Clinical Trials Register

Summary
EudraCT Number:	2016-002509-21
Sponsor's Protocol Code Number:	FIL-Rouge
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-06-17
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-002509-21

A.3

Full title of the trial

A randomized, open-label, multicenter, phase III, 2-arm study comparing efficacy and tolerability of the intensified variant ‘dose-dense/dose-intense ABVD’ (ABVD DD-DI) with an interim PET response-adapted ABVD program as upfront therapy in advanced-stage classical Hodgkin Lymphoma (HL).

Studio randomizzato, open-label, multicentrico, di fase III a 2 bracci di confronto dell’efficacia e della tollerabilità della variante intensificata ‘dose-dense/dose-intense ABVD’ (ABVD DD-DI) e un programma terapeutico con ABVD a dosi standard per 2 cicli e successivamente orientato in base alla risposta PET, come trattamento di prima linea di pazienti con Linfoma di Hodgkin classico (HL) in stadio avanzato

A.3.1

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

A randomized, open-label, multicenter, phase III, study comparing efficacy and tolerability of the intensified variant ‘dose-dense/dose-intense ABVD’ with an interim PET response-adapted ABVD program at first line therapy in advanced-stage classical Hodgkin Lymphoma (HL).

Studio randomizzato in aperto, multicentrico, di fase III di confronto dell’efficacia e della tollerabilità della variante intensificata ‘dose-dense/dose-intense ABVD con un programma terapeutico con ABVD a dosi standard per 2 cicli e successivamente orientato in base alla risposta PET, come trattamento di prima linea di pazienti con Linfoma di Hodgkin classico (HL) in stadio avanzato

A.3.2

Name or abbreviated title of the trial where available

FIL-Rouge

A.4.1

Sponsor's protocol code number

FIL-Rouge

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	FONDAZIONE ITALIANA LINFOMI ONLUS
B.1.3.4	Country	Italy
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	AIFA - Italian Medicines Agency
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	SIE, Società Italiana di Ematologia
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione Italiana Linfomi Onlus
B.5.2	Functional name of contact point	Uffici Studi FIL
B.5.3	Address:
B.5.3.1	Street Address	c/o Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto Università di Mode
B.5.3.2	Town/ city	Modena
B.5.3.3	Post code	41124
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390594222688
B.5.5	Fax number	00390594223602
B.5.6	E-mail	startup@filinf.it

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	DOXORUBICINA ACCORD HEALTHCARE ITALIA - " 2MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE" 1 FLACONCINO IN VETRO DA 100MG/50ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ACCORD HEALTHCARE ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Doxorubicina
D.3.2	Product code	[IMP1]
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	DOXORUBICINA CLORIDRATO
D.3.9.1	CAS number	23214-92-8
D.3.9.2	Current sponsor code	IMP1
D.3.9.3	Other descriptive name	DOXORUBICIN
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	2
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	antibiotico antraciclinico
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	BLEOPRIM - 15 MG POLVERE PER SOLUZIONE INIETTABILE 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Bleomicina
D.3.2	Product code	[IMP2]
D.3.4	Pharmaceutical form	Powder for solution for injection
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	BLEOMICINA SOLFATO
D.3.9.1	CAS number	11056-06-7
D.3.9.2	Current sponsor code	IMP2
D.3.9.3	Other descriptive name	Bleomycin
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15000
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	antibiotico ad azione antimitotica
D.IMP: 3
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	VINBLASTINA TEVA - 1 MG/ML SOLUZIONE INIETTABILE 1 FLACONCINO DA 10 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Vinblastina
D.3.2	Product code	[IMP3]
D.3.4	Pharmaceutical form	Solution for injection
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	VINBLASTINA SOLFATO
D.3.9.1	CAS number	865-21-4
D.3.9.2	Current sponsor code	IMP3
D.3.9.3	Other descriptive name	Vinblastine
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	alcaloide indolico
D.IMP: 4
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	DACARBAZINA LIPOMED - 200 MG POLVERE PER SOLUZIONE INIETTABILE O PER INFUSIONE 10 FLACONCINI
D.2.1.1.2	Name of the Marketing Authorisation holder	LIPOMED GMBH
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Dacarbazina
D.3.2	Product code	[IMP4]
D.3.4	Pharmaceutical form	Powder for solution for injection
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	DACARBAZINA
D.3.9.1	CAS number	4342-03-4
D.3.9.2	Current sponsor code	IMP4
D.3.9.3	Other descriptive name	DACARBAZINE
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	10
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	agente alchilante e citostatico

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

Advanced stage (IIB-IV) Hodgkin Lymphoma.

Linfoma di Hodgkin in stadio avanzato (IIB-IV).

E.1.1.1

Medical condition in easily understood language

Advanced-stage Hodgkin Lymphoma patients

Pazienti con Linfoma di Hodgkin in stadio avanzato

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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

The primary objective is to demonstrate the superiority of an intensified ABVD variant (ABVD DD-DI, Experimental arm) over an interim PET response-adapted ABVD treatment (Comparator arm) in improving PFS.

Dimostrare la superiorità della variante intensificata dell’ABVD (ABVD DD-DI, braccio sperimentale) su di un trattamento con ABVD standard response-adapted in base ad una PET precoce (braccio di confronto) in termini di malattia libera da progressione (PFS).

E.2.2

Secondary objectives of the trial

a) To compare the anti-lymphoma activity of ABVD DD-DI and interim PET response-adapted ABVD according to Lugano 2014 Classification.
b) To compare the Overall Survival of ABVD DD-DI vs. interim PET response-adapted ABVD
c) To compare the safety of ABVD DD-DI and interim PET response-adapted ABVD
d) To compare the effect of ABVD DD-DI and interim PET response-adapted ABVD on Quality of life (QoL)
e) To compare ABVD DD-DI vs. interim PET response-adapted ABVD in term of cost-effectiveness.

Confrontare la schedula ABVD DD-DI (intensificazione upfront) e la strategia ABVD PET-adpated (intensificazione deferita) in termini di: attività anti-linfoma secondo la Lugano Classification; sopravvivenza globale; sicurezza (tossicità); qualità della vita; rapporto costi/benefici.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Biological study ancillary to FIL-Rouge clinical trial

title: Circulating tumor DNA genotyping for biological monitoring of patients with advanced-stage classical HL receiving upfront ABVD-based chemotherapy. An ancillary study to the FIL-Rouge Phase III trial."

Version 1.0 of May 7, 2019

Primary Objective
To assess whether plasma circulating tumor DNA (ctDNA) analysis could be used as a radiation-free tool to monitor residual disease in patients with advanced classical Hodgkin lymphoma (cHL) treated in the context of the FIL-Rouge phase III clinical trial. All objectives involving clinical endpoints (response at the end of treatment, PFS) will be analyzed in the experimental arm (where the interim PET/CT has no role in modifying treatment).
In particular, the primary objective is: to assess the prognostic value of ctDNA analysis on clinical patients’ outcome in terms of response at the end of treatment.
Secondary Objectives
• To assess the diagnostic accuracy of ctDNA analysis on residual disease at interim PET/CT;
• To assess the prognostic value of ctDNA analysis on progression-free survival (PFS);
• To compare the prognostic value of ctDNA analysis with interim PET/CT and to evaluate if combined use of ctDNA and interim PET/CT could improve the prognostic value on patients’ outcome;
• To identify the best ctDNA threshold with the best discriminant prognostic value on clinical patients’ outcome;
• To analyze the concordance between prognostic information given by ctDNA analysis and PET/CT after 2 months of treatment;
• To assess the accuracy ctDNA analysis in documenting the clonal evolution of the tumor at recurrence, in comparison with baseline.;
• To assess the predictive/prognostic value of changes in circulating biomarkers (cytokines, chemokines, soluble receptors/ligands) in pts treated with standard or intensified ABVD.

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Studio Biologico ancillare dello studio FIL-Rouge

titolo: "Genotipizzazione del DNA tumorale circolante per il monitoraggio biologico di pazienti con linfoma di Hodgkin classico in stadio avanzato trattati con chemioterapia iniziale a base di ABVD.
Studio ancillare allo studio clinico di fase III FIL-Rouge."
Versione 1 del 7 maggio 2019

Obiettivo primario
Valutare se l’analisi del DNA tumorale circolante (ctDNA) può essere utilizzata, come strumento libero da radiazioni, per monitorare la malattia residua in pazienti con Linfoma di Hodgkin classico (cHL) in stadio avanzato sottoposti a trattamento nell’ambito dello studio clinico di fase III FIL-Rouge. Tutti gli obiettivi che riguardano endpoint clinici (risposta alla fine del trattamento, sopravvivenza libera da progressione o PFS) verranno analizzati solo sui pazienti del braccio sperimentale (quello in cui il risultato della PET/CT intermedia non ha alcun ruolo nel modificare il trattamento successivo dei pazienti). In particolare, l’obiettivo primario è: valutare il valore prognostico dell’analisi del ctDNA sull’outcome clinico dei pazienti in termini di risposte alla fine del trattamento.
Obiettivi secondari
• Valutare l’accuratezza diagnostica dell’analisi del ctDNA nello stimare la malattia minima residua alla valutazione PET/TAC intermedia;
• Valutare il ruolo prognostico dell’analisi del ctDNA sulla sopravvivenza libera da progressione (PFS);
• Confrontare il valore prognostico dell’analisi del ctDNA con quello della PET/CT intermedia e valutare se l’uso combinato dei risultati ottenuti dall’analisi del ctDNA e alla PET/CT intermedia può aumentare il valore prognostico sull’outcome dei pazienti;
• Identificare la soglia migliore del ctDNA con il migliore valore prognostico discriminante sull’outcome clinico dei pazienti;
• Analizzare la concordanza tra le informazioni sulla prognosi fornite dall’analisi del ctDNA e dal risultato della PET/CT dopo 2 mesi di trattamento;
• Valutare l'accuratezza dell'analisi ctDNA nel documentare l'evoluzione clonale del tumore alla recidiva, rispetto al basale;
• Valutare il ruolo predittivo/prognostico delle variazioni nei valori dei biomarcatori circolanti (citochine, chemochine, recettori/ligandi solubili) nei pazienti del braccio standard e del braccio sperimentale.

E.3

Principal inclusion criteria

- Histologically confirmed classical HL;
- Previously untreated disease;
- Age 18-60 years;
- Ann Arbor stage IIB with extranodal involvement
and/or mediastinal bulk, III and IV (Appendix A);
- At least one target PET-avid bidimensionally assessable lesion;
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ¿2 (Appendix B);
- Adequate organ and marrow function as defined below: absolute neutrophil count >1,0 x10^9/L; platelets >75 x10^9/L;
- Total bilirubin <2 mg/dl without a pattern consistent with Gilbert's syndrome;
- Aspartate Transaminase and Alanine Transaminase (AST/ALT) <3 X institutional Upper Limits of Normality (ULN);
- Creatinine within normal institutional limits or creatinine clearance >50 mL/min/1.73 m2 (Appendix C);
- Females of childbearing must have a negative pregnancy test at medical supervision even if had been using effective contraception;
- Life expectancy > 6 months;
- Able to adhere to the study visit schedule and other protocol requirements;
- Sign (or their legally acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study;
- Access to PET-CT scans facilities qualified by FIL;

- Conferma istologica di HL classico
- Pazienti vergini da precedenti trattamenti chemioterapici, di radioterapia o trattati con farmaci sperimentali per HL
- Età 18-60 anni
- Stadio IIB con coinvolgimento extranodale e/o bulky mediastinico, III e IV (Appendice A)
- Presenza di almeno una lesione bidimensionale PET-avida
- ECOG performance status¿ 2 (Appendice B)
- Adeguata funzionalità d’organo e midollo definita come segue: neutrofili >1,0 x10^9/L e piastrine >75 x10^9/L
- Adeguata funzionalità epatica (bilirubina totale <2 mg/dl in assenza di sindrome di Gilbert)
- Aspartato amino-transferasi (AST/GOT) e alanina amino-transferasi (ALT/GPT) <3 volte il limite superiore normale
- Adeguata funzionalità renale (creatinina nella norma o clearance della creatinina >50 mL/min/1.73 m2 (Appendice C)
- Test di gravidanza per le donne in età fertile, anche se utilizzano adeguati metodi contraccettivi
- Aspettativa di vita >6 mesi.
- Disponibilità del paziente ad essere seguito per tutte le fasi del trattamento chemioterapico e per il successivo follow-up
- Consenso informato scritto
- Accesso alla piattaforma PET-CT scans qualificata dalla FIL

E.4

Principal exclusion criteria

- Nodular Lymphocyte Predominant HL
- Ann Arbor stage IIB without extranodal involvement and/or bulky
- Prior chemotherapy or radiation therapy
- Pregnant or lactating females
- Known hypertension (as defined by the updated Guidelines [76]), cardiac arrhythmia, conduction abnormalities, ischemic cardiopathy, left ventricular hypertrophy or left ventricular ejection fraction (LVEF) =50% at echocardiography.
- Abnormal QTc interval prolonged (>450 msec in males; >470 msec in women)
- Diffusion lung capacity for CO (DLCO) and/or forced expiratory volume in the 1st second (FEV1) tests <50% of predicted not related to impaired respiratory capacity due to airway compression by mediastinal masses or parenchymal lymphoma (see chapter 16)
- Known cerebral or meningeal disease (HL or any other etiology)
- Prior history of malignancies unless the patient has been free of the disease for five years. Exceptions include the following:
o Basal cells carcinoma of the skin
o Squamous cell carcinoma of the skin
o Carcinoma in situ of the cervix
o Carcinoma in situ of the breast
o Prostate cancer with TNM stage T1a or T1b
- Uncontrolled infectious disease
- Human immunodeficiency virus (HIV) positivity or active infectious A, B or C hepatitis. HBsAg-negative patients with anti-HBc positive antibody can be enrolled provided that Hepatitis B Virus (HBV)-DNA are negative and that antiviral treatment with nucleos(t)ide analogs is provided
- Uncompensated diabetes
- Refusal of adequate contraception
- Any medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment.

• Diagnosi di linfoma di Hodgkin nodulare a predominanza linfocitaria (NLPHL)
• Stadio clinico IIB senza coinvolgimento extranodale e/o bulky mediastinico
• Precedente trattamento con chemioterapia o radioterapia
• Donne incinta o in allattamento
• Ipertensione (così come definita dalla versione aggiornata delle Linee Guida Internazionali), aritmia cardiaca, disordini di conduzione, cardiopatia ischemica, ipertrofia ventricolare sinistra o frazione di eiezione ventricolare sinistra (LVEF) =50% in ecocardiogramma.
• Intervallo QTcF anormalmente prolungato (> 450 msec negli uomini e > 470 msec nelle donne)
• Test sulla Capacità di diffusione del monossido di carbonio (DLCO) e/o volume espiratorio forzato nel primo secondo (FEV1) <50% del previsto se non relativo a una funzionalità respiratoria compromessa da compressione delle vie respiratoria da masse mediastiniche o da coinvolgimento parenchimale da parte del linfoma
• Nota malattia cerebrale o delle meningi (LH o altra eziologia)
• Anamnesi di neoplasia pregressa, ad eccezione di pazienti in remissione complete da almeno 5 anni. Le eccezioni riguardano il carcinoma delle cellule basali della cute, il carcinoma della cute a cellule squamose, il carcinoma in situ della cervice uterina, il carcinoma in situ della mammella, il carcinoma prostatico in TNM stadio T1a o T1b.
• Malattia infettiva non controllata
• Infezione da HIV nota o infezione attiva da virus dell’epatite di tipo A, B o C
• Diabete mellito difficilmente controllabile con adeguata terapia insulinica
• Rifiuto all’adozione di adeguate misure contraccettive
• Qualsiasi condizione medica o psichiatrica che potrebbe, a giudizio dello sperimentatore, potenzialmente interferire con la corretta e complete somministrazione del trattamento

E.5 End points

E.5.1

Primary end point(s)

PFS is defined as the interval elapsing from randomization until lymphoma progression or death as a result of any cause.

PFS, definita come l’intervallo di tempo dalla randomizzazione alla ripresa di malattia o alla morte per qualsiasi causa

E.5.1.1

Timepoint(s) of evaluation of this end point

3 years

3 anni

E.5.2

Secondary end point(s)

Complete remission rate (CR rate); PET/CT response rate after 2 months of chemotherapy ; Event Free Survival (EFS); Disease free survival (DFS); Overall survival (OS); Acute severe toxicity, acute and delayed pulmonary toxicity, acute and delayed cardiac toxicity. Late toxicity and second malignancies; Quality of life (QoL); Cost-effectiveness analyses

Tasso di remissioni complete (CR rate); Tasso di risposta alla PET/CT dopo 2 mesi di trattamento; Sopravvivenza libera da eventi (EFS); Sopravvivenza libera da malattia (DFS); Sopravvivenza globale (OS); Tossicità acuta seria, tossicità polmonare e cardiaca acuta e a lungo temine. Tossicità a lungo termine di qualsiasi tipo, secondi tumori ; Qualità di vita (QoL); Rapporto costi/benefici

E.5.2.1

Timepoint(s) of evaluation of this end point

After 2 months of chemotherapy, and after 6 months, at the end of treatment; After 2 months of chemotherapy ; 3 years; 3 years; 3 years; 6 months for acute toxicity and 5yrs for late toxicity; 36 months; 36 months

Dopo 2 mesi di chemioterapia e dopo 6 mesi, alla fine del trattamento, ; Dopo 2 mesi di trattamento; 3 anni; 3 anni; 3 anni; 6 mesi per le tossicità acute e 5 anni per le tossicità a lungo termine; 36 mesi; 36 mesi

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)

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

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)

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

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

Information not present in EudraCT

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 befalls when all of the following criteria have been satisfied:
1) Thirty 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.

La fine dello studio si ottiene nel momento in cui vengono soddisfatti tutti i seguenti criteri:
1) dopo 30 giorni dal momento in cui tutti i pazienti finiscono il trattamento;
2) la sperimentazione è pronta per l'analisi degli end-point primari così come definiti dal protocollo;
3) il database è stato ripulito e congelato per l'analisi dei dati.

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:

500

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

500

F.4.2

For a multinational trial

F.4.2.1

In the EEA

500

F.4.2.2

In the whole clinical trial

500

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)

According to clinical practise at the discretion of the investigator

A discrezione del medico curante secondo pratica clinica

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

2017-07-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-04-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-11-03

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