Clinical Trials Register

Summary
EudraCT Number:	2012-004508-36
Sponsor's Protocol Code Number:	FM-12-GCT01
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-03-07
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

2012-004508-36

A.3

Full title of the trial

Brentuximab vedotin (SGN-35) as salvage therapy for males with advanced and platinum-resistant germ-cell tumors. An open label, single group, Phase 2 trial

Terapia di salvataggio con brentuximab vedotin nei pazienti con neoplasie germinali chemioresistenti

A.3.1

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

Brentuximab vedotin (SGN-35) as salvage therapy for males with advanced and platinum-resistant germ-cell tumors. An open label, single group, Phase 2 trial

Terapia di salvataggio con brentuximab vedotin nei pazienti con neoplasie germinali chemioresistenti

A.4.1

Sponsor's protocol code number

FM-12-GCT01

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 Michelangelo - Avanzamento dello studio e cura dei tumori
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 Pharmaceutical INC, USA
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	Fondazione Michelangelo
B.5.2	Functional name of contact point	Operations Office
B.5.3	Address:
B.5.3.1	Street Address	Via Venezian, 1
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390223903452
B.5.5	Fax number	+390223902678
B.5.6	E-mail	nadia.malinverni@fondazionemichelangelo.org

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.2.1.2	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-35
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	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	Monoclonal antibody

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

Patients with histologically-confirmed germ-cell cancer with exclusive or prevalent CD30-positive embryonal carcinoma component

Neoplasia germinale del testicolo o extragonadica CD30

E.1.1.1

Medical condition in easily understood language

Patients with histologically-confirmed germ-cell cancer with exclusive or prevalent CD30-positive embryonal carcinoma component

Neoplasia germinale del testicolo o extragonadica CD30

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10061378
E.1.2	Term	Testicular germ cell cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the activity of single-agent brentuximab vedotin in a population of patients with platinum-resistant GCT.
Primary Endpoint:
- Overall response-rate (RR) as defined by CR+PRm-+PRm+.

Valutare l’attività terapeutica di un programma di trattamento di salvataggio di III-IV linea che prevede la somministrazione di Brentuximab vedotin fino a progressione di malattia.
Endpoint: Numero di risposte obiettive (definite come la somma delle risposte complete -RC- e delle risposte parziali si con marcatore negativo/negativizzato [PRm-] sia con marcatore ancora elevato [PRm+]).

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of the study drug.
To evaluate further efficacy parameters

Secondary Endpoints:
- Safety and tolerability (according to Common terminology Criteria for Adverse Events – CTCAE - v.4.03).
-
- 3-month Progression-free survival (PFS).
- Overall survival (OS).
- Quality of life assessment.
- Correlation of 18FDG-PET/CT response with STM and CT response and PFS.

Valutare la sicurezza e la tollerabilità del trattamento con Brentuximab vedotin.
Endpoint:
• Incidenza, natura e severità di eventi avversi correlati al trattamento in studio, definiti in base ai Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
• Sopravvivenza globale.
• Sopravvivenza libera da progressione a 3 mesi.
• Valutazione della Qualità della Vita con questionario ESAS (validato in italiano).
• Confronto tra risposta PET e TC e rapporto con PFS e OS.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years
2. Male patients, even if surgically sterilized, (i.e., status post vasectomy) agree to practice effective barrier contraception during the entire study period and through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse.
3. Confirmation of GCT histology based on pathologic review at Fondazione INT Milan.
4. Presence of a CD30-positive embryonal carcinoma component. It should be assessed on either research biopsy immediately prior to start of brentuximab (preferably) or on archival tissue of the most recent post-chemotherapy viable residual (in the absence of easily accessible disease or in presence of clinical contraindications to biopsy).
5. Unequivocal progression of measurable disease (measurable disease will consist of abnormalities on 2-dimensional imaging or raised tumor markers) as documented by either:
a. Tumor biopsy of new, growing or unresectable lesions demonstrating viable non-teratomatous GCT (enrollment on this study for consolidation treatment after resection of viable GCT is not allowed).
b. Increasing or abnormally elevated serum tumor markers (HCG or AFP). Increasing LDH alone does not constitute progressive disease.
6. A minimum of 2 and a maximum of 3 platinum-based chemotherapy lines for metastatic disease (enrollment will take place either as 3rd or 4th line of treatment). EXCEPT for primary mediastinal GCTs where failure of first-line chemotherapy ( 2nd line setting) is accepted.
7. First-line therapy should consist of at least 3 cycles of cisplatin-based chemotherapy.
8. Prior single, tandem or triple high-dose chemotherapy course given as front-line or salvage therapy is allowed.
9. Recovery from prior surgery.

• Età ≥ 18 anni.
• Sesso maschile.
• Eastern Cooperative Oncology Group (ECOG) Performance Status < 2.
• Diagnosi di neoplasia germinale (del testicolo o extragonadica) CD30+ documentata ad un esame istologico/biopsia immediatamente precedente il farmaco in studio (la sola positività per CD30 all’orchifuniculectomia non è ammessa).
• Ricaduta/Progressione dopo 2 o 3 linee di trattamento chemioterapico cisplatino-contenente. Tale condizione è definita come un incremento o una persistente positività di uno o più marcatori tumorali o da un incremento numerico e/o dimensionale di localizzazioni vitali non teratomatose di malattia.
• E’ ammesso un precedente trattamento chemioterapico ad alte dosi costituito da un singolo o multipli cicli di chemioterapia seguiti da reinfusione di progenitori emopoietici autologhi.
• E’ ammesso il trattamento con brentuximab in setting di seconda linea (dopo fallimento di I linea costituita da almeno 3 cicli di chemioterapia cisplatino-contenente) ESCLUSIVAMENTE per i pazienti con neoplasie germinali nonseminomatose primitive del mediastino.
• Adeguata funzionalità midollare e d’organo.
• Consenso informato scritto.

E.4

Principal exclusion criteria

1. Failure to meet any of the above inclusion criteria.
2. Less than 2 prior lines of cisplatin-based chemotherapy (including one cisplatin-based chemotherapy line followed by high-dose therapy). Except for primary mediastinal GCTs where less than 2 prior lines of cisplatin-based chemotherapy (2nd line setting) is accepted.
3. Prior Treatment with any of the following anti-cancer therapies:
4. radiation therapy, surgery or tumor embolization are allowed with a washout period of 14 days prior to enrolment OR
5. chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy are allowed with a washout period of 14 days or five half-lives of a drug (whichever is longer) prior to enrolment.
6. Patients with late-relapse (defined as relapse occurring after at least 2 years from the date of completion of the last chemotherapy regimen) whose disease is completely surgically resectable (and for whom initial surgical extirpation is recommended) are ineligible. Patients with unresectable late disease relapse are eligible.

• Co-morbidità significative che compromettono l’esecuzione in sicurezza del trattamento con brentuximab.
• Infezioni gravi in atto (di grado > 2 NCI-CTC versione 4.03).
• Pazienti con LATE RELAPSE (definita come recidiva di malattia dopo 2 anni dal termine del trattamento chemioterapico di I linea) e con malattia radicalmente resecabile. I pazienti con malattia non radicalmente operabile sono candidabili allo studio.
• Più di 3 linee di trattamento chemioterapico precedenti (salvo i casi in cui i pazienti hanno ricevuto 2 differenti regimi di trattamento chemioterapico come parte della I linea di chemioterapia. Ad esempio pazienti trattati con 2 cicli PEB e successivamente con 2 cicli PEI per tossicità polmonare possono essere arruolabili, così come i pazienti che hanno ricevuto 4 cicli PEB e successivamente, dopo asportazione di malattia attiva, altri 2 cicli PEB di consolidamento).
• Neoplasie precedenti o concomitanti differenti da quella in trattamento fatta eccezione per il carcinoma basocellulare o per ogni precedente neoplasia diagnosticata e curata almento 5 anni prima dell’ingresso nello studio.
• Ogni condizione medica, psichiatrica o dipendenza che può compromettere l’osservanza delle indicazioni previste nello studio.

E.5 End points

E.5.1

Primary end point(s)

- Overall response-rate (RR) as defined by CR+PRm -+PRm+.

Numero di risposte obiettive (definite come la somma delle risposte complete -RC- e delle risposte parziali si con marcatore negativo/negativizzato [PRm-] sia con marcatore ancora elevato [PRm+]).

E.5.1.1

Timepoint(s) of evaluation of this end point

Duration of follow up will be described by descriptive statistics such as median and interquartile range.

E.5.2

Secondary end point(s)

- Safety and tolerability (according to Common terminology Criteria for Adverse Events – CTCAE - v.4.03).
-
- 3-month Progression-free survival (PFS).
- Overall survival (OS).
- Quality of life assessment.
- Correlation of 18FDG-PET/CT response with STM and CT response and PFS.

• Incidenza, natura e severità di eventi avversi correlati al trattamento in studio, definiti in base ai Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
• Sopravvivenza globale.
• Sopravvivenza libera da progressione a 3 mesi.
• Valutazione della Qualità della Vita con questionario ESAS (validato in italiano).
• Confronto tra risposta PET e TC e rapporto con PFS e OS.

E.5.2.1

Timepoint(s) of evaluation of this end point

3-month for the PFS

3 mesi per PFS

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

E.6.5

Efficacy

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

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

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

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)

None

Nessuno

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

2013-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-03-26

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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