Clinical Trials Register

Summary
EudraCT Number:	2012-001676-11
Sponsor's Protocol Code Number:	FIL_MIRO
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:	2014-09-03
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

2012-001676-11

A.3

Full title of the trial

"MIRO" study (Molecularly Oriented Immuno-radio-therapy): a multicenter phase II trail for the treatment on molecular basis of stage I / II Follicular Lymphoma with local radiotherapy with / without Ofatumumab

Studio “MIRO” (Molecularly Immuno-radio-therapy Oriented): studio multicentrico di fase II per il trattamento su base molecolare dei Linfomi Follicolari stadio I/II con radioterapia locale con/senza Ofatumumab

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

FIL_MIRO

A.4.1

Sponsor's protocol code number

FIL_MIRO

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	GLAXO SMITH KLINE SPA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FONDAZIONE ITALIANA LINFOMI ONLUS
B.5.2	Functional name of contact point	SECRETARY
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	00390131206261
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	ARZERRA
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Ltd 980 Great West Road Brentford Middlesex TW8 9GS - UK
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	OFATUMUMAB
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 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	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

Stage I/II Follicular Lymphoma

Trattamento di pazienti con linfoma follicolare (FL) di stadio I/IIA.

E.1.1.1

Medical condition in easily understood language

Stage I/II Follicular Lymphoma

Trattamento di pazienti con linfoma follicolare (FL) di stadio I/IIA.

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 evaluate the proportion of patients obtaining disappearance of Bcl-2-IgH rearranged cells in peripheral blood and/or bone marrow by PCR, after treatment with Ofatumumab.

Valutare la proporzione di pazienti che ottiene la negativizzazione del riarrangiamento Bcl-2-IgH alla PCR qualitativa e quantitativa dopo il trattamento con Ofatumumab.

E.2.2

Secondary objectives of the trial

To evaluate clinical response rate, relapse-free survival (RFS) and progression-free survival (PFS) in patients treated with local radiotherapy and molecularly–based Ofatumumab consolidation and/or retreatment; these objectives will be defined by clinical and instrumental procedures, according to Cheson criteria.

To evaluate the role of quantitative PCR determination of basal Bcl-2-IgH rearranged cells in PB and BM in predicting the probability of negativization after local radiotherapy and the probability of relapse.

Valutare la percentuale di risposta clinica, sopravvivenza libera da recidiva (RFS) e sopravvivenza libera da progressione (PFS) nei pazienti trattati con radioterapia locale e trattamento molecolare di consolidamento e / o di ritrattamento con Ofatumumab; questi obiettivi saranno definiti da procedure cliniche e strumentali secondo i criteri di Cheson.
Valutare il ruolo della PCR quantitativa nella determinazione al basale delle cellule riarrangiate Bcl-2-IgH in PB e in BM nel predire la probabilità di negativizzazione dopo la radioterapia locale e la probabilità di recidiva.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histologically confirmed follicular lymphoma grade I-IIIa;
• Stage IA or IIA (no more than 2 contiguous nodal regions) non bulky (<7 cm);
• FLIPI <2, FLIPI2 <2;
• Previously untreated;
• Age ≥ 18;
• Informed consent;
• Staging with PET-CT, bone marrow biopsy;
• Qualitative/quantitative PCR basal evaluation of Bcl-2/IgH rearranged cells in peripheral blood and bone marrow.

• Linfoma follicolare di grado I-IIIa confermato istologicamente;
• Stadio IA o IIA (non più di 2 siti linfonodali contigui) non bulky (<7 cm);
• Pazienti non trattati in precedenza;
• FLIPI < 2, FLIPI2 < 2;
• Età ≥ 18;
• Firma del consenso informato;
• Stadiazione con PET-CT, biopsia del midollo osseo;
• Valutazione qualitativa / quantitativa della PCR basale delle cellule Bcl-2/IgH positive nel sangue periferico e midollo osseo.

E.4

Principal exclusion criteria

• Follicular lymphoma grade IIIb;
• Stage greater than II with more than 2 nodal sites and/or B symptoms and/or bulky disease (>7 cm);
• FLIPI >2, FLIPI2 >2;
• Age < 18;
• Previous treatments for non-Hodgkin’s lymphoma;
• Dementia;
• Impossibility to subscribe the informed consent;
• Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones or stable chronic liver disease per investigator assessment)
• Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study
• Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
• Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C.
• History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae
• Known HIV positive
• Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to start of treatment, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.
• Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
• Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a quantitative HBV-DNA test will be performed and if positive the subject will be excluded. Patients with HBcAb positivity and negative HBV DNA should be prophilactically treated with oral Lamivudine (100 mg /day) in case of treatment with Ofatumumab, to be prosecuted 12 months after treatment.
• Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HCV-RNA on the same sample to confirm the result;
• Hematologic and blood chemistry esclusion criteria:
platelets <50 x 109/L;
neutrophils <1.0 x 109/L;
creatinine >2.0 times upper normal limit;
total bilirubin >1.5 times upper normal limit;
ALT >2.5 times upper normal limit;
alkaline phosphatase >2.5 times upper normal limit.
• Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening.
Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence
• Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

• Linfoma follicolare di grado III b;
• Stadio superiore al II con più di 2 siti nodali e / o sintomi B e / o malattia bulky (> 7 cm);
• FLIPI >2, FLIPI2 >2;
• Età <18;
• Pazienti precedentemente trattati per il linfoma non-Hodgkin;
• Dementia
• Impossibilità a sottoscrivere il consenso informato
• Soggetti che hanno in corso malattia epatica attiva o biliare (ad eccezione dei pazienti con sindrome di Gilbert, calcoli biliari asintomatici, metastasi epatiche o malattie stabili croniche del fegato secondo valutazione dello sperimentatore);
• Pazienti trattati con qualsiasi sostanza farmaceutica non commercializzata o con terapia sperimentale con emivita di 5 o 4 settimane come periodo più lungo precedenti l'arruolamento, o che attualmente partecipano in qualsiasi altro studio clinico interventistico;
• Altro tumore maligno passato o attuale. I soggetti che sono in remissione completa da almeno 5 anni, o hanno una storia di asportazione completa del cancro della pelle di tipo non-melanoma, o soggetti con carcinoma in situ trattato con successo sono eleggibili;
• Malattia infettiva cronica o corrente che richiede come trattamento l’uso di antibiotici sistemici, antifungini o antivirali, escludendo l'infezione cronica renale, infezioni croniche al torace con bronchiectasie, tubercolosi e l'epatite C attiva;
• Storia di una significativa malattia cerebrovascolare negli ultimi 6 mesi o degli eventi in corso con sintomi attivi o sequele;
• Positività HIV;
• Malattia cardiaca clinicamente significativa, ivi incluso l'angina instabile, infarto miocardico acuto nei sei mesi precedenti l'inizio del trattamento, insufficienza cardiaca congestizia (NYHA III-IV), e aritmia non controllata da terapia, con l'eccezione di extrasistole o anomalie minori di conduzione;
• Significativa concomitante condizione clinica incontrollata, comprese, ma non limitato a, renale, epatica, gastrointestinale, endocrina, malattia polmonare, neurologica, cerebrale o psichiatrica che, a parere del ricercatore potrebbe rappresentare un rischio per il paziente;
• Sierologia positiva per epatite B (HB) definita come test positivo per HBsAg. Inoltre, se negativa per HBsAg ma positivo per HBcAb (indipendentemente dallo stato HBsAb), verrà eseguito un test per HBV-DNA e se l’esito sarà positivo il soggetto sarà da escludere;
• Sierologia positiva per epatite C (HC) definita come test positivo per HCAb. Se positivo in aggiunta si deve eseguire un test per HCV-RNA sullo stesso campione per confermare il risultato;
• Criteri di esclusione ematologici e biochimici :
o piastrine <50 x 109 / L;
o neutrofili <1,0 x 109 / L;
o creatinina> 2,0 volte il limite superiore della norma;
o bilirubina totale> 1,5 volte il limite superiore della norma;
o ALT> 2,5 volte il limite superiore della norma;
o fosfatasi alcalina> 2,5 volte il limite superiore della norma;
• Donne in gravidanza o allattamento. Le donne in età fertile devono risultare negative al test di gravidanza allo screening. Donne in età fertile, tra cui donne il cui ultimo periodo mestruale è stato inferiore a un anno prima dello screening, incapaci o riluttanti ad usare adeguati metodi contraccettivi dall'inizio studio e per un anno dopo l'ultima dose della terapia prevista dal protocollo. I metodi contraccettivi adeguati sono definiti come il controllo ormonale delle nascite, il dispositivo intrauterino, il metodo a doppia barriera o l’astinenza totale.
• I soggetti maschi che non possono o non vogliono utilizzare metodi contraccettivi adeguati dall'inizio studio per un anno dopo l'ultima dose di protocollo di terapia.

E.5 End points

E.5.1

Primary end point(s)

The proportion of Bcl-2 negativization after Ofatumumab treatment will be estimated by the proportion, and its confidence interval, of residual Bcl-2 positive cases after radiotherapy, which will became negative after Ofatumumab treatment.

Valutazione della percentuale di negativizzazione della Bcl-2 dopo il trattamento con Ofatumumab e il suo intervallo di confidenza nei casi residui Bcl-2 positivi dopo la radioterapia.

E.5.1.1

Timepoint(s) of evaluation of this end point

30 months

30 mesi

E.5.2

Secondary end point(s)

Clinical response rate will be evaluated by the proportion and its confidence interval of patients achieving overall response (OR) complete response (CR) and partial response (PR).

Progression Free Survival (PFS) is defined as the length of time between the date of treatment conclusion and the earliest date of disease progression or death due to any cause; If the patients doesn’t not have a documented date of progression or death, the PFS will be censored at the date of last adequate assessment. Relapse Free Survival (RFS) is defined as the length of time between the achievement of Complete Remission (CR) and Relapse of disease
RFS and PFS in patients treated with local radiotherapy and molecularly–based Ofatumumab consolidation and/or retreatment will be evaluated by Kaplan-Meier survival analysis.

• Risposta clinica: il tasso di risposta clinica sarà valutato in base alla proporzione ed al suo intervallo di confidenza della risposta globale (OR), della risposta completa (CR) e risposta parziale (PR).
• Sopravvivenza senza progressione (PFS) definita come l'intervallo di tempo tra la data di conclusione del trattamento e la prima data della progressione della malattia o morte per qualsiasi causa; se i pazienti non hanno una data documentata di progressione o morte, il PFS sarà censurato alla data dell'ultima valutazione adeguata. La sopravvivenza libera da recidiva (RFS) è definita come l'intervallo di tempo tra il conseguimento della remissione completa (CR) e la recidiva della malattia.
• RFS e PFS nei pazienti trattati con radioterapia locale e con Ofatumumab di consolidamento e / o ritrattamento valutate mediante analisi di sopravvivenza Kaplan-Meier.

E.5.2.1

Timepoint(s) of evaluation of this end point

72 months

72 mesi

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

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

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

110

F.4.2

For a multinational trial

F.4.2.1

In the EEA

110

F.4.2.2

In the whole clinical trial

110

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)

At the end of participation in the study patients will be followed as
required by standard practice.

Al termine della partecipazione allo studio i pazienti verranno seguiti
secondo quanto previsto dalla comune pratica clinica.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-10-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-09

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

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