Clinical Trials Register

Summary
EudraCT Number:	2015-001800-74
Sponsor's Protocol Code Number:	NEPA-15-18
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-09-23
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Poland - Office for Medicinal Products

A.2

EudraCT number

2015-001800-74

A.3

Full title of the trial

A phase 3, multicenter, randomized, double-blind, active control study to evaluate the safety and efficacy of IV pro-netupitant/palonosetron (260 mg/0.25 mg) combination for the prevention of chemotherapy-induced nausea and vomiting in repeated chemotherapy cycles in patients receiving highly emetogenic chemotherapy

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to evaluate the safety and efficacy of a combination of pro-netupitant/palonosetron intravenously administered for the prevention of chemotherapy-induced nausea and vomiting.

A.4.1

Sponsor's protocol code number

NEPA-15-18

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Helsinn Healthcare SA
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Helsinn Healthcare SA
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PSI CRO AG
B.5.2	Functional name of contact point	Medical Monitoring and Consulting
B.5.3	Address:
B.5.3.1	Street Address	V Parku 2343/24, Praha 4
B.5.3.2	Town/ city	Prague
B.5.3.3	Post code	14800
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	+42027700 48006206
B.5.5	Fax number	+42027700 4800
B.5.6	E-mail	david.skoda@psi-cro.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	pro-netupitant/palonosetron fixed dose combination
D.3.2	Product code	IV NEPA FDC
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PALONOSETRON
D.3.9.1	CAS number	135729-62-3
D.3.9.4	EV Substance Code	SUB09593MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not yet available
D.3.9.1	CAS number	1703748-89-3
D.3.9.2	Current sponsor code	08-PNET
D.3.9.3	Other descriptive name	204-NETU
D.3.9.4	EV Substance Code	SUB91142
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	260
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Akynzeo
D.2.1.1.2	Name of the Marketing Authorisation holder	Helsinn Birex Pharmaceuticals Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	oral netupitant/palonesetron fixed-dose combination
D.3.2	Product code	Oral NEPA FDC
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NETUPITANT
D.3.9.1	CAS number	290297-26-6
D.3.9.2	Current sponsor code	14-NETU
D.3.9.3	Other descriptive name	Roche Compound Code RO 0673189
D.3.9.4	EV Substance Code	SUB130488
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PALONOSETRON
D.3.9.1	CAS number	135729-62-3
D.3.9.4	EV Substance Code	SUB09593MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

nausea and vomiting in cancer patients receiving highly emetogenic therapy

E.1.1.1

Medical condition in easily understood language

nausea and vomiting in cancer patients receiving chemotherapy

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10036899
E.1.2	Term	Prophylaxis against chemotherapy induced vomiting
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to assess the safety and tolerability of a single dose of IV NEPA FDC (260 mg/0.25 mg) infused over 30 minutes, with oral dexamethasone, in initial and repeated cycles of HEC.

E.2.2

Secondary objectives of the trial

The secondary objective is to describe the efficacy of a single dose of IV NEPA FDC (260 mg/0.25 mg) infused over 30 minutes, with oral dexamethasone, during the acute (0-24 hours), delayed (>24-120 hours) and overall (0-120 hours) phases of initial and repeated cycles of HEC.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Cycle 1:
The following inclusion criteria must be checked prior to inclusion at Cycle 1:
1. Signed written informed consent.
2. Male or female patient ≥ 18 years of age.
3. Histologically or cytologically confirmed solid tumor malignancy.
4. Naïve to cytotoxic chemotherapy. Previous biological or hormonal therapy will be permitted.
5. Scheduled to receive at least 4 repeated consecutive cycles of the following highly emetogenic reference chemotherapies (HEC), alone or in combination with other chemotherapeutic agents* on Day 1:
- cisplatin administered as a single IV dose of ≥ 70 mg/m^2
- cyclophosphamide ≥ 1500 mg/m^2
- carmustine (BCNU) >250mg/m^2
- dacarbazine (DTIC)
- mechloretamine (nitrogen mustard)
* on Day 1, additional HEC or MEC chemotherapeutic agents have to be administered after the start of the reference chemotherapy administration and their administration must be completed no more than 6 hours after the start of reference chemotherapy infusion. Low, minimally or not emetogenic chemotherapies can be administered at any time after the start of the reference HEC.
6. ECOG Performance Status of 0, 1, or 2
7. If a patient is female, she shall be:
a) of non-childbearing potential or
b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test.
8. Hematologic and metabolic status adequate for receiving a HEC regimen and fulfillment of the following criteria:
a. Total Neutrophils ≥ 1500/mm^3 (Standard units: ≥ 1.5 x 10^9/L)
b. Platelets ≥ 100,000/mm^3 (Standard units: ≥ 100.0 x 10^9/L)
c. Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN)
d. Liver enzymes:
ii. Without known liver metastases, Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN
iii. With known liver metastases, AST and ALT ≤ 5.0 x ULN
e. Serum Creatinine ≤ 1.5 mg/dL (Standard units: ≤ 132.6 µMol/L) or Creatinine Clearance ≥ 60 mL/min.
9. Able to read, understand, follow the study procedure and complete patient diary.

Cycles 2 to 4:
The following inclusion criteria must be checked prior to inclusion at each repeated cycle:
1. Participation in the study during the next cycle of chemotherapy is considered appropriate by the Investigator and does not pose unwarranted risk to the patient.
2. Scheduled to receive the same chemotherapy regimen as Cycle 1 or one of the reference chemotherapies as defined in Inclusion criterion # 5 for Cycle 1.
3. If a patient is female, she shall be:
a) of non-childbearing potential or
b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test.
4. Adequate hematologic and metabolic status according to the Investigator’s opinion.

E.4

Principal exclusion criteria

to be checked prior to inclusion at Cycle 1:
1. Lactating woman.
2. Active infection or uncontrolled disease except for malignancy that may pose unwarranted risks in administering the study drugs to the patient.
3. Current use of illicit drugs or current evidence of alcohol abuse.
4. Scheduled to receive moderately or highly emetogenic chemotherapies from Day 2 to Day 5.
5. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to the start of the reference chemotherapy administration on Day 1 or between Days 1 to 5.
6. Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) within 24 hours prior to the start of the reference chemotherapy administration on Day 1.
7. Symptomatic primary or metastatic CNS malignancy.
8. Known hypersensitivity or contraindication to 5-HT3 receptor antagonists to dexamethasone or to NK-1 receptor antagonists.
9. Known contraindication to the IV administration of 50 mL 5% glucose solution.
10 . Previously received an NK-1 receptor antagonist.
11. Participation in a previous clinical trial involving IV pro-netupitant or oral netupitant administered alone or in combination with palonosetron.
12. Any investigational drugs (other than those given in this study) taken within 4 weeks prior to Day 1, and/or is scheduled to receive any investigational drug during the present study.
13. Systemic corticosteroid therapy at any dose within 72 hours prior to the start of reference chemotherapy administration on Day 1. However, topical and inhaled corticosteroids are permitted.
14. Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy.
15. Scheduled to receive any strong or moderate inhibitor of CYP3A4 or its intake within 1 week prior to Day 1
16. Scheduled to receive any of the following CYP3A4 substrates within 1 week prior to Day 1: terfenadine, cisapride, astemizole, pimozide.
17. Received within 4 weeks prior to Day 1 or scheduled to receive any CYP3A4 inducer
18. Any medication with known or potential antiemetic activity within 24 hours prior to the start of reference chemotherapy administration on Day 1 of Cycle 1, including:
a. 5-HT3 receptor antagonists
b. NK-1 receptor antagonists
c. benzamides
d. phenothiazines
e. benzodiazepines (except if the patient is receiving such medication for sleep or anxiety and has been on a stable dose for at least seven days prior to Day 1)
f. butyrophenones
g. anticholinergics
h. antihistamines
i. domperidone
j. mirtazapine
k. olanzapine
l. prescribed cannabinoides
m. Over The Counter (OTC) antiemetics, OTC cold or OTC allergy medications.
19. History or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block.
20. History of Torsade de Point or known history of risk factors for Torsade de Point
21. Severe cardiovascular diseases diagnosed within 3 months prior to Day 1 of first cycle, including myocardial infarction, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic Congestive Heart Failure (CHF) NYHA class III-IV, and severe uncontrolled arterial hypertension.
22. Any illness or condition that, in the opinion of the Investigator, may confound the results of the study or pose unwarranted risks in administering the investigational product to the patient.
23. Concurrent medical condition that would preclude administration of dexamethasone such as systemic fungal infection or uncontrolled diabetes.

to be checked prior to inclusion in each repeated cycle:
1. Lactating woman.
2. Active infection or uncontrolled disease except for malignancy that may pose unwarranted risks in administering the study drugs to the patient.
3. Started any of the restricted medications.
4. Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) within 24 hours prior to the start of reference chemotherapy administration on Day 1.
5. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to the start of the reference chemotherapy administration on Day 1 or between Days 1 to 5.
6. Symptomatic primary or metastatic CNS malignancy.

All exclusion criteria, with exception of criterion #4, will be checked at screening visit (Visit 1). Exclusion criterion #4 will be checked at Day 1 (Visit 2) only. Exclusion criteria #3 and 5 need to be re-checked at Day 1 (Visit 2).

E.5 End points

E.5.1

Primary end point(s)

Safety endpoints
• physical examination (PE)
• vital signs
• 12-lead electrocardiogram (ECG)
• laboratory test (hematology, blood chemistry, urinalysis)
• adverse events (AEs) assessment

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessments of safety parameters will be obtained in each cycle

E.5.2

Secondary end point(s)

Efficacy endpoints
Proportion of patients:
• with complete response (no emetic episodes and no rescue medication) during the acute, delayed and overall phases;
• with no emetic episodes during the acute, delayed and overall phases;
• with no significant nausea (Visual Analogue Scale (VAS) <25 mm) during the acute, delayed, and overall phases (since VAS is assessed daily, for delayed and overall phases the maximum VAS value in the relevant phase will be considered).

E.5.2.1

Timepoint(s) of evaluation of this end point

Acute phase (time interval 0 to 24 hours after the start of reference HEC), delayed phase (>24 to 120 hours after the start of reference HEC), and overall phase (0 to 120 hours after the start of reference HEC).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

double dummy

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Croatia

Czech Republic

Germany

Israel

Italy

Poland

Serbia

South Africa

Spain

Ukraine

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS (please see also study protocol, section 6.3 "Definition of Completion")

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

140

F.4.2

For a multinational trial

F.4.2.1

In the EEA

350

F.4.2.2

In the whole clinical trial

400

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the end of the study, patients will be treated according to their treating physician`s decision

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-10-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-08-02

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