Clinical Trials Register

Summary
EudraCT Number:	2019-003058-10
Sponsor's Protocol Code Number:	NADEJ201901
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-09-16
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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2019-003058-10

A.3

Full title of the trial

Prospective, multicentre phase II study of de-escalation of primary chemoradiotherapy of squamous cell carcinoma of oropharynx (OPC) associated with human papilloma virus (HPV)

Prospektívna multicentrická štúdia fázy II deeskalácie primárnej chemorádioterapie skvamocelulárnych karcinómov orofaryngu (OPC) asociovaných s ľudským papiloma vírusom (HPV)

A.3.1

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

NaDeJ (National Deescalation Study One)

NáDeJ (Národná deeskalačná štúdia jedna)

A.3.2

Name or abbreviated title of the trial where available

NaDeJ

NáDeJ

A.4.1

Sponsor's protocol code number

NADEJ201901

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	VÝCHODOSLOVENSKÝ ONKOLOGICKÝ ÚSTAV, a.s.
B.1.3.4	Country	Slovakia
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	VÝCHODOSLOVENSKÝ ONKOLOGICKÝ ÚSTAV, a.s.
B.4.2	Country	Slovakia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	VÝCHODOSLOVENSKÝ ONKOLOGICKÝ ÚSTAV, a.s.
B.5.2	Functional name of contact point	Oddelenia radiačnej onkológie
B.5.3	Address:
B.5.3.1	Street Address	Rastislavova 43
B.5.3.2	Town/ city	Košice
B.5.3.3	Post code	041 91
B.5.3.4	Country	Slovakia
B.5.4	Telephone number	+421556135511
B.5.6	E-mail	dubinsky@vou.sk

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	CISPLATIN EBEWE
D.2.1.1.2	Name of the Marketing Authorisation holder	EBEWE Pharma GmbH, Nfg.KG (AUT)
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	cisplatina
D.3.4	Pharmaceutical form	Concentrate 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	CISPLATINA
D.3.9.1	CAS number	15663-27-1
D.3.9.3	Other descriptive name	cisplatina
D.3.9.4	EV Substance Code	SUB07483MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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.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	Cisplatin Accord
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare Limited (GBR)
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	cisplatina
D.3.4	Pharmaceutical form	Concentrate 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	CISPLATIN
D.3.9.1	CAS number	15663-27-1
D.3.9.4	EV Substance Code	SUB07483MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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

Human Papillomavirus oropharyngeal squamous cell carcinoma

Skvamocelulárny karcinóm orofaryngu asociovaný s ľudským papiloma vírusom

E.1.1.1

Medical condition in easily understood language

Cancer of the throat associated with HPV

Karcinóm hrdla asociovaný s HPV

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	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Assesment of primary CRT de-escalation effectiveness in achieving two-year local disease control and late toxicity prevalence evaluated by CTC AE v.4 and PRO CTC v 4.

Hodnotenie efektivity deeskalácie primárnej CRT v zmysle dosiahnutia 2-ročnej lokoregionálnej kontroly ochorenia a prevalencie neskorej toxicity hodnotenej pomocou CTC AE v.4 a PRO CTC v 4.

E.2.2

Secondary objectives of the trial

Assessment of relapse-free and overall survival,
Assessment of acute toxicity and compliance with treatment,
Analysis of results according to known prognostic factors including smoking,
Assesment of PRO in terms of quality of life before and after treatment using validated questionnaires,
Assesment of the impact of treatment on sexual life using a validated questionnaire,
Standardization of RT OPC planning in participating centers,
Dosimetric risk analysis of xerostomy and dysphagia,
Central assessment of p16 status and its correlation with a specific test aimed at identifying HPV oncogenes,
Molecular profile and genomic analysis of tumors in non-smokers and smokers,
Assessment of negative predictive value of PETCT after CRT.

Hodnotenie prežívania bez recidívy a celkového prežívania,
Hodnotenie akútnej toxicity a kompliancie s liečbou,
Analýza výsledkov podľa známych prognostických faktorov vrátanie fajčenia,
Hodnotenie PRO v zmysle kvality života pred a po liečbe pomocou validovaných dotazníkov,
Hodnotenie vplyvu liečby na sexualitu pomocou validovaného dotazníka,
Štandardizácia plánovania RT OPC v zúčastnených centrách,
Dozimetrická analýza rizika xerostómie a dysfágie,
Centrálne hodnotenie p16 statusu a jeho korelácia s viac špecifickým testom zameraným na identifikáciu HPV onkogénov,
Molekulový profil a genómová analýza nádorov u nefajčiarov a fajčiarov,
Hodnotenie negatívnej prediktívnej hodnoty PETCT po CRT.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Oropharyngeal squamous cell carcinoma
• Positivity of p16 by imunohistochemistry
• Clinical stage T1-T2, N1-N2c or T3, N2-N2c, UICC 8th edition without distant metastases
• The lifetime cumulative history of smoking cannot exceed 20 packages / years
• WHO status 0-1
• Age ≥ 18 years
• Both genders
• Hemoglobin ≥ 10 g/l
• Platelets ≥1 00x 10x9/l
• Neutrophils ≥ 1,5 x 10x9/l
• Adequate renal functions enable one-week therapy of cisplatina
• Bilirubin, AST or ALT 3x upper limit of norm
• Negative pregnancy test
• Signed informed consent
• Slovak language

• Diagnóza skvamocelulárneho karcinómu (SCC) orofaryngu
• Pozitivita odobratého tkaniva p16 imunohistochemickým vyšetrením
• Klinické štádium T1-T2, N1-N2c alebo T3, N2-N2c, UICC 8. vydanie bez vzdialených metastáz
• Celková celoživotná história fajčenia nesmie prekročiť 20 balení / rokov
• WHO výkonnostný stav 0-1
• Vek ≥ 18 rokov
• Obe pohlavia
• Hemoglobín ≥ 10 g/l
• Trombocyty ≥1 00x 10x9/l
• Neutrofily ≥ 1,5 x 10x9/l
• Adekvátne renálne funkcie umožňujúce podanie týždennej cisplatiny
• Bilirubín, AST alebo ALT ˂ 3x vyšší limit normy
• Negatívny test tehotenstva u fertilných žien
• Podpísaný informovaný súhlas
• Slovenčina

E.4

Principal exclusion criteria

• Tumor in the oral cavity or in nasopharynx or in the hypopharynx or larynx if the p16 is also positive
• Tumor of unknown origin (p16 positivity too)
• Simultaneous tumors
• Patients with invasive malignancy (except non-melanoma skin cancer) and a history of tumor diagnosis less than 3 years
• Previous radiotherapy in the head and neck area to overlap the irradiated volume
• Unstable angina or congestive heart failure requiring hospitalization for the last 6 months
• Transmural myocardial infarction last 6 months
• Active infection requiring i.v. antibiotics at the time of registration
• Chronic obstructive bronchoplumonal disease with exacerbation or other respiratory disease requiring hospitalization or postponement of study treatment within 30 days of enrollment
• Hepatic insufficiency with clinical jaundice and impaired coagulation
• Active AIDS disease, but the protocol does not require HIV testing
• Pregnancy
• Previous allergic reaction to cisplatin

• Nádor nachádzajúci sa v ústnej dutine alebo v nosohltane alebo v hypofaryngu alebo laryngu ak je aj p16 pozitívny
• Karcinóm neznámeho pôvodu na krku (aj ak je p16 pozitívny)
• Simultánne nádory
• Pacienti s invazívnou malignitou (okrem nemelanómového karcinómu kože) a anamnézou diagnózy nádoru kratšou ako 3 roky
• Predchádzajúca rádioterapia v oblasti hlavy a krku, ktorá by znamenala prekrývanie ožarovaného objemu
• Nestabilná angína alebo kongestívne zlyhanie srdca vyžadujúce si hospitalizáciu posledných 6 mesiacov
• Transmurálny infarkt myokardu posledných 6 mesiacov
• Aktívna infekcia vyžadujúca si i.v. antibiotiká v čase registrácie
• Chronická obštrukčná bronchoplumonálna choroba s exacerbáciou alebo iné respiračné ochorenie vyžadujúce si hospitalizáciu alebo odloženie štúdiovej liečby v rámci 30 dní pri registrácii
• Hepatálna insufiencia s klinickou žltačkou a porušenou koaguláciou
• Aktívne ochorenie AIDS, avšak protokol si HIV testovanie nevyžaduje
• Tehotenstvo
• Predchádzajúca alergická reakcia na cisplatinu

E.5 End points

E.5.1

Primary end point(s)

Two-year locoregional control

Dvoj-ročná lokoregionálna kontrola

E.5.1.1

Timepoint(s) of evaluation of this end point

2 years

2 roky

E.5.2

Secondary end point(s)

Primary loco-regional control after initial intervention and CRT
Overall survival
Disease-specific survival
Survival without disease
Percentage of distant metastases
Adverse effects
Influencing QoL
Reliability and validity of biomarker p16
Difference in OPC-associated HPV molecular profile in non-smokers and smokers

Primárna loko-regionálna kontrola po úvodnej intervencii a CRT
Celkové prežívanie
Prežívanie špecifické pre ochorenie
Prežívanie bez recidívy
Podiel vzdialených metastáz
Nežiaduce účinky
Ovplyvnenie QoL
Spoľahlivosť a validita biomarkera p16
Rozdiel v molekulovom profile HPV asociovaných OPC u nefajčiarov a fajčiarov

E.5.2.1

Timepoint(s) of evaluation of this end point

2 years

2 roky

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

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

Yes

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.8.3

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

LVLS

Posledná návšteva posledného subjektu

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

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:

120

F.1.3

Elderly (>=65 years)

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2019-09-16.

Yes

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

120

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 will continue to receive clinical follow-up in accordance with local procedures.

Pacienti budú pokračovať v klinickom sledovaní v súlade s miestnymi postupmi.

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

2019-11-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-24

P. End of Trial
P.	End of Trial Status	Ongoing

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