Clinical Trials Register

Summary
EudraCT Number:	2013-000182-37
Sponsor's Protocol Code Number:	BREACH
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-02-24
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-000182-37

A.3

Full title of the trial

Brentuximab vedotin associated with chemotherapy in untreated patients with stage I/II unfavourable Hodgkin lymphoma. A randomized phase II LYSAFIL-EORTC intergroup study

Brentuximab Vedotin in associazione con chemioterapia nel trattamento di prima linea di pazienti con diagnosi di Linfoma di Hodgkin sfavorevole in stadio I-II. Studio intergruppo randomizzato di fase II LYSA-FIL-EORTC

A.3.1

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

Brentuximab vedotin associated with chemotherapy in untreated patients with stage I/II unfavourable Hodgkin lymphoma

Brentuximab associato a chemioterapia come trattamento di prima linea di pazienti con Linfoma di Hodgkin stadio I-II sfavorevole

A.4.1

Sponsor's protocol code number

BREACH

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	LYSARC
B.1.3.4	Country	France
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	Millennium: The Takeda Oncology Company
B.4.2	Country	United States
B.4.1	Name of organisation providing support	LYSARC
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dr Luc-Matthieu Fornecker
B.5.2	Functional name of contact point	Co-coordinating Investigator
B.5.3	Address:
B.5.3.1	Street Address	CHU Strasbourg, Service Hématologie Hautepierre, Hôpital de Hautepierre, BP. 428
B.5.3.2	Town/ city	Strasbourg
B.5.3.3	Post code	67098
B.5.3.4	Country	France
B.5.4	Telephone number	0033388127676
B.5.5	Fax number	0033388127681
B.5.6	E-mail	luc-matthieu.fornecker@chru-strasbourg.fr

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	Adcetris (Brentuximab Vedotin)
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Global Research and Development Centre (Europe) Ltd
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	Brentuximab Vedotin
D.3.2	Product code	SGN-01
D.3.4	Pharmaceutical form	Powder for 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.3.11 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)	Yes
	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	Yes
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

Hodgkin Lymphoma

Linfoma di Hodgkin

E.1.1.1

Medical condition in easily understood language

Hodgkin Lymphoma

Linfoma di Hodgkin

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10020328
E.1.2	Term	Hodgkin's lymphoma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To improve the PET negativity after two cycles of immuno-chemotherapy

Aumentare la percentuale PET negatività dopo due cicli di immunochemioterapia

E.2.2

Secondary objectives of the trial

Secondary efficacy endpoint:
- CR rate (according to Cheson 2007) at the end of treatment
- Progression-free survival (PFS)
- Overall survival

Secondary safety endpoint:
- Toxicity of brentuximab vedotin in combination with combined modality treatment

Endpoint secondari di efficacia:
- percentuale di risposte complete (RC) alla fine del trattamento; la
valutazione della risposta è prevista secondo i criteri di Cheson 2007
- sopravvivenza libera da progressione (PFS)
- sopravvivenza globale (OS)

Endpoint secondario di sicurezza:
- Tossicità del brentuximab vedotin associato a un trattamento combinato di chemioradioterapia

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically confirmed CD30+ classical Hodgkin lymphoma according to local evaluation
- Supradiaphragmatic Ann Arbor clinical stage I or II
- Previously untreated
- PET scan without IV contrast at diagnosis available for central review with at least one hypermetabolic lesion
- Unfavourable (U) characteristics according to the classic EORTC/LYSA clinical prognostic factors. Unfavourable (U) subset includes patients with at least one of the following factors:
a) CSII ≥ 4 nodal areas
b) age ≥ 50 yrs
c) M/T ratio ≥ 0.35
d) ESR ≥ 50 (without B-symptoms) or ESR ≥ 30 with B-symptoms
- ECOG performance status 0-2
- Life expectancy > 6 months
- Age 18 to 60 years (≥ 18 years to ≤ 60 years)
- Patients must be available for periodic blood sampling, study-related assessments, and management of toxicity at the treating institution.
- Female patients who:
a) Are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile,
OR
b) If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 6 months after the last dose of study drug, or agree to
completely abstain from heterosexual intercourse
- Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a) Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
- Patients must give written informed consent. A copy of the informed signed consent form will be retained in the patient’s chart.
- Required baseline laboratory data:
a) Absolute neutrophil count ≥ 1,500/µL
b) Platelet count ≥ 75,000/ µL
c) Hemoglobin ≥ 8g/dL
d) Serum total bilirubin ≤ 1.5 X ULN unless the elevation is known to be due to Gilbert syndrome.
e) Serum creatinine ≤ 2.0 mg/dL and/or calculated creatinine clearance > 40 mL/minute (Cockcroft-Gault formula or MDRD)
f) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN

- Diagnosi locale confermata istologicamente di linfoma di Hodgkin classico
CD30 positivo
- Localizzazione sovradiaframmatica di malattia in stadio di Ann-Arbor I-II
- Pazienti vergini da precedenti trattamenti
- PET/TAC senza mezzo di contrasto basale che documenti almeno una lesione ipermetabolica disponibile per la revisione centralizzata
- Malattia con profilo di rischio Sfavorevole (U) secondo i criteri EORTC/LYSA. Sulla base di questi criteri un paziente viene definito a rischio Sfavorevole (U) se presenta almeno uno dei seguenti fattori:
a) stadio clinico II con ≥ 4 aree nodali [NB: le aree nodali al di sopra del diaframma sono in tutto 5: cervicale destra e sinistra, mediastino, ascellare destra e sinistra; più lesioni nodali in una stessa area devono essere conteggiate come un’unica area coinvolta]
b) età ≥ 50 anni
c) M/T ratio (rapporto mediastino/torace) ≥ 0.35
d) VES ≥ 50 (in assenza di sintomi B) o VES ≥ 30 in presenza di sintomi B
- ECOG performance status 0-2
- Aspettativa di vita > 6 mesi
- Età 18-60 anni (≥ 18 anni e ≤ 60 anni)
- Disponibilità dei pazienti ad eseguire gli esami di laboratorio periodici previsti dal protocollo, a sottoporsi alle valutazioni strumentali e a tutte le procedure previste dallo studio, incluse visite periodiche per la valutazione di eventualieventi avversi da pianificare presso la struttura dove ricevono il trattamento.
- Pazienti femmine in menopausa conclamata da almeno un anno al momento della visita di screening oppure sterili per procedura chirurgica; donne in età fertile possono essere incluse se acconsentono ad adottare due diversi metodi contraccettivi sicuri contemporaneamente dal momento in cui firmano il consenso informato fino a 6 mesi dopo l’ultima dose di trattamento secondo protocollo oppure se accettano di astenersi completamente da rapporti
eterosessuali per lo stesso periodo
- Pazienti maschi, anche se sottoposti a vasectomia, che acconsentano ad adottare metodi contraccettivi di barriera sicuri per tutto il periodo di durata del trattamento e fino a 6 mesi dopo avere ricevuto l’ultima dose di trattamento o che acconsentano ad astenersi completamente da rapporti eterosessuali per lo stesso periodo
- Pazienti che rilascino un consenso informato scritto. Una copia del consensoinformato firmato dovrà essere conservata nella documentazione del paziente.
- Pazienti con i seguenti valori di laboratorio alla diagnosi:
a) Conta assoluta dei neutrofili (ANC) ≥ 1,500/µL
b) Piastrine ≥ 75,000/ µL
c) Emoglobina ≥ 8g/dL
d) Bilirubina sierica totale ≤ 1.5 volte il limite superiore di normalità, a meno che il valore elevato sia dovuto ad accertata sindrome di Gilbert.
e) Creatinina sierica ≤ 2.0 mg/dL e/o clearance della creatinina calcolata > 40 mL/minuto (formula di Cockcroft-Gault o formula MDRD)
f) Alanina aminotransferasi (ALT, GPT) e aspartato amino transferasi (AST, GOT) ≤ 3 volte il limite superiore di normalità

E.4

Principal exclusion criteria

- Histological diagnosis different from classical Hodgkin Lymphoma. Nodular lymphocyte predominant subtypes (nodular paragranuloma or Poppema paragranuloma) are excluded
- Known cerebral or meningeal disease of any etiology, including signs or symptoms of PML
- Any sensory or motor peripheral neuropathy ≥ Grade 2
- Known history of any of the following cardiovascular conditions
a) Myocardial infarction within 2 years of randomization
b) New York Heart Association (NYHA) Class III or IV heart failure
c) Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction
system abnormalities
d) Recent evidence (within 30 days before first dose of study drug) of a leftventricular ejection
fraction <50%
- Unstable diabetes mellitus (to avoid uninterpretable FDG-PET scan).
- Known HIV positive
- HCV positive
- HBV positive. This means:
a) HBsAg positive
b) HBsAg negative, anti-HBs positive and/or anti-HBc positive and
detectable viral DNA
c) Note:
* Patients who are HBsAg negative and viral DNA negative are eligible
* Patients who are seropositive due to a history of hepatitis B vaccine are eligible.
- Any history of cancer during the last 5 years, with the exception of nonmelanoma skin tumors. Carcinoma
in situ of any type are not excluded if they have undergone complete resection.
- Dementia or altered mental status that would preclude compliance with drug delivery
- Pregnancy or breastfeeding. Females of childbearing potential having a positive β-HCG pregnancy test result during screening or a positive pregnancy test (urinary or blood) within 1 day before start of treatment.
- Previous treatment with any anti-CD30 antibody
- Known hypersensitivity to any excipients contained in the brentuximabvedotin formulation or known contra-indication to any drug contained in thechemotherapy regimens (for ex.: pulmonary or neurological disease grade ≥2)
- Treatment with corticosteroids before baseline PET scan (PET-0)
- Patients with known active viral, bacterial, or fungal infection requiring treatment with antimicrobial therapy or with untreated known active Grade 3 viral, bacterial, or fungal infection, within 2 weeks prior to the first dose of brentuximab vedotin
- Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy or immuno-chemotherapy

- Diagnosi istologica diversa da quella di linfoma di Hodgkin classico. I sottotipi di Linfoma di Hodgkin a prevalenza linfocitaria (nodular paragranuloma o Poppema paragranuloma) sono esclusi.
- Presenza di malattia cerebrale o meningea di qualsiasi eziologia, inclusi segni o sintomi di Leucoencefalopatia Multifocale Progressiva
- Qualsiasi neuropatia sensoriale o motoria di grado ≥ 2
- Storia clinica di una qualsiasi delle seguenti patologie cardiovascolari:
a) Infarto miocardico nei 2 anni precedenti l’entrata in studio
b) Insufficienza cardiaca di Classe III-IV secondo la classificazione NYHA (New York Heart Association)
c) Evidenza di patologie cardiache non controllate in atto, incluse aritmie cardiache, insufficienza cardiaca congestizia, angina o evidenza elettrocardiografica di ischemia acuta o anomalie del sistema di conduzione
d) Riscontro recente (nei 30 giorni prima della somministrazione della prima
dose del trattamento previsto dal protocollo) di una LVEF <50%
- Diabete mellito non controllato (per evitare di avere FDG-PET non interpretabili)
- Pazienti HIV positivi
- Pazienti HCV positivi
- Pazienti HBV positivi, intendendo con questo:
a) Pazienti HBsAg positivi
b) Pazienti con HBsAg negativo, anti-HBs positivo e/o anti-HBc positivo e ricerca di DNA virale positiva
* Pazienti HBsAg negativi e DNA virale negativi sono eleggibili
* Pazienti sieropositivi per storia clinica di Epatite B o perché vaccinati
sono eleggibili
- Qualsiasi precedente diagnosi di neoplasia negli ultimi 5 anni, fatta eccezione per tumori della cute non melanomatosi e carcinomi in situ di qualsiasi tipo purché siano stati trattati con resezione chirurgica completa
- Demenza o altre condizioni mentali o psicologiche che rendano il paziente non compliante al trattamento secondo protocollo
- Gravidanza o allattamento. Donne in età fertile con β-HCG positivo durante le
procedure di screening o con un test di gravidanza positivo (eseguito su urine o sangue) entro il giorno prima l’inizio della somministrazione della prima dose di trattamento
- Precedente trattamento con qualsiasi anticorpo monoclonale anti-CD30
- Ipersensibilità nota a qualsiasi eccipiente contenuto nella formulazione di brentuximab vedotin o controindicazione nota alla somministrazione di uno dei farmaci previsti dalla schedula di chemioterapia del protocollo (ad es. patologie polmonari o neurologiche di grado ≥ 2)
- Trattamento con steroidi prima della PET basale (PET-0)
- Pazienti con infezione virale, batterica o fungina attiva che richieda trattamento con terapia antimicrobica o con infezione virale, batterica o fungina attiva nota di grado 3 riscontrata fino a 2 settimane prima della somministrazione della prima dose di brentuximab vedotin
- Trattamento con qualsiasi altro farmaco sperimentale nei 30 giorni prima del
previsto primo ciclo di chemioterapia o chemioimmunoterapia

E.5 End points

E.5.1

Primary end point(s)

PET 2 assessment according to the five-point scale Deauville criteria (Negative = 1, 2, 3 and Positive = 4, 5), based on central review.

Valutazione della PET 2 secondo i criteri di Deaville (five-point scale): PET negativa: score 1,2,3; PET positiva: score 4,5. Lo score viene definito mediante revisione centralizzata delle PET.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 2 cycles of chemotherapy or immuno-chemotherapy (ABVD or AVD/Brentuximab vedotin)- 2 months

Dopo due cicli di chemioterapia o immuno-chemioterapia (ABVD o AVD/Brentuximab vedotin)- 2 mesi

E.5.2

Secondary end point(s)

Endpoint secondari di efficacia:
- percentuale di risposte complete (RC) alla fine del trattamento; la valutazione della risposta è prevista secondo i criteri di Cheson 2007
- sopravvivenza libera da progressione (PFS)
- sopravvivenza globale (OS)

Endpoint secondario di sicurezza:
- Tossicità del brentuximab vedotin associato a un trattamento combinato
di chemioradioterapia

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary efficacy endpoint:
- Disease response evaluation at end of treatment (after radiotherapy) will be used to determine the Response Rate.
- PFS is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. If a subject has not progressed or died, PFS will be censored at the time of last visit assessment.
- Overall survival will be measured from date of randomization into the study to the date of death from any cause.

Secondary safety endpoint:
- End of treatment

Endpoint secondari di efficacia:
- La valutazione della risposta alla fine del trattamento (dopo radioterapia) sarà utilizzato per valutare il tasso di risposta (6 mesi circa)
- PFS sarà definita come il tempo dalla randomizzazione nello studio fino a progressione o morte per qualsiasi causa. Se per un soggetto non si verificano progressione o morte, la PSF sarà valutata al tempo dell’ultima visita effettuata.
- OS sarà misurata dalla data di randomizzazione nello studio fino alla data di morte per qualsiasi causa.

Endpoint secondario di sicurezza:
- Fine del trattamento (6 mesi circa)

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

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

105

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

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

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

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:

170

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

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

170

F.4.2.2

In the whole clinical trial

170

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)

At the end of treatment, if necessary, the patiennts will receive a salvage treatment according to local investigator

Alla fine del trattamento, se necessario, i pazienti riceveranno una terapia di salvataggio a discrezione dello sperimentatore locale.

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

2015-04-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-03-05

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

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