Clinical Trials Register

Summary
EudraCT Number:	2015-004741-54
Sponsor's Protocol Code Number:	SGN35-017
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:	2018-04-20
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

2015-004741-54

A.3

Full title of the trial

A phase 2 study of brentuximab vedotin in combination with standard of care treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [RCHOP]) or RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) as front-line therapy in patients with diffuse large B-cell lymphoma (DLBCL)

Studio di fase 2 di brentuximab vedotin in combinazione con il trattamento della terapia standard (rituximab, ciclofosfamide, doxorubicina, vincristina e prednisone [RCHOP]) o RCHP (rituximab, ciclofosfamide, doxorubicina e prednisone) come terapia di prima linea nei pazienti affetti da linfoma diffuso a grandi cellule B (Diffuse Large B-Cell Lymphoma)

A.3.1

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

Study of brentuximab vedotin combined with RCHOP or RCHP for front-line treatment of patients with diffuse large B-cell lymphoma (DLBCL)

Studio di brentuximab vedotin in combinazione con RCHOP o RCHP per il trattamento di prima linea dei pazienti con linfoma a grandi cellule B diffuso (DLBCL)

A.3.2

Name or abbreviated title of the trial where available

Study of brentuximab vedotin combined with RCHOP or RCHP for front-line treatment of patients with d

Studio di brentuximab vedotin in combinazione con RCHOP o RCHP per il trattamento di prima linea dei

A.4.1

Sponsor's protocol code number

SGN35-017

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01925612

A.5.4

Other Identifiers

Name:

SGN35-017

Number:

Amendment 5

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	SEATTLE GENETICS, INC.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Seattle Genetics, Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharmacuetical Research Associates
B.5.2	Functional name of contact point	Andrew Truckel
B.5.3	Address:
B.5.3.1	Street Address	8899 University Center Lane, Suite 400
B.5.3.2	Town/ city	San Diego - California
B.5.3.3	Post code	9212
B.5.3.4	Country	United States
B.5.4	Telephone number	0018584585222
B.5.5	Fax number	0
B.5.6	E-mail	TruckelAndrew@prahs.com

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
D.2.1.1.2	Name of the Marketing Authorisation holder	Seattle Genetics, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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-35
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Brentuximab vedotin
D.3.9.1	CAS number	914088-09-8
D.3.9.2	Current sponsor code	SGN-35
D.3.9.4	EV Substance Code	SUB32397
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	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)	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	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	Comparator
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	N/A
D.2.1.1.2	Name of the Marketing Authorisation holder	N/A
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	Vincristine
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VINCRISTINA
D.3.9.1	CAS number	2068-78-2
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	VINCRISTINA
D.3.9.4	EV Substance Code	SUB05101MIG
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	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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	N/A
D.2.1.1.2	Name of the Marketing Authorisation holder	N/A
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	Doxorubicin
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
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	25316-40-9
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	DOXORUBICINA CLORIDRATO
D.3.9.4	EV Substance Code	SUB01827MIG
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	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	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: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	N/A
D.2.1.1.2	Name of the Marketing Authorisation holder	N/A
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Cyclophosphamide
D.3.4	Pharmaceutical form	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CICLOFOSFAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	CICLOFOSFAMIDE
D.3.9.4	EV Substance Code	SUB06859MIG
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.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
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	N/A
D.2.1.1.2	Name of the Marketing Authorisation holder	N/A
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Prednisone
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PREDNISONE
D.3.9.1	CAS number	53-03-2
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	PREDNISONE
D.3.9.4	EV Substance Code	SUB10020MIG
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	50
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: 6
D.1.2 and D.1.3	IMP Role	Comparator
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	N/A
D.2.1.1.2	Name of the Marketing Authorisation holder	N/A
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Rituximab
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	RITUXIMAB
D.3.9.4	EV Substance Code	SUB12570MIG
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	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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	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

Diffuse large B-cell lymphoma (DLBCL)

Linfoma diffuso a grandi cellule B (Diffuse Large B-Cell Lymphoma, DLBCL)

E.1.1.1

Medical condition in easily understood language

Diffuse large B-cell lymphoma (DLBCL)

Linfoma diffuso a grandi cellule B (Diffuse Large B-Cell Lymphoma, DLBCL)

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	LLT
E.1.2	Classification code	10012820
E.1.2	Term	Diffuse large B-cell lymphoma NOS
E.1.2	System Organ Class	100000004864

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	10067070
E.1.2	Term	Follicular B-cell non-Hodgkin's lymphoma
E.1.2	System Organ Class	100000004864

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

To assess the antitumor activity of brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone, as measured by the CR rate at the end of treatment per investigator assessment in treatment-naive patients with high-intermediate or high risk systemic DLBCL

To assess the safety profile of brentuximab vedotin administered at dose levels of 1.2 mg/kg versus 1.8 mg/kg in combination with RCHOP or brentuximab vedotin 1.8 mg/kg in combination with RCHP in treatment-naive patients with high-intermediate or high risk systemic DLBCL

Valutare l’attività antitumorale di brentuximab vedotin somministrato in combinazione con RCHOP o RCHP e in combinazione con RCHP rispetto a RCHOP in monoterapia, come misurata dal tasso di remissione completa (Complete Remission, CR) al termine del trattamento secondo la valutazione dello sperimentatore nei pazienti naïve al trattamento affetti da DLBCL a rischio sistemico intermedio-alto o alto
Valutare il profilo di sicurezza di brentuximab vedotin somministrato a livelli di dose di 1,2 mg/kg rispetto a 1,8 mg/kg in combinazione con RCHOP o brentuximab vedotin alla dose di 1,8 mg/kg in combinazione con RCHP in pazienti naïve al trattamento affetti da DLBCL a rischio sistemico intermedio-alto o alto

E.2.2

Secondary objectives of the trial

To assess the antitumor activity of brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone, as measured by the objective response rate (ORR) at the end of treatment per investigator assessment

To assess the progression-free survival (PFS) associated with brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone

To assess survival associated with brentuximab vedotin administered in combination with RCHOP or RCHP, and in combination with RCHP versus RCHOP alone

Valutare l’attività antitumorale di brentuximab vedotin somministrato in combinazione con RCHOP o RCHP e in combinazione con RCHP rispetto a RCHOP in monoterapia, come misurata dal tasso di risposta obiettiva (Objective Response Rate, ORR) alla fine del trattamento secondo la valutazione dello sperimentatore
Valutare la sopravvivenza senza progressione (Progression-Free Survival, PFS) associata a brentuximab vedotin somministrato in combinazione con RCHOP o RCHP e in combinazione con RCHP rispetto a RCHOP in monoterapia
Valutare la sopravvivenza associata a brentuximab vedotin somministrato in combinazione con RCHOP o RCHP e in combinazione con RCHP rispetto a RCHOP in monoterapia

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Treatment-naive patients with systemic de novo or transformed DLBCL, or follicular NHL grade 3b; patients must have high-intermediate or high risk disease based on standard IPI (score ≥3 for patients >60 years of age) or aaIPI (score 2 or 3 for patients ≤60 years of age), and stage IAX (bulk defined as single lymph node mass >10 cm in diameter), IB–IV disease

2.Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist

3.An Eastern Cooperative Oncology Group (ECOG) performance status ≤2

4.Age 18 years or older

5.Patients must have the following baseline laboratory data:
●bilirubin ≤1.5X upper limit of normal (ULN) or ≤3X ULN for patients with Gilbert's disease or documented hepatic involvement with lymphoma
●alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3X ULN or ≤5X ULN for patients with documented hepatic involvement with lymphoma
●serum creatinine ≤2X ULN
●absolute neutrophil count (ANC) ≥1000/µL (unless documented bone marrow involvement with lymphoma)
●platelet count ≥50,000/µL (unless documented bone marrow involvement with lymphoma)

6.Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose of brentuximab vedotin. Females of non-childbearing potential are those who are post menopausal for more than 1 year or who have had a bilateral tubal ligation or hysterectomy.

7.Females of childbearing potential and males who have partners of childbearing potential must agree to use 2 effective contraception methods during the study and for 12 months following the last dose of study drug

8.Patients or their legally authorized representative must provide written informed consent

9.Patients in Parts 2 and 3 must have histologically confirmed diagnosis of CD30-positive DLBCL

1. Pazienti naïve al trattamento con linfoma diffuso a grandi cellule B (Diffuse large B-cell lymphoma, DLBCL) sistemico de novo o trasformato o linfoma non-Hodgkin (non-Hodgkin lymphoma, NHL) follicolare di grado 3b; i pazienti devono presentare una malattia a rischio intermedio-alto o alto sulla base dell’indice prognostico internazionale (International Prognostic Index, IPI) standard (punteggio ≥ 3 per i pazienti di età > 60 anni) o IPI aggiustato per età (age-adjusted IPI, aaIPI) (punteggio 2 o 3 per i pazienti di età ≤ 60 anni) e stadio IAX (adenopatia massiva definita come singola massa linfonodale di diametro > 10 cm), malattia di stadio IB-IV
2. Malattia avida di fluorodeossiglucosio (FDG) determinata da tomografia a emissione di positroni (positron emission tomography, PET) e malattia misurabile di almeno 1,5 cm determinata da tomografia computerizzata (TC), come da valutazione del radiologo del centro
3. Stato di validità del Gruppo Cooperativo Orientale dell’Oncologia (Eastern Cooperative Oncology Group, ECOG) ≤ 2
4. Età pari o superiore a 18 anni
5. I pazienti devono presentare i seguenti dati di laboratorio al basale:
• bilirubina ≤ 1,5X rispetto al limite superiore della norma (LSN) o ≤ 3X LSN per pazienti con malattia di Gilbert o coinvolgimento epatico documentato con linfoma
• alanina aminotransferasi (ALT) e aspartato aminotransferasi (AST) ≤ 3X LSN o ≤ 5X LSN per pazienti con coinvolgimento epatico documentato con linfoma
• creatinina sierica ≤ 2X LSN
• conta assoluta dei neutrofili (absolute neutrophil count, ANC) ≥ 1000/μL (salvo coinvolgimento documentato del midollo osseo con linfoma)
• conta piastrinica ≥ 50.000/μL (salvo coinvolgimento documentato del midollo osseo con linfoma)
6. I soggetti di sesso femminile in età fertile devono presentare negatività al test di gravidanza sulla beta-gonadotropina corionica umana (beta human chorionic gonadotropin, β-hCG) sierica o urinaria entro i 7 giorni che precedono la prima dose di brentuximab vedotin. I soggetti di sesso femminile in età non fertile sono donne postmenopausali da più di 1 anno o sottopostesi a una legatura bilaterale delle tube o a un’isterectomia.
7. I soggetti di sesso femminile in età fertile e quelli di sesso maschile che hanno compagne in età fertile devono acconsentire all’uso di 2 metodi contraccettivi efficaci durante lo studio e per i 12 mesi successivi all’ultima dose del farmaco in studio
8. I pazienti o il loro rappresentante legalmente autorizzato devono/e fornire il consenso informato scritto
9. I pazienti nelle Parti 2 e 3 devono presentare diagnosi istologicamente confermata di DLBCL positiva per CD30

E.4

Principal exclusion criteria

1.Previous history of treated indolent lymphoma. Newly diagnosed patients with DLBCL who are found to have small cell infiltration of the bone marrow or other diagnostic material (representing a discordant lymphoma) are eligible.

2.History of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome that has not been in remission for at least 3 years

3.History of progressive multifocal leukoencephalopathy (PML)

4.Cerebral/meningeal disease related to the underlying malignancy

5.Baseline peripheral neuropathy >/= Grade 2 (per the National Cancer Institute’s Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 4.03) or patients with the demyelinating form of Charcot-Marie-Tooth syndrome

6.Left ventricular ejection fraction less than 45% or symptomatic cardiac disease (including symptomatic ventricular dysfunction, symptomatic coronary artery disease, and symptomatic arrhythmias), or myocardial infarction within the past 6 months or previous treatment with complete cumulative doses of doxorubicin or other anthracyclines

7.Any active Grade 3 or higher (per the NCI CTCAE, Version 4.03) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study treatment

8.Current therapy with other systemic anti-neoplastic or investigational agents

9.Females who are breastfeeding

10.Known hypersensitivity to any excipient contained in any of the drug formulations of study treatments

11.Patients with known urinary outflow obstruction

12.Known human immunodeficiency virus (HIV) infection or known or suspected active hepatitis C infection. Patients with a positive hepatitis B polymerase chain reaction (PCR) assay who have also tested positive for hepatitis B surface antigen and/or anti-hepatitis B core antibody; patients with a negative PCR assay are permitted with effective anti-viral prophylaxis.

1. Precedente anamnesi di linfoma trattato indolente. Sono idonei i pazienti con nuova diagnosi di DLBCL, nei quali sia stata rilevata un’esigua infiltrazione cellulare del midollo osseo o altro materiale diagnostico (indicativo di un linfoma discordante).
2. Anamnesi di altro tumore primario invasivo, di malignità ematologica o di sindrome mielodisplastica non remittente da almeno 3 anni
3. Anamnesi di leucoencefalopatia multifocale progressiva (progressive multifocal leukoencephalopathy, PML)
4. Malattia cerebrale/meningea correlata a malignità sottostante
5. Neuropatia periferica al basale >/= Grado 2 (secondo i Criteri
terminologici comuni per gli eventi avversi dell’Istituto Nazionale Tumori [National Cancer Institute’s Common Terminology Criteria for Adverse Events, NCI CTCAE] versione 4.03) o pazienti con forma demielinizzante di sindrome di Charcot-Marie-Tooth
6. Frazione di eiezione ventricolare sinistra inferiore al 45% o malattia cardiaca sintomatica (compresa la disfunzione ventricolare sintomatica, la coronaropatia sintomatica e le aritmie sintomatiche) o infarto miocardico entro gli ultimi 6 mesi o precedente al trattamento con dosi cumulative complete di doxorubicina o altre antracicline
7. Una qualsiasi infezione attiva di tipo virale, batterico o micotico di grado 3 o superiore (secondo l’NCI CTCAE, Versione 4.03) entro le 2 settimane che precedono la prima dose del trattamento in studio
8. Attuale terapia con altri agenti sistemici antineoplastici o sperimentali
9. Soggetti di sesso femminile che allattano al seno
10. Ipersensibilità nota a un eccipiente contenuto in una qualsiasi delle formulazioni farmacologiche dei trattamenti in studio
11. Pazienti con ostruzione nota del flusso urinario
12. Infezione nota al virus di immunodeficienza umana (human immunodeficiency virus, HIV) o infezione attiva nota o sospetta al virus dell’epatite C. Pazienti risultati positivi al test di reazione a catena della polimerasi (polymerase chain reaction, PCR) per l’epatite B, che sono risultati positivi anche all’antigene di superficie dell’epatite B e/o all’anticorpo anti-core dell’epatite B; ai pazienti risultati negativi al test di PCR è consentito sottoporsi a efficace profilassi antivirale

E.5 End points

E.5.1

Primary end point(s)

Complete remission (CR) rate per investigator assessment following
the completion of study treatment
- Type, incidence, severity, seriousness, and relatedness of adverse
events and laboratory abnormalities

- Tasso di remissione completa (Complete remission, CR) secondo la valutazione dello sperimentatore, successiva al completamento del trattamento in studio
- Tipo, incidenza, severità, gravità e correlazione con eventi avversi e anomalie di laboratorio

E.5.1.1

Timepoint(s) of evaluation of this end point

CR rate is defined as the proportion of patients with CR at the end of
treatment according to the Revised Response Criteria for Malignant
Lymphoma (Cheson 2007), as assessed by the investigator.
The end of treatment response assessments are made 5 weeks after the last dose.

Il tasso di CR è definito come la percentuale di pazienti che presentano una CR di fine trattamento conforme ai Criteri di risposta revisionati riguardanti i linfomi maligni (Cheson 2007), come da valutazione dello sperimentatore. Le valutazioni della risposta di fine trattamento vengono eseguite 5 settimane dopo l’ultima dose.

E.5.2

Secondary end point(s)

- Objective response rate (ORR) per investigator
- Progression-free survival (PFS) per investigator
- Overall Survival (OS)

- Tasso di risposta obiettiva (Objective response rate, ORR) secondo lo sperimentatore
- Sopravvivenza senza progressione (Progression-free survival, PFS) secondo lo sperimentatore
- Sopravvivenza complessiva (Overall Survival, OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

The end of treatment response assessments are made 5 weeks after the
last dose.
Survival is assessed 4 months after the last scan for 2 years, then every 6 months.

Le valutazioni della risposta di fine trattamento vengono eseguite 5 settimane dopo l’ultima dose.
La sopravvivenza viene valutata 4 mesi dopo l’ultima scansione, per 2 anni e successivamente ogni 6 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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

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

Information not present in EudraCT

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

Czech Republic

Italy

Poland

Spain

United States

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

For the primary efficacy analysis, it is LVLS (5 weeks after last dose of study drug).

Per l'analisi di efficacia primaria, è LIVELLI (5 settimane dopo l'ultima dose di farmaco in studio).

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

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

Yes

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

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

Information not present in EudraCT

F.3.3.4

Nursing women

Information not present in EudraCT

F.3.3.5

Emergency situation

Information not present in EudraCT

F.3.3.6

Subjects incapable of giving consent personally

Information not present in EudraCT

F.3.3.7

Others

Information not present in EudraCT

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

F.4.2.2

In the whole clinical trial

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)

N/A

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

2016-04-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-04-26

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