Clinical Trials Register

Summary
EudraCT Number:	2013-003946-17
Sponsor's Protocol Code Number:	FIL_PTCL_BV
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:	2014-09-23
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

2013-003946-17

A.3

Full title of the trial

Phase II study on the role of brentuximab vedotin as single agent in the treatment of relapsed/refractory CD30 positive peripheral T cell lymphoma (PTCL) patients

Studio di fase 2 sul ruolo di brentuximab vedotin come singolo agente nel trattamento dei pazienti affetti da linfoma a cellule T periferiche ricaduto/refrattario CD30 positivo

A.3.1

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

Phase II study on the role of brentuximab vedotin as single agent in the treatment of relapsed/refractory CD30 positive peripheral T cell lymphoma (PTCL) patients

Studio di fase 2 sul ruolo di brentuximab vedotin come singolo agente nel trattamento dei pazienti affetti da linfoma a cellule T periferiche ricaduto/refrattario CD30 positivo

A.4.1

Sponsor's protocol code number

FIL_PTCL_BV

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	Millennium Pharmaceuticals, Inc., The Takeda Oncology Company
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	Segreteria Fondazione Italiana Linfomi Onlus
B.5.2	Functional name of contact point	Segreteria FIL
B.5.3	Address:
B.5.3.1	Street Address	Via Venezia 16
B.5.3.2	Town/ city	Alessandria
B.5.3.3	Post code	15121
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390131206071
B.5.5	Fax number	00390131263455
B.5.6	E-mail	segreteria@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	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.3.4	Pharmaceutical form	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	Brentuximab Vedotin
D.3.9.1	CAS number	914088-09-8
D.3.9.3	Other descriptive name	SGN-35
D.3.9.4	EV Substance Code	SUB32397
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
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

RELAPSED/REFRACTORY CD30 POSITIVE PERIPHERAL T CELL LYMPHOMA (PTCL)

linfoma a cellule T periferiche ricaduti/refrattari CD30 positivi

E.1.1.1

Medical condition in easily understood language

PTCL CD30+

E.1.1.2

Therapeutic area

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

MedDRA Classification

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 determine the antitumor efficacy of single-agent brentuximab vedotin (BV) (1.8 mg/kg administered intravenously every 3 weeks) as measured by the overall objective response rate in refractory/relapsed peripheral T-cell lymphoma (PTCL) patients.

Determinare l’efficacia antitumorale del singolo agente brentuximab vedotin (BV) (somministrato per via endovenosa ogni 3 settimane alla dose di 1.8 mg/kg) valutandola tramite il tasso di risposta oggettiva globale nei pazienti affetti da linfoma a cellule T periferiche ricaduto/refrattario.

E.2.2

Secondary objectives of the trial

• To assess duration of tumor control, including duration of response and progression-free survival
• To assess survival
• To assess the safety and tolerability of BV
• To assess correlation between CD30 expression and response

• Valutare la durata del controllo tumorale, comprese la durata della risposta e la sopravvivenza libera da malattia.
• Valutare la sopravvivenza
• Valutare la sicurezza e la tollerabilità di BV
• Valutare la correlazione tra espressione di CD30 e la risposta alla terapia

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed written informed consent.
2. Males and females ≥18 years at the time of enrolment.
3. Histologically confirmed diagnosis of PTCL (PTCL-not otherwise specified [PTCL-NOS], angioimmunoblastic T cell lymphoma [AILT] and transformed mycosis fungoides) according to World Health Organization (2008) classification.
4. Histologically confirmed CD30+ PTCL.
5. Availability of histological material for central review and pathobiological studies.
6. Failed or intolerant of at least one prior systemic antilymphoma therapy.
7. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 1 at study entry.
8. At least one site of disease measurable in two dimensions by computed tomography. Both nodal and extranodal disease will be considered (lymphnodes must have long axis of 1.5 cm regardless of short axis or long axis 1.1 to 1.5 cm and short axis >1.0 cm).
9. Hematology values within the following limits:
o Absolute neutrophil count (ANC) ≥ 1500/mm3 independent of growth factor support.
o Platelets ≥75,000/mm3 or ≥50,000/mm3 if bone marrow involvement is independent of transfusion support.
o Hemoglobin level ≥8 g/dL.
10. Biochemical values within the following limits:
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x upper limit of normal (ULN).
o Total bilirubin < 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin).
o Serum creatinine ≤ 2 x ULN.
o Serum albumin ≥ 3 g/dL.
11. Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days of receiving study medication.
12. WOCBP must agree to use effective contraception, defined as oral contraceptives, double barrier method or practice true abstinence from sexual intercourse during the study and for 6 months after the last dose of study drug.
13. Male subjects and their female partners of childbearing potential must be willing to use an appropriate method of contraception or practice true abstinence from sexual intercourse during the study and for 6 months after the last dose of study drug.

1. Consenso informato scritto firmato.
2. Maschio/femmina di età ≥18 anni all’arruolamento.
3. Diagnosi confermata istologicamente di PTCL (PTCL nos, non altrimenti specificato, linfoma T angioimmunoblastico e micosi fungoide trasformata) in accordo con la classificazione WHO 2008.
4. PTCL confermato istologicamente come CD30 positivo.
5. Disponibilità di materiale istologico per la revisione centralizzata e per studi patobiologici.
6. Ricaduto o refrattario dopo almeno una terapia sistemica antilinfoma.
7. Performance status ECOG ≤ 1 all’arruolamento.
8. Almeno un sito di malattia misurabile bidimensionalmente tramite esame di tomografia computerizzata assiale (TAC). Verrà presa in considerazione sia malattia nodale sia extranodale (i linfonodi devono avere l’asse maggiore di 1.5 indipendentemente dalla lunghezza dell’asse minore oppure l’asse maggiore di una lunghezza compresa tra 1.1 e 1.5 cm e il minore >1.0 cm).
9. I valori ematologici devono essere nei seguenti limiti:
o Conta assoluta dei neutrofili ≥ 1500 /mm3 senza supporto di fattori di crescita;
o Piastrine ≥ 75,000/mm3 o ≥ 50,000/mm3 se il coinvolgimento midollare è
indipendente dal supporto trasfusionale;
o Emoglobina ≥ 8 gr/dL.
10. I valori biochimici devono essere nei seguenti limiti:
o Alanina aminotransferasi (ALT) e aspartato aminotransferasi (AST) ≤3 ULN;
o Bilirubina totale ≤ 1.5 x ULN a meno che l’aumento di bilirubina non sia dovuta
alla sindrome di Gilbert o comunque di origine non epatica);
o Cretinina sierica ≤ 2 x ULN;
o Albumina sierica ≥ 3 gr/dL.
11. Le donne fertili devono avere un test di gravidanza negativo entro la settimana precedente la prima infusione di BV.
12. Le donne fertili devono accettare di utilizzare un contraccettivo efficace definito come contraccettivo orale, metodo di doppia barriera o praticare astinenza da rapporti sessuali durante lo studio e per 6mesi dopo l’ultima dose di BV.
13. I soggetti maschili e le loro compagne fertili devono accettare di utilizzare un appropriato metodo contraccettivo o praticare l’astinenza da rapporti sessuali durante lo studio e per 6 mesi dopo l’ultima dose di BV.

E.4

Principal exclusion criteria

1. Diagnosis of CTCL, ALCL, mycosis fungoides or Sezary Syndrome.
2. CD30 expression < 10 % as measured by IHC
3. Patients that have not completed any prior treatment chemotherapy and/or other investigational agents within at least 5 half-lives of last dose of that prior treatment.
4. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin.
5. Any serious active disease or co-morbid medical condition (according to investigator's decision).
6. Prior history of malignancies other than lymphoma (except for a history of a complete resection for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the subject has been free of the disease for ≥ 3 years.
7. Pre-existing peripheral neuropathy Grade ≥2.
8. Signs or symptoms of progressive multifocal leukoencephalopathy (PML).
9. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
10. Pregnant or lactating females or men or women of childbearing potential not willing to use an adequate method of birth control for the duration of the study or a positive pregnancy test on Day 1 before first dose of study drug.

11. CNS disease (meningeal and/or brain involvement by lymphoma) or testicular involvement
12. History of clinically relevant liver or renal insufficiency; significant pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances.
13. Known history of any of the following cardiovascular conditions
o Myocardial infarction within 2 years from enrollment
o New York Heart Association (NYHA) Class III or IV heart failure
o 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
o Recent evidence (within 6 months before first dose of study drug) of a left-ventricular ejection fraction <50%

14. Active opportunistic infection.
15. Known history of Human Immunodeficiency Virus (HIV) or Hepatitis C or active infection with Hepatitis B.
16. Prior allogeneic stem cell transplant.

1. Diagnosi di CTCL, ALCL, micosi fungoide o sindrome di Sezary;
2. Espressione di CD30 <10% misurati secondo i criteri IHC;
3. Pazienti che hanno completato trattamenti preventivi con chemioterapia e/o con altri agenti sperimentali per cui non siano trascorse almeno 5 emivite dall’ultima dose di tale trattamento preliminare.
4. Nota ipersensibilità alle proteine ricombinanti, alle proteine murine o a qualunque altro eccipiente contenuto nella formulazione farmacologica del brentuximab vedotin
5. Qualsiasi malattia o co-morbidità attiva seria (a discrezione dello Sperimentatore).
6. Precedente storia di neoplasie diverse dal linfoma (ad eccezione di carcinoma basocellulare o squamoso della cute o carcinoma in situ della cervice o della mammella) a meno che il soggetto non sia indenne da questa malattia da almeno 3 anni.
7. Neuropatia periferica preesistente di grado ≥2.
8. Segni o sintomi di leucoencefalopatia multifocale progressiva (PML).
9. Pazienti con una demenza o un alterato stato mentale o condizione medica che precluderebbe la reale comprensione e rilascio del consenso informato.
10. Donne in gravidanza o in allattamento o uomini e donne potenzialmente fertili che non sono disposti ad utilizzare un metodo adeguato di controllo delle nascite per tutta la durata dello studio o donne il cui test di gravidanza eseguito al giorno 1 del trattamento risulti positivo.
11. Malattie del SNC (meningea e / o coinvolgimento del cervello da linfoma) o coinvolgimento testicolare.
12. Storia di insufficienza epatica o renale clinicamente rilevante; disturbi significativi polmonari, gastrointestinali, endocrini, neurologici, reumatologici, ematologici, psichiatrici o metabolici.
13. Anamnesi positiva per una delle seguenti condizioni cardiovascolari:
o infarto del miocardico entro 2 anni dall’arruolamento nello studio
o Insufficienza cardiaca di Classe III o IV in accordo con New York Heart Association
(NYHA)
o Evidenza di patologie cardiovascolari non controllate, comprese le aritmie
cardiache, insufficienza cardiaca congestizia (CHF), angina pectoris, o prova
elettrocardiografica di ischemia acuta o di anomalie attive del sistema di
conduzione cardiaca;
o Evidenza di una frazione di eiezione ventricolare sinistra <50% (esame effettuato
entro 6 mesi dalla prima dose del farmaco sperimentale)
14. Infezioni opportunistiche attive.
15. Positività nota al virus dell’HIV (Virus dell’immunodeficienza acquisita umana), dell’Epatite C o infezione attiva da virus dell’Epatite B.
16. Precedente trapianto allogenico di cellule staminali.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study is the overall objective response rate (ORR).

tasso di risposta globale (ORR).

E.5.1.1

Timepoint(s) of evaluation of this end point

1 year

1 anno

E.5.2

Secondary end point(s)

• Duration of response
• Complete remission (CR) rate
• Progression-free survival (PFS) at one year
• Overall survival (OS) at one year
• Type, incidence, severity, seriousness, and relatedness of adverse events, and laboratory abnormalities

• Durata della risposta
• Tasso di Remissione completa (CR)
• Sopravvivenza libera da progressione (PFS) a un anno
• Sopravvivenza complessiva (OS) a un anno
• Tipo, incidenza, importanza, gravità, e grado di relazione degli eventi avversi e delle anomalie rilevate dagli esami di laboratorio

E.5.2.1

Timepoint(s) of evaluation of this end point

1 year

1 anno

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

E.8.1.1

Randomised

Information not present in EudraCT

E.8.1.2

Open

Information not present in EudraCT

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Information not present in EudraCT

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

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:

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

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

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.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 be followed for about 3 years and a half from the entrance into the study. At the end of this period, the patients will be followed according to the standards of the enrolling centers.

I pazienti saranno seguiti per circa 3 anni e mezzo dall’ingresso nello studio. Al termine di questo periodo i pazienti saranno seguiti secondo gli standard dei centri arruolanti.

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

2015-05-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-15

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

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