Clinical Trials Register

Summary
EudraCT Number:	2017-004031-37
Sponsor's Protocol Code Number:	17.14
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-10-10
Trial 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

Denmark - DHMA

A.2

EudraCT number

2017-004031-37

A.3

Full title of the trial

A multicentre, single-arm, phase II study to investigate the safety and antiemetic efficacy of Akynzeo® (a fixed dose combination of palonosetron and netupitant) plus dexamethasone in patients receiving concomitant chemo-radiotherapy with weekly cisplatin for at least five weeks.

A.3.1

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

A study to investigate the safety and antiemetic efficacy of 2 agents: Akynzeo® plus dexamethasone in patients receiving simultaneously radiotherapy and chemotherapy with weekly cisplatin for at least five weeks.

A.4.1

Sponsor's protocol code number

17.14

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	Department of oncology, Odense University Hospital
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-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	Department of oncology, Odense University Hospital
B.5.2	Functional name of contact point	Christina H Bruvik Ruhlmann
B.5.3	Address:
B.5.3.1	Street Address	Sdr. Boulevard 29
B.5.3.2	Town/ city	Odense C
B.5.3.3	Post code	5000
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004565413349
B.5.6	E-mail	christina.ruhlmann@rsyd.dk

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	Yes
D.2.1.1.1	Trade name	Dexamethason
D.2.1.1.2	Name of the Marketing Authorisation holder	Abcur AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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.3.4	Pharmaceutical form	Tablet
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.3.9.3	Other descriptive name	DEXAMETHASONE BASE
D.3.9.4	EV Substance Code	SUB125563
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	4 to 12
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	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	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	Ireland
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	Akynzeo
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.3.9.1	CAS number	290297-26-6
D.3.9.3	Other descriptive name	NETUPITANT
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.3.9.1	CAS number	135729-62-3
D.3.9.3	Other descriptive name	PALONOSETRON HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB20365
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Eligible patients will have a diagnosis of cervical cancer, and be scheduled to receive fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2 for at least five weeks. Patients must be naïve to both radiotherapy and chemotherapy.

E.1.1.1

Medical condition in easily understood language

Patients entering the study will have a diagnosis of cervical cancer, and be scheduled to receive simultaneously radiotherapy and chemotherapy with weekly infusion of cisplatin for at least 5 weeks.

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. The first co-primary objective is to explore the safety of an antiemetic regimen consisting of Akynzeo and dexamethasone during five weeks of fractionated (5 days a week) radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.
2. The second co-primary objective investigate Akynzeo and dexamethasone in terms of the proportion of subjects with no vomiting, i.e. sustained no emesis rate - during five weeks of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.

E.2.2

Secondary objectives of the trial

1. To investigate Akynzeo and dexamethasone in terms of the proportion of subjects with complete response (defined as no vomits, no dry retches and no need for rescue medication) in the 5 days and the 35 days following initiation of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.
2. To investigate Akynzeo and dexamethasone in terms of the proportion of subjects with no significant nausea (none or mild nausea) in the 5 days and the 35 days following initiation of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.
3. To investigate Akynzeo and dexamethasone in terms of the proportion of subjects with no nausea in the 5 days and the 35 days following initiation of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2.
4. To investigate Akynzeo and dexamethasone in terms of time to first emetic episode.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. The patient has a diagnosis of cervical cancer.
2. The patient understands the nature and purpose of this study and the study procedures and has signed informed consent.
3. The patient is aged ≥ 18 years.
4. The patient must be both chemo- and radiotherapy (RT) naïve. NB: previously low voltage RT or electron RT for non-melanoma skin cancers is allowed.
5. The patient is scheduled to receive fractionated radiotherapy and concomitant weekly cisplatin at a dose of ≥ 40 mg/m2 for at least five weeks.
6. Brachy therapy is scheduled to be initiated after the third cycle of weekly cisplatin, and preferentially after the fifth week of treatment.
7. Chemotherapy with an emetic risk potential of minimal or mild (up to 30%) is allowed on days 1-4 (see ref. 14).
8. The patient has a WHO Performance Status of ≤ 2.
9. Hematologic and metabolic status must be adequate for receiving weekly cisplatin in a dose of ≥ 40 mg/m2, and meet the following criteria:
• Total neutrophils ≥ 1500/mm3 (Standard units : ≥1.5 x 109/L)
• Platelets ≥ 100,000/mm3 (Standard units: ≥100.0 x 109/L)
• Bilirubin ≤ 1.5 x ULN (Upper Limits of Normal)
• Aspartate aminotransferase (AST) and/or
alanine aminotransferase (ALT) ≤ 2.5 x ULN
• GFR ≥ 50 ml/min
10. The patient is able to read, understand, and complete questionnaires and daily components of the Patient Diary for each study cycle.
11. For patients of childbearing potential, urine human chorionic gonadotropin (hCG) (urine dipstick pregnancy test) or blood hCG results must be negative at screening, and these patients must agree to one of the following methods of contraception:
• Oral contraceptives.
• Male partner who is sterile prior to the patient’s entry into the study and is the sole sexual partner for that patient.
• Double-barrier method of contraception consisting of spermicide with either condom or diaphragm.
• Complete abstinence from intercourse for two weeks before study entry and throughout the study period plus a period after the trial to account for elimination of the drug (minimum of eight days).

E.4

Principal exclusion criteria

1. The patient has a current malignant diagnosis other than cervical cancer, with exception of non-melanoma skin cancers.
2. The patient is pregnant or lactating.
3. The patient has experienced emesis (i.e., vomiting and/or retching) or clinically significant nausea (defined as nausea graded as moderate or severe) in the 24 hours preceding the first dose of study medication.
4. The patient has a history active peptic ulcer disease, gastrointestinal obstruction, gastrointestinal carcinoma, increased intracranial pressure, hypercalcemia, or any uncontrolled medical condition (other than malignancy) which in the opinion of the Investigator may confound the results of the study, represent another potential etiology for emesis and nausea (other than CINV/RINV) or pose an unwarranted risk to the patient.
5. The patient has a known hypersensitivity or contraindication to palonosetron, another 5-HT3 receptor antagonist, dexamethasone, or netupitant.
6. The patient has previously received an NK1 receptor antagonist.
7. The patient has received an investigational drug in the previous 30 days or is scheduled to receive any investigational drug during the study period.
8. The patient has taken/received any medication of moderate or high emetogenic potential within the 48 hours prior to the first dose of study medications. Opiate drugs for cancer pain will be permitted if the patient has been on a stable dose and has not experienced emesis or clinically significant nausea from the narcotics in the 24 hours preceding the first dose of study medication.
9. The patient has taken/received any medication with known or potential antiemetic activity within the 24-hour period prior to receiving study drugs. This includes, but is not limited to:
• 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, ramosetron). Palonosetron is not permitted within 7 days prior to receiving study drugs.
• Benzamide / benzamide derivatives (e.g., metoclopramide, alizapride).
• 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 the first dose of study medications).
• Phenothiazines (e.g., prochlorperazine, promethazine, metopimazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine).
• Butyrophenone (e.g., haloperidol, droperidol).
• Corticosteroids (e.g., dexamethasone, methylprednisolone, prednisolone; with the exception of topical steroids for skin disorders, inhaled steroids for respiratory disorders).
• Anticholinergics (e.g., scopolamine).
• Antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine).
• Domperidone.
• Cannabinoids.
• Mirtazapine.
• Olanzapine.
10. The patient has taken/received strong or moderate inhibitors of CYP3A4 within seven (7) days prior to administration of study drugs (see Section 10.3.1., “Inhibitors of CYP3A4”).
11. The patient has taken/received inducers of CYP3A4 within thirty (30) days prior to the administration of study drugs (see Section 10.3.2., “Inducers of CYP3A4”).

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

A study population of 80 patients is considered reasonable for the purpose of this study. Assuming a 49 % SNE rate for the previous standard antiemetic treatment, it is calculated that 61 patients should be included to test a 17 % difference between the previous standard treatment and the treatment including Akynzeo with 80% power and a two-sided level of significance of 0.05 (Wald test). A total of 80 patients will therefore be enrolled to ensure at least 61 eligible patients for full 5 weeks assessment and evaluation of the SNE rate.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

A total of 80 chemo- and radiotherapy naïve patients will be included.
The date for study initiation at all sites will be 2017.12.1. Based on the number of patients in the departments and on an accrual rate of 65%, the inclusion period will be approximately 24 months, and the follow-up period 6 weeks. LVLS is expected to be 26.02.2024.

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

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

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)

none

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

2017-12-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-02-21

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