An IV FDC of palonosetron and fosnetupitant is meanwhile under clinical development.
The present study will be a Phase 2 pharmacokinetic/pharmacodynamic (PK/PD) dose 
finding study of oral netupitant administered concomitantly with oral palonosetron in 
pediatric cancer patients for the prevention of nausea and vomiting associated with 
emetogenic chemotherapy. This will be part of the pediatric program of the oral NEPA 
FDC’s line extension, aiming at complying with the post-approval commitments after 
registration of oral NEPA FDC by FDA. 
1.2
Pre-clinical and Clinical Data of Palonosetron
1.2.1 Pre-clinical Data
For a detailed description of pre-clinical data on palonosetron, reference is made to the 
relevant Investigator’s Brochure (IB). [13]
1.2.2 Summary of Phase 1 Clinical Data (Human pharmacokinetics)
Pharmacokinetic in adult subjects
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 
(t1/2) of approximately 40 h 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 
maximum plasma concentration (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 
adult subjects and in adult 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 h. [13]
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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 have 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. [13]
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 intravenous administration. [13]
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 h 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 53±29 mL/min. The low total body clearance and 
large volume of distribution result in a terminal elimination half-life of approximately 
40 h, which is substantially longer than that of other 5-HT3 antagonists, i.e., ondansetron 
(4-6 h), granisetron (5-8 h), tropisetron (7 h) and dolasetron (7 h). Ten percent of patients 
revealed a mean terminal elimination half-life greater than 100 h. 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 h and 
between 192 and 216 h post-dose in plasma and urine respectively, 85% to 93% of the 
total radioactivity was excreted in urine, and 5% to 8% was eliminated in feces. The 
amount of unchanged palonosetron excreted in the urine represented approximately 40% 
of the administered dose. In cancer patients, t½ was 48 ± 19 h. After a single-dose of 
approximately 0.75 mg intravenous palonosetron, the total body clearance of 
palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± SD) and renal clearance 
was 66.5 ± 18.2 mL/h/kg. Quantifiable concentrations of M9 metabolite were reported 
for all subjects until at least 24 h and between 120 and 144 h post-dose in plasma and 
urine respectively. [13]
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Pharmacokinetic in pediatric patients
In pediatric cancer patients (PALO-99-07, [14]), IV administration of 3 and 10 µg/kg 
palonosetron was characterized by a rapid distribution followed by a slower elimination 
phase. Exposure, as measured by Cmax, AUC0-t and AUC0-, was generally proportional or 
slightly less than dose-proportional for the 3 to 10 µ/kg dose levels, across all three 
evaluated age groups (> 28 days to 23 months, 2 to 11 years, and 12 to 17 years). 
Both clearance and volume of distribution appeared to increase with increasing age. 
These increases were largely due to body weight differences between the three age 
groups. There were no apparent differences in the distribution of individual patient values 
across the age groups and doses evaluated. Mean terminal elimination half-life values 
ranged from 21 to 37 h across the three age groups (individual values ranging from 
approximately 11 to 81 h) and did not change with dose or age. There was no effect of 
gender on clearance, volume of distribution or half-life.
In study PALO-10-20 [15], PK parameters of two different IV doses (10 and 20 µg/kg) of 
palonosetron were determined in pediatric patients undergoing single and repeated cycles 
of HEC or MEC. 
Samples for the PK sub-study were drawn from a total of 95 patients (15 in the < 2 years, 
26 in the 2 to < 6 years, 24 in the 6 to < 12 years and 30 in the 12 to < 17 years age 
group). Of these, 64 patients received palonosetron, while 31 received ondansetron.
After a 15 min infusion, palonosetron PK profiles appear widely comparable for all age 
groups and both dose levels, with a peak generally reported immediately at the end of 
infusion, followed by a rapid palonosetron concentration decrease and a much slower 
elimination phase, with a terminal elimination t½ of about 20 to 30 h. A significant 
difference in t½ (p<0.008) was observed between age groups with a trend toward longer 
t½ for older patients, although an underestimated determination of t½ in patients aged less 
than 2 years administered with the lowest dose (10 µg/kg) could have influenced the 
statistical result. Both clearance and volume of distribution appear to increase with 
increasing age. AUCs values were clearly related to the palonosetron 10 µg/kg and 
palonosetron 20 µg/kg dose levels. A trend toward increased AUC values (both absolute 
and nominal dose-adjusted) with age was observed, for which statistical significance was 
assessed by analysis of variance (ANOVA) for the nominal dose-normalized AUC0-∞
(p = 0.0027). No clinically relevant differences were however observed in any of the PK 
parameters reported between genders or types of chemotherapy. The analyses do not 
indicate that the PK of palonosetron are strictly dependent on patient age Therefore, no 
further adjustment of dosing, beyond dosing palonosetron on an individual patient weight 
basis, is required for pediatric patients.
In conclusion, a PK/PD analysis of the results indicated no clear relationship between 
drug exposure and response in pediatric patients in the tested IV dose range. None of the 
patient factors tested, including body weight, age, gender, chemotherapy regimen, or total 
dose administered, had an impact on the response variables (CR in the acute and the 
delayed phase).
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1.2.3 Clinical Data
Efficacy data in adult patients
In a Phase II study (Study 2330) following HEC, the four highest palonosetron IV doses 
(3, 10, 30 and 90 µg/kg) were approximately equally effective, with the percentage of 
patients with CR ranging from 40% to 50% in comparison to the lowest dose cohort 
(24%; 0.3 to 1 µg/kg). This efficacy profile suggests a plateau in dose response for 
palonosetron when administered at doses greater than 3 µg/kg (approximately a 0.25 mg 
fixed dose). Evaluation of the secondary efficacy variables confirmed the clinical efficacy 
of palonosetron treatment at all tested doses with respect to the lowest dose level. 
Palonosetron was well tolerated at all dose levels. Adverse events (AEs) were essentially 
equally distributed across the dose groups, and no dose-related safety relationship was 
apparent.
Three Phase III studies with IV palonosetron in both moderately and highly emetogenic 
patient populations (PALO-99-03, PALO-99-04 and PALO-99-05) evaluated doses of 
0.25 mg and 0.75 mg (corresponding to 3 µg/kg and 10 µg/kg). These studies 
demonstrated that the 0.25 mg dose was the lowest effective dose, with no significant 
difference in safety profile between the doses. In 2003, the 0.25 mg dose was approved 
for marketing in the US, followed later by registration in several countries worldwide. 
[13]
Efficacy data in pediatric patients
The study PALO-99-07 [14] evaluated 3 and 10 µg/kg doses of IV palonosetron for 
preventing highly and moderately emetogenic CINV in the acute phase in the following 
pediatric age groups: > 28 days to 23 months, 2 to 11 years, and 12 to 17 years of age. 
Recognizing the overall sample size was limited (n=35, and n=37, respectively), in the 
pooled analysis which included randomized and open-label patients, the proportion of 
patients with a CR (no emesis and no rescue) during the first 24 h after chemotherapy 
was higher in the palonosetron 10 µg/kg group than in the 3 µg/kg group (54.1% vs. 
37.1%). 
The study PALO-10-20 [15] was a multicenter, active-controlled, double-blind, 
randomized, parallel group, stratified, double-dummy, Phase 3 study involving 3 study 
groups receiving palonosetron in two different doses or ondansetron standard therapy for 
the prevention of CINV. The lower palonosetron dose was 10 µg/kg up to a maximum of 
0.75 mg, and the higher palonosetron dose was 20 µg/kg up to a maximum dose of 1.5 
mg. The ondansetron dose was 0.15 mg/kg given three times (every 4 h - maximum dose 
of 32 mg).
The primary objective of this study was to evaluate the efficacy of two different doses of 
IV palonosetron, compared to ondansetron, in the prevention of CINV in pediatric 
patients receiving HEC or MEC through 120 h after start of chemotherapy in single and 
repeated chemotherapy cycles. A total of 494 patients were treated with study drug 
(167 palonosetron 10 µg/kg, 163 palonosetron 20 µg/kg and 164 ondansetron). Patients 
were stratified per age group (< 2 years, 2 to < 6 years, 6 to < 12 years and 12 to 
<17 years) and by emetogenicity (MEC and HEC). 
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At Cycle 1, the CR in the acute phase of the first study cycle in the Full Analysis Set 
(FAS) population was reported for 54.2% of patients treated with palonosetron 10 µg/kg, 
59.4% of patients treated with palonosetron 20 µg/kg and 58.6% of patients treated with 
ondansetron. These results indicated an effect of palonosetron 10 µg/kg that was 
numerically lower, but comparable to that of ondansetron and an effect of palonosetron 
20 µg/kg that was numerically similar or comparable to that of ondansetron. Similar 
results were obtained in the As Treated and Per Protocol populations, with the latter 
showing a numerically higher effect of palonosetron 20 µg/kg compared to that of the 
other treatment groups. The study supported the conclusion that palonosetron is non-
inferior to ondansetron for the prevention of acute CINV. In patients receiving HEC, CR 
was the highest in the palonosetron 20 µg/kg group and the lowest in the palonosetron 
10 µg/kg in each age group, except in the 2 to < 6 years group where the highest response 
was shown by palonosetron 10 µg/kg. In the HEC strata, CR rate of palonosetron 
20 µg/kg was higher than ondansetron in each age group. In patients receiving MEC, 
opposite results were observed in the 2 to < 6 years age stratum. In contrast, the CR rate 
was higher in the ondansetron group than in either palonosetron groups in the 0 to < 2, 
6 to < 12 and 12 to < 17 years age strata. For patients receiving HEC, the CR rate in the 
delayed phase was notably higher in the palonosetron 20 µg/kg group, while for patients 
receiving MEC the CR rates were comparable across treatment groups.
In line with results observed at Cycle 1, throughout study Cycles 2 to 4, and across all 
phases, the palonosetron 20 µg/kg treatment group reported in the majority of the cases 
the highest CR rate, the highest proportions of patients with no vomiting, patients with no 
emetic episodes and patients with no use of antiemetic rescue medications. Likely due to 
the progressively lower number of patients, different response rates were reported across 
the cycles, and statistical significance could not be ascertained for these comparisons as 
indicated by overlapping 95% CIs.
Safety in adult patients
In adult patients, 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 marketed active comparators 
[13]. 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 post-operative nausea and vomiting 
(PONV).
The results of a thorough QT/QTc study (Study PALO-03-11) in adult healthy volunteers 
demonstrated that palonosetron is not associated with QT prolongation at doses up to 
2.25 mg, which provides a 9-fold safety margin for the approved market dose for CINV 
IV indication, 0.25 mg for adults. [13]
Safety in pediatric patients
As for the pediatric use of palonosetron, its safety has been investigated in two CINV 
studies (PALO-99-07, PALO-10-20) [14, 15], in children aged between 1 month and 
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17 years, receiving HEC or MEC, who were administered 3, 10 or 20 µg/kg, up to a 
maximum total fixed dose of 0.25, 0.75 mg or 1.5 mg, respectively.
The safety profile of palonosetron has been also assessed in two PONV studies (PALO-
07-29, PALO-10-14) [18, 19], in pediatric patients aged > 28 days up to 16 years 
inclusive, undergoing elective surgical procedures requiring general endotracheal 
inhalation anesthesia, who were administered 1 or 3 µg/kg, up to a maximum total fixed 
dose of 0.075 or 0.25 mg, respectively. 
In these studies, palonosetron was safe and well tolerated at all tested doses, no relevant 
clinical findings were observed, confirming its safety and efficacy in the prevention of 
CINV and PONV in pediatric population. [14, 15, 18, 19]
In study PALO-10-20, clinically relevant differences between treatments in the safety 
profile were not observed in the overall study population or in subgroups of patients 
based on age, gender, race, ethnicity or emetogenicity of chemotherapy. Safety 
assessments in this study were consistent with the established safety profiles of 
palonosetron and ondansetron in adults and did not indicate a significant risk to pediatric 
patients receiving HEC or MEC for up to 4 consecutive cycles.
Overall, palonosetron was safe and well tolerated at all dosages employed in clinical 
trials, and no remarkable differences were observed for any safety parameters in both 
adults and pediatric patients. [13]
For 
further 
information 
about 
palonosetron, 
including 
pharmacokinetics, 
pharmacodynamics, clinical efficacy and safety, please refer to the current edition of the 
IB. [13]
1.3
Pre-clinical and Clinical Data of Netupitant
1.3.1 Pre-clinical data 
1.3.1.1
Netupitant
A detailed description of the netupitant animal data is provided in the current IB for the 
oral NEPA FDC. [16]
1.3.2 Summary of Phase 1 Clinical Data (Human pharmacokinetics) of 
Netupitant
1.3.2.1
Absorption
In single dose oral studies conducted with the administration to healthy volunteers, 
measurable plasma netupitant concentrations were detected between 45 minutes and 3 h 
after dosing. Plasma concentrations followed a first order absorption process and reached 
Cmax in approximately 5 h. [16]
1.3.2.2
Distribution
The mean apparent 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 
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highly bound to plasma proteins (> 99%) with apparently no large differences in free 
fraction between healthy subjects and patients with hepatic failure. [16]
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 was not affected by co-
administration of the CYP3A4 substrates erythromycin (500 mg) or midazolam (7.5 mg). 
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. [16]
Four metabolites have been identified in human plasma at netupitant doses ≥ 30mg; 
metabolites M1, M2, and M3 are considered major metabolites. In a human radiolabeled 
absorption, distribution, metabolism, and excretion (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 h and was about 17-32 h 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. [16]
1.3.2.4
Elimination
The apparent mean elimination half-life of netupitant generally ranged from 30 to 
approximately 100 h (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. [16]
1.3.3 Clinical Data 
1.3.3.1
Netupitant Alone or in Combination with Palonosetron
The oral formulation of netupitant, as single agent or in combination with other 
compounds, including the 5-HT3 receptor antagonist palonosetron, has been investigated 
in 27 studies; 20 of them were conducted in healthy adult volunteers. A total of 
1,939 adult subjects and patients received netupitant in combination with palonosetron 
and 206 adult subjects and patients received oral netupitant alone.
Oral netupitant was generally well tolerated at all dose levels tested. In healthy 
volunteers, the most frequently reported treatment-emergent adverse events (TEAEs) 
related to netupitant alone (not in combination) were headache, fatigue, somnolence, 
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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. [16]
In the Phase 2 and Phase 3 studies, leading to oral NEPA FDC (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 
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 current IB of oral NEPA FDC. [16]
Pediatric studies have not been performed so far on the netupitant alone, or as a 
component in combination such as Akynzeo®.
1.4
Study Rationale
This study (NEPA-15-31) will be a Phase 2 PK/PD dose-finding study of oral netupitant 
administered concomitantly with oral palonosetron in pediatric cancer patients for the 
prevention of nausea and vomiting associated with emetogenic chemotherapy. This will 
be part of the pediatric program of the oral NEPA FDC’s line extension, aiming at 
complying with the post-approval commitments after registration of oral NEPA FDC 
(Akynzeo®) by US FDA. 
The selection of the netupitant doses to be used in this study is supported by efficacy and 
safety data in adults from Akynzeo® pivotal studies NETU-07-07 (HEC) [20] and 
NETU-08-18 (MEC) [21]. In those studies, the efficacy and safety of oral netupitant 
doses of 100, 200 and 300 mg (NETU-07-07 [20]) and 300 mg (NETU-08-18 [21] and 
NETU-10-29 [22]) in combination with oral palonosetron (0.5 mg) were assessed.
During the development of oral Akynzeo®, netupitant doses of 100, 200, 300 and 450 mg 
have been tested in the adult population (see studies NP16601, NP16603, NETU-06-27, 
NETU-06-07, NETU-07-01, NETU-10-29). All doses proved to be well tolerated and 
doses of 100 and 300 mg showed antiemetic efficacy in pivotal clinical trials in cancer 
patients undergoing emetogenic chemotherapy treatments. [16, 20, 21, 22] 
In this study (NEPA-15-31), the following two different netupitant dosages will be tested
in patients aged from 3 months to < 18 years: 1.33 mg/kg up to a maximum of 100 mg, 
and 4 mg/kg up to a maximum of 300 mg. Because netupitant elimination is mainly 
mediated by CYP3A4 metabolism, due to CYP3A4 ontogeny (where CYP3A4 capacity 
in 12 month olds is about 40% of adult levels), the youngest patient age classes 
(< 3 months of age) will be treated at lower doses: i.e., 0.8 mg/kg and 2.4 mg/kg. All 
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netupitant doses in all age classes will be concomitantly administered with palonosetron 
20 µg/kg (up to a maximum dose of 1.5 mg).
Study NEPA-15-31 is planned to be the first pediatric clinical trial involving netupitant, 
together with oral palonosetron. A single oral palonosetron dose of 20 µg/kg (up to a 
maximum dose of 1.5 mg) will be used in this study. This corresponds to the IV 
palonosetron dose approved by USA FDA for the pediatric population. The approval was 
based on efficacy and safety data from IV palonosetron study PALO-10-20 [15] in 
pediatric patients (HEC/MEC) aged 1 month to < 17 years. Since the absolute 
bioavailability of oral palonosetron is approximately 97% in adult subjects (as stated in 
IV Aloxi® labeling), similar safety and efficacy as demonstrated in PALO-10-20 [15] is 
expected in NEPA-15-31 from the 20 µg/kg palonosetron component given as an oral 
solution.
The role of corticosteroids in concomitance with 5-HT3 and NK1 receptor antagonists to 
prevent CINV is controversial and less well established in pediatric cancer patients when 
compared to adults, partially because they are commonly used in pediatric population as 
part of chemotherapy regimens. [2]
Overall, a number of common pediatric chemotherapy regimens include a corticosteroid, 
usually prednisone or dexamethasone, as an essential component of chemotherapy. [2]
Netupitant is expected to increase systemic exposure to dexamethasone and prednisone. 
[23]
Moreover, due to the interaction, pediatric oncologists may decide not to use netupitant in 
pediatric cancer patients receiving dexamethasone or prednisone as part of their 
chemotherapy. The same safety concerns are true for other clinical trials with any NK1
receptor antagonist given with steroids, and these were also reported in previous pediatric 
CINV trials with aprepitant. [11]
The Sponsor has concerns to safely enroll a “broader” population involving pediatric 
patients receiving systemic corticosteroids as part of their chemotherapy regimen, even 
though it is recognized that these safety considerations may reduce the pool of pediatric 
cancer patients available to enroll in NEPA-15-31. 
Therefore, any pediatric patients receiving systemic corticosteroid therapy started within 
72 h prior to study drug administration and/or scheduled to receive a corticosteroid as 
part of their chemotherapy regimen during the study should not be eligible for this study 
since there are too many risks and unknowns.
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2
STUDY OBJECTIVES
2.1
Primary
The primary objective is to investigate the PK/PD correlation between netupitant 
exposure and antiemetic efficacy after a single oral netupitant administration, 
concomitantly with oral palonosetron in pediatric cancer patients receiving MEC or HEC 
treatments. Efficacy parameter to be used in the correlation is the proportion of patients 
with CR (i.e., no emetic episodes and no rescue medication) during the delayed phase 
(> 24-120 h after the start of chemotherapy on Day 1).
2.2
Secondary
The secondary objectives are the following:
-
to assess the safety and tolerability after single oral administration of netupitant given 
concomitantly with a single oral administration of palonosetron;
-
to evaluate the PK profile of oral palonosetron at the fixed dose of 20 µg/kg in 
pediatric patients with the concomitant administration of netupitant.
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3
STUDY PLAN
3.1
Study Design
This is a multicenter, multinational, randomized, double-blind, stratified (by age class; by 
emetogenicity; by chemotherapy schedule), dose-finding, Phase 2 study involving two 
treatment groups receiving a single oral dose of netupitant administered concomitantly 
with oral palonosetron. 
The study is planned to be performed at a minimum of approximately 16 sites in USA, 
Russia, Ukraine and Serbia; more sites and/or countries may be added if necessary.
A total of 92 pediatric cancer patients receiving either HEC or MEC will be enrolled in 
the study. 
The patients will be enrolled into one of two netupitant dose treatment groups 
(46 patients/group): 
Treatment group 1: from 1.33 mg/kg up to a maximum of 100 mg (for patients 
< 3 months of age the netupitant dose will be 0.8 mg/kg)
Treatment group 2: from 4 mg/kg up to a maximum of 300 mg (for patients 
< 3 months of age the netupitant dose will be 2.4 mg/kg)
Each netupitant dose is administered with 20 µg/kg palonosetron (up to a maximum of 
1.5 mg).
The study will be stratified by the following criteria:
Age class:
•
Birth to < 1 month 
•
1 to < 3 months 
•
3 to < 6 months 
•
6 to < 12 months 
•
1 to < 2 years 
•
2 to < 5 years
•
5 to < 12 years 
•
12 to < 18 years 
Emetogenicity:
•
HEC
•
MEC
Chemotherapy schedule:
•
HEC/MEC on Day 1 only
•
HEC/MEC on multiple days 
Within each stratum, patients will be randomized prior to study drug administration to 
one of the two previously mentioned netupitant treatment groups. 
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An exception will be the younger age classes (all age classes < 12 months) for which the 
safety of the lowest netupitant dose(s) will be evaluated before escalating to the 
subsequent netupitant dose groups. For these age classes the Emetogenicity and 
Chemotherapy schedule strata will not be considered, even not when randomization will 
start in relevant class.
The treatment plan is described in detail here below and is summarized in Appendix 1.
At the beginning of the study enrolment is open only to:
-
patients aged 1 year, who will be randomized to one of the two netupitant doses 
-
patients aged 6 months to < 12 months who will be treated with the netupitant lower 
dose (1.33 mg/kg)
At the beginning of the study three patients aged 6 to < 12 months will be first enrolled 
in the lower netupitant dose group (1.33 mg/kg). As soon as these first 3 patients have 
completed the study, without safety and tolerability concerns as assessed by Data Safety 
Monitoring Board (DSMB), enrolment in the higher netupitant dose group (4 mg/kg) of 
the same age class (6 to < 12 months) can start. 
As soon as 6 patients in the age class 6 to < 12 months (3 patients for each netupitant 
dose group) have completed the study without safety and tolerability concerns, decision 
by DSMB will have to be taken whether a) all remaining patients 6 to <12 months can be 
randomized to one of the two netupitant treatment doses and start the assigned treatment, 
and b) the lower age class 3 to < 6 months may start the treatment with the lower dose. 
The enrollment of the remaining cohorts will occur in parallel keeping the original 
treatment dose escalation scheme: 3 patients will be first treated with the lower netupitant 
dose. As soon as these first 3 patients will have completed the study and no safety and 
tolerability concerns are shown, as assessed by the DSMB, enrolment in the higher dose 
group in the same age class will start [37].
3.2
Study Duration
The planned duration of the study is a maximum of 31 days for each patient, which 
includes screening up to 14 days before randomization (up to 7 days for patients aged 
< 2 years), day of enrolment/randomization, administration of study drugs and 
chemotherapy (Study Day 1), and the PK visit (Study Days 2 to 5). The final visit will be 
6, 7 or 8 days after study drug administration, and a follow up visit / telephone contact 
will be performed between 14 and 17 days after study drug administration. 
3.3
Study Population
Male and female pediatric cancer patients from birth up to < 18 years, scheduled to 
receive HEC or MEC to be administered as single day chemotherapy on Day 1 only or 
for multiple days.
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3.3.1 Number of Patients
The number of patients to be treated is estimated to be 92, distributed in two treatment 
groups (i.e., 46 patients/group). For each age class included in the stratification, the 
relevant planned number of patients to be enrolled is provided below. For the sample size 
calculation please refer to Section 8.1 Sample Size Determination.
Age classes
Number of patients 
to be included
Birth to < 1 month
12
1 to < 3 months
12
3 to < 6 months
8
6 to < 12 months
8
1 to < 2 years
8
2 to < 5 years
12
5 to < 12 years
16
12 to < 18 years
16
Overall
92
3.3.2 Inclusion Criteria
Patients must meet the following criteria to be eligible to participate in the study: 
1.
Signed written informed consent by parent(s)/legal guardians of the pediatric patient 
in compliance with the local laws and regulations. In addition signed children’s 
assent form according to local requirements.
2.
Male or female in- or out-patient from birth to < 18 years at the time of 
randomization.
3.
Patient weight at least 3.3 kg.
4.
Naïve or non-naïve patient with histologically, and/or cytologically (or imaging in 
the case of brain tumors or nephroblastoma) confirmed malignant disease.
5.
Scheduled and eligible to receive at least one moderately or highly emetogenic 
chemotherapeutic agent on Day 1 only or for multiple days (Appendix 2).
6.
For patient aged ≥ 10 years: Eastern Cooperative Oncology Group Performance 
Status (ECOG PS) ≤ 2 (Appendix 3).
7.
Adequate hepatic function defined as serum ALT and AST ≤ 2.5 ULN, and total 
bilirubin ≤ 1.5 ULN.
8.
Adequate renal function defined as estimated glomerular filtration rate (eGFR) ≥ 70 
ml/min/1.73m2 (≥50 ml/min/1.73m2 for children < 3 months old). The eGFR should 
be calculated using the modified Schwartz equation (Appendix 5).
9.
For patient with known history or predisposition to cardiac abnormalities: in the 
Investigator’s opinion the history/predisposition should not jeopardize patient’s 
safety during the study.
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10. If the patient is female, she shall: a) not have attained menarche yet or b) have 
attained menarche and have a negative pregnancy test at the screening visit and at
Day 1. 
11. Male or female fertile patient using reliable contraceptive measures (such measures, 
for patient and sexual partner, include: implants, injectables, combined oral 
contraceptives, intrauterine devices, vasectomized/sterilized partner, use of a double-
barrier method or sexual abstinence). The patient and his/her parent(s)/legal 
guardians must be counseled on the importance of avoiding pregnancy before or 
during the study.
All inclusion criteria will be checked at screening visit (Visit 1). Inclusion criteria #3, 5, 
10 will be re-checked at Day 1 (Visit 2).
Local laboratory results from an appropriately certified local laboratory could be used at 
the discretion of Investigator to evaluate patients’ eligibility.
3.3.3 Exclusion Criteria
Patients who meet any of the following criteria will not be eligible for admission into the 
study:
1. The patient and/or parents/caregivers are expected by the Investigator to be non-
compliant with the study procedures. 
2.
Patient has received or is scheduled to receive total body irradiation, total nodal 
irradiation, upper abdomen radiotherapy, half or upper body irradiation, radiotherapy 
of the cranium, craniospinal regions, head and neck, lower thorax region or the pelvis 
within 1 week prior to study entry (Day 1) or within 120 h after start of chemotherapy 
administration on Day 1. 
3.
Known history of allergy to any component or other contraindications to any NK1 or 
5-HT3 receptor antagonists.
4.
Active infection.
5.
Any illness or condition that, in the opinion of the Investigator, may pose 
unwarranted risks in administering the investigational product to the patient.
6.
Patient suffering from ongoing vomiting from any organic etiology (including 
patients with history of gastric outlet obstruction or intestinal obstruction due to 
adhesions or volvulus, patients with a symptomatic CNS tumor causing nausea and/or 
vomiting) or patient with hydrocephalus.
7.
Patient who experienced any vomiting, retching, or nausea within 24 h prior to the 
administration of the study drug (note: functional vomiting for infants, which is 
normally seen during the first 3 months of life, is not to be considered as vomiting).
8.
Patient who received any drug with potential anti-emetic effect within 24 h prior to 
the start of reference chemotherapy, including but not limited to:
-
NK1- receptor antagonists (e.g., aprepitant or any other new drug of this class);
-
5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, 
ramosetron);
-
Benzamides (e.g., metoclopramide, alizapride);
-
Phenothiazines 
(e.g., 
prochlorperazine, 
promethazine, 
perphenazine, 
fluphenazine, chlorpromazine, theithylperazine);
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-
Benzodiazepines initiated 48 h prior to study drug administration or expected to 
be received within 120 h following initiation of chemotherapy, except for single 
doses of midazolam, temazepam or triazolam;
-
Butyrophenones (e.g., droperidol, haloperidol);
-
Anticholinergics 
(e.g., 
scopolamine, 
with 
the 
exception 
of 
inhaled 
anticholinergics for respiratory disorders, e.g., ipratropium bromide); 
-
Antihistamines 
(e.g., 
diphenhydramine, 
cyclizine, 
hydroxyzine, 
chlorphenhyramine, dimenhydrinate, meclizine);
-
Domperidone; 
-
Mirtazapine; 
-
Olanzapine ;
-
Prescribed cannabinoides (e.g., tetrahydrocannabinol, nabilone);
-
Over the Counter (OTC) antiemetics, OTC cold or OTC allergy medications;
-
Herbal preparations containing ephedra or ginger.
9.
Patient who received palonosetron within 1 week prior to administration of study 
drug. 
10. Patient who has been started on systemic corticosteroid therapy within 72 h prior to 
study drug administration or is planned to receive a corticosteroid as part of the 
chemotherapy regimen.
Exceptions:
-
Patient who is receiving chronic (> 72 h), daily steroid therapy can be enrolled 
provided the steroid dose is not > 0.14 mg/kg (up to 10 mg) of prednisone daily or 
equivalent.
-
For supportive care, patient is permitted to receive a single dose of corticosteroid 
during the 72 h prior to study drug administration (but not < 12 h prior to study 
drug administration) provided it is less than the equivalent of 20 mg of 
prednisone.
11. Patient aged < 6 years who received any investigational drug (defined as a 
medication with no marketing authorization granted for any age class and any 
indication) within 90 days prior to Day 1, or patient aged 6 years who received any 
investigational drug within 30 days prior to Day 1 or is expected to receive 
investigational drugs prior to study completion.
12. Intake of alcohol, food or beverages (e.g., grapefruit, cranberry, pomegranate and 
aloe vera juices, German chamomile) known to interfere with either CYP3A4 or 
CYP2D6 metabolic enzymes within 1 week prior to Day 1 and during the overall 
study period (Appendix 4).
13. Use of any drugs or substances known to be strong or moderate inhibitors of 
CYP3A4 and CYP2D6 enzymes within 1 week prior to Day 1 or planned to be used 
during the overall study period (Appendix 4).
14. Use of any drugs or substances known to be CYP3A4 substrates with narrow 
therapeutic range within 1 week prior to Day 1, or planned to be used during the 
overall study period (Appendix 4).
15. Use of any drugs or substances known to be inducers of CYP3A4 enzymes within 
4 weeks prior to Day 1 or planned to be used during the overall study period 
(Appendix 4).
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16. Lactating female patient. 
17. Patient with clinically relevant Grade 3 or 4 non-hematological abnormal laboratory 
values.
20. Enrolment in a previous study with netupitant (either alone or in combination with 
palonosetron).
21. Marked baseline prolongation of QTc interval [QTcB or QTcF > 460 msec] at 
screening.
NOTE: Exclusion criteria ## 18 and 19 were skipped intentionally to maintain 
consistency in exclusion criteria numbering between protocol amendments.
All exclusion criteria will be checked at screening visit (Visit 1). Exclusion criteria #2, 4, 
7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 21 will be re-checked at Day 1 (Visit 2). In case of ERT 
central ECG report pending, the assessment of compliance with exclusion criterion #21 
could be made based on automatic interpretation of QTcB and QTcF results by ECG 
machine at the discretion of Investigator.
All eligible patients must be approved for randomization by authorized Medical Monitor.
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4
STUDY DRUG MANAGEMENT
4.1
Description of Investigational Medicinal Products
The following investigational medicinal products (IMPs) will be used during the study:
Name:
Oral Netupitant (IMP 1)
Dosage form:
glass vial with liquid formulation (suspension)
Strength:
100 mg netupitant / 7 mL
Dosing:
netupitant will be administered based on the body weight as a 
single oral dose 1 h (± 10 minutes) prior to start of emetogenic 
chemotherapy on Day 1
Route of administration:
oral
Name:
Oral Netupitant (IMP 2)
Dosage form:
glass vial with liquid formulation (suspension)
Strength:
300 mg netupitant / 7 mL
Dosing:
netupitant will be administered based on the body weight as a 
single oral dose 1 h (± 10 minutes) prior to start of emetogenic 
chemotherapy on Day 1
Route of administration:
oral
Name:
Oral Palonosetron (IMP 3)
Dosage form:
glass vial with liquid formulation (solution)
Strength:
0.75 mg palonosetron / 5 mL (oral administration of the 
0.75 mg/5 mL solution for IV use)
Dosing:
palonosetron will be administered based on the body weight at 
the dosage of 20 µg/kg (max 1.5 mg), immediately (within 5 
minutes) after netupitant, i.e., 1 h (± 10 minutes) prior to start 
of emetogenic chemotherapy on Day 1
Route of administration:
oral
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4.2
Treatment Groups
A total of 92 pediatric cancer patients will be enrolled to one of two treatment groups 
(46 patients/group): 
-
Treatment group 1 – patients ≥ 3 months of age will receive a single oral 
netupitant dose of 1.33 mg/kg (up to a maximum of 100 mg for patients weighting 
75 kg or more) concomitantly with a single oral palonosetron dose of 20 µg/kg 
(up to a maximum of 1.5 mg for patients weighting 75 kg or more). For patients 
< 3 months of age, the netupitant dose will be 0.8 mg/kg.
-
Treatment group 2 – patients ≥ 3 months of age will receive a single oral 
netupitant dose of 4 mg/kg (up to a maximum of 300 mg for patients weighting 
75 kg or more) concomitantly with a single oral palonosetron dose of 20 µg/kg 
(up to a maximum of 1.5 mg for patients weighting 75 kg or more). For patients 
< 3 months of age, the netupitant dose will be 2.4 mg/kg.
4.3
Dose and Administration
The netupitant doses to be tested in the pediatric population will match exposures to adult 
doses of 100 up to 300 mg as tested in pivotal Phase 2 trial NETU-07-07 [20], and 
300 mg as tested in pivotal Phase 3 trials (NETU-08-08 [21] and NETU-10-29 [22]. 
These doses proved to be safe and effective. Basic assumption behind this choice is that 
efficacious netupitant AUC values in children are similar to those observed in adults at 
effective doses. 
In order to predict the pediatric doses matching exposures to adult doses of 100 and 300, 
CL/F values in different age classes were estimated by pharmacokinetic allometry scaling 
according to the following model:
(CL/F)p = (CL/F)a ∗BWp
70 

where (CL/F)p and (CL/F)a are the systemic clearances in pediatric patients and adults, 
respectively, BWp is the body weight of children, 70 is the standard adult BW expressed 
in kg, and ADE is an age-dependent exponent [24]. ADE values across the age classes 
were assumed to be the following [24]: 1.2 for children aged ≤ 3 months, 1.0 for those 
aged > 3 months to 2 years, 0.9 for those aged > 2 years to 5 years, and 0.75 for those 
aged > 5 years. The model accounts for the effect of the body size change and organ 
maturation. An age-dependent exponent that decreases with the age increase, is consistent 
with a faster functional maturation occurring during the youngest age ranges. 
Reference body weights for children were taken from growth charts compiled by the 
CDC (Centers for Disease Control and Prevention, Atlanta, GA, USA) [25].
Average AUC values in adults receiving 100 and 300 netupitant have been calculated by 
dividing these doses by the geometric mean of netupitant clearance in adults, 
(CL/F)a = 20.27 L/h, obtained from the population PK study (Study NETU-10-02 [26]), 
assuming linear kinetics. The netupitant doses for each pediatric age classes that are 
expected to yield these target AUC values have been calculated by multiplying AUCs by 
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the respective predicted CL/F in children, assuming the same netupitant oral 
bioavailability (F) in pediatric patients and adults. 
In conclusion, netupitant doses per age class to be tested in the PK/PD-based dose finding 
study in pediatric patients resulted to be the following:
Age class
Dose 1
(mg/kg)
Dose 2
(mg/kg)
Birth to < 1 month
0.8
2.4
1 month to < 3 months
0.8
2.4
3 months to < 6 months
1.33
4
6 months to < 12 months
1.33
4
1 year to < 2 years
1.33
4
2 years to < 5 years
1.33
4
5 years to < 12 years
1.33
4
12 years to < 18 years
1.33
4
ADULTS and children 
with BW ≥ 75 kg
100 mg
300 mg
Patients enrolled in each of the two treatment groups will receive a single oral dose of 
netupitant per kg body weight as described in Section 4.2 Treatment Groups, 1 h 
(± 10 minutes) prior to start of emetogenic (HEC or MEC) chemotherapy on Day 1 and a 
single oral dose of palonosetron at the dosage of 20 µg/kg (maximum 1.5 mg), 
immediately (within 5 minutes) after netupitant, i.e., 1 h (± 10 minutes) prior to start of 
emetogenic (HEC or MEC) chemotherapy on Day 1. 
4.4
Packaging and Shipment
The investigational products (netupitant vials and palonosetron vials) will be provided in 
sealed and appropriately labeled study kits. The netupitant vials included in the kits will
have the same appearance for all the dosages; the different concentrations of the active 
pharmaceutical ingredient (API) permit to have different netupitant dosages by using the 
same volume, which is weight-based defined.
Packaging and labeling of the study drugs will be carried out in accordance with all 
applicable regulatory/legal requirements by CSM Europe SA (previously B&C Group) 
(Belgium).
Study kit is inside of a carton box and contains 2 vials of palonosetron (up to 1.5 mg 
dosage), 1 vial netupitant suspension and the ancillaries to be used for the collection and 
administration of the drugs. All the components of the study kits are identifiable with 
differently colored labels.
The procedure to be followed for the preparation and administration of the drugs will be 
included in the Drug Manual provided to the site staff before the start of the study (also 
refer Section 4.8 Randomization, Blinding and Assignment of Study Drug).
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The study kits will be delivered either to a designated person at the site’s Pharmacy or 
directly to the Investigator or designated staff, as applicable.
4.5
Storage
The study drug will be delivered and stored at room temperature (below 25°C), 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 the 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.
4.6
Drug Depots
The study drugs kits will be shipped from the central depot to either local drug depots, or 
directly to the study sites, as applicable. 
4.7
Accountability
Once the kits are received at the study site, the pharmacist or designated responsible 
person will sign a drug receipt form. Adequate records of the receipt, dispensation and 
return of study drugs must be maintained throughout the study. Used study drug kits will 
be retained until the drug accountability has been checked by a designated monitor; a 
peel-off portion of the study drug label will also be affixed to the drug preparation form 
as an additional accountability measure in case internal policies require immediate 
disposal of the vials. Unused study drug kits remaining at investigational sites at the end 
of the study will be returned to the drug depots for destruction or will be destroyed at the 
sites as applicable. At the end of the study, delivery records will have to be reconciled 
with those of used and returned stocks. Any discrepancy will have to be accounted for. 
Destruction of unused medication will be documented in writing according to FDA IND 
regulation 21CFR312.59, ICH Good Clinical Practice (GCP) and the drug depot Standard 
Operating Procedures (SOPs). Any destruction of remaining study drugs material is to be 
first approved in writing by the study Sponsor. 
4.8
Randomization, Blinding and Assignment of Study Drug
Randomization will be used to avoid bias in assigning patients to treatment and to 
increase the likelihood that known and unknown patient attributes are evenly balanced 
across treatment groups.
A computer-generated list of the kit numbers (“packaging list”) will be prepared by the 
Contract Research Organization (CRO) to allow for blinding of the two treatment groups.
Sealed cartons (kits) containing the study drugs will be prepared according to this 
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. Kits are indistinguishable, i.e., the netupitant vials contained in the kits have the 
same appearance for all the dosages; the different concentrations of the API permit to 
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have different netupitant dosages by using the same volume, which is weight-based 
defined.
The computer-generated patient randomization list(s) will be prepared by the CRO to 
allow for random treatment allocation where/when a random treatment allocation is 
foreseen. The Interactive Web Response System (IWRS) provider and a designated 
person at Helsinn will retain master copies of the packaging and patient randomization 
lists in a secure fashion to maintain the blind. 
Sponsor project team members and members of the Investigator’s team will not have 
access to the lists. Patients will enter the study according to the design described in 
Section 3.1 Study Design and in Appendix 1.
Randomization/treatment assignment of eligible patients will be done using IWRS 
integrated with EDC system. Patients will be registered in the EDC at screening visit, and 
patient identification number will be automatically assigned by the system. Once a 
patient fulfills the inclusion and exclusion criteria, at Day 1 (Visit 2) the Investigator will 
ask for randomization/treatment assignment through the EDC. The patient’s date of birth, 
the emetogenicity and the schedule of the chemotherapy (all the information is necessary 
for identifying the patient’s strata) and the body weight (necessary to establish the total 
dosages of netupitant and palonosetron to be administered) are taken into consideration. 
These and other demographic data are stored in the IWRS module, together with the 
assigned treatment.
The IWRS will assign the treatment to be administered to the patient through a static 
central blocked randomization for patients to be randomized and treated in a double-blind 
fashion. The IWRS will assign the treatment to be administered to the patient in the 
youngest age classes (all age classes < 12 months) according to the study design, i.e. the 
lowest netupitant dose(s) will be assigned and evaluated before escalating to the 
subsequent netupitant dose groups. 
Using the assigned dosage and the patient’s weight, IWRS will customize patient-specific 
instructions for study drug preparation and send them to designated person at the study 
site. 
The designated person at site will prepare the study drug following the instructions 
provided by the IWRS.
The IWRS will be open for randomization / treatment assignment only for the 
age-class(es) that are allowed to include patients, according to the design and to the 
DSMB decisions. The IWRS will be closed for each age class once the relevant number 
of enrolled patients reached the planned target number of patients. 
4.8.1 Emergency Unblinding Procedure
As all patients will be treated with netupitant, it is unlikely that knowledge of the specific 
doses administered to an individual patient will provide sufficient additional information 
to the Investigator to warrant breaking the blind for the patient. 
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However, if the Investigator considers it essential to know the dose of netupitant 
administered in order to adequately respond to a medical emergency, the Investigator can 
obtain the treatment assignment of an individual patient through the IWRS. If possible, 
the Investigator should discuss with the CRO Medical Monitor whether unblinding is 
essential prior to contacting IWRS for the unblinding of the patient’s treatment 
assignment.
In case of unblinding, the Sponsor and CRO will be notified in a blinded fashion 
immediately through an automatic communication of the IWRS. Moreover, the 
Investigator should notify the CRO Medical Monitor and the Sponsor Drug Safety within
24 h of the performed emergency unblinding.
If the blind is broken for an individual patient, the Investigator must record the following 
information in the patient’s source documents:
-
The date and time the blind was broken.
-
The reason the blind was broken.
In case of unblinding by the Investigator, the patient will be withdrawn from the study. 
If the blind is broken by the Sponsor (via IWRS) for pharmacovigilance reporting 
purposes in case of a suspected unexpected serious adverse reaction (SUSAR), the blind 
will be maintained for all other persons involved in this study. The patient will not be
withdrawn from the study in case of unblinding by the Sponsor’s Drug Safety Unit for 
pharmacovigilance reporting purposes. 
Any unblinding will be performed through IWRS (24-h coverage), and the unblinding 
procedure is described in detail in the IWRS instruction manual that will be provided 
separately. For the DSMB the unblinding process is described in the DSMB charter.
4.9
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 or palonosetron to 
date. No antidote for palonosetron or netupitant overdose is known.
4.10
Prior and Concomitant Medications
Information on prior and concomitant medications will be collected beginning 14 days 
prior to Day 1 up to the follow-up visit (Day 14 [+3]). 
4.10.1Prior and Concomitant Treatments for the Prevention of Nausea and 
Vomiting or with Potential Antiemetic Effect
The use of any medication for the prevention of nausea and vomiting or the use of any 
medication with potential antiemetic effects within the 24 h prior to the start of 
emetogenic chemotherapy or during the 120 h after the start of emetogenic chemotherapy 
is prohibited. For patients undergoing multiday emetogenic chemotherapy, preventive 
antiemetic medication can be administered starting from > 24 h after start of emetogenic 
chemotherapy (HEC or MEC) on Day 1. The antiemetic treatment shall be administered 
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as per local practice; however any further administration of netupitant or palonosetron is 
prohibited.
The list of prohibited medications includes, but is not limited to:
-
NK1- receptor antagonists (e.g., aprepitant or any other new drug of this class); 
-
5-HT3
receptor antagonists (e.g., ondansetron, granisetron, dolasetron, 
tropisetron, ramosetron);
-
Benzamides (e.g., metoclopramide, alizapride);
-
Phenothiazines 
(e.g., 
prochlorperazine, 
promethazine, 
perphenazine, 
fluphenazine, chlorpromazine, theithylperazine);
-
Benzodiazepines initiated 48 h prior to study drug administration or expected to 
be received within 120 h following initiation of chemotherapy, except for single 
doses of midazolam, temazepam or triazolam;
-
Butyrophenones (e.g., droperidol, haloperidol);
-
Anticholinergics 
(e.g., 
scopolamine, 
with 
the 
exception 
of 
inhaled 
anticholinergics for respiratory disorders e.g., ipratropium bromide);
-
Antihistamines 
(e.g., 
diphenhydramine, 
cyclizine, 
hydroxyzine, 
chlorphenhyramine, dimenhydrinate, meclizine);
-
Domperidone; 
-
Mirtazapine; 
-
Olanzapine; 
-
Prescribed cannabinoides (e.g., tetrahydrocannabinol, nabilone);
-
Over the Counter (OTC) antiemetics, OTC cold or OTC allergy medications;
-
Herbal preparations containing ephedra or ginger.
The intake of palonosetron is not permitted within 1 week prior to administration of study 
drug. 
The start of any systemic corticosteroid therapy within 72 h prior to study drug 
administration or the administration of a corticosteroid as part of the chemotherapy 
regimen is not permitted. 
The following exceptions are allowed:
-
Patients who are receiving chronic (> 72 h), daily steroid therapy can be enrolled, 
provided the steroid dose is not > 0.14 mg/kg (up to 10 mg) of prednisone daily or 
equivalent.
-
For supportive care, patients will be permitted to receive a single dose of 
corticosteroid during the 72 h prior to study drug administration (but not < 12 h 
prior to study drug administration) provided it is less than the equivalent of 20 mg 
of prednisone. 
Rescue medication for treatment of nausea and vomiting is permitted after the start of 
emetogenic chemotherapy administration; however any further administration of 
netupitant or palonosetron is prohibited; use of metoclopramide is not permitted as rescue 
medication (see Section 4.11 Rescue Medication).
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4.10.2Prior and Concomitant Cancer Chemotherapy and Radiotherapy
Patients must be scheduled to receive a course of HEC or MEC, administered on Day 1 
only or on multiple Days, either alone or in combination with other chemotherapeutic 
agents (see Appendix 2). For consistency of interpretation, “multiple days” schedule 
would include regimens with additional HEC/MEC given between Day 1 and Day 6 
(within 120 hours from the start of first HEC/MEC administration on Day 1). 
Any low emetogenic chemotherapy (LEC) agent or minimally emetogenic agent given, as 
part of the aforementioned chemotherapy regimens using HEC or MEC, is allowed at any 
time during the study and does not have any impact on the time of study drugs 
administration.
Total body irradiation, total nodal irradiation, upper abdomen radiotherapy, half or upper 
body irradiation, radiotherapy of the cranium, craniospinal regions, head and neck, lower 
thorax region or the pelvis within 1 week prior to study entry (Day 1) or within 120 h 
after study drug administration on Day 1 are not permitted. 
4.10.3Other Prior and Concomitant Medications
All medications used within 14 days prior to Day 1, or administered during the study as 
clinically indicated, are to be recorded on the appropriate electronic case report form 
(eCRF) pages. Prophylactic infusion of saline solution in order to prevent toxic reactions 
related to chemotherapy is to be recorded. Infusion of blood products has to be recorded. 
All medications administered in relation to diagnostic procedures (e.g., anesthetics, or 
antibiotics) are to be recorded.
According to protocol exclusion criterion #11, any investigational drug taken within 
90 days prior to Day 1 for patients aged < 6 years, or any investigational drug within 
30 days prior to Day 1 for patients aged ≥ 6 years, or through the entire study period are 
not allowed. For this purpose “Any investigational drug" has to be intended as a 
medication with no marketing authorization granted for any age class and any indication.
Based on exclusion criteria #13 and 14, the intake of any drugs or substances known to 
be strong or moderate inhibitors of CYP3A4 and CYP2D6 enzymes, including any of the 
narrow therapeutic range CYP3A4 substrates, within 1 week prior to Day 1 or use of such 
medications during the overall study period (until Visit 5 inclusive) is not permitted 
(Appendix 4).
Based on exclusion criterion #15, the intake of drugs or substances known to be inducers 
of CYP3A4 enzymes within 4 weeks prior to the dosing day or use of such medications
during the overall study period (until Visit 5 inclusive) is not permitted (Appendix 4).
4.11
Rescue Medication
Rescue medication should be administered to alleviate established, refractory or 
persistent nausea or vomiting and will be permitted on an as-needed basis.
Anti-emetic medications are not allowed as prevention of emesis, nor to increase the 
expected antiemetic effects of the study drugs, except for patients receiving HEC or MEC 
beyond Day 1. 
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Rescue medication is defined as any medication taken to alleviate nausea or vomiting 
(i.e., with indication nausea or vomiting) during the period from start of emetogenic 
chemotherapy to 120 h later. The choice of rescue medication will be at the discretion of 
the Investigator. Investigator must ensure that rescue medication is made available to 
patients whenever needed.
Use of palonosetron or netupitant other than study drugs administration is not permitted.
Use of metoclopramide is not permitted as rescue medication.
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5
STUDY CONDUCT
5.1
General Instructions
During the course of the study, patients will undergo the following visits (see also the 
Flow chart):
-
Visit 1, screening (Day -14 to -1 or Day -7 to -1 for patients aged < 2 year), 
during which patients will be assessed for eligibility.
-
Visit 2 (Day 1), during which patients fulfilling eligibility criteria will be enrolled, 
randomized (as applicable), administered study drugs and treated with 
chemotherapy; selected eligibility criteria will be re-checked at this visit prior to 
randomization/treatment assignment and treatment.
-
Visit 3 (Day 2, 3, 4 and/or 5, depending on PK sampling times), during which 
patients will have a PK sample(s) drawn and will be assessed for AEs and 
concomitant medications.
-
Visit 4 (Day 6, 7 or 8), final visit, during which a PK sample will be drawn, 
patient diary will be collected and patients will be assessed for AEs, concomitant 
medications, overall safety and laboratory safety data.
-
Visit 5 (Day 14 [+3]), follow-up visit or telephone contact for AEs and 
concomitant medications.
5.2
Study Procedures by Time Point
5.2.1 Visit 1 (screening, Day -14 to -1 or Day -7 to -1 for patients aged < 2 
years)
If the Investigator considers a patient to be potentially eligible for the study, the written 
informed consent/assent for participation in the study must be obtained before any 
study-related procedures. The patient will be screened within 14 days (or within 7 days 
for patients aged < 2 years) prior to the first study drug administration and the following 
procedures will be performed/data collected during this visit:
-
Informed consent signed by parent(s)/legal guardian(s) of the pediatric patient in 
compliance with the local laws and regulations. In addition signed children’s 
assent form according to local requirements. Informed consent/assent may also be 
collected before Visit 1.
-
Eligibility criteria.
-
Demographic data (gender, race, date of birth).
-
Medical and surgical history (including current cancer history and naivety to 
chemotherapy).
-
History of nausea and vomiting in previous chemotherapy (if applicable).
-
Prior and concomitant medications.
-
Laboratory tests, including: hematology, serum chemistry and urinalysis. Urine 
samples will be obtained only if the patient is capable of providing a urine sample.
-
Urine pregnancy test (for female patients having reached menarche only).
-
Full physical examination.
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-
Vital signs (pulse rate, systolic and diastolic blood pressure), height/length, 
weight.
-
12-lead ECG (single recording).
-
AE recording.
-
ECOG PS (assessed for patients aged ≥ 10 years).
-
Instruction to patient and to parent(s)/legal guardians of the pediatric patient on 
how to fill in the patient diary. 
Based on the outcome of the assessments, the Investigator will be able to decide if the 
patient is eligible for the study.
5.2.2 Visit 2 (Day 1)
The following procedures will be performed/data collected:
-
The patient will undergo pre-dose assessments, including confirmation of 
inclusion and exclusion criteria (local laboratory results from an appropriately 
certified local laboratory could be used at the discretion of Investigator to evaluate 
patients’ eligibility; in case of ERT central ECG report pending, the assessment of 
compliance with exclusion criterion #21 could be made based on automatic 
interpretation of QTcB and QTcF results by ECG machine at the discretion of 
Investigator).
-
Urine pregnancy test (for female patients having reached menarche only; if 
screening visit is performed on Day -1, it is not necessary to repeat the test on 
Day 1.).
-
Concomitant medications and AEs recording
-
Weight 
-
Treatment assignment / Randomization through IWRS. 
After randomization/treatment assignment, the study drug administration schedule is the 
following:
-
Netupitant will be administered based on the body weight as a single oral dose 1 h 
(± 10 minutes) prior to start of emetogenic (HEC or MEC) chemotherapy on Day 
1. 
-
Palonosetron will be administered orally immediately (within 5 minutes) after 
netupitant, i.e., 1 h (± 10 minutes) prior to start of emetogenic (HEC or MEC) 
chemotherapy on Day 1.
-
Any LEC or minimally emetogenic agent given, as part of the aforementioned 
chemotherapy regimens using HEC or MEC, is allowed at any time during the 
study and does not have any impact on the time of study drugs administration.
The date and the precise time (hh:mm) of the study drug administration must be recorded 
in the source records as well as on the relevant eCRF page for each medication given. 
Information on completeness of study drug administration must be recorded as well. The 
relevant tear-off labels from the study drugs kit will be attached to the drug 
administration form. 
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-
PK sampling: a single blood sample will be collected from each patient within the 
time window from 2 to 8 h after netupitant administration. Sampling will take into 
account the time of the 12-lead ECG and vital signs (see below).
-
Vital signs (pulse rate, systolic and diastolic blood pressure) will be obtained 
4-6 h after study drugs administration, before PK sampling or at least 30 minutes 
after PK sampling.
-
A 12-lead ECG (single recording) will be obtained 4-6 h after study drugs 
administration, before PK sampling or at least 30 minutes after PK sampling.
-
The diary covering 120 h after start of emetogenic chemotherapy will be supplied 
to all patients. Patient or patient’s parents/legal care holders have to record emetic 
episodes and use of any rescue medication. 
5.2.3 Visit 3 (Day 2, 3, 4 and/or 5 depending on the PK sampling times)
The following procedures will be performed/data collected:
-
Concomitant medications
-
AEs recording
-
PK sampling: a single blood sample will be collected from each patient within the 
time window from 24-48 h after netupitant administration. For pediatric patients 
≥5 years, an additional PK sample will be collected from each patient within the 
time window from 72-96 h after netupitant administration.
-
Review of patient diary and instructions. During the visit, after the diary has been 
reviewed, the patient will be asked to correct errors, omissions, or ambiguities, if 
any.
5.2.4 Visit 4 (final visit, Day 6, 7 or 8 depending on PK sampling times)
The following procedures will be performed/data collected:
-
Concomitant medications
-
Laboratory evaluations (hematology, serum chemistry and urinalysis; pregnancy 
test [(for female patients having reached menarche only])
-
Full physical examination
-
Vital signs (pulse rate, systolic and diastolic blood pressure; to be measured 
before PK sampling or at least 30 minutes after PK sampling)
-
12-lead ECG (single recording), before PK sampling or at least 30 minutes after 
PK sampling.
-
AEs recording
-
Check and retrieval of the completed patient diary 
-
PK sampling: a single blood sample will be collected from each patient within the 
time window from 120 to 168 h after netupitant administration.
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5.2.5 Visit 5 (follow up visit, Day 14 [+3])
On Day 14 (+3) the following follow up procedures will be performed/data collected 
during a visit or via telephone contact:
-
Concomitant medications
-
AEs recording.
5.3
Definition of Completion
A patient will be defined as “completed” if s/he completes the study until Visit 5
(inclusive). 
5.4
Premature Discontinuation
Patients may discontinue the study or may be withdrawn at any time for any of the 
following reasons:
-
An AE that, in the opinion of the Investigator, makes it unsafe for the patient to 
continue the study. In this case, the appropriate measures will be taken.
-
Any clinically significant laboratory abnormalities that in the Investigator’s 
opinion endanger the patient.
-
The patient’s safety is affected by violation of inclusion or exclusion criteria.
-
The patient and/or the parent(s)/ legal guardian(s) requests withdrawal from the 
study. 
-
The Investigator, for any reasons, terminates the entire study, or terminates the 
study for this patient; or the attending physician requests that the patient be 
withdrawn for any other medical reasons.
-
The patient is unwilling or unable to adhere to the study requirements after 
randomization/enrollment, e.g., non-compliance. 
-
Whenever the study blind is broken by the Investigator, the patient will be 
automatically withdrawn from the study. 
-
The patient is lost to follow-up.
-
The patient dies.
-
The Sponsor or the Regulatory Authorities or the Ethics Committees, for any 
reason, terminates the entire study, or terminates the study for that patient or study 
center.
In all cases where a patient is withdrawn from the study, CRO must be informed 
immediately, and the date and reason for withdrawal must be recorded on the eCRF and 
in the patient’s medical records. If more than one reason for withdrawal is recorded, the 
primary reason must be given. 
If the patient is withdrawn due to an AE, including concomitant disease, full details of the 
event and treatment must be recorded in the patient’s source documents and the eCRF. 
For non-serious AEs, the patient must be followed up until the cause of the event is 
established with follow-up information recorded up to 14[+3] days post-dose. For SAEs, 
the patient must be followed up until the cause of the event is established and should be 
followed up until they are completely resolved or until a stable condition has been 
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reached as no further improvement or change is expected according to conventional 
medical practice and according to the Investigator’s judgment or until the patient is lost to 
follow-up (see Section 7.1.3 Reporting of Adverse Events and Section 7.1.4.1 Reporting 
of Serious Adverse Events). 
If the patient is lost to follow up, all attempts to contact the patient should be documented 
in the patient’s medical records. 
All patients included in the study will be administered study drug (netupitant and 
palonosetron) on Day 1 (Visit 2); patients receiving the study drug will be evaluated 
regardless of completion of all study visits. An effort will be made to gather as much 
information as possible. Every attempt should be made to perform a final evaluation 
(Visit 4 procedures - see Flow Chart) for any patient who is withdrawn from the study for 
any reason excluding withdrawal of consent/assent. In addition, the Investigator must try 
his/her best to contact the patient within 14 to 17 days after the study drug administration 
to assess safety issues by collecting information suggestive of AEs and concomitant 
medications. Withdrawn patients will not be replaced. If the study is discontinued 
prematurely, all study materials (study drug, etc.) must be returned to the Sponsor. A 
written statement fully documenting the reasons for termination will be provided to the 
Investigators, the IEC/IRB, and Regulatory Authority (as appropriate to local 
regulations).
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6
METHODS OF ASSESSMENT
6.1
Pharmacokinetic Assessments
The PK profiles of netupitant, its active metabolites M1, M2, M3, and palonosetron will 
be evaluated in pediatric cancer patients according to a sparse sampling schedule and a 
population PK approach.
A single blood sample will be collected from each patient in each of the following time 
windows:

Pediatric patients ≥ 5 years: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h, and 
from 120 to 168 h after netupitant administration.

Pediatric patients < 5 years: from 2 to 8 h, from 24 to 48 h, and from 120 to 168 h 
after netupitant administration.
The actual sampling times will be recorded in the individual source documents and in the 
eCRF, and will be used in PK calculation.
The nominal number of plasma samples collected from all patients from each of the two 
treatment groups will be 154. The expected total number of plasma samples collected 
from the two treatment groups will be 308. 
The volume of each blood sample will be 2.0 mL. For patient with body weight < 5.4 kg, 
the volume of each blood sample will be limited to 1.0 mL [38].
Data modelling will be based on a previous population PK study in adults receiving oral 
NEPA administration (study NETU-10-02 [26]). A two- compartment open model with 
first order absorption and elimination with lag-time adequately described the netupitant 
and palonosetron plasma concentration-time profiles, whereas a one-compartment model 
best fit the metabolite M1 and M3 concentration data, and a three-compartment model 
described the metabolite M2 data. 
If the same structural models apply to the pediatric population, the typical values (TV) of 
the following structural model parameters will be assessed for netupitant and 
palonosetron: 
-
Ka: absorption rate constant for netupitant or formation rate constant for 
netupitant metabolites
-
tlag: lag time
-
Vi/F: apparent volume of compartment i, i.e., central and peripheral 
compartment(s), for extravascular administration
-
CL/F: apparent systemic clearance for extravascular administration
-
Q/F: inter-compartmental clearance
F is the absolute oral bioavailability for the parent compounds netupitant and 
palonosetron. 
Different structural models could also be explored for netupitant, its metabolites, and 
palonosetron according to the findings of the present PK/PD study in pediatric patients 
after oral administration of netupitant and palonosetron. The final model parameters will 
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reflect the model structure and include possible continuous or categorical covariates that 
significantly correlate with PK parameters and explain inter-subject variability.
Individual model-predicted PK parameter values will be estimated from the final 
population pharmacokinetic models, based on mean population parameter values (typical 
values, TVs) and on the individual random effect (ηi). From final model parameters, 
individual plasma concentration-time profiles will be simulated and secondary PK 
parameters such as Cmax, tmax, AUC and t1/2 estimated by non-compartmental methods.
6.1.1 PK Sampling and Sample Handling
Blood samples will be collected for the determination of netupitant, netupitant 
metabolites, and palonosetron concentrations. 
A total of 3 or 4 (only for pediatric patients aged ≥ 5 years) blood samples (2.0 mL each;
for patients with body weight < 5.4 kg, the volume of each blood sample will be 1.0 mL)
per patient will be taken according to the foreseen schedule.
The total number of data points from all patients will be 308. The total blood volume 
collected per patient will be approximately 3.0 to 8.0 mL.
In case of blood samples withdrawn from a central access or via an indwelling catheter, 
the cannula will be rinsed after each sampling with sterile saline solution containing 
20 IU/mL Na-heparin. At each sampling time, the first ca.1.0 mL of blood will be 
discarded to avoid contamination of the sample with the Na-heparin solution. Then 
2.0 mL blood (for patients with body weight < 5.4 kg, the volume of each blood sample 
will be 1.0 mL) will be collected into tubes containing K2-EDTA as anticoagulant. After 
collection, blood samples will be centrifuged immediately or stored, before 
centrifugation, in a refrigerator at +4 2°C or in a melting ice bath for a maximum of 
30 min. Centrifugation will be done by a centrifuge to obtain plasma. 
Each plasma sample will be immediately divided into 4 aliquots (2 aliquots for patients
with body weight < 5.4 kg) in pre-labeled polypropylene tubes: 2 aliquots (1 aliquot for 
patients with body weight < 5.4 kg) ≥130 μL each (sample and back-up sample) for the 
analysis of netupitant and its metabolites (M1, M2, M3), 2 aliquots (1 aliquot for patients
with body weight < 5.4 kg) of ≥ 250 μL each (sample and back-up sample, for patients
with body weight < 5.4 kg no back-up samples are to be obtained) for the analysis of 
palonosetron. Plasma samples will be stored frozen at -20° C or -70°C until analysis.
Further instructions on collection, handling, labeling, storage and shipment of PK 
samples are reported in the Laboratory manual.
6.1.2 Analytical Procedures
Netupitant, netupitant metabolites M1, M2 and M3, and palonosetron concentrations will 
be determined in plasma samples at an accredited bioanalytical laboratory. 
Validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods 
with appropriate lower limits of quantification (LLOQ) will be used. 
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The method for the determination of netupitant and its metabolites requires a sample 
volume of 50 µL and has a LLOQ of 2 ng/mL for each analyte. For palonosetron 
determination, the method requires a sample volume of 100 µL and the LLOQ is 
50 pg/mL.
Details of determination of netupitant, netupitant metabolites and palonosetron in human 
plasma of this clinical study will be included in the bioanalytical study plan. Analyses 
will be performed according to the general principles of “OECD Good Laboratory 
Practices for testing of chemicals" C(81)30(Final). The bioanalytical report will be 
appended to the CSR.
6.2
Efficacy Assessments
Efficacy assessments will be collected through a paper diary, which will be used to 
record emetic episodes and use of rescue medication. 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). Regurgitation (defined 
as the sudden effortless return of small volumes of gastric contents into the pharynx and 
mouth – typically after breastfeeding or bottle feeding) is a physiological event and must 
not be considered as an emetic episode (for patients up to 12 months of age). Patients, 
parents/guardians or caregivers should complete the diaries. Instructions on how to 
compile the paper diary will be given at the Screening Visit (Visit 1). Paper diary will be 
distributed at Day 1 (Visit 2) and will be collected at Final Visit (Visit 4). 
6.2.1 Primary Endpoint
PK/PD relationship between netupitant exposure (AUC, Cmax) and antiemetic efficacy in 
the delayed phase after a single oral netupitant administration, concomitantly with oral 
palonosetron, in pediatric cancer patients receiving HEC or MEC treatments. Efficacy 
parameter to be used in the correlation is the proportion of patients with CR (i.e., no 
emetic episodes and no rescue medication) during the delayed phase (> 24-120 h after the 
start of chemotherapy on Day 1). 
6.2.2 Secondary Endpoints
-
Pharmacokinetic (PK) endpoints: 

AUC, Cmax, tmax and t1/2 of netupitant, netupitant metabolites M1, M2, M3, and 
palonosetron.
-
Pharmacodynamic (PD) endpoints: 

proportion of patients with complete response (CR, i.e., no emetic episodes and 
no rescue medication) during the delayed (> 24-120 h), acute (0-24 h), and overall 
phases (0-120 h) after start of chemotherapy administration on Day 1.

proportion of patients with no emetic episodes during the delayed (> 24-120 h), 
acute (0-24 h), and overall phases (0-120 h) after start of chemotherapy 
administration on Day 1.
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
proportion of patients with no rescue medication during the delayed (> 24-120 h), 
acute (0-24 h), and overall phases (0-120 h) after start of chemotherapy 
administration on Day 1.
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6.3
Safety Assessments
Safety assessments will consist of full physical examination (PE) and clinical laboratory 
tests (serum chemistry, hematology, urinalysis): these assessments will be performed at 
screening and at final visit (Visit 4). Moreover, vital signs measurements (pulse rate, 
systolic and diastolic blood pressure) and 12-lead ECGs (single recordings) will be 
obtained at screening, on Day 1 at 4-6 h after study drug administration, and at final visit. 
Adverse events (AEs) will be monitored throughout the study.
6.3.1 Physical Examination
A full physical examination will be performed at Visit 1 (screening) and Visit 4 (Day 6, 7 
or 8). 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. Information about the physical examination will be 
recorded in the source documentation at the site and in the eCRF. Significant 
findings/illnesses, discovered after the first study drug administration and which meet the 
definition of an AE, will also be recorded in the eCRF.
6.3.2 Vital Signs
Vital signs assessments will include: pulse rate, systolic and diastolic blood pressure, 
height/length (only at Visit 1, screening), and body weight (at Visit 1 and Visit 2). Pulse 
rate, systolic and diastolic blood pressure will be measured after the patient has been in 
the sitting or lying position for at least 5 minutes at Visit 1 (screening), Visit 2 (4-6 h 
after study drugs administration; Day 1) and Visit 4 (Final visit, Day 6, 7 or 8). 
Vital signs shall be measured before PK sampling or at least 30 minutes after PK 
sampling.
6.3.3 12-lead ECG
Twelve-lead ECGs (single recording) will be recorded for each patient at Visit 1 
(screening), Visit 2 at 4-6 h after study drugs administration, and Visit 4 (Day 6, 7 or 8, 
final visit). A digitally recorded ECG will be transmitted from the study site to a central 
reading facility, where ECG interpretations will be timely performed by a cardiologist (in 
case cardiologist’s report is pending, the assessment of compliance with exclusion 
criterion #21 could be made based on automatic interpretation of QTcB and QTcF results 
by ECG machine at the discretion of Investigator). ECG interpretation scheme will 
include the analysis of the morphology, rhythm, conduction, ST segment, PR, QRS, QT 
and QTc intervals, T waves, U waves and the presence or absence of any pathological 
changes. The investigator will receive more detailed information regarding the ECG 
recording and assessment procedures in a separate manual.
After review of the results received from the central reading facility, the investigator must 
sign and date each ECG report.
ECGs shall be obtained before PK sampling or at least 30 minutes after PK sampling.
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6.3.4 Clinical Laboratory Tests
The following parameters will be assessed at Visit 1 (screening) and Visit 4 (final visit):
a) Hematology: hematocrit, hemoglobin, erythrocytes (RBC), platelets, leukocytes 
(WBC), neutrophils, lymphocytes, basophils, eosinophils, monocytes.
b) Blood Chemistry: urea, creatinine/eGFR, total bilirubin, alkaline phosphatase 
(ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
sodium, potassium, albumin, total protein, blood glucose and total creatine kinase 
(CK).
c) Urinalysis: protein, glucose, WBC, RBC, and bacteria.
Female patients having reached menarche will have to undergo a urine pregnancy test at 
screening and on Day 1, as well as a blood pregnancy test on Visit 4 (final visit) as part of 
the clinical laboratory assessments. 
All blood and urine samples collected at Visit 1 and Visit 4 will be sent to a central 
laboratory for analysis. Local laboratory results obtained from an appropriately certified 
local laboratory within the screening period could be used to support eligibility criteria at 
the discretion of Investigator. Only the confirmation of eligibility will be recorded in the 
eCRF as local laboratory values will not be entered into the eCRF.
After review of the results received from the central laboratory, the investigator must sign 
and date each laboratory report. The laboratory will provide normal reference ranges for 
the laboratory results report and will flag all abnormal values. The investigator will 
consider the values outside the normal range and repeat the test, if needed. In case 
clinically significant laboratory abnormalities are assessed by the Investigator, 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. 
Clinically significant laboratory abnormalities (including those values ≥ grade 3 severity) 
detected after screening, if not justified by an underlying disease already recorded in the 
medical history, are to be recorded as AEs. 
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7
ADVERSE EVENTS
7.1
Method of Assessment
7.1.1 Definition of Adverse Events
Adverse Event (AE)
As defined by the current ICH Guideline for Good Clinical Practice [27] 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 the subject (and/or 
subject’s parent/guardian, as applicable) had already signed the Informed Consent/Assent 
Form.
This definition includes intercurrent illnesses or injuries, exacerbation of pre-existing 
conditions, and adverse events occurring as a result of drug withdrawal, abuse, 
medication errors, misuse or overdose. Adverse events observed during all periods of a 
clinical trial are to be recorded, including adverse events occurring during a period 
without trial medication. 
Planned surgical interventions or planned hospitalizations scheduled prior to the 
Informed Consent but performed during the study 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 
drug or meet the definition of serious AE.
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 
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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 IB for oral NEPA FDC [16].
Expedited Adverse Event Reporting
Any serious and unexpected AE that the Investigator or the Sponsor considers to be at 
least possibly related to study drug is subject to expedited reporting to the appropriate 
Health Authorities. Events for which causality is unknown/unassessable or unreported by 
the Investigator are considered to be possibly related.
Non-serious Adverse Events
Non-serious adverse events should be included in tabulations in the end-of-study and do 
not need to be submitted separately.
Preexisting Condition
A pre-existing condition is one that is present at the start of the study. A pre-existing 
condition should be recorded as an AE if the frequency, intensity, or the character of the 
condition worsens during the study period. 
7.1.2 Classification of Adverse Events
The Investigator will classify AEs based on their severity and relationship to IMP. 
Every effort must be made by the Investigator to categorize each AE according to its 
severity (see Section 7.1.2.1 Severity) and its relationship (see Section 7.1.2.2
Relationship to Investigational Medicinal Product).
7.1.2.1
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) [28], as summarized below:
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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.
7.1.2.2
Relationship to Investigational Medicinal Product
For this trial, an AE cause and effect relationship to the study drug will be classified by 
the Investigator as reported hereafter.
Scale
Definition
Definitely Related
The evidence is compelling that the study drug caused the adverse event. There is 
a clear temporal relationship of the event to the study drug; the event is consistent 
with a known pattern of drug (or drug class) effects; the event cannot be explained 
by concurrent disease or other drugs or chemicals; the event diminished upon 
cessation of study drug exposure or reduction in dose; the event worsened or 
recurred upon unintentional re-exposure to the study drug (intentional rechallenge 
for the purpose of assigning causality should not be performed).
Probably Related
It is more likely that the event is due to the study drug than due to other etiologies, 
an alternative explanation is unlikely. There is a reasonable temporal relationship 
of the event to the study drug; the event may be consistent with a known pattern of 
drug (or drug class) effects; the drug seems more likely than other etiologies to 
cause the effect; the event diminished upon cessation of study drug exposure or 
reduction in dose.
Possibly Related
It is equally likely that the event is due to the study drug as it is due to other 
etiologies. There is a reasonable temporal relationship of the event to the study 
drug; follows a known or expected response pattern of the suspected drug but 
could also have been easily produced by a number of other etiologies.
Unlikely related
It is more likely that the event is due to other etiologies than due to the study drug. 
The event could have been reasonably related to patient's underlying diseases or 
concomitant treatments and/or the temporal relationship is doubtful between the 
study drug and the suspected adverse event.
It the temporal relationship of the event to the study drug is reasonable, but there 
are important confounding factors/reasonably convincing alternative explanations, 
causality is considered unlikely.
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Scale
Definition
Not related
The study drug almost certainly (or certainly) did not cause the event. Sufficient 
information exists to indicate that the etiology is unrelated to the study drug, e.g., 
the event is more likely related to patient's underlying diseases or concomitant 
treatments and/or there is no temporal relationship between the study drug and the 
suspected adverse event, e.g., the event occurred before the study drug was 
administrated.
Unassessable
The data are insufficient or contradictory to make a meaningful medical 
assessment.
7.1.3 Reporting of Adverse Events
AE reporting has to be in accordance with the ICH E6 Guidance on GCP and ICH E2A 
Guidance on Clinical Safety Management. [27, 29]
During the course of the study, all AEs (including SAEs), irrespective of the relatedness
to the study drugs, will be recorded in detail in the source records and transcribed onto 
the AEs pages of the eCRF. During each monitoring visit, 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.
The reporting period for AEs is the period starting from the time of Informed Consent 
Form signature and lasting until Visit 5 or up to 14[+3] days post-dose. All non-resolved 
AEs (including SAEs) beyond this date will be documented on the eCRF as “ongoing”.
7.1.4
Reporting of Serious Adverse Events
All SAEs occurring from the time of signing of the Informed Consent Form/Assent until 
14[+3] days post-dose must be reported immediately to the CRO Pharmacovigilance 
e-mail address or sent by fax (see Section General Information). 
The investigator or designated study coordinator must transmit the completed SAE Form 
to the CRO within 24 h of observation or notification of a SAE. 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 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 EU Clinical Trial Directive 2001/20/EC, the US Code of Federal Regulations 
313.32 and ICH E6 Guidance on GCP and ICH E2A Guidance on Clinical Safety 
Management and all the applicable country regulations, will also be the responsibility of 
the Sponsor (or Sponsor’s designee). [27, 29]
A safety contact sheet will be provided to the investigator and will be maintained in the 
investigator file at the site. Refer to the instructions and definitions for completing the 
SAE Form and for submitting all SAEs to the CRO.
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7.1.4.1
Follow-up of Serious Adverse Events
For safety monitoring purpose, SAEs will be followed up by the Investigator until they 
are completely resolved or until a stable condition has been reached as no further 
improvement or change is expected according to conventional medical practice and 
according to the Investigator’s judgment or until the patient is lost to follow-up. When 
the investigational site receives any information about a serious adverse event which 
changes or adds information to the initial investigational SAE form, the site will fill out a 
new investigational SAE form, tick the”follow-up” box and send the form via e-mail or 
fax within 24 h to the CRO, especially if this new information has an effect on the 
seriousness, relatedness or expectedness of an adverse event.
7.1.4.2
Adverse Events of Special Interest
Special attention will be paid to QT prolongation and constipation, in particular to severe 
forms of constipation (CTCAE grade 3 or 4 [28]). In such cases, an accurate follow up 
will be performed by the Sponsor. 
7.1.5 Pregnancy Report
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 pharmacovigilance e-mail address or sent 
by fax (see Section General Information) within 24 h of becoming aware of the 
pregnancy. Even though pregnancy is not considered as SAE itself, pregnancy has to be 
reported within the timelines defined for SAE.
Pregnant patients, as well as partners of male patients who become pregnant during the 
study, will be followed by the Investigator and CRO / Sponsor until the fetus / newborn is 
delivered. Reports of Pregnancy Outcome will be sent by the sites directly to Helsinn 
Corporate Drug Safety. The patient’s/partner’s primary care physician (or obstetrician) 
will be requested by the Investigator to provide further information on the pregnancy 
outcome and to complete the Pregnancy Information Letter. If pregnancy occurs in a 
female patient between the screening and randomization phase, that patient will be 
removed from the study.
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8
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 [30].
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 data analysis.
8.1
Sample Size Determination
A total of 92 pediatric patients (i.e., 46 for each treatment group) will be enrolled in the 
study. 
For each age class used for stratification, a sample size was computed. Each age class is 
powered to target a 95% confidence interval within 60% and 140% of the geometric 
mean estimate of clearance with at least 80% power.
The sample size was computed for the following age classes: Birth-<1 month, 
1 <3 months, 3-<6 months, 6-<12 months, 1-<2 years, 2-<5 years, 5-<12 years, 
12-<18 years.
Variability of clearance in each pediatric age class was estimated based on the same 
model used to determine the dose to be administered, which is:
Log(CL/F)p = log(CL/F)a + ADE ∗log(BWp/70)
where (CL/F)p and (CL/F)a are the systemic clearances in pediatric patients and adults, 
respectively, BWp is the body weight of children and ADE is an age-dependent exponent 
considered constant within each age class. 
Variance of log (CL/F)p was then calculated as:
ADE2 * Variance (log (BWp))
considering log (CL/F)a as a constant term.
Variance (log (BWp)) was obtained from published data in Fryar et al 2012 [31], where
mean values in each age class and related standard errors were available.
Based on these data, the variance of log weight was obtained as:
Variance (BWp) = standard error2 * N
and
Variance (log BWp) ≈ Variance (BWp) / Mean2
(i.e., no assumption on the statistical distribution was made); 
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The table below reports the values as selected from published data in Fryar et al 2012
[31] and the further elaboration
Age class 
planned for the 
study
Age class 
[31]&
Weight (kg)
N/ Mean / SE / 
gender [31]
ADE
Estimated 
SD (BWp)
Estimated SD 
(log BWp)
Estimated SD 
(log CL/F)
Birth to <1 month
Birth-2 
months
82 / 5.0 / 0.11 / F
1.2
1.00
0.199
0.239
1 to <3 months
Birth-2 
months
82 / 5.0 / 0.11 / F
1.2
1.00
0.199
0.239
3 to <6 months
3-5 months
111 / 7.1 / 0.11 / M
1
1.16
0.163
0.163
6 to <12 months
6-8 months
9-11 months
103 / 8.7 / 0.13 / M
108 / 9.6 / 0.15 / M *
1
1
1.32
1.56
ND
0.162
ND
0.162
1 to <2 years
1 year 
297 / 10.9 / 0.10 / F
1
1.72
0.158
0.158
2 to <5 years
3 years
191 / 15.7 / 0.24 / F
0.9
3.32
0.211
0.190
5 to <12 years
9 years
191 / 36.6  / 1.17 / M
0.75
16.2
0.442
0.331
12 <18 years
17 years
188 / 77.4 / 2.41 / M
0.75
33.0
0.427
0.320
& only data related to the age period actually used for the sample size calculations are reported in this table. 
* given that mean values were very similar, data from the class with the larger SD of weights was used 
ADE = age-dependent exponent; BWp= body weight of children; CL/F= systemic clearance; F= Female; M = Male; 
ND= Not Done; SD = Standard Deviation
Sample size was then computed by the R program described in Wang et al 2012 [32] for 
each age class.
The resulted sample size for each treatment group, and the relevant power are provided in 
the table below:
Age class for the study
N estimated / dose
Power
Birth to < 1 month
6
0.891
1 to <3 months
6
0.891
3 to <6 months
4
0.832
6 to <12 months.
4
0.836
1 to <2 years
4
0.854
2 to <5 years
5
0.913
5 to <12 years
8
0.830
12 to <18 years
8
0.865
In order to facilitate the management of the study, the calculated sample size in the age 
class 2 to <5 years will be rounded up to 6 patients. 
8.2
Definition of Study Populations for Analysis
The following analysis populations are defined:
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The Full Analysis Set (FAS) includes all patients randomized or to whom a study drug 
was assigned and who received a HEC or MEC regimen and the entire planned volume of 
netupitant and palonosetron. Following the intent-to-treat principle, patients will be 
assigned to the treatment group according to the treatment assigned/randomized. FAS 
will be used for demography, other baseline characteristics and efficacy analyses.
The PK population includes all patients who received the entire planned volume of 
netupitant and/or the entire planned volume of palonosetron and who have at least one 
measurable concentration of netupitant and/or palonosetron. PK population will be used 
for all PK analyses. 
The Safety population includes all patients who received at least part of the planned 
volume of netupitant or at least part of the planned volume of palonosetron. 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.
8.3
Statistical Analysis
General Considerations
General descriptive statistics for numeric variables will include n (number of observed 
values), mean, standard deviation (SD), median, minimum and maximum values. For 
categorical variables, the number and percentage of patients will be presented.
8.3.1 Missing Data
Due to the descriptive nature of the analysis, no procedure for handling missing data will 
be applied to pharmacokinetic or safety data.
For the efficacy analysis, any patients who do not provide data about occurrence of 
emetic episode and rescue medication intake after chemotherapy administration (which 
are needed to assess CR) will be considered as treatment failures in the relevant phase
with missing information. 
The same approach will be also applied to each component of CR, i.e. emetic episodes 
and rescue medication intake.
8.3.2 Covariates, Interactions and Subgroups
There are some factors expected to influence the efficacy endpoints, i.e., age class, 
emetogenicity of chemotherapy and schedule of chemotherapy. These factors will be 
taken into consideration for randomization. Efficacy endpoints will be presented by 
strata. 
8.3.3 Analysis of Demographics and Baseline Variables
Demographics and baseline characteristic will be summarized by treatment group by 
means of descriptive statistics, in addition to be listed. Descriptive statistics will be 
presented overall and by strata.
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8.3.4 Pharmacokinetic Analysis
Exploratory PK analyses will be applied to evaluate in the pediatric population the 
disposition characteristics of netupitant, its metabolites and palonosetron observed in 
adult patients. The initial population PK model (base model) will be developed by 
comparing structural models and random error models based on parameters such as the 
objective function values, the log-likelihood values, the Akaike’s and the Bayesian’s 
Information Criteria (AIC and BIC), the residual errors, the random distribution in 
conditional weighted residual plots, the graphical correlation between the observed 
versus predicted concentration values.
The final population PK model will include possible additional fixed effects represented 
by relevant covariates that will prove to correlate with one or more population PK 
parameters and contribute to significantly explain and minimize the inter-subject 
variability. 
The final model will be qualified via a visual predictive check.
Inter-subject / inter-occasion variability (level 1 random-effect) and observation-level 
random error (level 2 random effect) will also be modeled.
Individual model-predicted PK parameter values will be estimated from the final 
population pharmacokinetic models, based on mean population parameter values (TVs) 
and on the individual random effect (ηi). Individual plasma-concentration-time curves 
will be simulated from final model parameters, and secondary parameters such as Cmax, 
tmax, AUC and t1/2 estimated by non-compartmental methods.
Mean and coefficient of variation (CV) of the pharmacokinetic parameters will be 
calculated from the individual predictions.
The effect of continuous and categorical covariates on the PK parameter variability will 
be evaluated by step-wise forward addition and backward elimination procedures. 
Continuous covariates will include at least age, BW, albumin, total bilirubin, creatinine,
ALT, AST, ALP. Categorical covariates will include at least gender, chemotherapy 
schedule, HEC/MEC, rescue medication (yes/no), concomitant medications.
Adult data from previous population PK study NETU-10-02 [26] after oral administration 
of the netupitant-palonosetron fixed combination will be used as prior information and 
included in the analysis. 
8.3.5 Efficacy Analyses
All results will be interpreted in a descriptive manner, since the study is not powered to 
compare the treatment groups for the efficacy assessments.
For each phase (delayed, acute, and overall), numbers and percentages (including 95%
CI) of patients with CR, with no emetic episodes and no rescue medication will be 
summarized by treatment. The difference in response rate between the groups and 
relevant 95% CI will be provided as well.
Efficacy analysis will be presented for the overall population and by strata.
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8.3.6 Pharmacokinetic/Pharmacodynamic Analysis
PK/PD relationships between predicted individual exposure metrics (Cmax and AUC) of 
netupitant versus efficacy (CR delayed phase) will be investigated via graphical 
exploratory analyses. In addition, a logistic regression analysis will be used to link the 
exposure metrics (Cmax, AUC) to categorical response (CR delayed phase).
The dose-exposure relationship and the PK/PD correlation (exposure-response 
relationship) for netupitant in pediatric cancer patients will be compared to that observed 
in adult cancer patients in order to support the dose selection for netupitant in the 
pediatric population. Similar exposures in adult and pediatric patients are assumed to 
produce similar efficacy.
8.3.7 Safety Analyses
All AEs will be listed by SOC, described and summarized by frequency tables. 
Summaries will be made by treatment arm with respect to the percentage of patients 
having at least one occurrence of that event during the study and the total number of 
events.
For safety analysis, the laboratory data will be analyzed and described as follows: listings 
(including flag for values outside the normal range), count (number and percentage) of 
value below, within and above normal range, descriptive statistics for change from 
baseline values. Shift tables with respect to normal range (Low/Normal/High) will be 
presented. ECG data will be summarized highlighting differences from baseline for 
quantitative variables and frequencies of treatment emergent abnormalities. Vital signs 
will be summarized using descriptive statistics for observed values and change from 
baseline, in addition to being listed. 
Safety analysis will be presented for the overall safety population and by strata.
8.4
Interim Analysis
No interim analysis is planned for this study.
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9
DATA SAFETY MONITORING BOARD
A Data Safety Monitoring Board (DSMB) will be convened for the evaluation of safety 
data during the study. The DSMB will not include employees of the Sponsor. 
Composition, role and responsibilities of the DSMB will be given in a separate document 
named DSMB charter. The purpose of the DSMB is to perform a qualitative safety 
assessment. Study data will be provided to the DSMB, as foreseen by the study design 
and at periodical intervals. Any additional information will be promptly made available 
by the Sponsor upon request of DSMB members.
The DSMB will have periodical face-to-face and/or telephone meetings, as appropriate 
and as foreseen by the study design, and a set of minutes will be issued after each 
meeting. A charter for the DSMB will be completed before patients enrollment begins.
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10 ETHICAL AND REGULATORY CONSIDERATIONS
10.1
Ethical Considerations
The study will be performed in accordance with the principles contained in the 
Declaration of Helsinki [33] 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 USA 
and other countries where the study is conducted, as applicable.
10.1.1
Laws and Regulations
This clinical study will be conducted in compliance with all international laws and 
regulations and national laws and regulations of the USA and other countries wherethe 
trial is performed, as applicable, as well as any applicable guidelines. 
10.1.2
Patient’s Information Sheet, Informed Consent Form and Assent 
Form 
Before starting any study-specific evaluations or procedures, parent(s)/legal guardian(s) 
of all patients invited to participate in the study and patients of appropriate age and 
intellectual maturity as defined by local laws and regulations must be given written and 
verbal information about the aims, methods, anticipated benefits and potential hazards of 
the study. Furthermore, the patients and their parent(s)/legal guardian(s) must be notified 
that participation is voluntary, and that the patient is free to withdraw from the study at 
any time without any disadvantages for the patient’s subsequent care. The parent(s)/legal 
guardian(s) is/are also free to withdraw their child from the study at any time without any 
disadvantages for the child’s subsequent care. 
In addition, parent(s)/legal guardian(s) will be given the Information for Parents and 
Informed Consent Form in native language expressed in clear, concise and lay language 
for review and consideration. As required by local laws and regulations, all patients of 
appropriate age and intellectual maturity will be given the Children’s Information Sheet 
and Assent Form explaining the study in age-appropriate terms.
Information for Parents and Informed Consent Form as well as the Children’s 
Information Sheet and Assent Form will tell potential patients and their parent(s)/legal 
guardian(s) about the nature of the drugs, its efficacy and safety profile, the route of 
administration, and the available clinical experiences in humans. It will also outline the 
steps of the protocol as they will apply to the individual including the number of visits, 
the number of procedures and types of assessments/measurements to be performed so that 
the individual has a clear picture of the risks, inconveniences and benefits that may 
accrue.
The patients and their parent(s)/legal guardian(s) must also know that patient’s personal 
medical records may be reviewed in strict confidence by the Sponsor’s staff or 
representatives 
and 
by 
Regulatory 
Authorities 
and 
Independent 
Ethics 
Committees(IEC)/Institutional Review Board (IRB) and that personal information about 
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patients will be held on a confidential database. Conditions for ensuring the anonymity of 
data and the security and confidentiality of the database should be explained.
Both the Informed Consent Form and the assent form must be previously approved by 
relevant IEC(s)/IRB and may further be updated as new important information becomes 
available that may affect patient’s or parent(s)/legal guardian(s) willingness to participate 
or continue in the trial.
Written Informed Consent Form signed by the parent(s)/legal guardian(s) must be 
obtained prior to enrollment of all pediatric patients and the signed assent form should be 
obtained from all patients of appropriate age and intellectual maturity in compliance with 
local laws and regulations.
Two copies of the Informed Consent Form and Assent Form shall be signed. The 
Investigator shall provide one signed copy of the Informed Consent Form to the 
parent(s)/legal guardian(s) and one copy of the assent form to the child (if applicable), 
and will keep the second copy of the original signed forms in the Investigator’s study file.
10.1.3
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 EC/IRB for review and 
approval (as well as to Competent Authorities, where applicable for authorization) unless 
it covers administrative issues only. In this case, the EC/IRB and Competent Authorities 
will be notified of the amendment for information purposes only, as applicable.
10.1.4
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 patient.
In order to obtain interpretable results, neither the Investigator nor the Sponsor/CROs 
will alter the study conditions agreed upon and set out in this protocol. 
In the event that an isolated, unforeseen instance resulting in a protocol deviation occurs, 
the Investigator is to document this deviation and notify it to the clinical CRO as soon as 
possible, in writing. In no instance should this increase the patient’s risk or affect the 
validity of the study data.
10.1.5
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 
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study. A screening log will be completed for screening failures. Data of these patients 
will be handled separately from the data of patients 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. 
Data Clarification Forms (DCFs) will be used to validate/clarify data entered on an eCRF 
page. Some DCFs 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, other DCFs will 
be created manually.
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 DCF 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/hospital. 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.
10.1.6
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, GCP guideline and applicable regulatory requirements. During 
the monitoring visits, monitors will verify the following including but not limited to: 
patient/parental Informed Consent Form/Assent Form, 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 will 
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.
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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.
10.1.7
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 [27] should be retained at the sites until when the 
Sponsor informs the Investigators/institutions in writing 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. Should the Investigator wish to assign the 
study documentation to another party or move to another location, the Sponsor should 
promptly be notified.
10.1.8
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 the 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.
10.1.9
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 
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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).
10.1.10
Insurance
The Sponsor will obtain liability coverage compliant with the regulations of each country 
involved in the study. This insurance will cover health impairments resulting from drugs 
and/or substances/investigational products administered in the course of this study for 
which the patient (and/or patient’s parent or guardian) has given his/her written Informed 
Consent/Assent. This insurance also covers health impairments resulting from study 
procedures.
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Investigator’s Drug Brochure Palonosetron, Revised Edition: Apr 2018.
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14
Study Report PALO-99-07. Double-Blind Pediatric Study to Assess the Safety, 
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10.0 μg/kg, in the Prevention of Chemotherapy-Induced Nausea and Vomiting. 06 
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Group Study to Evaluate the Efficacy and Safety of Two Different Doses of 
Palonosetron Compared to Ondansetron in the Prevention of CINV in Pediatric 
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Mahmood I. Dosing in children: a critical review of the pharmacokinetic allometry 
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38 Ethical considerations for clinical trials on medicinal products conducted with 
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(https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/2017_09_18_ethical_consid_ct_with_minors.pdf)
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12 APPENDICES
Appendix 1: 
Treatment scheme
Appendix 2:
Emetogenic potential of IV and oral antineoplastic agents
Appendix 3:
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
Appendix 4:
List of CYP3A4 Inducers, strong and moderate Inhibitors, and Substrates
Appendix 5:
Schwartz equation for determining estimated glomerular filtration rate 
(eGFR)
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Appendix 1:
Treatment Scheme
Enrollment 
Age classes 1 -
<18years
All randomized to NETU 
1.33mg/kg or 4mg/kg
Planned patient numbers 
by age class: 
•
12 - <18years    N=16
•
5 - <12years   N=16
•
2 - <5years   N=12
•
1 - <2years   N=8
Enrollment    N=3
Age class 6 - <12months
Open treatment with 
NETU 1.33mg/kg
Start
YES
YES
Enrollment    N=3
Age class 6 - <12months
Open treatment with 
NETU 4mg/kg
Enrollment    N=2
Age class 6 - <12months
All randomized to NETU 
1.33mg/kg or 4mg/kg
YES
Enrollment    N=3
Age class 3 - <6months
Open treatment with 
NETU 1.33mg/kg
Enrollment    N=3
Age class 3 - <6 months
Open treatment with 
NETU 4mg/kg
Enrollment    N=2
Age class 3 - <6months
All randomized to NETU 
1.33mg/kg or 4mg/kg
NO
STOP
DSMB 
approved?
STOP
NO
DSMB 
approved?
DSMB 
approved?
NO
STOP
YES
DSMB 
approved?
STOP
NO
YES
Enrollment    N=3
Age class 1 - <3months
Open treatment with 
NETU 0.8mg/kg
Enrollment    N=3
Age class 1 - <3 months
Open treatment with 
NETU 2.4mg/kg
Enrollment    N=6
Age class 1 - <3 months
All randomized to NETU 
0.8mg/kg or 2.4mg/kg
STOP
NO
DSMB 
approved?
YES
DSMB 
approved?
STOP
NO
YES
Enrollment    N=3
Age class <1month
Open treatment with 
NETU 0.8mg/kg
Enrollment    N=3
Age class  <1 month
Open treatment with 
NETU 2.4mg/kg
Enrollment    N=6
Age class <1month
All randomized to NETU 
0.8mg/kg or 2.4mg/kg
STOP
NO
DSMB 
approved?
YES
DSMB 
approved?
STOP
NO
YES
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Appendix 2:
POGO Guideline for Classification of the Acute 
Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer 
Patients [35]*
Emetogenicity
IV Agents
Oral Agents
High
(>90% frequency of 
emesis in absence of 
prophylaxis)
Altretamine 
Carboplatin 
Carmustine >250 mg/m2
Cisplatin 
Cyclophosphamide ≥1 g/m2
Cytarabine 3 g/m2/dose 
Dacarbazine
Dactinomycin
Mechlorethamine
Methotrexate >12 g/m2
Streptozocin
Thiotepa ≥300 mg/m2
Procarbazine 
Moderate 
(30–90% 
frequency 
of emesis in absence 
of prophylaxis)
Aldesleukin >12 to 15 million U/m2
Amifostine >300 mg/m2
Arsenic trioxide
Azacitidine
Bendamustine 
Busulfan
Carmustine ≤ 250 mg/m2
Clofarabine 
Cyclophosphamide <1 g/m2
Cytarabine >200 mg/m2 to <3 g/m2
Daunorubicin 
Doxorubicin
Epirubicin 
Idarubicin
Ifosfamide
Intrathecal 
therapy 
(methotrexate, 
hydrocortisone, and cytarabine)
Irinotecan
Lomustine
Melphalan >50 mg/m2
Methotrexate ≥ 250 mg/m2 to <12 g/m2
Oxaliplatin >75 mg/m2
Cyclophosphamide 
Etoposide 
Imatinib 
Temozolomide 
Vinorelbine 
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Emetogenicity
IV Agents
Oral Agents
Low 
(10 
to 
<30% 
frequency of emesis 
in 
absence 
of 
prophylaxis)
Amifostine ≤300 mg/m2
Amsacrine 
Bexarotene
Capecitabine 
Cytarabine ≤ 200 mg/m2
Docetaxel 
Doxorubicin (liposomal) 
Etoposide
5-Fluorouracil
Gemcitabine
Ixabepilone
Methotrexate >50 mg/m2 to <250 mg/m2
Mitomycin
Mitoxantrone
Nilotinib
Paclitaxel
Paclitaxel-albumin
Pemetrexed
Teniposide
Thiotepa <300 mg/m2
Topotecan
Vorinostat
Busulfan 
Fludarabine 
Minimal 
(<10% frequency of 
emesis in absence of 
prophylaxis)
Alemtuzumab 
Alpha interferon 
Asparaginase (IM or IV) 
Bevacizumab 
Bleomycin 
Bortezomib 
Cetuximab 
Cladribine (2-chlorodeoxyadenosine) 
Dasatinib
Decitabine
Denileukin diftitox 
Dexrazoxane 
Erlotinib 
Fludarabine
Gefitinib
Gemtuzumab ozogamicin
Lapatinib
Chlorambucil 
Hydroxyurea 
Melphalan 
(low-dose) 
Mercaptopurine 
Thioguanine 
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Emetogenicity
IV Agents
Oral Agents
Lenalidomide
Methotrexate ≤ 50 mg/m2
Nelarabine
Panitumumab
Pentostatin
Rituximab
Sorafenib
Sunitinib 
Temsirolimus
Thalidomide
Trastuzumab
Valrubicin
Vinblastine
Vincristine
Vindesine
Vinorelbine
* Although not mentioned in this POGO Guideline, Temozolomide given intravenously 
should be considered as moderately emetogenic chemotherapy (MEC).
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Appendix 3: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 Clin 
Oncol 5:649-655; 1982 [34].
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Appendix 4:CYP3A4 and CYP2D6 Inhibitors, Inducers and Substrates
Strong inhibitors: ≥ 5-fold increase in AUC or > 80% decrease in CL
Moderate inhibitors: ≥ 2 but < 5-fold increase in AUC or 50-80% decrease in CL
Strong inducers: ≥ 80% decrease in AUC
Moderate Inducers: 50-80% decrease in AUC
Type
Agent
Strong and Moderate Inducers
Strong CYP3A4 inducers: carbamazepine, phenytoin, rifampin, St. 
John’s wort
Moderate
CYP3A4 inducers: bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
Strong and moderate CYP2D6 inducers: none known
Strong and Moderate Inhibitors
Strong CYP3A4 inhibitors: boceprevir, clarithromycin, conivaptan, 
grapefruit 
juice, 
indinavir, 
itraconazole, 
ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, voriconazole 
Moderate CYP3A4 inhibitors: amprenavir, aprepitant, atazanavir, 
ciprofloxacin, 
darunavir/ritonavir, 
diltiazem, 
erythromycin, 
fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil
Strong CYP2D6 inhibitors: bupropion, fluoxetine, paroxetine, 
quinidine
Moderate CYP2D6 inhibitors: cinacalcet, duloxetine, terbinafine
Substrates 
with 
narrow 
therapeutic range
CYP3A4: 
alfentanil, 
astemizole, 
cisapride, 
cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine
CYP2D6: thioridazine
Lists of in vivo inhibitors, inducers and substrates are taken from the following FDA 
website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm
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Appendix 5:Schwartz equation for determining estimated glomerular 
filtration rate (eGFR)
eGFR = 0.413 x height (cm)/serum creatinine (mg/dl)
To convert serum creatinine from µmol/l to mg/dl, the following equation should be 
used:
Serum creatinine (mg/dl) = Serum creatinine (µmol/l) x 0.0113
Schwartz GJ and Work DF, 2009 [36]
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