Clinical Trials Register

Summary
EudraCT Number:	2019-002196-34
Sponsor's Protocol Code Number:	Neo.Lu.Pa.NET
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-06-15
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

2019-002196-34

A.3

Full title of the trial

A Prospective Phase II Single-Arm Trial on Neoadjuvant Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE Followed by Surgery for resectable Pancreatic Neuroendocrine Tumors (Neo.Lu.Pa.NET)

Studio prospettico single-arm di fase II su terapia neoadiuvante Peptide Receptor Radionuclide con 177Lu-DOTATATE seguita da intervento per tumori resecabili neuroendocrini del pancreas (PanNETs)

A.3.1

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

Clinical study to assess neoadjuvant therapy Peptide Receptor Radionuclide with 177Lu-DOTATATE followed by surgery for resectable pancreatic tumors

Sperimentazione per valutare la terapia neoadiuvante Peptide Receptor Radionuclide con 177Lu-DOTATATE seguita da intervento chirurgico per tumori resecabili del pancreas

A.3.2

Name or abbreviated title of the trial where available

Neo.Lu.Pa.NET

A.4.1

Sponsor's protocol code number

Neo.Lu.Pa.NET

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	OSPEDALE SAN RAFFAELE
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	Advanced Accelerator Application International SA (AAA)
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	Pharmaceutical Development and Services srl
B.5.2	Functional name of contact point	Monitoraggio e dati sulla sicurezza
B.5.3	Address:
B.5.3.1	Street Address	Via dei Pratoni 16
B.5.3.2	Town/ city	Scandicci, Firenze
B.5.3.3	Post code	50018
B.5.3.4	Country	Italy
B.5.4	Telephone number	0557224179
B.5.5	Fax number	0557227014
B.5.6	E-mail	edimartino@pharmades.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	Lutathera 370 MBQ/ML- SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 20,5- 25 ML- 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	Advanced Accelerator Applications
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/523
D.3 Description of the IMP
D.3.1	Product name	Lutathera
D.3.2	Product code	[Lutezio (177Lu) oxodotreotide]
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	Lutezio (177Lu) oxodotreotide
D.3.9.2	Current sponsor code	OSR
D.3.10	Strength
D.3.10.1	Concentration unit	MBq/ml megabecquerel(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	370
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

Resectable pancreatic neuroendocrine tumors

Tumori resecabili neuroendocrini del pancreas

E.1.1.1

Medical condition in easily understood language

Pancreatic tumors

Tumori del pancreas

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10067518
E.1.2	Term	Pancreatic neuroendocrine tumor
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main aim of this study is to evaluate the safety of neoadjuvant PRRT with 177Lu-DOTATATE followed by surgical resection for resectable non-functioning PanNETs at high risk of recurrence.

L'obiettivo principale di questo studio è valutare la sicurezza della terapia neoadiuvante PRRT con 177Lu-DOTATATE seguito dalla resezione chirurgica per PanNET non funzionanti resecabili ad alto rischio di recidiva.

E.2.2

Secondary objectives of the trial

The secondary aim is to evaluate the efficacy of neoadjuvant PRRT with 177Lu-DOTATATE.

L'obiettivo secondario è quello di valutare l'efficacia dellla terapia neoadiuvante PRRT con 177Lu-DOTATATE.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Conservation and use of human biological material in spontaneous monocentric or multicentric studies with OSR as promoter: whole blood, plasma and serum will be stored in the internal biobank for further investigations regarding tumor biology, genetics and predictive biomarkers after signing of the specific informed consent.

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Conservazione e utilizzo di materiale biologico umano studi spontanei monocentrici o multicentrici con OSR promotore, v.1 22.05.2019: i campioni sanguigni saranno conservati in una biobanca per future ricerche riguardanti la biologia del tumore, genetica e marker predittivi solo dopo aver firmato il consenso informato.

E.3

Principal inclusion criteria

o Age > 18 years
o Morphological confirmation by high-quality imaging technique (MR or CT scan)
o Cytological or histologically confirmed sporadic resectable nonfunctioning PanNETs (NF-PanNETs) with positive 68Ga-DOTATOC PET/CT (with primary lesion uptake greater than the normal liver and SUV bw max = 15) and at least one of the following “high-risk features”:
o Radiological tumour size > 40 mm
o Well differentiated G2 NF-PanNETs with Ki67 >10% or well differentiated NF-PanNETs G3
o Presence of nearby organs involvement
o Vascular invasion (excluding the presence of superior mesenteric vein/portal vein invasion > 180° and/or celiac trunk/superior mesenteric artery invasion)
o Mesenteric and/or portal and/or splenic vein thrombosis
o Presence of a single resectable liver metastasis
o Presence of enlarged hypervascularized lymph nodes at imaging that are positive at 68Ga-DOTATOC PET/CT
o Absence of extra-abdominal disease
o Absence of peritoneal carcinomatosis
o Karnofsky Performance Status = 90 or o ECOG-PS=0
o ASA <= 3
o Preserved hematologic, hepatic and renal parameters (WBC> 2,500/ml [ANC> 1,500/mcl]; Hb> 10g/dL; PTL> 100,000/mcl; bilirubin< 2.5 mg/dl, creatinine< 2 mg/dl);
o Absence of serious disease which can compromise safety (cardiac failure, previous myocardial infarction within prior 6 months, history of psychiatric disabilities, synchronous malignancy)
o Informed consent

o Età> 18 anni
o Conferma morfologica mediante tecnica di imaging di alta qualità (RM o TC)
o PanNET non funzionanti resecabili sporadici citologicamente o istologicamente confermati (NF-PanNETs) con PET / CT 68Ga-DOTATOC positivo (con assorbimento della lesione primaria maggiore del fegato normale e SUV bw max = 15) e almeno uno dei seguenti punti “ad alto rischio":
o Dimensione del tumore alla radiografia> 40 mm
o G2 NF-PanNET ben differenziati con Ki67> 10% o NF-PanNET G3 ben differenziati
o Presenza di coinvolgimento di organi vicini
o Invasione vascolare (esclusa la presenza di invasione > 180 ° della vena mesenterica superiore/della vena porta e/o invasione del tronco celiaco/dell'arteria mesenterica superiore)
o Trombosi venosa mesenterica e/o portale e/o splenica
o Presenza di una singola metastasi epatica resecabile
o Presenza di linfonodi ipervascolarizzati ingrossati all'imaging positivi a 68Ga-DOTATOC PET / CT
o Assenza di malattia extra-addominale
o Assenza di carcinomatosi peritoneale
o Stato prestazioni Karnofsky = 90 o o ECOG-PS = 0
o ASA <= 3
o Parametri ematologici, epatici e renali conservati (WBC> 2.500 / ml [ANC> 1.500 / mcl]; Hb> 10g / dL; PTL> 100.000 / mcl; bilirubina <2,5 mg / dl, creatinina <2 mg / dl);
o Assenza di patologie gravi che possono compromettere la sicurezza (insufficienza cardiaca, precedente infarto del miocardio entro 6 mesi precedenti, anamnesi di disabilità psichiatriche, presenza contemporanea di malignità)
o consenso informato

E.4

Principal exclusion criteria

o Age < 18 years
o Negative functional Imaging (68Ga-DOTATOC PET/CT)
o Presence of genetic syndrome (MEN1, VHL, NF)
o Functioning PanNET
o NF-PanNEC G3
o Absence of “high-risk features” as defined above
o Presence of extra abdominal disease
o Presence of multiple liver metastases
o Presence of peritoneal carcinomatosis
o Previous PanNET-directed treatment
o Karnofsky Performance Status < 90% or ECOG-PS > 0
o ASA > 3
o Inadequate bone marrow, liver and kidney function.
o Presence of serious disease which can compromise safety (cardiac failure, previous myocardial infarction within prior 6 months, history of psychiatric disabilities, synchronous malignancy)
o Bone marrow invasion
o Life expectancy less than 6 months
o Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product,
o Known or suspected non-compliance, drug or alcohol abuse.
o Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant,
o Participation in another study with investigational drug within the 30 days preceding and during the present study or 5 half-life of the experimental drug.
o Enrolment of the investigator, his/her family members, employees and other dependent persons
o Creatinine clearance < 30 mL/min calculated by the Cockroft Gault method
o Uncontrolled congestive heart failure (NYHA III, IV).
o Total bilirubin > 3 x normal rate
o Serum albumin < 3.0 g/dL u
o Hb concentration < 5.0 mmol/L (<8.0 g/dL); WBC < 2x10E9/L (2000/mm3); platelets < 75x10E9/L (75x10E3/mm3)
o Pregnancy or lactation
o Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant are not allowed to participate in this study UNLESS they are using highly effective methods of highly effective contraception (failure rate <1%/year) throughout the study and for 12 months after the administration of the last cycle of 177Lu-DOTATATE (see par. 8.1)
o Potential fertile men with female partner of child-bearing potential, during the study period and for at least 1 cycle of spermatogenesis (90 days) after the administration of the last cycle of 177Lu-DOTATATE (see par. 8.1)

o Età <18 anni
o Imaging funzionale negativo (68Ga-DOTATOC PET / CT)
o Presenza di sindrome genetica (MEN1, VHL, NF)
o PanNET funzionante
o NF-PanNEC G3
o Assenza di "caratteristiche ad alto rischio" come definiti precedentemente
o Presenza di malattia extra-addominale
o Presenza di più metastasi epatiche
o Presenza di carcinomatosi peritoneale
o Trattamento diretto precedente da PanNET
o Stato prestazioni Karnofsky <90% o ECOG-PS> 0
o ASA> 3
o Insufficiente funzionalità del midollo osseo, del fegato e dei reni.
o Presenza di malattia grave che può compromettere la sicurezza (insufficienza cardiaca, precedente infarto del miocardio nei 6 mesi precedenti, anamnesi di disabilità psichiatriche, presenza contemporanea di malignità)
o Invasione del midollo osseo
o Speranza di vita inferiore a 6 mesi
o Controindicazioni alla classe di farmaci in studio, ad es. ipersensibilità nota o allergia alla classe di farmaci o al prodotto sperimentale,
o Non compliance nota o sospetta, abuso di droghe o alcol.
o Incapacità di seguire le procedure dello studio, ad es. a causa di problemi linguistici, disturbi psicologici, demenza, ecc. del partecipante,
o Partecipazione ad un altro studio con farmaco sperimentale nei 30 giorni precedenti e durante il presente studio o 5 emivita del farmaco sperimentale.
o Partecipazione dello sperimentatore, dei suoi familiari, dipendenti e altre persone a carico
o Clearance della creatinina <30 mL / min calcolata con il metodo Cockroft Gault
o Insufficienza cardiaca congestizia incontrollata (NYHA III, IV).
o Bilirubina totale> 3 volte il valore normale
o Albumina sierica <3,0 g / dL u
o concentrazione di Hb <5,0 mmol / L (<8,0 g / dL); WBC <2x10E9 / L (2000 / mm3); piastrine <75x10E9 / L (75x10E3 / mm3)
o Gravidanza o allattamento
o Le donne in età fertile, definite come tutte le donne fisiologicamente in grado di rimanere incinta, non sono autorizzate a partecipare a questo studio A MENO CHE non stiano utilizzando metodi altamente efficaci di contraccezione altamente efficace (tasso di fallimento <1% / anno) durante lo studio e per 12 mesi dopo la somministrazione dell'ultimo ciclo di 177Lu-DOTATATE (vedi par. 8.1)
o Potenziali uomini fertili con partner femminile in età fertile, durante il periodo di studio e per almeno 1 ciclo di spermatogenesi (90 giorni) dopo la somministrazione dell'ultimo ciclo di 177Lu-DOTATATE (vedere paragrafo 8.1)

E.5 End points

E.5.1

Primary end point(s)

Rate of postoperative 90-day morbidity and mortality after neoadjuvant PRRT with 177Lu-DOTATATE followed by pancreatic resection

Tasso di morbilità e mortalità postoperatoria a 90 giorni dopo terapia neoadiuvante PRRT con 177Lu-DOTATATE seguito da resezione del pancreas

E.5.1.1

Timepoint(s) of evaluation of this end point

12 week (from week 40 until week 52)

12 settimane (dalla settimana 40 alla settimana 52)

E.5.2

Secondary end point(s)

Rate of objective radiological response to PRRT with 177Lu-DOTATATE according to modified RECIST criteria (mRECIST); Quality of life (QoL) after neoadjuvant PRRT followed by pancreatic surgical resection.

Tasso di risposta radiologica obiettiva a PRRT con 177Lu-DOTATATE secondo i criteri RECIST modificati (mRECIST); Qualità della vita dopo PRRT neoadiuvante seguito da resezione chirurgica del pancreas.

E.5.2.1

Timepoint(s) of evaluation of this end point

at 38th week; Week 0, Week 38, Week 52

alla settimana 38; Alla settimana 0, 38 e 52

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

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

E.8.1.2

Open

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.8.2.4

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

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

The study will end 2 months after operation of the last patient enrolled.

Lo studio terminerà 2 mesi dopo l'operazione dell'ultimo paziente arruolato

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)

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

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

2019-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-11-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-06-26

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