Clinical Trials Register

Summary
EudraCT Number:	2015-004727-31
Sponsor's Protocol Code Number:	IRST100.26
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:	2019-09-06
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

2015-004727-31

A.3

Full title of the trial

RANDOMIZED PHASE II TRIAL IN SSTr2 POSITIVE TUMORS TO OPTIMIZE THE INTERVAL BETWEEN CYCLES OF PRRT WITH 177LU DOTATATE (LUTHREE)

Studio di fase II randomizzato finalizzato ad ottimizzare l’intervallo tra i cicli di terapia radiorecettoriale con 177Lutezio Dotatate nei tumori positivi ai recettori 2 della somatostatina.

A.3.1

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

RANDOMIZED PHASE II TRIAL IN SSTr2 POSITIVE TUMORS TO OPTIMIZE THE INTERVAL BETWEEN CYCLES OF PRRT WITH 177LU DOTATATE (LUTHREE)

Studio di fase II randomizzato finalizzato ad ottimizzare l’intervallo tra i cicli di terapia radiorecettoriale con 177Lutezio Dotatate nei tumori positivi ai recettori 2 della somatostatina.

A.3.2

Name or abbreviated title of the trial where available

LUTHREE

A.4.1

Sponsor's protocol code number

IRST100.26

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	ISTITUTO SCIENTIFICO ROMAGNOLO PER LO STUDIO E LA CURA DEI TUMORI (IRST) S.R.L. IRCCS
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	IRST IRCCS
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	IRST IRCCS
B.5.2	Functional name of contact point	Centro di Coordinamento Studi IRST
B.5.3	Address:
B.5.3.1	Street Address	Viale Randi, 5
B.5.3.2	Town/ city	Ravenna
B.5.3.3	Post code	48121
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 0544 285813
B.5.5	Fax number	+39 0544 285330
B.5.6	E-mail	cc.ubsc@irst.emr.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	No
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	LU-DOTATATE_IRSTIRCCS
D.3.2	Product code	LU-DOTATATE_IRSTIRCCS
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	LU-DOTATATE_IRSTIRCCS
D.3.9.2	Current sponsor code	LU-DOTATATE_IRSTIRCCS
D.3.9.3	Other descriptive name	LU-DOTATATE_IRSTIRCCS
D.3.9.4	EV Substance Code	SUB179162
D.3.10	Strength
D.3.10.1	Concentration unit	GBq gigabecquerel(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	3.7 to 5.5
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
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

SSTr2 POSITIVE TUMORS

tumori con recettori sst2-positivi

E.1.1.1

Medical condition in easily understood language

SSTr2 POSITIVE TUMORS

tumori con recettori sst2-positivi

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	20.1
E.1.2	Level	HLGT
E.1.2	Classification code	10027655
E.1.2	Term	Miscellaneous and site unspecified neoplasms malignant and unspecified
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

1) Progression free survival (PFS)
2) Safety

1) Sopravvivenza libera da progressione (PFS)
2) Sicurezza

E.2.2

Secondary objectives of the trial

1) Disease Control Rate (DCR)
2) frequency of late toxicity
3) Overal Survival (OS) in both arms
4) dosimetry in the 6 patient for each risk population (3 for each ARM) to measure pharmacokinetics, activity biodistribution and absorbed dose to kidneys (critical organ) and tumour.
5) To confirm the prognostic and predictive role of PET FDG in subgroup of GEP NET and bronchial NET patients.

1) tasso di controllo della malattia (DCR)
2) frequenza di tossicità tardiva
3) Sopravvivenza Globale (OS) in entrambi i bracci
4) dosimetria in 6 pazienti per ciascuna popolazione a rischio (3 per ogni braccio) per misurare la farmacocinetica, l'attività di biodistribuzione e la dose assorbita dai reni (organo critico) e dal tumore.
5) Conferma del ruolo prognostico e predittivo della PET FDG nel sottogruppo di pazienti GEP NET e NET bronchiali.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age >18 years.
2. Patients must have histologically or cytologically confirmation of neuroendocrine tumors or any other tumor histology type documented as sst2-positive, that may benefit from receptor radionuclide therapy and for which there aren’t any other effective treatments.
3. Measurable disease according to RECIST 1.1.criteria; also patients without measurable but with evaluable disease can be enrolled.
4. Any disease stage is allowed. Patients with documented disease will be admitted to therapeutic phase only if the diagnostic OctreoScan (the tumour uptake will be evaluated with a 3-grade scale, where 1 = liver uptake, 2 > liver uptake and < kidney uptake and 3 > kidney uptake: only tumour uptakes grade 2 and 3 will be considered for therapy) and/or PET/CT 68Ga-peptide images demonstrate a significant uptake in the tumour.
5. Patients with progressive disease in pre-study period (PD within the last 12 months), refractory to conventional standard treatments; clinical progression is allowed
6. Patients with or without concurrent therapy with somatostatin analogs
7. ECOG performance status <2
8. Adequate haematological, liver and renal function

1. Età≥18 anni.
2. Tumori neuroendocrini o di qualsiasi altro istotipo tumorale confermati istologicamente o citologicamente con recettori sst2-positivi, che possono trarre beneficio da una terapia radiorecettoriale e per i quali non ci siano altri trattamenti efficaci.
3. Malattia misurabile secondo i criteri RECIST 1.1.; sono inclusi anche i pazienti che non hanno malattia misurabile, ma con malattia valutabile (cioè lesioni ossee, ascite).
4. È consentito qualsiasi stadio della malattia. I pazienti con malattia documentata saranno ammessi alla fase terapeutica solo se la diagnostica per immagini mediante OctreoScan e/o PET/TC 68Ga-peptide dimostra un significativo incremento della captazione a livello del tumore (valutata con una scala di 3 gradi: grado1 = captazione epatica, grado 2 > captazione epatica e < captazione renale e grado 3 > captazione renale; solo tumori di grado 2 e 3 saranno accettati per lo studio).
5. Pazienti con progressione di malattia nel periodo pre-studio (PD negli ultimi 12 mesi), refrattari ai trattamenti standard convenzionali; è permessa la progressione clinica.
6. E’ permessa l’assunzione concomitante di analoghi della somatostatina.
7. ECOG performance status ≤2
8. Adeguata funzionalità ematologica, epatica e renale

E.4

Principal exclusion criteria

1. Patients treated with chemotherapy and therapeutic radiotherapy within 4 weeks and treated within 2 weeks with palliative radiotherapy, hormonal or biological therapy).
2. Patients treated with previous radiometabolic therapy with an adsorbed dose to the kidney more than 23 Gy and more than 1.8 Gy for the bone marrow or as surrogate of dosimetry.
3. All acute toxic effects of any prior therapy (including surgery radiation therapy, chemotherapy) must have resolved to a grade ≤ 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE)
4. ECOG performance status >2
5. Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
7. Assessed bone marrow invasion > 50% (with Bone Marrow biopsy or instrumental exams i.e bone scan or CT or MRI)
8. Pregnant or breastfeeding women are excluded from the present study

1. sono esclusi i pazienti trattati con chemioterapia e radioterapia terapeutica entro 4 settimane e trattati con la radioterapia palliativa, ormonale o terapia biologica entro 2 settimane.
2. I pazienti trattati con una precedente terapia radiometabolica con una dose assorbita a livello renale superiore a 23 Gy e con una dose assorbita a livello del midollo osseo superiore a 1,8 Gy o come surrogati della dosimetria.
3. Tutti gli effetti tossici acuti di qualsiasi precedente terapia (tra cui la radioterapia chirurgia, chemioterapia) devono essere stati risolti ad un grado ≤ 1, in accordo con i criteri del National Cancer Institute Common Terminology per gli eventi avversi Versione 4.0 (CTCAE)
4. ECOG performance status> 2
5. La partecipazione in un altro studio clinico con farmaci sperimentali nei 30 giorni precedenti alla fase di screening.
6. malattia non controllata intercorrente tra cui, ma non solo, infezione in corso o attiva, insufficienza cardiaca congestizia sintomatica, angina pectoris instabile, aritmia cardiaca, malattia psichiatrica / situazioni sociali che limiterebbero la conformità ai requisiti di studio.
7. Invasione del midollo osseo> 50% (con biopsia del midollo osseo o esami strumentali, cioè scintigrafia ossea o TC o RM)
8. Le donne incinte o che allattano sono escluse dal presente studio

E.5 End points

E.5.1

Primary end point(s)

1) PFS
2) Safety

1) PFS
2) Sicurezza

E.5.1.1

Timepoint(s) of evaluation of this end point

5 years

5 anni

E.5.2

Secondary end point(s)

Prognostic and predictive role of PET FDG

Ruolo prognostico e predittivo PET FDG

E.5.2.1

Timepoint(s) of evaluation of this end point

5 years

5 anni

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

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

valutazione dei 4 bracci di trattamento paralleli:
A. paz. con fattori di rischio (RF): 3,7 GBq di

evaluation of 4 parallel treatment arms:
A. patients with risk factors (RF): 3.7 GBq of 177Lu-DOT

E.8.2.4

Number of treatment arms in the trial

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.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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:

410

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

208

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

Yes

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

618

F.4.2

For a multinational trial

F.4.2.1

In the EEA

618

F.4.2.2

In the whole clinical trial

618

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)

Follow-up visits are scheduled every 4 months until month 24 is reached (starting from Randomization); It will carry out the following evaluations:
• Physical examination;
• Lab test
• tumor instrumental evaluation (CT and/or MRI)
• If a suspect of relapse occurs, a CT scan (or MRI) and/or OctreoScan and/or PET/CT 68Ga-peptide will be done.

Le visite di Follow-up sono programmate ogni 4 mesi fino al 24° mese dopo la randomizzazione; si effettueranno le seguenti valutazioni:
• Esame fisico;
• Test di laboratorio
• rivalutazione strumentale del tumore (TC o RM)
• In caso di sospetto di recidiva verrà effettuata una TAC (o RM) e / o OctreoScan e / o PET / TC 68Ga-peptide.

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

2016-02-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-03-16

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

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