Clinical Trials Register

Summary
EudraCT Number:	2013-002441-12
Sponsor's Protocol Code Number:	1219
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-07
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2013-002441-12

A.3

Full title of the trial

A blind randomized multicenter study of accelerated fractionated chemo-radiotherapy with or without the hypoxic radiosensitizer nimorazole (Nimoral), using a 15 gene signature for hypoxia in the treatment of squamous cell carcinoma of the head and neck.

A.3.1

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

A.4.1

Sponsor's protocol code number

1219

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01880359

A.5.4

Other Identifiers

Name:

DAHANCA

Number:

DAHANCA-29

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	European Organisation for Research and Treatment of Cancer
B.1.3.4	Country	Belgium
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	European Organisation for Research and Treatment of Cancer
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Azanta A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	European Organisation for Research and Treatment of Cancer
B.5.2	Functional name of contact point	Project, Budget and Regulatory Dep
B.5.3	Address:
B.5.3.1	Street Address	Avenue E. Mounier 83/11
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3227741542
B.5.5	Fax number	+3227741030
B.5.6	E-mail	regulatory@eortc.be

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	Nimoral
D.2.1.1.2	Name of the Marketing Authorisation holder	Azanta A/S
D.2.1.2	Country which granted the Marketing Authorisation	India
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/093/10
D.3 Description of the IMP
D.3.1	Product name	Nimorazole
D.3.4	Pharmaceutical form	Film-coated 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.3.8	INN - Proposed INN	NIMORAZOLE
D.3.9.1	CAS number	6506-37-2
D.3.9.3	Other descriptive name	Nimoral
D.3.9.4	EV Substance Code	SUB09298MIG
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	500
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	Film-coated tablet
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

Squamous cell carcinoma of the head and neck

E.1.1.1

Medical condition in easily understood language

Squamous cell carcinoma of the head and neck

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	18.1
E.1.2	Level	PT
E.1.2	Classification code	10060121
E.1.2	Term	Squamous cell carcinoma of head and neck
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

There are two primary objectives in this study:
- to evaluate in a blinded randomized trial, whether the hypoxic cell radiosensitizer nimorazole can improve the effect of primary curative accelerated fractionated concomitant chemo-radiotherapy with cisplatin given to patients with locally advanced (HNSCC) larynx, hypopharynx and HPV/p16 negative oropharynx.
- To investigate if patients who may have such benefit can be predicted by the use of a hypoxic gene profile, i.e. if the treatment benefit is larger and essentially restricted to the subset of patients who are hypoxic cell signature positive.

E.2.2

Secondary objectives of the trial

The secondary objective will aim to evaluate the feasibility and morbidity of such a treatment strategy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

REGISTRATION STEP:
♦written informed consent must be given
newly diagnosed tumors classified as stage III-IV located in the pharynx, oropharynx and hypopharynx (unknown primary and oral cavity are not eligible)
♦ HPV/p16 negative (= or < 70% positively stained cells), assessed locally for tumors of the oropharynx
♦tumor of the larynx and hypopharynx regardless of the HPV status
histopathological diagnosis of invasive squamous cell carcinoma in the primary tumour
♦no distant metastasis (M0)
♦= or > 18 years old
♦tumor material available for central testings of the hypoxic gene signature
RANDOMIZATION STEP
♦ WHO performance 0-2.
♦ All hematology and biochemical investigations, should be done within 4 weeks before randomization (maximum 6 weeks before treatment starts)
♦ Normal bone marrow function based on routine blood samples, i.e. neutrophils ≥ 1.0 x 109/L, platelets ≥ 75 x 109/L, hemoglobin ≥ 10.0 g/dL or 6.2 mmol/L
♦ Normal kidney function creatinine clearance ≥ 60 mL/min, and Electrolyte balance: calcium ≤ 11.5 mg/dl or 2.9 mmol/L, magnesium ≥ 1.2 mg/dl or 0.5 mmol/L
♦ Normal liver function assessed by routine laboratory examinations, i.e. bilirubin < 1.5 x ULN, ALT< 3 x ULN, alkaline phosphatases < 3 x ULN
♦ No prior or current anticancer treatment to the head and neck area (e.g. radical attempted or tumor reductive surgery, neo-adjuvant chemotherapy, EGFR inhibitors or radiotherapy).
♦ Patients must be candidate for curative intent external beam chemo-radiotherapy, and must be expected to complete the treatment.
♦ All patients should have an oral and dental examination including preferably clinical and radiological examination. Whenever indicated, extraction of dental elements should be carried out at least 10 days before treatment start; for 1-2 (max 2) monoradicular single tooth extractions (if not continuous a max of 4) without bone resection 5 days (as a minimum) are allowed
♦ Radiotherapy planned to start within acceptable delay (preferably within 2 weeks and a maximum of 4 weeks from randomization).
♦ Radiotherapy planned to start within 8 weeks from baseline imaging tumor assessment.
♦ Patients should not have symptoms of peripheral neuropathy, assessed by medical history.
♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial.
♦ All subjects must:
♦ Agree to abstain from donating blood while receiving therapy and for four weeks following discontinuation of therapy.
♦ Agree not to share study medication with another person and to return all unused study drug to the investigator.

E.4

Principal exclusion criteria

♦ Patients who have received treatment with any investigational drug substance within 4 weeks prior to randomization.
♦ Current participation in any other interventional clinical study.
♦ Pregnant or breast-feeding female patient. Pregnancy test should be done within 72 hours from treatment start.
♦ Female subjects of childbearing potential (defined as a sexually mature woman who 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally post-menopausal (amenorrhoea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)) not willing to use adequate contraception during study and for 6 month after last dose of study drug.
♦ Male subjects not willing to use condoms throughout study drug therapy, and for 6 months after cessation of study therapy if their partner is of childbearing potential and has no contraception.
♦ Known or suspected HIV infection.
♦ Second malignancies in the 3 years prior to study entry with the exception of surgically cured carcinoma in situ of the cervix, in situ breast cancer, incidental finding of stage T1a or T1b prostate cancer, and basal/squamous cell carcinoma of the skin.
♦ Uncontrolled or chronic bacterial, fungal or viral infection.
♦ Known or suspected hypersensitivity to component(s) of investigational product or cisplatin contraindication.

E.5 End points

E.5.1

Primary end point(s)

Locoregional control rate

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will have a follow-up visit 3 months after treatment and then every 2 months for the subsequent 2 years (at 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 months) then every 4 months for the next 3 visits (at 27, 31, 35 months) and then every 6 months thereafter up to year 5 (at 41, 47, 53, 59 months).

E.5.2

Secondary end point(s)

♦ Local control (T-site)
♦ Regional control (N-site)
♦ Time to distant metastasis
♦ Overall survival
♦ Disease-free survival
♦ Disease-specific survival
♦ Acute and late morbidity

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

Australia

Belgium

Canada

France

Germany

Netherlands

New Zealand

Poland

Switzerland

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

End of study occurs when all of the following criteria have been satisfied:
1. Ninety days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis

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:

350

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

290

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

470

F.4.2.2

In the whole clinical trial

640

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)

Patients discontinuing therapy in the absence of progression should not receive any other anti-cancer treatment before their disease progresses, unless this is clearly in the interest of the patient. After progression, the treatment will be left to the discretion of the treating physician.

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

2013-11-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-09-06

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