Clinical Trials Register

Summary
EudraCT Number:	2013-005179-41
Sponsor's Protocol Code Number:	FIL_PTCL13
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:	2014-04-10
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

2013-005179-41

A.3

Full title of the trial

ROMIDEPSIN IN COMBINATION WITH CHOEP AS FIRST LINE TREATMENT BEFORE HEMATOPOIETIC STEM CELL TRANSPLANTATION IN YOUNG PATIENTS WITH NODAL PERIPHERAL T-CELL LYMPHOMAS: A PHASE I-II STUDY.

ROMIDEPSINA IN COMBINAZIONE CON CHOEP COME TERAPIA DI PRIMA LINEA IN PREPARAZIONE AL TRAPIANTO DI CELLULE STAMINALI EMOPOIETICHE NEI PAZIENTI GIOVANI CON LINFOMA A CELLULE T PERIFERICHE A LOCALIZZAZIONE NODALE: STUDIO DI FASE I-II

A.3.1

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

ROMIDEPSIN IN COMBINATION WITH CHOEP AS FIRST LINE TREATMENT BEFORE HEMATOPOIETIC STEM CELL TRANSPLANTATION IN YOUNG PATIENTS WITH NODAL PERIPHERAL T-CELL LYMPHOMAS: A PHASE I-II STUDY.

A.3.2

Name or abbreviated title of the trial where available

FIL_PTCL13

A.4.1

Sponsor's protocol code number

FIL_PTCL13

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 (FIL-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	CELGENE Corporation
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione Italiana Linfomi ONLUS (FIL-ONLUS)
B.5.2	Functional name of contact point	Segreteria FIL-ONLUS
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	+390131206071
B.5.5	Fax number	+390131263455
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	ISTODAX
D.2.1.1.2	Name of the Marketing Authorisation holder	CELGENE CORPORATION
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/05/328 PTCL EU/3/05/279 CTCL
D.3 Description of the IMP
D.3.1	Product name	Romidepsin
D.3.2	Product code	FK228
D.3.4	Pharmaceutical form	Powder and solvent 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	ROMIDEPSIN
D.3.9.1	CAS number	128517-07-7
D.3.9.4	EV Substance Code	SUB26362
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	5 to 5
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.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.2.1.2	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.3.4	Pharmaceutical form	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	CYCLOPHOSPHAMIDE MONOHYDRATE
D.3.9.1	CAS number	6055-19-2
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	CYCLOPHOSPHAMIDE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB16414MIG
D.3.10	Strength
D.3.10.3	Concentration number	NA
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	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.2.1.2	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.3.4	Pharmaceutical form	Powder and solvent 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	DOXORUBICIN HYDROCHLORIDE
D.3.9.1	CAS number	25316-40-9
D.3.9.3	Other descriptive name	DOXORUBICIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB01827MIG
D.3.10	Strength
D.3.10.3	Concentration number	NA
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	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.2.1.2	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.3.4	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	VINCRISTINE SULFATE
D.3.9.1	CAS number	2068-78-2
D.3.9.3	Other descriptive name	VINCRISTINE SULFATE
D.3.9.4	EV Substance Code	SUB05101MIG
D.3.10	Strength
D.3.10.3	Concentration number	NA
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	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.2.1.2	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.3.4	Pharmaceutical form	Powder and solution 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	ETOPOSIDE
D.3.9.1	CAS number	33419-42-0
D.3.9.3	Other descriptive name	ETOPOSIDE
D.3.9.4	EV Substance Code	SUB07337MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100 to 100
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	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.2.1.2	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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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.3.9.3	Other descriptive name	PREDNISONE
D.3.9.4	EV Substance Code	SUB10020MIG
D.3.10	Strength
D.3.10.3	Concentration number	NA
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.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

Newly diagnosed patients with Peripheral T-cell lymphomas including: Peripheral T-cell lymphomas not otherwise specified (PTCL-NOS), Angioimmunoblastic T-cell lymphoma (AITL) and ALK– Anaplastic large-cell lymphoma (ALCL).

Pazienti di nuova diagnosi con linfoma a cellule T periferiche ovvero: Linfoma a Cellule T Non Altrimenti Specificato (PTCL-NOS),
Linfoma a Cellule T Angioimmunoblastico (AITL)
Linfoma Anaplastico a Grandi Cellule ALK negativo (ALCL).

E.1.1.1

Medical condition in easily understood language

Newly diagnosed patients with Peripheral T-cell lymphomas.

Pazienti di nuova diagnosi con linfoma a cellule T periferiche.

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 define the maximum tolerated dose (MTD) of Ro-CHOEP-21 (PHASE I)
• To evaluate the efficacy in term of Progression Free Survival (PFS) of Ro-CHOEP-21 (PHASE II)

• Identificazione della Massima Dose Tollerata (MTD) di Ro-CHOEP-21 (FASE I)
• Valutare l’efficacia di Ro-CHOEP-21 in termini di sopravvivenza libera da malattia (PFS) (FASE II)

E.2.2

Secondary objectives of the trial

• To assess the feasibility of the Ro-CHOEP-21 treatment strategy combined with SCT (PHASE I)
• To evaluate ORR and in particular CR rate achieved before and after SCT. (PHASE II)
• To evaluate event free survival (EFS) and overall survival (OS) (PHASE II)
• To evaluate the safety of treatment (PHASE II)
• To evaluate the outcome of early allogeneic SCT in patients in PR at the end of induction phase (PHASE II)
• To estimate the treatment-related mortality (TRM) (PHASE II)
• To evaluate the incidence of acute and chronic GVHD in allografted patients (PHASE II)
• To improve the knowledge on PTCL diagnosis, classification and biology. (PHASE II)

• Valutare la fattibilità di Ro-CHOEP-21 incorporato in un programma terapeutico comprensivo di SCT. (FASE I)
· Valutare la percentuale di risposte globali (ORR) ottenute prima e dopo SCT. (FASE II)
· Valutare la percentuale di risposte complete (CR) ottenute prima e dopo SCT. (FASE II)
· Valutare la sicurezza del programma terapeutico (FASE II)
· Valutare la sopravvivenza libera da eventi (EFS) (FASE II)
· Valutare la sopravvivenza globale (OS) (FASE II)
· Valutare l’efficacia del trapianto allogenico precoce di cellule staminali emopoietiche (SCT) eseguito in pazienti in risposta parziale (PR) al termine della terapia di induzione (FASE II)
· Valutare la mortalità correlata al trattamento (TRM) (FASE II)
· Valutare l’ incidenza di GvHD acuta e cronica nei pazienti sottoposti a trapianto allogenico (FASE II)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. age ≥18 e ≤ 65 years
2. Peripheral T-cell lymphomas at diagnosis including: PTCL-NOS,
AITL, ALK–ALCL
3. Stage II-IV
4. Written informed consent
5. No prior treatment for lymphoma
6. No Central Nervous System (CNS) disease (meningeal and/or brain
involvement by lymphoma)
7. HIV negativity
8. Absence of active hepatitis C virus (HCV) infection
9. HBV negativity or patients with HBcAb +, HBsAg -, HBs Ab+/-
with HBV-DNA negativity (in these patients Lamivudine
prophylaxis is mandatory)
10. Levels of serum bilirubin, alkaline phosphatase and transaminases <
2 the upper normal limit, if not disease related
11. No psychiatric illness that precludes understanding concepts of the
trial or signing informed consent
12. Ejection fraction > 50% and myocardial stroke in the last year nor
QT prolongation (QTc interval < 480 msec using the Fridericia
formula)
13. Clearance of creatinine > 60 ml/min if not disease related
14. Spirometry Diffusion Capacity (DLCO) > 50%
15. Absence of active, uncontrolled infection
16. For males and females of child-bearing potential, agreement upon
the use of effective contraceptive methods prior to study entry, for
the duration of study participation and in the following 90 days after
discontinuation of study treatment
17. Availability of histological material for central review and
pathobiological studies.

1. età ≥18 e ≤ 65 anni
2. nuova diagnosi di PTCL-NOS, AITL, o ALK–ALCL.
3. stadio II-IV
4. consenso informato scritto
5. non aver ricevuto in precedenza trattamenti per il linfoma
6. no localizzazione SNC della malattia (coinvolgimento meningeo e /
o coinvolgimento del cervello da parte del linfoma)
7. sierologia negativa per HIV
8. assenza di infezione attiva da parte del virus dell’Epatite C (HCV)
9. assenza di infezione attiva da parte del virus dell’Epatite B (HBV) o
pazienti con HBcAb +, HBsAg -, HBs Ab + / -, ma con negatività
HBV-DNA (in questi pazienti la profilassi lamivudina è
obbligatoria)
10. livelli di bilirubina sierica, di fosfatasi alcalina e di transaminasi < 2
volte il limite normale superiore
11. assenza di alcuna malattia psichiatrica che possa precludere la
comprensione dei dettagli dello Studio o impedire di firmare il
consenso informato
12. frazione di eiezione > 50%, nessun infarto del miocardico
nell’ultimo anno antecedente l’inizio della terapia e assenza di
prolungamento dell’intervallo QT (intervallo QT corretto < 480
msec calcolato con il metodo Fridericia)
13. clearance della creatinina > 60 ml / min, se non direttamente
correlata alla malattia
14. Spirometria per valutazione della capacità di diffusione del CO
(DLCO) > 50%
15. assenza di infezioni attive clinicamente significative
16. per pazienti in età fertile, consenso ad utilizzare metodi di
contraccezione efficaci prima e durante la partecipazione allo studio
e nei 90 giorni successive al termine della terapia
17. disponibilità di materiale istologico per eseguire la revisione
centralizzata e studi biologici.

E.4

Principal exclusion criteria

1. age <18 e > 65 years
2. Hystology other than: PTCL-NOS, AITL, ALK–ALCL
3. Stage I
4. Prior treatment for lymphoma
5. Positive serologic markers for human immunodeficiency virus (HIV)
6. Active hepatitis B virus (HBV) infection
7. Active hepatitis C virus (HCV) infection
8. Serum bilirubin levels > 2 the upper normal limit, if not disease related
9. Ejection fraction < 50% and no myocardial stroke in the last year nor QT prolongation (QTc interval > 480 msec using the Fridericia formula)
10. Clearance of creatinine < 60 ml/min if not disease related
11. DLCO < 50%
12. Pregnancy or lactation
13. Patient not agreeing to take adequate contraceptive measures during the study
14. Psychiatric disease that precludes understanding concepts of the trial or signing informed consent
15. Any active, uncontrolled infection
16. Prior history of malignancies other than PTCLs in the last five years (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast).

1. età < 18 e > 65 anni
2. Diagnosi istologica diversa da: PTCL-NOS, AITL, ALK-ALCL
3. Stadio I della malattia
4. aver ricevuto in precedenza trattamenti per il linfoma
5. Marcatori sierologici positivi per infezioni da virus
dell’immunodeficienza acquisita umana (HIV),
6. Infezione attiva da virus epatite B (HBV)
7. Infezione attiva da virus epatite C (HCV)
8. livelli di bilirubina sierica, di fosfatasi alcalina e di transaminasi > 2
volte il limite normale superiore, se non correlato alla malattia
9. Frazione d’eiezione < 50% nessun infarto del miocardico
Sinossi Protocollo FIL_PTCL13 V. 1.0 18/11/2013 Pag. 4 of 12
nell’ultimo anno antecedente l’inizio della terapia e assenza di
prolungamento dell’intervallo QT (intervallo QT corretto > 480
msec calcolato con il metodo Fridericia)
10. Clearance della creatininina < 60 ml/min se non correlata alla
malattia
11. Spirometria per valutazione della capacità di diffusione del CO
(DLCO) < 50%
12. Gravidanza o allattamento
13. Paziente non consenziente ad adottare adeguate misure di
contraccezione nel periodo della durata dello studio
14. Patologia psichiatrica che possa precludere la comprensione dei
dettagli dello Studio o impedire di firmare il consenso informato
15. Qualunque infezione attiva non controllata
16. Storia di altra patologia neoplastica nei precedenti 5 anni oltre alla
diagnosi di PTCL (con l’eccezione del basalioma, carcinoma
squamocellulare della pelle e del carcinoma in situ della cervice o
della mammella).

E.5 End points

E.5.1

Primary end point(s)

• Incidence of dose-limiting toxicity (DLT) of Ro-CHOEP-21, considering as maximum dose the one causing induction of any grade ≥ 3 non hematologic toxicity or a delay >15 days of planned cycle date observed during the first two cycles according to the definitions of NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (2009) (PHASE I)
• PFS on intention to treatment (ITT) evaluated at 18 months. PFS will be defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause. (PHASE II)

• Incidenza della tossicità della dose limitante (DLT) di Ro-CHOEP-21, considerando come dose massima tollerata quella causante qualunque grado ≥ 3 di tossicità non ematologica o un ritardo > 15 giorni dell’inizio del ciclo terapeutico programmato, nel corso dei primi due cicli di terapia in accordo con i criteri definiti dal NCI Common Terminology Criteria for Adverse Events (CTCAE), versione 4.0 (2009) (FASE I)
• Valutazione a 18 mesi della sopravvivenza libera da progressione (PFS) basata sulla intenzione di trattamento (ITT). La PFS sarà definita come il tempo intercorso fra la data di arruolamento e la data di progressione, ricaduta, o morte per qualsiasi causa. (FASE II)

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I: 3 months
Phase II: 18 months

FASE I: 3 mesi
FASE II: 18 mesi

E.5.2

Secondary end point(s)

• Proportion of patients reaching SCT (PHASE I)
• Overall response rate (ORR, defined according to the Cheson 2007 response criteria) of the combination of Ro-CHOEP-21. (PHASE I)
• ORR and CR (defined according to the Cheson 2007 response criteria), after Ro-CHOEP-21 and after SCT Event free survival (EFS) induction treatment and after SCT (PHASE II)
• Event free survival (EFS) defined as the time between the date of enrollment and the date of discontinuation of treatment for any reason (PHASE II)
• Overall survival (OS) defined as the time between the date of enrolment and the date of death from any cause in the ITT population enrolled in the study (PHASE II)
• PFS and OS in patients not responding to the first 3 courses of Ro-CHOEP-21 (PHASE II)
• Evaluation during the interim analyses of any grade III or higher toxicities, recorded and classified according to the definitions of NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (2009) (PHASE II)
• Evaluation during all the pretransplant phase of any grade III or higher toxicities, recorded and classified according to the definitions of NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (2009) (PHASE II)
• Any grade III or higher toxicities, recorded and classified according to the definitions of NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (2009) (PHASE II)
• Treatment-related mortality defined as any death that was not attributable to the lymphoma. (PHASE II)
• Incidence of acute and chronic GVHD in allografted patients (PHASE II)

FASE I:
· Proporzione di pazienti che eseguono il trapianto (SCT)
· Proporzione di risposte globali (ORR) definite secondo i criteri di Cheson 2007.
FASE II:
· Proporzione di risposte globali (ORR), definite come Risposte Complete (CR) e
Risposte Parziali (PR), definite secondo i criteri di Cheson 2007.
· Proporzione di Risposte Complete (CR), definite secondo i criteri di Cheson
2007.
· Sopravvivenza libera da eventi (EFS) definita come il tempo intercorso fra la
data di arruolamento e la data di interruzione del trattamento per qualsiasi
causa.
· Sopravvivenza globale (OS) definita come il tempo intercorso fra la data di
arruolamento e la data di decesso per qualsiasi causa basata sulla popolazione
ITT.
· Tossicità di grado 3 o superiore, registrata e definite secondo NCI Common
Terminology Criteria for Adverse Events (CTCAE), versione 4.0 (2009)
· Mortalità trattamento correlata (TRM), definita come qualsiasi decesso non
attribuibile al linfoma
· Incidenza di GVHD acuta e cronica nei pazienti trapiantati

E.5.2.1

Timepoint(s) of evaluation of this end point

• rate of patients who undergo transplantation (SCT): 6 months
• rate of overall response rate (ORR): 6 months
• rate of complete responses (CR): 6 months
• Event Free Survival (EFS): 18 months
• Overall survival (OS): 24 months
• Toxicity: 18 months
• Treatment-related mortality (TRM): 24 months
• Incidence of acute and chronic GVHD in transplant patients: 24 months

Proporzione di pazienti che eseguono il trapianto (SCT): 6 mesi
· Proporzione di risposte globali (ORR): 6 mesi
· Proporzione di risposte complete (CR): 6 mesi
· Sopravvivenza libera da eventi (EFS): 18 mesi
· Sopravvivenza globale (OS): 24 mesi
· Tossicità: 18 mesi
· Mortalità trattamento correlata (TRM): 24 mesi
· Incidenza di GVHD acuta e cronica nei pazienti trapiantati: 24 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

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose finding study

Studio di dose finding

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