Clinical Trials Register

Summary
EudraCT Number:	2014-003067-38
Sponsor's Protocol Code Number:	IRST100.17
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:	2018-09-19
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

2014-003067-38

A.3

Full title of the trial

177Lutethium - Peptide Receptor Radionuclide Therapy (Lu-PRRT) plus Capecitabine versus Lu-PRRT in FDG positive, gastro-entero-pancreatic neuroendocrine tumors: a randomized phase II study. (Lu-Ca-S)

A.3.1

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

177Lutethium - Peptide Receptor Radionuclide Therapy (Lu-PRRT) plus Capecitabine versus Lu-PRRT in FDG positive, gastro-entero-pancreatic neuroendocrine tumors: a randomized phase II study. (Lu-Ca-S)

Terapia radiorecettoriale con 177Lu-dotatate (Lu-PRRT) più capecitabina verso Lu-PRRT in pazienti FDG positivi con neoplasia neuroendocrina gastro-entero-pancreatica: studio randomizzato di fase II.
(Lu-Ca-S)

A.3.2

Name or abbreviated title of the trial where available

Lu-Ca-S

A.4.1

Sponsor's protocol code number

IRST100.17

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	Dipartimento di Oncologia ed Ematologia, Ospedale Civile S. Maria delle Croci, 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	+390544285813
B.5.5	Fax number	+390544285330
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	Yes
D.2.1.1.1	Trade name	CAPECITABINA ACCORD - 500 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER (PVC/PVDC/ALU) - 60X1 COMPRESSE (DOSE UNITARIA)
D.2.1.1.2	Name of the Marketing Authorisation holder	ACCORD HEALTHCARE LIMITED
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.3.1	Product name	CAPECITABINE_IRSTIRCCS
D.3.2	Product code	CAPECITABINE_IRSTIRCCS
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.3.11 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	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	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	Intravenous use
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	equal
D.3.10.3	Concentration number	3.7
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

gastro-entero-pancreatic neuroendocrine tumors (GEP-NET)

NET (tumori neuroendocrini) del tratto gastro-entero-pancreatico (GEP)

E.1.1.1

Medical condition in easily understood language

gastro-entero-pancreatic neuroendocrine tumors (GEP-NET)

NET (tumori neuroendocrini) del tratto gastro-entero-pancreatico (GEP)

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10052399
E.1.2	Term	Neuroendocrine tumour
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 progression free survival (PFS) in the two arms.

valutare la sopravvivenza libera da progressione (PFS) nei due bracci.

E.2.2

Secondary objectives of the trial

- the efficacy (disease control rate, DCR)
- acute and late toxicity
- overall survival (OS).

- efficacia (tasso di controllo della malattia, DCR)
- tossicità acuta e tardiva
- sopravvivenza globale (OS)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histopathologic diagnosis of gastro-entero-pancreatic neuroendocrine tumor, well differentiated G1 – G2 (ki67≤ 20%) and G3 (ki67≤ 50%)
2. Male or Female, aged >18 years
3. Measurable disease according to RECIST 1.1 criteria
4. Patients with documented disease will be admitted to therapeutic phase only if the diagnostic receptor imaging, OctreoScan, with a significant uptake in the tumor (grade 2 or 3, according to Rotterdam scale) and/or PET/CT 68Ga-peptide images with a tumor uptake at least equal to liver background
5. Patients with documented disease will be admitted to therapeutic phase only if the 18FDG PET/CT is positive with a SUV > 2.5 at least in one documented lesion.
6. Non operable advanced disease
7. Documented progression after standard therapy such as long acting octreotide or lanreotide (SS-LAR), Everolimus in P-NETs or platinum based therapy in G3 patients.
8. Patients have to finish prior standard chemotherapy or therapeutical radiotherapy (less then 25% body surface) at least 6 weeks

1. Diagnosi istopatologica di tumore neuroendocrino gastro-entero-pancreatico, G1-G2 ben differenziato (ki67≤ 20%) e G3 (ki67≤ 50%)
2. Maschio o femmina, di età> 18 anni
3. Malattia misurabile secondo i criteri RECIST 1.1
4. I pazienti con malattia documentata saranno ammessi alla fase terapeutica solo se la diagnostica per immagini di tipo recettoriale OctreoScan, mostrerà una captazione significativa del tumore (grado 2 o 3, secondo la scala Rotterdam) e / o la diagnostica per immagini di tipo PET/TAC 68Ga-peptide avrà una captazione del tumore almeno pari al sottofondo epatico
5. I pazienti con malattia documentata saranno ammessi alla fase terapeutica solo se la 18-FDG PET/TAC sarà positiva, con un SUV> 2.5 in almeno una lesione documentata.
6. Malattia non operabile avanzata
7. Progressione documentata dopo la terapia standard, come octreotide o lanreotide (SS-LAR), everolimus nei P-NETs o la terapia a base di platino nei pazienti G3.
8. I pazienti devono avere terminato la precedente chemioterapia o radioterapia terapeutica standard (meno del 25% della superficie corporea) da almeno 6 settimane

E.4

Principal exclusion criteria

1. Ki67 index > 50%
2. FDG PET negative
3. Patients treated with chemotherapy and therapeutic radiotherapy within 6 weeks
4. More then 25% body surface radiotherapy
5. Patients treated with previous radiometabolic therapy with an adsorbed dose to the kidney more than 23 Gy and 1,2 Gy for the bone marrow or as surrogate of dosimetry, a Total Cumulative Activity of >250 mCi of 90Y dotatoc or >800 mCi of 177Lu dotatate
6. 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)
7. Life expectancy minor than 6 months.
8. ECOG performance status >2
9. Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
10. 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.
11. History of allergic reactions attributed to compounds of similar chemical or biologic composition
12. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
13. Known hypersensitivity to Octreotide and/or Lanreotide, and/or somatostatin correlate peptides
14. Known hypersensitivity to capecitabine or to any of its components
15. Known hypersensitivity to 5 - fluorouracil.
16. Other known malignant neoplastic diseases in the patient’s medical history with a disease-free interval of less than 5 years (except for previously treated basal cell carcinoma and in situ carcinoma of the uterine cervix);

1. indice Ki67> 50%
2. FDG PET negativa
3. pazienti trattati con chemioterapia e radioterapia terapeutica entro 6 settimane
4. radioterapia in più del 25% della superficie corporea
5. pazienti trattati con una precedente terapia radiometabolica, con una dose assorbita a livello renale superiore a 23 Gy e 1,2 Gy a livello del midollo osseo o, come surrogato della dosimetria, un attività cumulativa totale > 250 mCi di 90Y DOTATOC o > 800 mCi di 177Lu DOTATATE
6. Tutti gli effetti tossici acuti di qualsiasi precedente terapia (tra cui chirurgia, radioterapia, chemioterapia) devono essere ridotti ad un grado ≤ 1 secondo i criteri National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE)
7. Aspettativa di vita inferiore a 6 mesi.
8. ECOG performance status> 2
9. La partecipazione a un altro studio clinico con eventuali farmaci sperimentali nei 30 giorni precedenti allo screening per lo studio.
10. concomitante malattia non controllata tra cui, ma non solo, infezione attiva o in corso, insufficienza cardiaca congestizia sintomatica, angina pectoris instabile, aritmia cardiaca, malattia psichiatrica / situazioni sociali che limiterebbero la conformità ai requisiti di studio.
11. storia di reazioni allergiche attribuite a composti simili dal punto di vista chimico o di composizione biologica
12. nota deficienza di deidrogenasi diidropirimidina (DPD).
13. Ipersensibilità a Octreotide e / o Lanreotide, e / o ai peptidi correlati alla somatostatina
14. Ipersensibilità alla capecitabina o ad uno qualsiasi dei suoi componenti
15. Ipersensibilità a 5 - fluorouracile.
16. Altre note malattie neoplastiche maligne nella storia clinica del paziente, con un intervallo libero da malattia inferiore a 5 anni (ad eccezione di carcinoma basocellulare precedentemente trattato e del carcinoma in situ della cervice uterina);

E.5 End points

E.5.1

Primary end point(s)

progression free survival (PFS)

sopravvivenza libera da progressione (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

7 years

7 anni

E.5.2

Secondary end point(s)

1) disease control rate (DCR)
2) acute and late toxicity
3) overall survival (OS)

1) tasso di controllo della malattia (DCR)
2) tossicità acuta e tardiva
3) sopravvivenza globale (OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 7 years
2) 7 years
3) 7 years

1) 7 anni
2) 7 anni
3) 7 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

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

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

Lu-PRRT + capecitabina vs Lu-PRRT

Lu-PRRT + capecitabine vs Lu-PRRT

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:

116

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

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

176

F.4.2

For a multinational trial

F.4.2.1

In the EEA

176

F.4.2.2

In the whole clinical trial

176

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)

One month after the end of the 7 cycles of Lu-PRRT patients will receive somatostatine analogues i.m. according to the standard dosage. Each patient will perform periodic revaluations, every 4 months, for a follow-up period of 3 years.

Un mese dopo la fine dei 7 cicli di Lu-PRRT, ciascun paziente riceverà analoghi della somatostatina im secondo il dosaggio standard. Ogni paziente sarà sottoposto a rivalutazioni periodiche, ogni 4 mesi, per un periodo di follow-up di 3 anni.

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

2016-02-19

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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